U.S. patent application number 11/169197 was filed with the patent office on 2006-01-05 for imidazolo-5-yl-2-anilino-pyrimidines as agents for the inhibition of the cell proliferation.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Gloria Anne Breault, Nicholas John Newcombe, Andrew Peter Thomas.
Application Number | 20060004033 11/169197 |
Document ID | / |
Family ID | 9898838 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060004033 |
Kind Code |
A1 |
Breault; Gloria Anne ; et
al. |
January 5, 2006 |
Imidazolo-5-yl-2-anilino-pyrimidines as agents for the inhibition
of the cell proliferation
Abstract
Compounds of the formula (I): wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, p, q, and n are as defined within and a
pharmaceutically acceptable salts and in vivo hydrolysable esters
are described. Also described are processes for their preparation
and their use as medicaments, particularly medicaments for
producing a cell cycle inhibitory (anti-cell-proliferation) effect
in a warm-blooded animal, such as man.
Inventors: |
Breault; Gloria Anne;
(Macclesfield, GB) ; Newcombe; Nicholas John;
(Macclesfield, GB) ; Thomas; Andrew Peter;
(Macclesfield, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
ASTRAZENECA AB
|
Family ID: |
9898838 |
Appl. No.: |
11/169197 |
Filed: |
June 29, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10363655 |
Mar 4, 2003 |
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PCT/GB01/03864 |
Aug 30, 2001 |
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11169197 |
Jun 29, 2005 |
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Current U.S.
Class: |
514/275 ;
544/330 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 405/14 20130101; A61P 35/00 20180101; C07D 417/14 20130101;
A61P 17/06 20180101; A61P 19/08 20180101; A61P 27/02 20180101; A61P
35/02 20180101; C07D 403/14 20130101; C07D 413/14 20130101; A61P
37/02 20180101; C07D 403/04 20130101; A61P 19/02 20180101; A61P
29/00 20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/275 ;
544/330 |
International
Class: |
A61K 31/506 20060101
A61K031/506; C07D 43/04 20060101 C07D043/04 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 5, 2000 |
GB |
0021726.5 |
Claims
1-17. (canceled)
18. A method for treating cancer in a warm-blooded animal in need
thereof, said method comprising administering to said animal an
effective amount of a compound of formula (I): ##STR13## wherein:
R.sup.1 is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,
mercapto, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl or
C.sub.2-6alkynyl; p is 0-4; wherein the values of R.sup.1 may be
the same or different; R.sup.2 is sulphamoyl or a group
R.sup.a--R.sup.b--; q is 0-2; wherein the values of R.sup.2 maybe
the same or different; and wherein p+q=0-5; R.sup.3 is halo, nitro,
cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-3alkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, C.sub.1-3alkoxy, C.sub.1-3alkanoyl,
N-(C.sub.1-3alkyl)amino, N,N-(C.sub.1-3alkyl).sub.2amino,
C.sub.1-3alkanoylamino, N-(C.sub.1-3alkyl)carbamoyl,
N,N-(C.sub.1-3alkyl).sub.2carbamoyl, C.sub.1-3alkylS(O).sub.a
wherein a is 0 to 2, N-(C.sub.1-3alkyl)sulphamoyl or
N,N-(C.sub.1-3alkyl).sub.2sulphamoyl; wherein R.sup.3 may be
optionally substituted on carbon by one or more R.sup.c; n is 0 to
2, wherein the values of R.sup.3 may be the same or different;
R.sup.4 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, phenyl or a carbon-linked
heterocyclic group; wherein R.sup.4 may be optionally substituted
on carbon by one or more R.sup.d; and wherein if said heterocyclic
group contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.n; R.sup.5 and R.sup.6
are independently selected from hydrogen, halo, nitro, cyano,
hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N-(C.sub.1-6alkyl)amino, N,N-(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkanoylamino, N-(C.sub.1-6alkyl)carbamoyl,
N,N-(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N-(C.sub.1-6alkyl)sulphamoyl, N,N-(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, C.sub.3-8cycloalkyl or a 4-7 membered
saturated heterocyclic group; wherein R.sup.5 and R.sup.6
independently of each other may be optionally substituted on carbon
by one or more R.sup.e; and wherein if said 4-7 membered saturated
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from R.sup.f; R.sup.a is
selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl, a
heterocyclic group, phenylC.sub.1-6alkyl or (heterocyclic
group)C.sub.1-6alkyl; wherein R.sup.a may be optionally substituted
on carbon by one or more R.sup.g; and wherein if said heterocyclic
group contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.h; R.sup.b is --C(O)--,
--N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--, --S(O).sub.r--,
--OC(O)N(R.sup.m)SO.sub.2--, --SO.sub.2N(R.sup.m)-- or
--N(R.sup.m)SO.sub.2--; wherein R.sup.m is hydrogen or
C.sub.1-6alkyl optionally substituted by one or more and R.sup.i
and r is 1-2; R.sup.d, R.sup.g and R.sup.i are independently
selected from halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxyC.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N-(C.sub.1-6alkyl)amino,
N,N-(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N-(C.sub.1-6alkyl)carbamoyl, N,N-(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N-(C.sub.1-6alkyl)sulphamoyl,
N,N-(C.sub.1-6alkyl).sub.2sulphamoyl, C.sub.1-6alkylsulphonylamino,
C.sub.3-8cycloalkyl, phenyl, heterocyclic group,
phenylC.sub.1-6alkyl-R.sup.o--, (heterocyclic
group)C.sub.1-6alkyl-R.sup.o--, phenyl-R.sup.o--or (heterocyclic
group)-R.sup.o--; wherein R.sup.d, R.sup.g and R.sup.i
independently of each other may be optionally substituted on carbon
by one or more R.sup.j; and wherein if said heterocyclic group
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.k; R.sup.o is --O--,
--N(R.sup.p)--, --C(O)--, --N(R.sup.p)C(O)--, --C(O)N(R.sup.p)--,
--S(O).sub.s--, --SO.sub.2N(R.sup.p)-- or --N(R.sup.p)SO.sub.2--;
wherein R.sup.p is hydrogen or C.sub.1-6alkyl and s is 0-2;
R.sup.f, R.sup.h, R.sup.k and R.sup.n are independently selected
from C.sub.1-4alkyl, C.sub.1-4alkanoyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4alkoxycarbonyl, carbamoyl, N-(C.sub.1-4alkyl)carbamoyl,
N,N-(C.sub.1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl
and phenylsulphonyl; wherein R.sup.f, R.sup.h, R.sup.k and R.sup.n
independently of each other may be optionally substituted on carbon
by on or more R.sup.1; and R.sup.c, R.sup.e, R.sup.l and R.sup.j
are independently selected from halo, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl,
acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt
or an in vivo hydrolysable ester thereof.
19. The method according to claim 18 wherein R.sup.1 is halo,
amino, C.sub.1-6alkyl or C.sub.1-6alkoxy.
20. The method according to claim 18 wherein p is 0-2 and wherein
the values of R.sup.1 may be the same or different.
21. The method according to claim 18 wherein R.sup.2 is sulphamoyl
or a group R.sup.a--R.sup.b--; wherein R.sup.a is selected from
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-8cycloalkyl, phenyl or a heterocyclic group; wherein
R.sup.a may be optionally substituted on carbon by one or more
R.sup.g; R.sup.b is --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--S(O).sub.r--, --OC(O)N(R.sup.m)SO.sub.2--, --SO.sub.2N(R.sup.m)--
or --N(R.sup.m)SO.sub.2--; wherein R.sup.m is hydrogen or
C.sub.1-6alkyl and r is 2; R.sup.g is selected from halo, hydroxy,
amino, cyano, carbamoyl, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxyC.sub.1-6alkoxy,
N,N-(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylS(O).sub.a wherein a
is 2, C.sub.3-8cycloalkyl, phenyl, heterocyclic group,
phenylC.sub.1-6alkyl-R.sup.o-- or (heterocyclic group)-R.sup.o--;
wherein R.sup.g may be optionally substituted on carbon by one or
more R.sup.j; R.sup.o is --O--; and R.sup.j is selected from halo,
hydroxy, methyl or methoxy.
22. The method according to claim 18 wherein q is 0 or 1.
23. The method according to claim 18 wherein q is 1 and R.sup.2 is
para to the --NH-- of the aniline of formula (I).
24. The method according to claim 18 wherein R.sup.3 is halo.
25. The method according to claim 18 wherein n is 0.
26. The method according to claim 18 wherein R.sup.4 may be
optionally substituted on carbon by one or more R.sup.d; wherein
R.sub.d is selected from halo, amino, C.sub.1-6alkoxy,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, phenyl or
heterocyclic group.
27. The method according to claim 18 wherein R.sup.5 and R.sup.6
are independently selected from hydrogen or C.sub.1-6alkyl; wherein
R.sup.5 and R.sup.6 independently of each other may be optionally
substituted on carbon by one or more R.sup.e; wherein R.sup.e is
selected from halo or methoxy.
28. The method according to claim 18 wherein: R.sup.1 is chloro,
amino, methyl or methoxy; p is 0-2; wherein the values of R.sup.1
may be the same or different; R.sup.2 is sulphamoyl,
N-(tetrahydrofur-2-ylmethyl)sulphamoyl,
N-(cyclopropylmethyl)sulphamoyl, N-(fur-2-ylmethyl)sulphamoyl,
N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)sulphamoyl,
N-(cyanomethyl)sulphamoyl, N-(carbamoylmethyl)sulphamoyl,
N-methylsulphamoyl, N-(4-fluorobenzyl)sulphamoyl,
N-(pyridin-2-ylmethyl)sulphamoyl, N-(pyridin-3-ylmethyl)sulphamoyl,
N-(4-methylthiazol-2-yl)sulphamoyl,
N-(3-methylisoxazol-5-ylmethyl)sulphamoyl,
N-(tetrahydropyran-2-ylmethyl)sulphamoyl,
N-(2-methylpyrazin-5-yl)sulphamoyl,
N-[2-(2-hydroxyethoxy)ethyl]sulphamoyl,
N-(2-hydroxyethyl)sulphamoyl, N-(2,2,2-trifluoroethyl)sulphamoyl,
N-(2-methoxyethyl)sulphamoyl, N-(2-mesylethyl)sulphamoyl,
N-(2-benzyloxyethyl)sulphamoyl, N-(2,2-dimethoxyethyl)sulphamoyl,
N-[2-(N,N-dimethylamino)ethyl]sulphamoyl,
N-(2-piperidin-1-ylethyl)sulphamoyl,
N-[2-(methoxymethoxy)ethyl]sulphamoyl, N-ethylsulphamoyl,
N-[2-(2-methoxyethoxy)ethyl]sulphamoyl,
N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulphamoyl,
N-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl)sulphamoyl,
N-(2-pyridin-2-ylethyl)sulphamoyl,
N-(2-pyridin-4-ylethyl)sulphamoyl,
N-(2-isoxazol-3-yloxyethyl)sulphamoyl,
N-(2-isothiazol-3-yloxyethyl)sulphamoyl,
N-(2-1,2-5-thiadiazol-3-yloxyethyl)sulphamoyl,
N-methyl-N-(2-methoxyethyl)sulphamoyl,
N-[3-(2-oxopyrrolidin-1-yl)propyl]sulphamoyl,
N-(3-methoxypropyl)sulphamoyl, N-propylsulphamoyl,
N-(2,3-dihydroxypropyl)sulphamoyl,
N-(3-morpholinopropyl)sulphamoyl,
N-[3-(N,N-dimethylamino)propyl]sulphamoyl,
N-(3,3,3-trifluoropropyl)sulphamoyl,
N-(2,2-dimethyl-3-hydroxypropyl)sulphamoyl,
N-(3-hydroxypropyl)sulphamoyl, N-(3-ethoxypropyl)sulphamoyl,
N-(2-hydroxypropyl)sulphamoyl, N-(3-isopropoxypropyl)sulphamoyl,
N-(3-isopropoxy-2-hydroxypropyl)sulphamoyl,
N-(3-isoxazol-3-yloxypropyl)sulphamoyl,
N-(3-isothiazol-3-yloxypropyl)sulphamoyl,
N-(3-1,2-5-thiadiazol-3-yloxypropyl)sulphamoyl,
N-(1,1-dimethylpropyl)sulphamoyl,
N-methyl-N-(3-morpholinopropyl)sulphamoyl, N-butylsulphamoyl,
N-t-butylsulphamoyl, N-(2-hydroxybutyl)sulphamoyl,
N-methyl-N-t-butylsulphamoyl, N-pentylsulphamoyl,
N-(5-hydroxypentyl)sulphamoyl,
N-(4,5-dimethyloxazol-2-yl)sulphamoyl, N-(cyclopropyl)sulphamoyl,
N-(cyclobutyl)sulphamoyl, N-(3-trifluoromethylphenyl)sulphamoyl,
N-allylsulphamoyl, N-(2-propynyl)sulphamoyl, N-methylcarbamoyl,
acetamido, mesylamino or mesyl; q is 0 or 1; R.sup.3 is bromo or
chloro; n is 0 or 1; R.sup.4 is hydrogen, methyl, ethyl, isopropyl,
3-butenyl, benzyl, 2-phthalimidoethyl, 2-aminoethyl,
2-methoxyethyl, 2-acetamidoethyl, 2-mesylaminoethyl or
2,2,2-trifluoroethyl; and R.sup.5 and R.sup.6 are independently
selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl
or methoxymethyl.
29. The method according to claim 18 wherein the compound of
formula (I) is selected from:
2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}-4-(1,2-dimethylimidazol-5--
yl)pyrimidine;
4-(1-ethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anil-
ino}pyrimidine;
4-(1-ethyl-2-methylimidazol-5-yl)-2-{4-[N-(3-methoxypropyl)sulphamoyl]ani-
lino}pyrimidine;
4-(1-ethyl-2-methylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]a-
nilino}pyrimidine;
4-(1-ethyl-2-methylimidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]p-
yrimidine;
4-(1-methyl-2-isopropylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamo-
yl]anilino}pyrimidine;
4-(1,2-dimethylimidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrim-
idine;
4-(1,2-dimethylimidazol-5-yl)-2-[4-(N-cyclobutylsulphamoyl)anilino-
]pyrimidine;
4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2,2,2-trifluoroethyl)sulphamoyl]an-
ilino}pyrimidine; and
4-(1-isopropyl-2-methylimidazol-5-yl)-2-[4-(N-cyclobutylsulphamoyl)anilin-
o]pyrimidine; or a pharmaceutically acceptable salt or an in vivo
hydrolysable ester thereof.
Description
[0001] The invention relates to pyrimidine derivatives, or
pharmaceutically acceptable salts or in vivo hydrolysable esters
thereof which possess cell-cycle inhibitory activity and are
accordingly useful for their anti-cell-proliferation (such as
anti-cancer) activity and are therefore useful in methods of
treatment of the human or animal body. The invention also relates
to processes for the manufacture of said pyrimidine derivatives, to
pharmaceutical compositions containing them and to their use in the
manufacture of medicaments of use in the production of an
anti-cell-proliferation effect in a warm-blooded animal such as
man.
[0002] A family of intracellular proteins called cyclins play a
central role in the cell cycle. The synthesis and degradation of
cyclins is tightly controlled such that their level of expression
fluctuates during the cell cycle. Cyclins bind to cyclin-dependent
serine/threonine kinases (CDKs) and this association is essential
for CDK (such as CDK1, CDK2, CDK4 and/or CDK6) activity within the
cell. Although the precise details of how each of these factors
combine to regulate CDK activity is poorly understood, the balance
between the two dictates whether or not the cell will progress
through the cell cycle.
[0003] The recent convergence of oncogene and tumour suppressor
gene research has identified regulation of entry into the cell
cycle as a key control point of mitogenesis in tumours. Moreover,
CDKs appear to be downstream of a number of oncogene signalling
pathways. Disregulation of CDK activity by upregulation of cyclins
and/or deletion of endogenous inhibitors appears to be an important
axis between mitogenic signalling pathways and proliferation of
tumour cells.
[0004] Accordingly it has been recognised that an inhibitor of cell
cycle kinases, particularly inhibitors of CDK2, CDK4 and/or CDK6
(which operate at the S-phase, G1-S and G1-S phase respectively)
should be of value as a selective inhibitor of cell proliferation,
such as growth of mammalian cancer cells.
[0005] The present invention is based on the discovery that certain
pyrimidine compounds surprisingly inhibit the effects of cell cycle
kinases showing selectivity for CDK2, CDK4 and CDK6, and thus
possess anti-cell-proliferation properties. Such properties are
expected to be of value in the treatment of disease states
associated with aberrant cell cycles and cell proliferation such as
cancers (solid tumours and leukemias), fibroproliferative and
differentiative disorders, psoriasis, rheumatoid arthritis,
Kaposi's sarcoma, haemangioma, acute and chronic nephropathies,
atheroma, atherosclerosis, arterial restenosis, autoimmune
diseases, acute and chronic inflammation, bone diseases and ocular
diseases with retinal vessel proliferation.
[0006] Accordingly, the present invention provides a compound of
formula (I): ##STR1## wherein:
[0007] R.sup.1 is halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.2-6alkenyl or C.sub.2-6alkynyl;
[0008] p is 0-4; wherein the values of R.sup.1 may be the same or
different;
[0009] R.sup.2 is sulphamoyl or a group R.sup.a--R.sup.b--;
[0010] q is 0-2; wherein the values of R.sup.2 maybe the same or
different; and wherein p+q=0-5;
[0011] R.sup.3 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.1-3alkoxy, C.sub.1-3alkanoyl, N-(C.sub.1-3alkyl)amino,
N,N-(C.sub.1-3alkyl).sub.2amino, C.sub.1-3alkanoylamino,
N-(C.sub.1-3alkyl)carbamoyl, N,N-(C.sub.1-3alkyl).sub.2carbamoyl,
C.sub.1-3alkylS(O).sub.a wherein a is 0 to 2,
N-(C.sub.1-3alkyl)sulphamoyl or
N,N-(C.sub.1-3alkyl).sub.2sulphamoyl; wherein R.sup.3 may be
optionally substituted on carbon by one or more R.sup.c;
[0012] n is 0 to 2, wherein the values of R.sup.3 may be the same
or different;
[0013] R.sup.4 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, phenyl or a carbon-linked
heterocyclic group; wherein R.sup.4 may be optionally substituted
on carbon by one or more R.sup.d; and wherein if said heterocyclic
group contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.n;
[0014] R.sup.5 and R.sup.6 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N-(C.sub.1-6alkyl)amino,
N,N-(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N-(C.sub.1-6alkyl)carbamoyl, N,N-(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N-(C.sub.1-6alkyl)sulphamoyl,
N,N-(C.sub.1-6alkyl).sub.2sulphamoyl, C.sub.1-6alkylsulphonylamino,
C.sub.3-8-cycloalkyl or a 4-7 membered saturated heterocyclic
group; wherein R.sup.5 and R.sup.6 independently of each other may
be optionally substituted on carbon by one or more R.sup.e; and
wherein if said 4-7 membered saturated heterocyclic group contains
an --NH-- moiety that nitrogen may be optionally substituted by a
group selected from R.sup.f;
[0015] R.sup.a is selected from C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl, a heterocyclic group,
phenylC.sub.1-6alkyl or (heterocyclic group)C.sub.1-6alkyl; wherein
R.sup.a may be optionally substituted on carbon by one or more
R.sup.g; and wherein if said heterocyclic group contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.h;
[0016] R.sup.b is --C(O)--, --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--S(O).sub.r--, --OC(O)N(R)SO.sub.2--, --SO.sub.2N(R.sup.m)-- or
--N(R.sup.m)SO.sub.2--; wherein R.sup.m is hydrogen or
C.sub.1-6alkyl optionally substituted by one or more R.sup.i and r
is 1-2;
[0017] R.sup.d, R.sup.g and R.sup.i are independently selected from
halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxyC.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N-(C.sub.1-6alkyl)amino,
N,N-(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N-(C.sub.1-6alkyl)carbamoyl, N,N-(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N-(C.sub.1-6alkyl)sulphamoyl,
N,N-(C.sub.1-6alkyl).sub.2sulphamoyl, C.sub.1-6alkylsulphonylamino,
C.sub.3-8cycloalkyl, phenyl, heterocyclic group,
phenylC.sub.1-6alkyl-R.sup.o--, (heterocyclic
group)C.sub.1-6-alkyl-R.sup.o--, phenyl-R.sup.o-- or (heterocyclic
group)-R.sup.o--; wherein R.sup.d, R.sup.g and R.sup.i
independently of each other may be optionally substituted on carbon
by one or more R.sup.j; and wherein if said heterocyclic group
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.k;
[0018] R.sup.o is --O--, --N(R.sup.p)--, --C(O)--,
--N(R.sup.p)C(O)--, --C(O)N(R.sup.p)--, --S(O).sub.s--,
--SO.sub.sN(R.sup.p)-- or --N(R.sup.p)SO.sub.2--; wherein R.sup.p
is hydrogen or C.sub.1-6alkyl and s is 0-2;
[0019] R.sup.f, R.sup.h, R.sup.k and R.sup.n are independently
selected from C.sub.1-4alkyl, C.sub.1-4alkanoyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4alkoxycarbonyl, carbamoyl,
N-(C.sub.1-4alkyl)carbamoyl, N,N-(C.sub.1-4alkyl)carbamoyl, benzyl,
benzyloxycarbonyl benzoyl and phenylsulphonyl; wherein R.sup.f,
R.sup.h, R.sup.k and R.sup.n independently of each other may be
optionally substituted on carbon by on or more R.sup.1; and
[0020] R.sup.c, R.sup.e, R.sup.l and R.sup.j are independently
selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl amino, carboxy, carbamoyl, mercapto, sulphamoyl,
methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,
ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,
acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl;
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof.
[0021] In another aspect the present invention provides a compound
of formula (I): ##STR2## wherein:
[0022] R.sup.1 is halo, nitro, cyano, hydroxy, amino, carboxy,
carbamoyl, mercapto, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.2-6alkenyl or C.sub.2-6alkynyl;
[0023] p is 0-4; wherein the values of R.sup.1 may be the same or
different;
[0024] R.sup.2 is sulphamoyl or a group R.sup.a--R.sup.b--;
[0025] q is 0-2; wherein the values of R.sup.2 maybe the same or
different; and wherein p+q=0-5;
[0026] R.sup.3 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.1-3alkoxy, C.sub.1-3alkanoyl, N-(C.sub.1-3alkyl)amino,
N,N-(C.sub.1-3alkyl).sub.2amino, C.sub.1-3alkanoylamino,
N-(C.sub.1-3alkyl)carbamoyl, N,N-(C.sub.1-3alkyl).sub.2carbamoyl,
C.sub.1-3alkylS(O).sub.a wherein a is 0 to 2,
N-(C.sub.1-3alkyl)sulphamoyl or
N,N-(C.sub.1-3alkyl).sub.2sulphamoyl; wherein R.sup.3 may be
optionally substituted on carbon by one or more R.sup.c;
[0027] n is 0 to 2, wherein the values of R.sup.3 may be the same
or different;
[0028] R.sup.4 is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, phenyl or a carbon-linked
heterocyclic group; wherein R.sup.4 may be optionally substituted
on carbon by one or more R.sup.d; and wherein if said heterocyclic
group contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.n;
[0029] R.sup.5 and R.sup.6 are independently selected from
hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N-(C.sub.1-6alkyl)amino,
N,N-C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkanoylamino,
N-(C.sub.1-6alkyl)carbamoyl, N,N-(C.sub.1-6alkyl).sub.2carbamoyl,
C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2,
C.sub.1-6alkoxycarbonyl, N-(C.sub.1-6alkyl)sulphamoyl,
N,N-(C.sub.1-6alkyl).sub.2sulphamoyl, C.sub.1-6alkylsulphonylamino,
C.sub.3-6cycloalkyl or a 4-7 membered saturated heterocyclic group;
wherein R.sup.5 and R.sup.6 independently of each other may be
optionally substituted on carbon by one or more R.sup.e; and
wherein if said 4-7 membered saturated heterocyclic group contains
an --NH-- moiety that nitrogen may be optionally substituted by a
group selected from R.sup.f;
[0030] R.sup.a is selected from C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl, a heterocyclic group,
phenylC.sub.1-6alkyl or (heterocyclic group)C.sub.1-6alkyl; wherein
R.sup.a may be optionally substituted on carbon by one or more
R.sup.g; and wherein if said heterocyclic group contains an --NH--
moiety that nitrogen may be optionally substituted by a group
selected from R.sup.h;
[0031] R.sup.b is --C(O)--, --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--S(O).sub.r--, --SO.sub.2N(R.sup.m)-- or --N(R.sup.mSO.sub.2--;
wherein R.sup.m is hydrogen or C.sub.1-6alkyl optionally
substituted by one or more R.sup.i and r is 1-2;
[0032] R.sup.d, R.sup.g and R.sup.l are independently selected from
halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,
sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N-(C.sub.1-6alkyl)amino, N,N-(C.sub.1-6alkyl).sub.2amino,
C.sub.1-6-alkanoylamino, N-(C.sub.1-6alkyl)carbamoyl,
N,N-(C.sub.1-6alkyl).sub.2carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N-(C.sub.1-6alkyl)sulphamoyl, N,N-(C.sub.1-6alkyl).sub.2sulphamoyl,
C.sub.1-6alkylsulphonylamino, C.sub.3-8cycloalkyl, phenyl,
heterocyclic group, phenyl-R.sup.o-- or (heterocyclic
group)-R.sup.o--; wherein R.sup.d, R.sup.g and R.sup.i
independently of each other may be optionally substituted on carbon
by one or more R.sup.j; and wherein if said heterocyclic group
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from R.sup.k;
[0033] R.sup.o is --O--, --N(R.sup.p)--, --C(O)--,
--N(R.sup.p)C(O)--, --C(O)N(R.sup.p)--, --S(O).sub.s--,
--SO.sub.2N(R.sup.p)-- or --N(R.sup.p)SO.sub.2--; wherein R.sup.p
is hydrogen or C.sub.1-6alkyl and s is 0-2;
[0034] R.sup.f, R.sup.h, R.sup.k and R.sup.n are independently
selected from C.sub.1-4alkyl, C.sub.1-4alkanoyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4alkoxycarbonyl, carbamoyl,
N-(C.sub.1-4alkyl)carbamoyl, N,N-(C.sub.1-4alkyl)carbamoyl, benzyl,
benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R.sup.f,
R.sup.h and R.sup.k independently of each other may be optionally
substituted on carbon by on or more R.sup.1; and
[0035] R.sup.c, R.sup.e, R.sup.l and R.sup.j are independently
selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,
ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,
acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,
N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or
N-methyl-N-ethylsulphamoyl;
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof.
[0036] In this specification the term "alkyl" includes both
straight and branched chain alkyl groups but references to
individual alkyl groups such as "propyl" are specific for the
straight chain version only. For example, "C.sub.1-6alkyl" includes
C.sub.1-4alkyl, C.sub.1-3alkyl, propyl, isopropyl and t-butyl.
However, references to individual alkyl groups such as `propyl` are
specific for the straight chained version only and references to
individual branched chain alkyl groups such as `isopropyl` are
specific for the branched chain version only. A similar convention
applies to other radicals, for example "phenylC.sub.1-6alkyl"
includes phenylC.sub.1-4alkyl, benzyl, 1-phenylethyl and
2-phenylethyl. The term "halo" refers to fluoro, chloro, bromo and
iodo.
[0037] Where optional substituents are chosen from "one or more"
groups it is to be understood that this definition includes all
substituents being chosen from one of the specified groups or the
substituents being chosen from two or more of the specified
groups.
[0038] A "heterocyclic group" is a saturated, partially saturated
or unsaturated, mono or bicyclic ring containing 4-12 atoms of
which at least one atom is chosen from nitrogen, sulphur or oxygen,
which may, unless otherwise specified, be carbon or nitrogen
linked, wherein a --CH.sub.2-- group can optionally be replaced by
a --C(O)--, a ring nitrogen atom may optionally bear a
C.sub.1-6alkyl group and form a quaternary compound or a ring
nitrogen and/or sulphur atom may be optionally oxidised to form the
N-oxide and or the S-oxides. Examples and suitable values of the
term "heterocyclic group" are morpholino, piperidyl, pyridyl,
pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl,
1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl,
pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl,
3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl,
pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone,
1-isoquinolone, 2-pyrrolidone, 4thiazolidone, pyridine-N-oxide and
quinoline-N-oxide. Preferably a "heterocyclic group" is a
saturated, partially saturated or unsaturated, mono or bicyclic
ring containing 5 or 6 atoms of which at least one atom is chosen
from nitrogen, sulphur or oxygen, it may, unless otherwise
specified, be carbon or nitrogen linked, a --CH.sub.2-- group can
optionally be replaced by a --C(O)-- and a ring sulphur atom may be
optionally oxidised to form the S-oxides. More preferably a
"heterocyclic group" is tetrahydrofuryl, pyridyl, pyrrolidinonyl,
morpholino, imidazolyl, piperidinyl or pyrrolidinyl. Particularly a
"heterocyclic group" is tetrahydrofuryl or morpholino. In another
aspect of the invention, particularly a "heterocyclic group" is
tetrahydrofuran-2-yl, 2-oxopyrrolidin-1-yl, furan-2-yl, oxazolyl,
morpholino, piperidinyl, thiazolyl, pyrazinyl, isoxazolyl,
tetrahydropyran, pyridyl, isoxazolyl, isothiazolyl,
1,2,5-thiadiazolyl, phthalimido.
[0039] A "4-7 membered saturated heterocyclic group" is a saturated
monocyclic ring containing 4-7 atoms of which at least one atom is
chosen from nitrogen, sulphur or oxygen, which may, unless
otherwise specified, be carbon or nitrogen linked, wherein a
--CH.sub.2-- group can optionally be replaced by a --C(O)-- and a
sulphur atom may be optionally oxidised to form the S-oxides.
Examples and suitable values of the term "heterocyclic group" are
morpholino, piperidyl, 1,4-dioxanyl, 1,3-dioxolanyl,
1,2-oxathiolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl,
thiazolidinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl and
tetrahydropyranyl.
[0040] An example of "C.sub.1-6alkanoyloxy" is acetoxy. Examples of
"C.sub.1-6alkoxycarbonyl" include C.sub.1-4alkoxycarbonyl,
methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples
of "C.sub.1-6alkoxy" include C.sub.1-4alkoxy, C.sub.1-3alkoxy,
methoxy, ethoxy and propoxy. Examples of "C.sub.1-6alkanoylamino"
include formamido, acetamido and propionylamino. Examples of
"C.sub.1-6alkylS(O).sub.a wherein a is 0 to 2" include
C.sub.1-4alkylsulphonyl, methylthio, ethylthio, methylsulphinyl,
ethylsulphinyl, mesyl and ethylsulphonyl. Examples of
"C.sub.1-6alkylS(O).sub.r wherein r is 1 to 2" include
methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples
of "C.sub.1-6alkanoyl" include C.sub.1-4alkanoyl, propionyl and
acetyl. Examples of "N-C.sub.1-6alkylamino" include methylamino and
ethylamino. Examples of "N,N-(C.sub.1-6alkyl).sub.2amino" include
di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.
Examples of "C.sub.2-6alkenyl" are vinyl, allyl and 1-propenyl.
Examples of "C.sub.2-6alkynyl" are ethynyl, 1-propynyl and
2-propynyl. Examples of "N-(C.sub.1-6alkyl)sulphamoyl" are
N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of
"N-(C.sub.1-6alkyl).sub.2sulphamoyl" are N,N-(dimethyl)sulphamoyl
and N-(methyl)-N-(ethyl)sulphamoyl. Examples of
"N-(C.sub.1-6alkyl)carbamoyl" are N-(C.sub.1-4alkyl)carbamoyl,
methylaminocarbonyl and ethylaminocarbonyl. Examples of
"N,N-(C.sub.1-6alkyl).sub.2carbamoyl" are
N,N-(C.sub.1-4alkyl).sub.2carbamoyl, dimethylaminocarbonyl and
methylethylaminocarbonyl. Examples of "C.sub.3-8cycloalkyl" are
cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl. Examples of
"(heterocyclic group)C.sub.1-6alkyl" include pyridylmethyl,
3-morpholinopropyl and 2-pyrimid-2-ylethyl. Examples of
"C.sub.3-8cycloalkylC.sub.1-6alkyl" are cyclopropylethyl,
cyclobutylmethyl, 2-cyclopropylpropyl and cyclohexylethyl.
[0041] A suitable pharmaceutically acceptable salt of a compound of
the invention is, for example, an acid-addition salt of a compound
of the invention which is sufficiently basic, for example, an
acid-addition salt with, for example, an inorganic or organic acid,
for example hydrochloric, hydrobromic, sulphuric, phosphoric,
trifluoroacetic, citric or maleic acid. In addition a suitable
pharmaceutically acceptable salt of a compound of the invention
which is sufficiently acidic is an alkali metal salt, for example a
sodium or potassium salt, an alkaline earth metal salt, for example
a calcium or magnesium salt, an ammonium salt or a salt with an
organic base which affords a physiologically-acceptable cation, for
example a salt with methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[0042] An in vivo hydrolysable ester of a compound of the formula
(I) containing carboxy or hydroxy group is, for example, a
pharmaceutically acceptable ester which is hydrolysed in the human
or animal body to produce the parent acid or alcohol. Suitable
pharmaceutically acceptable esters for carboxy include
C.sub.1-6alkoxymethyl esters for example methoxymethyl,
C.sub.1-6alkanoyloxymethyl esters for example pivaloyloxymethyl,
phthalidyl esters, C.sub.3-8cycloalkoxycarbonyloxyC.sub.1-6alkyl
esters for example 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-ioxolen-2-onylmethyl; and
C.sub.1-6alkoxycarbonyloxyethyl esters for example
1-methoxycarbonyloxyethyl and maybe formed at any carboxy group in
the compounds of this invention.
[0043] An in vivo hydrolysable ester of a compound of the formula
(I) containing a hydroxy group includes inorganic esters such as
phosphate esters and .alpha.-acyloxyalkyl ethers and related
compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give the parent hydroxy group. Examples of
.alpha.-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxy-methoxy. A selection of in vivo
hydrolysable ester forming groups for hydroxy include alkanoyl,
benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,
alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl
and N-dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl. Examples of substituents on
benzoyl include morpholino and piperazino linked from a ring
nitrogen atom via a methylene group to the 3- or 4-position of the
benzoyl ring.
[0044] Some compounds of the formula (I) may have chiral centres
and/or geometric isomeric centres (E- and Z-isomers), and it is to
be understood that the invention encompasses all such optical,
diastereoisomers and geometric isomers that possess CDK inhibitory
activity.
[0045] The invention relates to any and all tautomeric forms of the
compounds of the formula (I) that possess CDK inhibitory activity.
In particular the skilled reader will appreciate that when R.sup.4
is hydrogen, the imidazole ring as drawn in formula (I) may
tautomerise.
[0046] It is also to be understood that certain compounds of the
formula (I) can exist in solvated as well as unsolvated forms such
as, for example, hydrated forms. It is to be understood that the
invention encompasses all such solvated forms which possess CDK
inhibitory activity.
[0047] Preferred values of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, n, p and q are as follows. Such values may be
used where appropriate with any of the definitions, claims or
embodiments defined hereinbefore or hereinafter.
[0048] Preferably R.sup.1 is halo, amino, C.sub.1-6alkyl or
C.sub.1-6alkoxy.
[0049] More preferably R.sup.1 is halo, C.sub.1-4alkyl or
C.sub.1-4alkoxy.
[0050] Particularly R.sup.1 is chloro, C.sub.1-3alkyl or
C.sub.1-3alkoxy.
[0051] More particularly R.sup.1 is chloro.
[0052] In another aspect of the invention, preferably R.sup.1 is
halo, amino, C.sub.1-6alkyl or C.sub.1-6alkoxy.
[0053] In another aspect of the invention; more preferably R.sup.1
is chloro, amino, methyl or methoxy.
[0054] Preferably p is 0-2; wherein the values of R.sup.1 may be
the same or different.
[0055] More preferably p is 0 or 1.
[0056] In one aspect of the invention, preferably p is 0.
[0057] In another aspect of the invention, preferably p is 1.
[0058] Preferably when p is 1, R.sup.1 is meta or para to the
--NH-- of the aniline of formula (I).
[0059] More preferably when p is 1, R.sup.1 is meta to the --NH--
of the aniline of formula (I).
[0060] Preferably R.sup.2 is sulphamoyl or a group
R.sup.a--R.sup.b--; wherein
[0061] R.sup.a is selected from C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl, a
heterocyclic group, phenylC.sub.1-6alkyl or (heterocyclic
group)C.sub.1-6alkyl; wherein R.sup.a may be optionally substituted
on carbon by one or more R.sup.g;
[0062] R.sup.b is --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--SO.sub.2N(R.sup.m)-- or --N(R.sup.m)SO.sub.2--; wherein R.sup.m
is hydrogen;
[0063] R.sup.g is selected from halo, hydroxy, amino, carbamoyl,
C.sub.1-6alkyl or C.sub.1-6alkoxy, and
[0064] R.sup.j is selected from halo or hydroxy.
[0065] More preferably R.sup.2 is sulphamoyl or a group
R.sup.a--R.sup.b--, wherein
[0066] R.sup.a is selected from C.sub.1-6alkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, phenylC.sub.1-6alkyl or
(heterocyclic group)C.sub.1-6alkyl; wherein R.sup.a may be
optionally substituted on carbon by one or more R.sup.g;
[0067] R.sup.b is --N(R.sup.m)SO.sub.2--; wherein R.sup.m is
hydrogen;
[0068] R.sup.g is selected from halo, hydroxy, carbamoyl or
C.sub.1-6alkoxy; and
[0069] R.sup.j is selected from hydroxy.
[0070] Particularly R.sup.2 is sulphamoyl,
N-(tetrahydrofuran-2-ylmethyl)sulphamoyl,
N-[3-(2-oxopyrrolidin-1-yl)propyl]sulphamoyl,
N-(3-methoxypropyl)sulphamoyl, N-(4-fluorobenzyl)sulphamoyl,
N-(cyclopropyhnethyl)sulphamoyl, N-propylsulphamoyl,
N-(2,3-dihydroxypropyl)sulphamoyl,
N-[2-(2-hydroxyethoxy)ethyl]sulphamoyl,
N-(furan-2-ylmethyl)sulphamoyl, N-(2-hydroxyethyl)sulphamoyl or
N-(carbamoylmethyl)sulphamoyl.
[0071] In another aspect of the invention, preferably R.sup.2 is
sulphamoyl or a group R.sup.a--R.sup.b--; wherein
[0072] R.sup.a is selected from C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, phenyl or a heterocyclic
group; wherein R.sup.a may be optionally substituted on carbon by
one or more R.sup.g;
[0073] R.sup.b is --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--S(O).sub.r, --OC(O)N(R.sup.m)SO.sub.2--, --SO.sub.2N(R.sup.m)--
or --N(R.sup.m)SO.sub.2--; wherein R.sup.m is hydrogen or
C.sub.1-6alkyl and r is 2;
[0074] R.sup.g is selected from halo, hydroxy, amino, cyano,
carbamoyl, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxyC.sub.1-6alkoxy,
N,N-(C.sub.1-6alkyl).sub.2amino, C.sub.1-6alkylS(O).sub.a wherein a
is 2, C.sub.3-8cycloalkyl, phenyl, heterocyclic group,
phenylC.sub.1-6alkyl-R.sup.o-- or (heterocyclic group)-R.sup.o--;
wherein R.sup.g may be optionally substituted on carbon by one or
more R.sup.j;
[0075] R.sup.o is --O--; and
[0076] R.sup.j is selected from halo, hydroxy, methyl or
methoxy.
[0077] In another aspect of the invention, more preferably R.sup.2
is sulphamoyl or a group R.sup.a--R.sup.b--; wherein
[0078] R.sup.a is selected from methyl, ethyl, propyl, t-butyl,
pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, allyl, 2-propynyl,
cyclopropyl, cyclobutyl, phenyl or oxazolyl; wherein R.sup.a maybe
optionally substituted on carbon by one or more R.sup.g;
[0079] R.sup.b is --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--S(O).sub.2--, --OC(O)N(R.sup.m)SO.sub.2--, --SO.sub.2N(R.sup.m)--
or --N((R.sup.m)SO.sub.2--; wherein R.sup.m is hydrogen or
methyl;
[0080] R.sup.g is selected from fluoro, hydroxy, amino, cyano,
carbamoyl, methyl, methoxy, ethoxy, isopropoxy, ethoxyethoxy,
ethoxyethoxyethoxy, N,N-dimethylamino, mesyl cyclopropyl, phenyl,
tetrahydrofuranyl, 2-oxopyrrolidinyl, 1,3-dioxolanyl, morpholino,
piperidinyl, furan, thiazolyl pyrazinyl, isoxazolyl,
tetrahydropyran, pyridyl, benzyloxy, isoxazolyloxy,
isothiazolyloxy, 1,2,5-thiadiazolyloxy; wherein R.sup.g may be
optionally substituted on carbon by one or more R.sup.j; and
[0081] R.sup.j is selected from fluoro, hydroxy, methyl or
methoxy.
[0082] In another aspect of the invention, particularly R.sup.2 is
sulphamoyl, N-(t-butoxycarbonyl)sulphamoyl,
N-(tetrahydrofur-2-ylmethyl)sulphamoyl,
N-(cyclopropylmethyl)sulphamoyl, N-(fur-2-ylmethyl)sulphamoyl,
N-(cyanomethyl)sulphamoyl,
N-2,2-dimethyl-1,3-dioxolan-4-ylmethyl)sulphamoyl,
N-(carbamoylmethyl)sulphamoyl, N-methylsulphamoyl,
N-(4-fluorobenzyl)sulphamoyl, N-(pyridin-2-ylmethyl)sulphamoyl,
N-(pyridin-3-ylmethyl)sulphamoyl,
N-(4-methylthiazol-2-yl)sulphamoyl,
N-(3-methylisoxazol-5-ylmethyl)sulphamoyl,
N-(tetrahydropyran-2-ylmethyl)sulphamoyl,
N-(2-methylpyrazin-5-yl)sulphamoyl,
N-[2-(2-hydroxyethoxy)ethyl]sulphamoyl,
N-(2-hydroxyethyl)sulphamoyl, N-(2,2,2-trifluoroethyl)sulphamoyl,
N-(2-methoxyethyl)sulphamoyl, N-(2-mesylethyl)sulphamoyl,
N-(2-benzyloxyethyl)sulphamoyl, N-(2,2-dimethoxyethyl)sulphamoyl,
N-[2-(N,N-dimethylamino)ethyl]sulphamoyl,
N-(2-piperidin-1-ylethyl)sulphamoyl,
N-[2-(methoxymethoxy)ethyl]sulphamoyl, N-ethylsulphamoyl,
N-[2-(2-methoxyethoxy)ethyl]sulphamoyl,
N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulphamoyl,
N-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl)sulphamoyl,
N-(2-pyridin-2-ylethyl)sulphamoyl, N-(2-pyridinylethyl)sulphamoyl,
N-(2-isoxazol-3-yloxyethyl)sulphamoyl,
N-(2-isothiazol-3-yloxyethyl)sulphamoyl,
N-(2-1,2-5-thiadiazol-3-yloxyethyl)sulphamoyl,
N-methyl-N-(2-methoxyethyl)sulphamoyl,
N-[3-(2-oxopyrrolidin-1yl)propyl]sulphamoyl,
N-(3-methoxypropyl)sulphamoyl, N-propylsulphamoyl,
N-(2,3-dihydroxypropyl)sulphamoyl,
N-(3-morpholinopropyl)sulphamoyl,
N-[3-(N,N-dimethylamino)propyl]sulphamoyl,
N-(3,3,3-trifluoropropyl)sulphamoyl,
N-(2,2-dimethyl-3-hydroxypropyl)sulphamoyl,
N-(3-hydroxypropyl)sulphamoyl, N-(3-ethoxypropyl)sulphamoyl,
N-(2-hydroxypropyl)sulphamoyl, N-(3-isopropoxypropyl)sulphamoyl,
N-(3-isopropoxy-2-hydroxypropyl)sulphamoyl,
N-(3-isoxazol-3-yloxypropyl)sulphamoyl,
N-(3-isothiazol-3-yloxypropyl)sulphamoyl,
N-(3-1,2-5-thiadiazol-3-yloxypropyl)sulphamoyl,
N-(1,1-dimethylpropyl)sulphamoyl,
N-methyl-N-(3-morpholinopropyl)sulphamoyl, N-butylsulphamoyl,
N-t-butylsulphamoyl, N-(2-hydroxybutyl)sulphamoyl,
N-methyl-N-t-butylsulphamoyl, N-pentylsulphamoyl,
N-(5-hydroxypentyl)sulphamoyl,
N-(4,5-dinethyloxazol-2-yl)sulphamoyl, N-(cyclopropyl)sulphamoyl,
N-(cyclobutyl)sulphamoyl, N-(3-trifluoromethylphenyl)sulphamoyl,
N-allylsulphamoyl, N-(2-propynyl)sulphamoyl, N-methylcarbamoyl,
acetamido, mesylamino or mesyl.
[0083] In another aspect of the invention, more particularly
R.sup.2 is N-(cyclopropylmethyl)sulphamoyl,
N-(2,2,2-trifluoroethyl)sulphamoyl, N-(2-methoxyethyl)sulphamoyl,
N-(3-methoxypropyl)sulphamoyl, N-(cyclopropyl)sulphamoyl or
N-(cyclobutyl)sulphamoyl.
[0084] Preferably q is 0 or 1.
[0085] In one aspect of the invention, preferably q is 0.
[0086] In another aspect of the invention, preferably q is 1.
[0087] Preferably when q is 1, R.sup.2 is meta or para to the
--NH-- of the aniline of formula (I).
[0088] More preferably when q is 1, R.sup.2 is para to the --NH--
of the aniline of formula (I).
[0089] Preferably p+q=0-3.
[0090] More preferably p+q is 0-2.
[0091] Particularly p+q is 0 or 1.
[0092] In one aspect of the invention, preferably p+q is 0.
[0093] In another aspect of the invention, preferably p+q is 1.
[0094] Preferably R.sup.3 is halo.
[0095] More preferably R.sup.3 is bromo.
[0096] In another aspect of the invention preferably R.sup.3 is
bromo or chloro.
[0097] Preferably n is 0 or 1.
[0098] In one aspect of the invention, more preferably n is 0.
[0099] In another aspect of the invention, more preferably n is
1.
[0100] Preferably when n is 1, R.sup.3 is in the 5-position of the
pyrimidine ring.
[0101] Preferably R.sup.4 is hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl; wherein R.sup.4 may be
optionally substituted on carbon by one or more R.sup.d; wherein
R.sup.d is as defined herein before.
[0102] More preferably R.sup.4 is hydrogen or C.sub.1-6alkyl;
wherein R.sup.4 may be optionally substituted on carbon by one or
more R.sup.d;
[0103] R.sup.d is selected from amino, C.sub.1-6alkoxy,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, phenyl,
heterocyclic group, or (heterocyclic group)-R.sup.o--; wherein
R.sup.d may be optionally substituted on carbon by one or more
R.sup.j;
[0104] R.sup.o is --C(O)N(R.sup.p)--; wherein R.sup.p is hydrogen;
and
[0105] R.sup.j is halo.
[0106] Particularly R.sup.4 is hydrogen or C.sub.1-6alkyl; wherein
R.sup.4 may be optionally substituted on carbon by one or more
R.sup.d;
[0107] R.sup.d is selected from amino, C.sub.1-6alkoxy, phenyl or
heterocyclic group.
[0108] More particularly R.sup.4 is hydrogen, methyl, ethyl,
benzyl, 2-phthalmidoethyl, 2-aminoethyl or 2-methoxyethyl.
[0109] Particularly preferred R.sup.4 is methyl or ethyl.
[0110] In another aspect of the invention, preferably R.sup.4 is
hydrogen, C.sub.1-6alkyl or C.sub.2-6alkenyl; wherein R.sup.4 may
be optionally substituted on carbon by one or more R.sup.d;
wherein
[0111] R.sup.d is selected from halo, amino, C.sub.1-6alkoxy,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, phenyl or
heterocyclic group.
[0112] In another aspect of the invention, more preferably R.sup.4
is hydrogen, methyl, ethyl, isopropyl or 3-butenyl; wherein R.sup.4
may be optionally substituted on carbon by one or more R.sup.d;
wherein
[0113] R.sup.d is selected from fluoro, amino, methoxy, acetamido,
mesylamino, phenyl or phthalimido.
[0114] In another aspect of the invention, particularly R.sup.4 is
hydrogen, methyl, ethyl, isopropyl, 3-butenyl, benzyl,
2-phthalimidoethyl, 2-aminoethyl, 2-methoxyethyl, 2-acetamidoethyl,
2-mesylaminoethyl or 2,2,2-trifluoroethyl.
[0115] In another aspect of the invention, more particularly
R.sup.4 is methyl, ethyl or isopropyl.
[0116] Preferably R.sup.5 and R.sup.6 are independently selected
from hydrogen or C.sub.1-6alkyl.
[0117] More preferably R.sup.5 and R.sup.6 are independently
selected from hydrogen or methyl.
[0118] Particularly R.sup.5 is selected from hydrogen or methyl and
R.sup.6 is hydrogen.
[0119] In another aspect of the invention, preferably R.sup.5 and
R.sup.6 are independently selected from hydrogen or C.sub.1-6alkyl;
wherein R.sup.5 and R.sup.6 independently of each other may be
optionally substituted on carbon by one or more R.sup.e;
wherein
[0120] R.sup.e is selected from halo or methoxy.
[0121] In another aspect of the invention, more preferably R.sup.5
and R.sup.6 are independently selected from hydrogen, methyl, ethyl
or isopropyl; wherein R.sup.5 and R.sup.6 independently of each
other may be optionally substituted on carbon by one or more
R.sup.e; wherein
[0122] R.sup.e is selected from fluoro or methoxy.
[0123] In another aspect of the invention, more preferably R.sup.5
and R.sup.6 are independently selected from hydrogen, methyl,
ethyl, isopropyl, trifluoromethyl or methoxymethyl.
[0124] In another aspect of the invention, more preferably R.sup.5
is methyl or isopropyl and R.sup.6 is hydrogen.
[0125] Therefore in another aspect of the invention, there is
provided a compound of formula (I) (as depicted above) wherein:
[0126] R.sup.1 is chloro;
[0127] p is 0 or 1;
[0128] R.sup.2 is sulphamoyl or a group R.sup.a--R.sup.b--;
[0129] R.sup.a is selected from C.sub.1-6alkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, phenylC.sub.1-6alkyl or
(heterocyclic group)C.sub.1-6alkyl; wherein R.sup.a may be
optionally substituted on carbon by one or more R.sup.g;
[0130] R.sup.b is --N(R.sup.m)SO.sub.2--; wherein R.sup.m is
hydrogen;
[0131] R.sup.g is selected from halo, hydroxy, carbamoyl or
C.sub.1-6alkoxy;
[0132] R.sup.j is selected from hydroxy;
[0133] q is 0 or 1;
[0134] p+q is 0or 1;
[0135] n is 0;
[0136] R.sup.4 is hydrogen or C.sub.1-6alkyl; wherein R.sup.4 may
be optionally substituted on carbon by one or more R.sup.d;
[0137] R.sup.d is selected from amino, C.sub.1-6alkoxy, phenyl or
heterocyclic group; and
[0138] R.sup.5 and R.sup.6 are independently selected from hydrogen
or C.sub.1-6alkyl;
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof.
[0139] Therefore in a further aspect of the invention, there is
provided a compound of formula (I) (as depicted above) wherein:
[0140] R.sup.1 is chloro;
[0141] p is 0 or 1; and when p is 1, R.sup.1 is meta to the --NH--
of the aniline of formula (I);
[0142] R.sup.2 is sulphamoyl,
N-(tetrahydrofuran-2-ylmethyl)sulphamoyl,
N-[3-(2-oxopyrrolidin-1-yl)propyl]sulphamoyl,
N-(3-methoxypropyl)sulphamoyl, N-(4-fluorobenzyl)sulphamoyl,
N-(cyclopropylmethyl)sulphamoyl, N-propylsulphamoyl,
N-(2,3-dihydroxypropyl)sulphamoyl,
N-[2-(2-hydroxyethoxy)ethyl]sulphamoyl,
N-(furan-2-ylmethyl)sulphamoyl, N-(2-hydroxyethyl)sulphamoyl or
N-(carbamoylmethyl)sulphamoyl;
[0143] q is 0 or 1; and when q is 1, R.sup.2 is para to the --NH--
of the aniline of formula (I);
[0144] p+q is 1;
[0145] n is 0;
[0146] R.sup.4 is methyl or ethyl; and
[0147] R.sup.5 is selected from hydrogen or methyl and R.sup.6 is
hydrogen;
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof.
[0148] Therefore in an a further additional aspect of the
invention, there is provided a compound of formula (I) (as depicted
above) wherein:
[0149] R.sup.1 is halo, amino, C.sub.1-6allyl or
C.sub.1-6alkoxy;
[0150] p is 0-2; wherein the values of R.sup.1 may be the same or
different;
[0151] R.sup.2 is sulphamoyl or a group R.sup.a--R.sup.b--;
wherein
[0152] R.sup.a is selected from C.sub.1-6alkyl, C.sub.2-6-alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, phenyl or a heterocyclic
group; wherein R.sup.a may be optionally substituted on carbon by
one or more R.sup.g;
[0153] R.sup.b is --N(R.sup.m)C(O)--, --C(O)N(R.sup.m)--,
--S(O).sub.r--, --OC(O)N(R.sup.m)SO.sub.2--, --SO.sub.2N(R.sup.m)--
or --N(R.sup.m)SO.sub.2--; wherein R.sup.m is hydrogen or
C.sub.1-6alkyl and r is 2;
[0154] R.sup.g is selected from halo, hydroxy, amino, cyano,
carbamoyl, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkoxyC.sub.1-6alkoxy,
N,N-(C.sub.1-6alkyl)amino, C.sub.1-6alkylS(O).sub.a wherein a is 2,
C.sub.3-8cycloalkyl, phenyl, heterocyclic group,
phenylC.sub.1-6alkyl-R.sup.o-- or (heterocyclic group)-R.sup.o--;
wherein R.sup.g may be optionally substituted on carbon by one or
more R.sup.j;
[0155] R.sup.o is --O--;
[0156] R.sup.j is selected from halo, hydroxy, methyl or
methoxy;
[0157] q is 0 or 1;
[0158] R.sup.3 is halo;
[0159] n is 0 or 1;
[0160] R.sup.4 is hydrogen, C.sub.1-6alkyl or C.sub.2-6alkenyl;
wherein R.sup.4 may be optionally substituted on carbon by one or
more R.sup.d; wherein
[0161] R.sup.d is selected from halo, amino, C.sub.1-6alkoxy,
C.sub.1-6alkanoylamino, C.sub.1-6alkylsulphonylamino, phenyl or
heterocyclic group; and
[0162] R.sup.5 and R.sup.6 are independently selected from hydrogen
or C.sub.1-6alkyl; wherein R.sup.5 and R.sup.6 independently of
each other may be optionally substituted on carbon by one or more
R.sup.e; wherein
[0163] R.sup.e is selected from halo or methoxy.
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof.
[0164] Therefore in another further additional aspect of the
invention, there is provided a compound of formula (I) (as depicted
above) wherein:
[0165] R.sup.1 is chloro, amino, methyl or methoxy;
[0166] p is 0-2; wherein the values of R.sup.1 may be the same or
different;
[0167] R.sup.2 is sulphamoyl
N-(tetrahydrofur-2-ylmethyl)sulphamoyl,
N-(cyclopropylmethyl)sulphamoyl, N-(fur-2-ylmethyl)sulphamoyl,
N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)sulphamoyl,
N-(cyanomethyl)sulphamoyl, N-(carbamoylmethyl)sulphamoyl,
N-methylsulphamoyl, N-(4-fluorobenzyl)sulphamoyl,
N-(pyridin-2-ylmethyl)sulphamoyl, N-(pyridin-3-ylmethyl)sulphamoyl,
N-(4-methylthiazol-2-yl)sulphamoyl,
N-(3-methylisoxazol-5-ylmethyl)sulphamoyl,
N-(tetrahydropyran-2-ylmethyl)sulphamoyl,
N-(2-methylpyrazin-5-yl)sulphamoyl,
N-[2-(2-hydroxyethoxy)ethyl]sulphamoyl,
N-(2-hydroxyethyl)sulphamoyl, N-2,2,2-trifluoroethyl)sulphamoyl,
N-(2-methoxyethyl)sulphamoyl, N-(2-mesylethyl)sulphamoyl,
N-(2-benzyloxyethyl)sulphamoyl, N-(2,2-dimethoxyethyl)sulphamoyl,
N-[2-(N,N-dimethylamino)ethyl]sulphamoyl,
N-(2-piperidin-1-ylethyl)sulphamoyl,
N-[2-(methoxymethoxy)ethyl]sulphamoyl, N-ethylsulphamoyl,
N-[2-(2-methoxyethoxy)ethyl]sulphamoyl,
N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}sulphamoyl,
N-(2-{2-[2-(2methoxyethoxy)ethoxy]ethoxy}ethyl)sulphamoyl,
N-(2-pyridin-2-ylethyl)sulphamoyl,
N-(2-pyridin-4-ylethyl)sulphamoyl,
N-(2-isoxazol-3-yloxyethyl)sulphamoyl,
N-(2-isothiazol-3-yloxyethyl)sulphamoyl,
N-(2-1,2-5-thiadiazol-3-yloxyethyl)sulphamoyl,
N-methyl-N-(2-methoxyethyl)sulphamoyl,
N-[3-(2-oxopyrrolidin-1yl)propyl]sulphamoyl,
N-(3-methoxypropyl)sulphamoyl, N-propylsulphamoyl,
N-(2,3-dihydroxypropyl)sulphamoyl,
N-(3-morpholinopropyl)sulphamoyl,
N-[3-(N,N-dimethylamino)propyl]sulphamoyl,
N-(3,3,3-trifluoropropyl)sulphamoyl,
N-(2,2-dimethyl-3-hydroxypropyl)sulphamoyl,
N-(3-hydroxypropyl)sulphamoyl, N-(3-ethoxypropyl)sulphamoyl,
N-(2-hydroxypropyl)sulphamoyl, N-(3-isopropoxypropyl)sulphamoyl,
N-(3-isopropoxy-2-hydroxypropyl)sulphamoyl,
N-(3-isoxazol-3-yloxypropyl)sulphamoyl,
N-(3-isothiazol-3-yloxypropyl)sulphamoyl,
N-(3-1,2-5-thiadiazol-3-yloxypropyl)sulphamoyl,
N-(1,1-dimethylpropyl)sulphamoyl,
N-methyl-N-(3-morpholinopropyl)sulphamoyl, N-butylsulphamoyl,
N-t-butylsulphamoyl, N-(2-hydroxybutyl)sulphamoyl,
N-methyl-N-t-butylsulphamoyl, N-pentylsulphamoyl,
N-(5-hydroxypentyl)sulphamoyl,
N-(4,5-dimethyloxazol-2-yl)sulphamoyl, N-(cyclopropyl)sulphamoyl,
N-(cyclobutyl)sulphamoyl, N-(3-trifluoromethylphenyl)sulphamoyl,
N-allylsulphamoyl, N-(2-propynyl)sulphamoyl, N-methylcarbamoyl,
acetamido, mesylamino or mesyl;
[0168] q is 0 or 1;
[0169] R.sup.3 is bromo or chloro;
[0170] n is 0 or 1;
[0171] R.sup.4 is hydrogen, methyl, ethyl, isopropyl, 3-butenyl,
benzyl, 2-phthalimidoethyl, 2-aminoethyl, 2-methoxyethyl,
2-acetamidoethyl, 2-mesylaminoethyl or 2,2,2-trifluoroethyl;
[0172] R.sup.5 and R.sup.6 are independently selected from
hydrogen, methyl, ethyl, isopropyl, trifluoromethyl or
methoxymethyl;
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof.
[0173] In another aspect of the invention, preferred compounds of
the invention are any one of the Examples or a pharmaceutically
acceptable salt or an in vivo hydrolysable ester thereof.
[0174] In a further aspect of the invention, preferred compounds of
the invention are Examples 25, 37, 42, 43, 53, 67, 121, 122, 123
and 136.
[0175] Preferred aspects of the invention are those which relate to
the compound of formula (I) or a pharmaceutically acceptable salt
thereof.
[0176] Another aspect of the present invention provides a process
for preparing a compound of formula (I) or a pharmaceutically
acceptable salt or an in vivo hydrolysable ester thereof which
process (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, n, p and q are, unless otherwise specified, as defined in
formula (I)) comprises of: [0177] Process a) reaction of a
pyrimidine of formula (II): ##STR3## wherein L is a displaceable
group; with an aniline of formula (III): ##STR4## or [0178] Process
b) reacting a compound of formula (IV): ##STR5## with a compound of
formula (V): ##STR6## wherein T is O or S; R.sup.x may be the same
or different and is selected from C.sub.1-6alkyl; [0179] Process c)
for compounds of formula (I) where R.sup.2 is sulphamoyl or a group
R.sup.a--R.sup.b-- and R.sup.b is --NHSO.sub.2--; reacting a
pyrimidine of formula (VI): ##STR7## wherein X is a displaceable
group; with an amine of formula (VII): R.sup.a--NH.sub.2 (VII)
[0180] Process d) for compounds of formula (I); reacting a
pyrimidine of formula (VIII) ##STR8## with a compound of formula
(IX): ##STR9## where Y is a displaceable group; and thereafter if
necessary: [0181] i) converting a compound of the formula (I) into
another compound of the formula (I); [0182] ii) removing any
protecting groups; [0183] iii) forming a pharmaceutically
acceptable salt or in vivo hydrolysable ester.
[0184] L is a displaceable group, suitable values for L are for
example, a halogeno or sulphonyloxy group, for example a chloro,
bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
[0185] X is a displaceable group, suitable values for X are for
example, a fluoro or chloro group. Preferably X is fluoro.
[0186] Y is a displaceable group, suitable values for Y are for
example, a halogeno or sulphonyloxy group, for example a bromo,
iodo or trifluoromethanesulphonyloxy group. Preferably Y is
iodo.
[0187] Specific reaction conditions for the above reactions are as
follows. [0188] Process a) Pyrimidines of formula (II) and anilines
of formula (III) may be reacted together: [0189] i) in the presence
of a suitable solvent for example a ketone such as acetone or an
alcohol such as ethanol or butanol or an aromatic hydrocarbon such
as toluene or N-methyl pyrrolidine, optionally in the presence of a
suitable acid for example an inorganic acid such as hydrochloric
acid or sulphuric acid, or an organic acid such as acetic acid or
formic acid (or a suitable Lewis acid) and at a temperature in the
range of 0.degree. C. to reflux, preferably reflux; or [0190] ii)
under standard Buchwald conditions (for example see J. Am. Chem.
Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62,
1568 and 6066) for example in the presence of palladium acetate, in
a suitable solvent for example an aromatic solvent such as toluene,
benzene or xylene, with a suitable base for example an inorganic
base such as caesium carbonate or an organic base such as
potassium-t-butoxide, in the presence of a suitable ligand such as
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and at a temperature in
the range of 25 to 80.degree. C.
[0191] Pyrimidines of the formula (II) where L is chloro maybe
prepared according to Scheme 1: ##STR10##
[0192] Anilines of formula (III) are commercially available
compounds, or they are known in the literature, or they are
prepared by standard processes known in the art. [0193] Process b)
Compounds of formula (IV) and compounds of formula (V) are reacted
together in a suitable solvent such as N-methylpyrrolidinone or
butanol at a temperature in the range of 100-200.degree. C.,
preferably in the range of 150-170.degree. C. The reaction is
preferably (conducted in the presence of a suitable base such as,
for example, sodium hydride, sodium methoxide or potassium
carbonate.
[0194] Compounds of formula (V) may be prepared according to Scheme
2: ##STR11##
[0195] Compounds of formula (IV) and (IVa) are commercially
available compounds, or they are known in the literature, or they
are prepared by standard processes known in the art. [0196] Process
c) Compounds of formula (VI) and amines of formula (VII) may be
reacted together in the presence of an inert solvent such as
N-methylpyrrolidinone or pyridine, in the presence of a base for
example an inorganic base such as caesium carbonate or in the
presence of an organic base such as excess (VII) and at a
temperature in the range of 25 to 80.degree. C.
[0197] Compounds of formula (VI) (wherein X is chloro) may be
prepared according to Scheme 3: ##STR12##
[0198] Compounds of formula (VIa) may be prepared according to
Process a, Process b or Process d wherein q is 0. [0199] Process d)
Compounds of formula (VIII) and amines of formula (X) maybe reacted
together under standard Buchwald conditions as described in Process
a.
[0200] The synthesis of compounds of formula (VI) is described in
Scheme 1.
[0201] Compounds of formula (IX) are commercially available
compounds, or they are known in the literature, or they are
prepared by standard processes known in the art.
[0202] Amines of formula (VI) are commercially available compounds,
or they are known in the literature, or they are prepared by
standard processes known in the art.
[0203] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogeno group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl.
[0204] It will also be appreciated that in some of the reactions
mentioned herein it may be necessary/desirable to protect any
sensitive groups in the compounds. The instances where protection
is necessary or desirable and suitable methods for protection are
known to those skilled in the art. Conventional protecting groups
may be used in accordance with standard practice (for illustration
see T. W. Green, Protective Groups in Organic Synthesis, John Wiley
and Sons, 1991). Thus, if reactants include groups such as amino,
carboxy or hydroxy it may be desirable to protect the group in some
of the reactions mentioned herein.
[0205] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl or an aroyl group, for example
benzoyl. The deprotection conditions for the above protecting
groups necessarily vary with the choice of protecting group. Thus,
for example, an acyl group such as an alkanoyl or alkoxycarbonyl
group or an aroyl group may be removed for example, by hydrolysis
with a suitable base such as an alkali metal hydroxide, for example
lithium or sodium hydroxide. Alternatively an acyl group such as a
t-butoxycarbonyl group may be removed, for example, by treatment
with a suitable acid as hydrochloric, sulphuric or phosphoric acid
or trifluoroacetic acid and an arylmethoxycarbonyl group such as a
benzyloxycarbonyl group may be removed, for example, by
hydrogenation over a catalyst such as palladium-on-carbon, or by
treatment with a Lewis acid for example boron
tris(trifluoroacetate). A suitable alternative protecting group for
a primary amino group is, for example, a phthaloyl group which may
be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0206] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0207] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
[0208] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
[0209] As stated hereinbefore the compounds defined in the present
invention possesses anti-cell-proliferation activity such as
anti-cancer activity which is believed to arise from the CDK
inhibitory activity of the compound. These properties may be
assessed, for example, using the procedure set out below:
Assay
[0210] The following abbreviations have been used: [0211] HEPES is
N-[2-Hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] [0212] DTT
is Dithiothreitol [0213] PMSF is Phenylmethylsulphonyl fluoride
[0214] The compounds were tested in an in vitro kinase assay in 96
well format using Scintillation Proximity Assay (SPA--obtained from
Amersham) for measuring incorporation of [.gamma.-33-P]-Adenosine
Triphosphate into a test substrate (GST-Retinoblastoma protein;
GST-Rb). In each well was placed the compound to be tested (diluted
in DMSO and water to correct concentrations) and in control wells
either roscovitine as an inhibitor control or DMSO as a positive
control.
[0215] Approximately 0.2 .mu.l of CDK2/Cyclin E partially-purified
enzyme (amount dependent on enzyme activity) diluted in 25 .mu.l
incubation buffer was added to each well then 20 .mu.l of
GST-Rb/ATP/ATP33 mixture (containing 0.5 .mu.g GST-Rb and 0.2 .mu.M
ATP and 0.14 .mu.Ci [.gamma.-33-P]-Adenosine Triphosphate in
incubation buffer), and the resulting mixture shaken gently, then
incubated at room temperature for 60 minutes.
[0216] To each well was then added 150 .mu.L stop solution
containing (0.8 mg/well of Protein A-PVT SPA bead (Amershaam)), 20
.mu.M/well of Anti-Glutathione Transferase, Rabbit IgG (obtained
from Molecular Probes), 61 mM EDTA and 50 mM HEPES pH 7.5
containing 0.05% sodium azide.
[0217] The plates were sealed with Topseal-S plate sealers, left
for two hours then spun at 2500 rpm, 1124.times.g., for 5 minutes.
The plates were read on a Topcount for 30 seconds per well.
[0218] The incubation buffer used to dilute the enzyme and
substrate mixes contained 50 mM HEPES pH7.5, 10 mM MnCl.sub.2, 1 mM
DTT, 100 .mu.M Sodium vanadate, 100 .mu.M NaF, 10 mM Sodium
Glycerophosphate, BSA (1 mg/ml final).
Test Substrate
[0219] In this assay only part of the retinoblastoma protein
(Science 1987 March 13;235(4794):1394-1399; Lee W. H., Bookstein
R., Hong F., Young L. J., Shew J. Y., Lee E. Y.) was used, fused to
a GST tag. PCR of retinoblastoma gene encoding amino acids 379-928
(obtained from retinoblastoma plasmid ATCC pLRbRNL) was performed,
and the sequence cloned into pGEx 2T fusion vector (Smith D. B. and
Johnson, K. S. Gene 67, 31 (1988); which contained a tac promoter
for inducible expression, internal lac I.sup.q gene for use in any
E. Coli host, and a coding region for thrombin cleavage--obtained
from Pharmacia Biotech) which was used to amplify amino acids
792-928. This sequence was again cloned into pGEx 2T.
[0220] The retinoblastoma 792-928 sequence so obtained was
expressed in E. Coli (BL21 (DE3) pLysS cells) using standard
inducible expression techniques, and purified as follows.
[0221] E. coli paste was resuspended in 10 ml/g of NETN buffer (50
mM Tris pH 7.5, 120 mM NaCl, 1 mM EDTA, 0.5% v/v NP-40, 1 mM PMSF,
1 .mu.g/ml leupepin, 1 .mu.g/ml aprotinin and 1 .mu.g/ml pepstatin)
and sonicated for 2.times.45 seconds per 100 ml homogenate. After
centrifugation, the supernatant was loaded onto a 10 ml glutathione
Sepharose column (Pharmacia Biotech, Herts, UK), and washed with
NETN buffer. After washing with kinase buffer (50 mM HEPES pH 7.5,
10 mM MgCl.sub.2, 1 mM DTT, 1 mM PMSF, 1 .mu.g/ml leupeptin, 1
.mu.g/ml aprotinin and 1 .mu.g/ml pepstatin) the protein was eluted
with 50 mM reduced glutathione in kinase buffer. Fractions
containing GST-Rb (792-927) were pooled and dialysed overnight
against kinase buffer. The final product was analysed by Sodium
Dodeca Sulfate (SDS) PAGE (Polyacrylamide gel) using 8-16%
Tris-Glycine gels (Novex, San Diego, USA).
CDK2 and Cyclin E
[0222] The open reading frames of CDK2 and Cyclin E were isolated
by reverse transcriptase-PCR using HeLa cell and activated T cell
mRNA as a template and cloned into the insect expression vector
pVL1393 (obtained from Invitrogen 1995 catalogue number: V1392-20).
CDK2 and cyclin E were then dually expressed [using a standard
virus Baculogold co-infection technique] in the insect SF21 cell
system (Spodoptera frugiperda cells derived from ovarian tissue of
the Fall Army Worm--commercially available).
Example Production of Cyclin E/CDK2
[0223] The following Example provides details of the production of
Cyclin E/CDK2 in SF21 cells (in TC100+10% FBS(TCS)+0.2% Pluronic)
having dual infection MOI 3 for each virus of Cyclin E &
CDK2.
[0224] SF21 cells grown in a roller bottle culture to
2.33.times.10.sup.6 cells/ml were used to inoculate 10.times.500 ml
roller bottles at 0.2.times.10E6 cells/ml. The roller bottles were
incubated on a roller rig at 28.degree. C.
[0225] After 3 days (72 hrs.) the cells were counted, and the
average from 2 bottles found to be 1.86.times.10E6 cells/ml. (99%
viable). The cultures were then infected with the dual viruses at
an MOI 3 for each virus.
[0226] The viruses were mixed together before addition to the
cultures, and the cultures returned to the roller rig 28.degree.
C.
[0227] After 2 days (48 hrs.) post infection the 5 litres of
culture was harvested. The total cell count at harvest was
1.58.times.10E6 cells/ml. (99% viable). The cells were spun out at
2500 rpm, 30 mins., 4.degree. C. in Heraeus Omnifuge 2.0 RS in 250
ml. lots. The supernatant was discarded.
Partial Co-Purification of Cdk2 and Cyclin E
[0228] Sf21 cells were resuspended in lysis buffer (50 mM Tris pH
8.2, 10 mM MgCl.sub.2, 1 mM DTT, 10 mM glycerophosphate, 0.1 mM
sodium orthovanadate, 0.1 mM NaF, 1 mM PMSF, 1 .mu.g/ml leupeptin
and 1 .mu.g/ml aprotinin) and homogenised for 2 minutes in a 10 ml
Dounce homogeniser. After centrifugation, the supernatant was
loaded onto a Poros HQ/M 1.4/100 anion exchange column (PE
Biosystems, Hertford, UK). Cdk2 and Cyclin E were coeluted at the
beginning of a 0-1M NaCl gradient (run in lysis buffer minus
protease inhibitors) over 20 column volumes. Co-elution was checked
by western blot using both anti-Cdk2 and anti-Cyclin E antibodies
(Santa Cruz Biotechnology, California, US).
[0229] By analogy, assays designed to assess inhibition of CDK4 and
CDK6 may be constructed. CDK2 (EMBL Accession No. X62071) may be
used together with Cyclin A or Cyclin E (see EMBL Accession No.
M73812), and further details for such assays are contained in PCT
International Publication No. WO99/21845, the relevant Biochemical
& Biological Evaluation sections of which are hereby
incorporated by reference.
[0230] Although the pharmacological properties of the compounds of
the formula (I) vary with structural change, in general activity
possessed by compounds of the formula (I) may be demonstrated at
IC.sub.50 concentrations or doses in the range 250 .mu.M to 1
nM.
[0231] When tested in the above in-vitro assay the CDK2 inhibitory
activity of Example 14 was measured as IC.sub.50=0.146 .mu.M.
[0232] The in vivo activity of the compounds of the present
invention may be assessed by standard techniques, for example by
measuring inhibition of cell growth and assessing cytotoxicity.
[0233] Inhibition of cell growth may be measured by staining cells
with Sulforhodamine B (SRB), a fluorescent dye that stains proteins
and therefore gives an estimation of amount of protein (i.e. cells)
in a well (see Boyd, M. R. (1989) Status of the NCI preclinical
antitumour drug discovery screen. Prin. Prac Oncol 10:1-12). Thus,
the following details are provided of measuring inhibition of cell
growth:
[0234] Cells were plated in appropriate medium in a volume of 100
.mu.l in 96 well plates; media was Dulbecco's Modified Eagle media
for MCF-7, SK-UT-1B and SK-UT-1. The cells were allowed to attach
overnight, then inhibitor compounds were added at various
concentrations in a maximum concentration of 1% DMSO (v/v). A
control plate was assayed to give a value for cells before dosing.
Cells were incubated at 37.degree. C., (5% CO.sub.2) for three
days.
[0235] At the end of three days TCA was added to the plates to a
final concentration of 16% (v/v). Plates were then incubated at
4.degree. C. for 1 hour, the supernatant removed and the plates
washed in tap water. After drying, 100 .mu.l SRB dye (0.4% SRB in
1% acetic acid) was added for 30 minutes at 37.degree. C. Excess
SRB was removed and the plates washed in 1% acetic acid. The SRB
bound to protein was solubilised in 10 mM Tris pH7.5 and shaken for
30 minutes at room temperature. The ODs were read at 540 nm, and
the concentration of inhibitor causing 50% inhibition of growth was
determined from a semi-log plot of inhibitor concentration versus
absorbance. The concentration of compound that reduced the optical
density to below that obtained when the cells were plated at the
start of the experiment gave the value for toxicity.
[0236] Typical IC.sub.50 values for compounds of the invention when
tested in the SRB assay are in the range 1 mM to 1 nM.
[0237] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a pyrimidine
derivative of the formula (I), or a pharmaceutically acceptable
salt or in vivo hydrolysable ester thereof, as defined hereinbefore
in association with a pharmaceutically-acceptable diluent or
carrier.
[0238] The composition maybe in a form suitable for oral
administration, for example as a tablet or capsule, for parenteral
injection (including intravenous, subcutaneous, intramuscular,
intravascular or infusion) as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for
rectal administration as a suppository.
[0239] In general the above compositions may be prepared in a
conventional manner using conventional excipients.
[0240] The compound of formula (I) will normally be administered to
a warm-blooded animal at a unit dose within the range 5-5000 mg per
square meter body area of the animal, i.e. approximately 0.1-100
mg/kg, and this normally provides a therapeutically-effective dose.
A unit dose form such as a tablet or capsule will usually contain,
for example 1-250 mg of active ingredient. Preferably a daily dose
in the range of 1-50 mg/kg is employed. However the daily dose will
necessarily be varied depending upon the host treated, the
particular route of administration, and the severity of the illness
being treated. Accordingly the optimum dosage may be determined by
the practitioner who is treating any particular patient.
[0241] According to a further aspect of the present invention there
is provided a compound of the formula (I), or a pharmaceutically
acceptable salt or in vivo hydrolysable ester thereof, as defined
hereinbefore for use in a method of treatment of the human or
animal body by therapy.
[0242] We have found that the compounds defined in the present
invention, or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof, are effective cell cycle inhibitors
(anti-cell proliferation agents), which property is believed to
arise from their CDK inhibitory properties. Accordingly the
compounds of the present invention are expected to be useful in the
treatment of diseases or medical conditions mediated alone, or in
part by CDK enzymes, i.e. the compounds may be used to produce a
CDK inhibitory effect in a warm-blooded animal in need of such
treatment. Thus the compounds of the present invention provide a
method for treating the proliferation of malignant cells
characterised by inhibition of CDK enzymes, i.e. the compounds
maybe used to produce an anti-proliferative effect mediated alone
or in part by the inhibition of CDKs. Such a compound of the
invention is expected to possess a wide range of anti-cancer
properties as CDKs have been implicated in many common human
cancers such as leukaemia and breast, lung, colon, rectal, stomach,
prostate, bladder, pancreas and ovarian cancer. Thus it is expected
that a compound of the invention will possess anti-cancer activity
against these cancers. It is in addition expected that a compound
of the present invention will possess activity against a range of
leukaemias, lymphoid malignancies and solid tumours such as
carcinomas and sarcomas in tissues such as the liver, kidney,
prostate and pancreas. In particular such compounds of the
invention are expected to slow advantageously the growth of primary
and recurrent solid tumours of, for example, the colon, breast,
prostate, lungs and skin. More particularly such compounds of the
invention, or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof, are expected to inhibit the growth of
those primary and recurrent solid tumours which are associated with
CDKs, especially those tumours which are significantly dependent on
CDKs for their growth and spread, including for example, certain
tumours of the colon, breast, prostate, lung, vulva and skin.
[0243] It is further expected that a compound of the present
invention will possess activity against other cell-proliferation
diseases in a wide range of other disease states including
leukaemias, fibroproliferative and differentiative disorders,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma,
acute and chronic nephropathies, atheroma, atherosclerosis,
arterial restenosis, autoimmune diseases, acute and chronic
inflammation, bone diseases and ocular diseases with retinal vessel
proliferation.
[0244] Thus according to this aspect of the invention there is
provided a compound of the formula (I), or a pharmaceutically
acceptable salt or in vivo hydrolysable ester thereof, as defined
hereinbefore for use as a medicament; and the use of a compound of
the formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof, as defined hereinbefore in the
manufacture of a medicament for use in the production of a cell
cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded
animal such as ma Particularly, an inhibitory effect is produced by
preventing entry into or progression through the S phase by
inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.
[0245] According to a further feature of the invention, there is
provided a compound of the formula (I), or a pharmaceutically
acceptable salt or in vivo hydrolysable ester thereof, as defined
herein before in the manufacture of a medicament for use in the
treatment of cancers (solid tumours and leukaemias),
fibroproliferative and differentiative disorders, psoriasis,
rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and
chronic nephropathies, atheroma, atherosclerosis, arterial
restenosis, autoimmune diseases, acute and chronic inflammation,
bone diseases and ocular diseases with retinal vessel
proliferation, particularly in the treatment of cancers.
[0246] According to a further feature of this aspect of the
invention there is provided a method for producing a cell cycle
inhibitory (anti-cell-proliferation) effect in a warm-blooded
animal, such as man, in need of such treatment which comprises
administering to said animal an effective amount of a compound as
defined immediately above. Particularly, an inhibitory effect is
produced by preventing entry into or progression through the S
phase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.
[0247] According to a further feature of this aspect of the
invention there is provided a method for producing a cell cycle
inhibitory (anti-cell-proliferation) effect in a warm-blooded
animal, such as man, in need of such treatment which comprises
administering to said animal an effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof as defined herein before. Particularly,
an inhibitory effect is produced by preventing entry into or
progression through the S phase by inhibition of CDK2, CDK4 and/or
CDK6, especially CDK2.
[0248] According to an additional feature of this aspect of the
invention there is provided a method of treating cancers (solid
tumours and leukaemias), fibroproliferative and differentiative
disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,
haemangioma, acute and chronic nephropathies, atheroma,
atherosclerosis, arterial restenosis, autoimmune diseases, acute
and chronic inflammation, bone diseases and ocular diseases with
retinal vessel proliferation, in a warm-blooded animal, such as
man, in need of such treatment which comprises administering to
said animal an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof as defined herein before.
[0249] Particularly there is provided a method of treating cancer
in a warm-blooded animal, such as man, in need of such treatment
which comprises administering to said animal an effective amount of
a compound of formula (I) or a pharmaceutically acceptable salt or
in vivo hydrolysable ester thereof as defined herein before.
[0250] In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the
formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof, as defined herein before in association
with a pharmaceutically-acceptable diluent or carrier for use in
the production of a cell cycle inhibitory (anti-cell-proliferation)
effect in a warm-blooded animal such as man.
[0251] In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the
formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof, as defined herein before in association
with a pharmaceutically-acceptable diluent or carrier for use in
the treatment of cancers (solid tumours and leukaemias),
fibroproliferative and differentiative disorders, psoriasis,
rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and
chronic nephropathies, atheroma, atherosclerosis, arterial
restenosis, autoimmune diseases, acute and chronic inflammation,
bone diseases and ocular diseases with retinal vessel
proliferation, in a warm-blooded animal such as man.
[0252] In a further aspect of the invention there is provided a
pharmaceutical composition which comprises a compound of the
formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof, as defined herein before in association
with a pharmaceutically-acceptable diluent or carrier for use in
the treatment of cancer in a warm-blooded animal such as man.
[0253] Preventing cells from entering DNA synthesis by inhibition
of essential S-phase initiating activities such as CDK2 initiation
may also be useful in protecting normal cells of the body from
toxicity of cycle-specific pharmaceutical agents. Inhibition of
CDK2 or 4 will prevent progression into the cell cycle in normal
cells which could limit the toxicity of cycle-specific
pharmaceutical agents which act in S-phase, G2 or mitosis. Such
protection may result in the prevention of hair loss normally
associated with these agents.
[0254] Therefore in a further aspect of the invention there is
provided a compound of formula (I) as defined above or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof for use as a cell protective agent.
[0255] Therefore in a further aspect of the invention there is
provided a compound of formula (I) as defined above or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof for use in preventing hair loss arising from the treatment
of malignant conditions with pharmaceutical agents.
[0256] Examples of pharmaceutical agents for treating malignant
conditions that are known to cause hair loss include alkylating
agents such as ifosfamide and cyclophosphamide; antimetabolites
such as methotrexate, 5-fluorouracil, gemcitabine and cytarabine;
vinca alkaloids and analogues such as vincristine, vinbalstine,
vindesine, vinorelbine; taxanes such as paclitaxel and docetaxel;
topoisomerase I inhibitors such as irintotecan and topotecan;
cytotoxic antibiotics such as doxorubicin, daunorubicin,
mitoxantrone, actinomycin-D and mitomycin; and others such as
etoposide and tretinoin.
[0257] In another aspect of the invention, the compound of formula
(I), or a pharmaceutically acceptable salt or in vivo hydrolysable
ester thereof, may be administered in association with a one or
more of the above pharmaceutical agents. In this instance the
compound of formula (I) may be administered by systemic or non
systemic means. Particularly the compound of formula (I) my may
administered by non-systemic means, for example topical
administration.
[0258] Therefore in an additional feature of the invention, there
is provided a method of preventing hair loss during treatment for
one or more malignant conditions with pharmaceutical agents, in a
warm-blooded animal, such as man, which comprises administering to
said animal an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof.
[0259] In an additional feature of the invention, there is provided
a method of preventing hair loss during treatment for one or more
malignant conditions with pharmaceutical agents, in a warm-blooded
animal, such as man, which comprises administering to said animal
an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof in simultaneous, sequential or separate administration with
an effective amount of said pharmaceutical agent.
[0260] According to a further aspect of the invention there is
provided a pharmaceutical composition for use in preventing hair
loss arising from the treatment of malignant conditions with
pharmaceutical agents which comprises a compound of formula (I), or
a pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof, and said pharmaceutical agent, in association with a
pharmaceutically acceptable diluent or carrier.
[0261] According to a further aspect of the present invention there
is provided a kit comprising a compound of formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof, and a pharmaceutical agent for treating malignant
conditions that is known to cause hair loss.
[0262] According to a further aspect of the present invention there
is provided a kit comprising: [0263] a) a compound of formula (I),
or a pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof in a first unit dosage form; [0264] b) a pharmaceutical
agent for treating malignant conditions that is known to cause hair
loss; in a second unit dosage form; and [0265] c) container means
for containing said first and second dosage forms.
[0266] According to another feature of the invention there is
provided the use of a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof in the manufacture of a medicament for the prevention of
hair loss during treatment of malignant conditions with
pharmaceutical agents.
[0267] According to a further aspect of the present invention there
is provided a combination treatment for the prevention of hair loss
comprising the administration of an effective amount of a compound
of the formula (I), or a pharmaceutically acceptable salt or in
vivo hydrolysable ester thereof, optionally together with a
pharmaceutically acceptable diluent or carrier, with the
simultaneous, sequential or separate administration of an effective
amount of a pharmaceutical agent for treatment of malignant
conditions to a warm-blooded animal, such as man.
[0268] As stated above the size of the dose required for the
therapeutic or prophylactic treatment of a particular
cell-proliferation disease will necessarily be varied depending on
the host treated, the route of administration and the severity of
the illness being treated. A unit dose in the range, for example,
1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
[0269] The CDK inhibitory activity defined hereinbefore may be
applied as a sole therapy or may involve, in addition to a compound
of the invention, one or more other substances and/or treatments.
Such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate administration of the individual components
of the treatment. In the field of medical oncology it is normal
practice to use a combination of different forms of treatment to
treat each patient with cancer. In medical oncology the other
component(s) of such conjoint treatment in addition to the cell
cycle inhibitory treatment defined hereinbefore may be: surgery,
radiotherapy or chemotherapy. Such chemotherapy may cover three
main categories of therapeutic agent: [0270] (i) other cell cycle
inhibitory agents that work by the same or different mechanisms
from those defined hereinbefore; [0271] (ii) cytostatic agents such
as antioestrogens (for example tamoxifen, toremifene, raloxifene,
droloxifene, iodoxyfene), progestogens (for example megestrol
acetate), aromatase inhibitors (for example anastrozole, letrazole,
vorazole, exemestane), antiprogestogens, antiandrogens (for example
flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH
agonists and antagonists (for example goserelin acetate,
luprolide), inhibitors of testosterone 5.alpha.-dihydroreductase
(for example finasteride), anti-invasion agents (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function) and inhibitors
of growth factor function, (such growth factors include for example
platelet derived growth factor and hepatocyte growth factor such
inhibitors include growth factor antibodies, growth factor receptor
antibodies, tyrosine kinase inhibitors and serine/threonine kinase
inhibitors); and [0272] (iii) antiproliferative/antineoplastic
drugs and combinations thereof, as used in medical oncology, such
as antimetabolites (for example antifolates like methotrexate,
fluoropyrimidines like 5-fluorouracil, purine and adenosine
analogues, cytosine arabinoside); antitumour antibiotics (for
example anthracyclines like doxorubicin, daunomycin, epirubicin and
idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum
derivatives (for example cisplatin, carboplatin); alkylating agents
(for example nitrogen mustard, melphalan, chlorambucil, busulphan,
cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic
agents (for example vinca alkaloids like vincristine and taxoids
like taxol, taxotere); topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amisacrine,
topotecan). According to this aspect of the invention there is
provided a pharmaceutical product comprising a compound of the
formula (I) as defined hereinbefore and an additional anti-tumour
substance as defined hereinbefore for the conjoint treatment of
cancer.
[0273] In addition to their use in therapeutic medicine, the
compounds of formula (I) and their pharmaceutically acceptable
salts are also useful as pharmacological tools in the development
and standardisation of in vitro and in vivo test systems for the
evaluation of the effects of inhibitors of cell cycle activity in
laboratory animals such as cats, dogs, rabbits, monkeys, rats and
mice, as part of the search for new therapeutic agents.
[0274] In the above other pharmaceutical composition, process,
method, use and medicament manufacture features, the alternative
and preferred embodiments of the compounds of the invention
described herein also apply.
EXAMPLES
[0275] The invention will now be illustrated by the following non
limiting examples in which, unless stated otherwise: [0276] (i)
temperatures are given in degrees Celsius (.degree. C.); operations
were carried out at room or ambient temperature, that is, at a
temperature in the range of 18-25.degree. C.; [0277] (ii) organic
solutions were dried over anhydrous magnesium sulphate; evaporation
of solvent was carried out using a rotary evaporator under reduced
pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of
up to 60.degree. C.; [0278] (iii) chromatography means flash
chromatography on silica gel; thin layer chromatography (TLC) was
carried out on silica gel plates; [0279] (iv) in general, the
course of reactions was followed by TLC and reaction times are
given for illustration only; [0280] (v) final products had
satisfactory proton nuclear magnetic resonance (NMR) spectra and/or
mass spectral data; [0281] (vi) yields are given for illustration
only and are not necessarily those which can be obtained by
diligent process development; preparations were repeated if more
material was required; [0282] (vii) when given, NMR data is in the
form of delta values for major diagnostic protons, given in parts
per million (ppm) relative to tetramethylsilane (TMS) as an
internal standard, determined at 300 MHz using perdeuterio dimethyl
sulphoxide (DMSO-d.sub.6) as solvent unless otherwise indicated;
[0283] (viii) chemical symbols have their usual meanings; SI units
and symbols are used; [0284] (ix) solvent ratios are given in
volume:volume (v/v) terms; and [0285] (x) mass spectra were run
with an electron energy of 70 electron volts in the chemical
ionization (CI) mode using a direct exposure probe; where indicated
ionization was effected by electron impact (EI), fast atom
bombardment (FAB) or electrospray (ESP); values for m/z are given;
generally, only ions which indicate the parent mass are reported;
and unless otherwise stated, the mass ion quoted is (MH).sup.+;
[0286] (xi) unless stated otherwise compounds containing an
asymmetrically substituted carbon and/or sulphur atom have not been
resolved; [0287] (xii) where a synthesis is described as being
analogous to that described in a previous example the amounts used
are the millimolar ratio equivalents to those used in the previous
example; [0288] (xvi) the following abbreviations have been used:
[0289] THF tetrahydrofuran; [0290] DMF N,N-dimethylformamide;
[0291] DMFDMA dimethylformamide dimethylacetal; [0292] EtOAc ethyl
acetate; [0293] MeOH methanol; [0294] EtOH ethanol; [0295] DCM
dichloromethane; and [0296] DMSO dimethylsulphoxide. [0297] xvii)
where an Isolute SCX-2 column is referred to, this means an "ion
exchanger" extraction cartridge for adsorption of basic compounds,
i.e. a polypropylene tube containing a benzenesulphonic acid based
strong cation exchange sorbent, used according to the manufacturers
instructions obtained from International Sorbent Technologies
Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82
7RJ; [0298] xviii) where an Isolute amine column is referred to,
this means an "ion exchange" extraction cartridge for adsorption of
acidic compounds, i.e. a polypropylene tube containing a amino
silane covalently bonded to a silica particle used according to the
manufacturers instructions obtained from International Sorbent
Technologies Limited, Dyffryn Business Park, Hengeod, Mid
Glamorgan, UK, CF82 7RJ; [0299] xix) where a Chemelut column is
referred to, this means an extraction cartridge for removal of
water, i.e. a polypropylene tube containing diatomaceous earth used
according to the manufacturers instructions obtained from Varian,
Harbor City, Calif., USA.
Example 1
2-(3-Chloroanilino)-4-(2-methylimidazol-5-yl)pyrimidin
[0300] Sodium hydride (45 mg of a 60% suspension in mineral oil,
1.12 mmol) was added to a stirred suspension of
5-(3-dimethylaminoprop-2-en-1-oyl)-2-methylimidazole (100 mg, 0.56
mmol) and 3-chlorophenylguanidine (95 mg, 0.56 mmol) in dry
1-butanol (4.0 ml) under nitrogen. The mixture was stirred at
ambient temperature for 15 minutes then heated at 126.degree. C.
for 26 hours. The reaction mixture was allowed to cool and the
volatiles were removed by evaporation. The residue was suspended in
water (20 ml) and acetic acid (67 .mu.l) was added and the solution
extracted with DCM (3.times.20 ml). The extracts were combined,
dried (NaSO.sub.4) and the solvent removed by evaporation. The
residue was purified by column chromatography eluting with DCM/MeOH
(100:0 increasing in polarity to 92:8) to give the title compound
33 mg, (21%) as a solid. NMR: 2.35 (s, 3H), 6.95 (d, 1H), 7.23 (d,
1H), 7.30 (t, 1H), 7.67 (s, 1H), 7.72 (s, 1H), 8.05 (s, 1H), 8.43
(d, 1H), 9.62 (s, 1H), 12.15 (s, 1H); m/z: 286.
Example 2
2-(3-Chloroanilino)-4-(1,2-dimethylimidazol-5-yl)pyrimidine
[0301] 5-(3-Dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole
(Method 1; 111 mg, 0.58 mmol) and 3-chlorophenylguanidine (97 mg,
0.58 mmol) were treated as described in Example 1 to give the title
compound 51 mg, (29%) as a solid. NMR: 2.40 (s, 3H), 3.97 (s, 3H),
6.98 (d, 1H), 7.15 (d, 1H), 7.30 (t, 1H), 7.58 (d, 1H), 7.67 (s,
1H), 7.97 (s, 1H), 8.40 (d, 1H), 9.68 (s, 1H); m/z: 300.
Example 3
2-Anilino-4-(2-methylimidazol-5-yl)pyrimidine
[0302] Sodium hydride (167 mg of a 60% suspension in mineral oil,
4.18 mmol) was added to a stirred suspension of
5-(3-dimethylaminoprop-2-en-1-oyl)-2-methylimidazole (250 mg, 1.39
mmol) and phenylguanidine hydrogen carbonate (275 mg, 1.39 mmol)
was suspended in dry 1-butanol (10 ml) under nitrogen and the
mixture stirred and heated under nitrogen at 126.degree. C. for 18
hours. The reaction mixture was allowed to cool and further
phenylguanidine hydrogen carbonate (275 mg, 1.39 mmol) and sodium
hydride (111 mg of a 60% suspension in mineral oil, 2.78 mmol)
added and the mixture stirred and heated at 126.degree. C. for a
further 20 hours. The reaction mixture was then worked-up as
described in Example 1 to give the title compound 159 mg, (46%) as
a solid. NMR: 2.33 (s, 3H), 6.92 (t, 1H), 7.18 (d, 1H), 7.27 (t,
2H), 7.67 (s, 1H), 7.80 (d, 2H), 8.36 (d, 1H), 9.37 (s, 1H), 12.12
(s, 1H); m/z: 252.
Example 4
4-(2-Methylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine
[0303] Thionyl chloride (2.0 ml) was added to
2-anilino-4-(2-methylimidazol-5-yl)pyrimidine (Example 3; 98 mg,
0.39 mmol) cooled at 0.degree. C. under nitrogen. Chlorosulphonic
acid (104 .mu.l, 1.56 mmol) was added and the mixture was stirred
at 0.degree. C. for 30 minutes. Excess thionyl chloride was removed
by evaporation and the residue treated with a mixture of THF (4.0
ml) and concentrated aqueous ammonia solution (1.0 ml). The mixture
was stirred for 15 minutes and the volatiles were removed by
evaporation. The residue was triturated with water, and the
precipitated solid collected by filtration, washed with distilled
water and dried under vacuum to give the title compound 62 mg,
(48%). NMR: 2.33 (s, 3H), 7.10 (s, 2H), 7.24 (d, 1H), 7.72 (m, 3H),
7.95 (d, 2H), 8.43 (d, 1H), 9.83 (s, 1H); m/z: 331.
Example 5
2-Anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine
[0304] 5-(3-Dimethylaminoprop-2-enoyl)-1,2-dimethylimidazole Method
1; 314 mg, 1.62 mmol) and phenylguanidine hydrogen carbonate (321
mg, 1.62 mmol) were treated as described in Example 1 to give the
title compound 113 mg, (26%) as a solid. NMR: 2.37 (s, 3H), 3.93
(s, 3H), 6.95 (t, 1H), 7.08 (d, 1H), 7.28 (t, 2H), 7.59 (s, 1H),
7.69 (d, 2H), 8.35 (d, 1H), 9.43 (s, 1H); m/z: 266.
Example 6
4-(1,2-Dimethylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine
[0305] Thionyl chloride (2.0 ml) was added to
2-anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Example 5; 94
mg, 0.36 mmol) cooled at 0.degree. C. under nitrogen.
Chlorosulphonic acid (94 .mu.l, 1.56 mmol) was added and the
mixture was stirred at 0.degree. C. for 30 minutes, then allowed to
warm and stirred for two hours at ambient temperature and then
heated at 90.degree. C. for one hour. Excess thionyl chloride was
removed by evaporation and the residue azeotroped with toluene. The
resulting crude sulphonyl chloride was treated with a mixture of
THF (4.0 ml), water (2.0 ml), and concentrated aqueous ammonia
solution (1.0 ml). The mixture was stirred for 15 minutes and the
volatiles were removed by evaporation. The residue was triturated
with water (5 ml), and the precipitated solid collected by
filtration, washed with distilled water and dried under vacuum. The
crude product was then suspended and stirred in DCM (10 ml)
containing a few drops of MeOH. The solid product was collected by
filtration, washed with DCM and dried under vacuum to give the tile
compound 67 mg, (54%). NMR: 2.38 (s, 3H), 3.96 (s, 3H), 7.13 (s,
2H), 7.20 (d, 1H), 7.63 (s, 1H), 7.73 (d, 2H), 7.88 (d, 2H), 8.43
(d, 1H), 9.88 (s, 1H); m/z: 345.
Example 7
4(1-Benzyl-2-methylimidazol-5-yl)-2-(3-chloroanilino)pyrimidine
[0306] Sodium methoxide (36.8 mg, 0.68 mmol) was added to a stirred
suspension of
1-benzyl-5-(3-dimethylaminoprop-2-en-1-oyl)-2-methylimidazole
(Method 5; 153 mg, 0.57 mmol) and 3-chlorophenylguanidine (106 mg,
0.62 mmol) in dry 1-butanol (1.0 ml) under nitrogen. The reaction
mixture heated at reflux for 4 hours then allowed to cool. The
volatiles were removed by evaporation and the residue partitioned
between EtOAc and saturated aqueous sodium hydrogen carbonate
solution. The organic phase was separated, dried and the solvent
removed by evaporation. The residue was purified by column
chromatography, eluting with DCM and 7M methanolic ammonia solution
(97:3) to give the title compound 73 mg, (34%). NMR: 2.35 (s, 3H),
5.78 (s, 2H), 6.84-7.00 (m, 5H), 7.07 (t, 1H), 7.15-7.30 (m, 4H),
7.56-7.65 (m, 2H), 8.29 (d, 1H); m/z 374.
Example 8
2-(3-Chloroanilino)-4-[1-(2-methoxyethylimidazol-5-yl]pyrimidine
hydrochloride
[0307] Trifluoromethylsulphonic anhydride (0.16 ml, 0.93 mmol) was
added to a solution of 2-methoxyethanol (73.7 ml, 0.88 mmol) and
diisopropylethylamine (0.20 ml, 1.17 mmol) in DCM (1 ml) at
-20.degree. C. and the solution stirred for 30 minutes. This
mixture was then added to a solution of
2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine
(Method 2; 300 mg, 0.58 mmol) in DCM (5 ml) at -20.degree. C. and
the reaction mixture allowed to warm and stirred for 2 hours at
ambient temperature. The mixture was extracted between EtOAc and
saturated aqueous sodium hydrogen carbonate solution. The organic
phase was separated, dried and the volatiles removed by
evaporation. The residue was purified by column chromatography,
eluting with DCM and 7M methanolic ammonia solution (99.5:0.5
increasing in polarity to 96:4). The purified product was dissolved
in either and treated with ethereal hydrogen chloride. The
precipitate was collected by filtration washed with ether and dried
to give the title compound 132 mg, (69%). NMR: 3.17 (s, 3H), 3.63
(t, 2H), 4.96 (t, 2H), 5.86 (br s, 1H), 7.04 (d, 1H), 7.28-7.44 (m,
2H), 7.60 (d, 1H), 7.88 (s, 1H), 8.56 (s, 1H), 8.64 (d, 1H), 9.28
(s, 1H), 10.0 (s, 1H); m/z: 330.
Example 9
2-(3-Chloroanilino)-4-(imidazol-5-yl)pyrimidine
[0308] A mixture of
2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine
(Method 2; 256 mg, 0.5 mmol) in MeOH (3 ml) and 2M hydrochloric
acid (1 ml) was stirred for 15 minutes. The volatiles were removed
by evaporation and the residue partitioned between EtOAc and
saturated aqueous sodium hydrogen carbonate solution. The organic
layer was separated, dried and the solvent removed by evaporation.
The residue was purified by column chromatography eluting with DCM
and 7M methanolic ammonia solution (99.5:0.5 increasing in polarity
to 93:7) to give the title compound 102 mg, (75%) as a solid. NMR:
6.95 (dd, 1H), 7.25-7.33 (m, 2H), 7.73 (dd, 1H), 7.81 (d, 2H), 8.06
(s, 1H), 8.46 (d, 1H), 9.68 (s, 1H), 12.48 (br s, 11H); m/z:
270.
Example 10
2-(3-Chloroanilino)-4-[1-(2-phthalimidoethyl)imidazol-5-yl]pyrimidine
[0309] 2-Phthalimidoethyl triflate (660 mg, 2.04 mmol) was added to
solution of the
2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine
(Method 2; 1.00 g, 1.95 mmol) in DCM (5 ml) and the reaction
mixture stirred for 4 hours. The solvent was removed by evaporation
and MeOH (6 ml) and 2M hydrochloric acid (1.5 ml) was added to the
residue. The mixture was stirred for 5 minutes, the volatiles were
removed by evaporation and the residue partitioned between EtOAc
and saturated aqueous sodium hydrogen carbonate solution. The
resulting precipitate was collected by filtration, washed with
water and EtOAc and dried to give the title compound 350 mg, (40%)
as a solid. NMR: 3.81-3.96 (m, 2H), 4.77-4.92 (m, 2H), 6.98 (d,
1H), 7.06 (d, 1H), 7.31 (t, 1H), 7.37 (d, 1H), 7.63-7.80 (m, 6H),
7.92 (s, 1H), 8.27 (d, 1H), 9.50 (s, 1H); m/z: 443.
Example 11-12
[0310] The following compounds were prepared by an analogous method
to that described in Example 10 using with the appropriate starting
materials.sup.1, but in the work-up the organic layer was
separated, dried, the solvent removed by evaporation and the
residue purified by column chromatography eluting with DCM and 7M
methanolic ammonia solution (99.5:0.5 increasing in polarity to
93:7). TABLE-US-00001 Ex Compound NMR m/z 11 2-(3-Chloroanilino)-
1.26(t, 3H), 4.56(q, 2H), 7.00(d, 1H), 300 4-(1-ethylimidazol-
7.21(d, 1H), 7.30(t, 1H), 7.57(d, 1H), 5-yl)pyrimidine 7.87-7.91(m,
1H), 8.44(d, 1H), 9.62(s, 1H) 12 2-(3-Chloroanilino)- 4.03(s, 3H),
6.95-7.10(m, 2H), 286 4-(1-methylimidazol- 7.15-7.38(m, 3H),
7.45-7.60(m, 5-yl)pyrimidine 2H), 7.65(s, 1H), 7.87(s, 1H), 8.38(d,
1H) .sup.1In the case of Example 12, the triflate starting material
used was trimethylsilymethyl triflate
Example 13
4-[1-(2-Aminoethyl)imidazol-5-yl]-2-(3-chloroanilino)pyrimidine
[0311] Hydrazine hydrate (54 ml, 1.73 mmol) was added to a
suspension of
2-(3-chloroanilino)-4-[1-(2-phthalimidoethyl)imidazol-5-yl]pyrimidine
(Example 10; 163 mg, 0.37 mmol) in EtOH (5 ml) and the mixture was
heated at reflux for 2 hours. The mixture was allowed to cool, the
volatiles removed by evaporation and the residue purified by column
chromatography eluting with DCM and 7M methanolic ammonia solution
(90:10) to give the title compound 69 mg, (59%) as a solid product.
NMR: 1.41 (brs, 2H), 2.99 (t, 2H), 4.55 (t, 2H), 7.00-7.09 (m, 2H),
7.22-7.35 (m, 3H), 7.65-7.70 (m, 2H), 7.73-7.78 (m, 1H), 8.39 (d,
1H); m/z: 315.
Example 14
2-Anilino-4-[1-methylimidazol-5-yl]pyrimidine
[0312] Sodium methoxide (2.63 g, 48.7 mmol) was added to a solution
of 5-(3-dimethylaminoprop-2-en-1-oyl)-1-methylimidazole (Method 4;
2.91 g, 16.2 mmol) and phenylguanidine hydrogen carbonate (3.52 g,
17.9 mmol) in 2-propanol (14 ml) and the reaction mixture heated at
reflux for 3 hours. The reaction mixture was allowed to cool and
partitioned between EtOAc and saturated aqueous sodium hydrogen
carbonate solution. The organic phase was separated, dried and the
solvent removed by evaporation. The residue was purified by column
chromatography eluting with DCM and 7M methanolic ammonia solution
(97:3) to give the title compound 2.57 g, (64%) as a solid. M/z:
252.
Example 15
4-(1-Methylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine
[0313] Chlorosulphonic acid (0.48 ml, 7.16 mmol) was added to a
suspension of 2-anilino-4-(1-methylimidazol-5-yl)pyrimidine
(Example 14; 449 mg, 1.79 mmol) in thionyl chloride (9 ml) cooled
at 0.degree. C. The mixture was allowed to warm to ambient
temperature then heated at reflux for 30 minutes. The volatiles
were removed by evaporation and the residue dried under high
vacuum. 7M methanolic ammonia (30 ml) was added to the residue and
the mixture stirred for 10 minutes. The volatiles were removed by
evaporation to give the title compound 360 mg, (61%) as a solid
product. NMR: 4.04 (s, 3H), 7.15 (s, 2H), 7.27 (d, 1H), 7.73 (d,
2H), 7.84-7.91 (m, 3H), 8.06 (s, 1H), 8.50 (d, 1H), 9.92 (s, 1H);
m/z: 331.
Example 16
2-{4-[N-(3-Methoxypropylsulphamoyl]anilino}-4-(1-methylimidazol-5-yl)pyrim-
idine
[0314] Chlorosulphonic acid (0.22 ml, 3.18 mmol) was added to
suspension of 2-anilino-4-(1-methylimidazol-5-yl)pyrimidine
(Example 14; 200 mg, 0.80 mmol) in thionyl chloride (4 ml) cooled
at 0.degree. C. The mixture was allowed to warm to ambient
temperature, stirred for 15 minutes then heated at reflux for 20
minutes. The volatiles were removed by evaporation and the solid
residue dried under high vacuum. The residue was suspended in
pyridine (3 ml), cooled to -20.degree. C. and diisopropylethyl
amine (0.56 ml, 3.98 mmol) followed by 3-methoxypropyl amine (0.16
ml, 1.60 mmol) was added. The reaction mixture was allowed to warm
to ambient temperature and stirred for 30 minutes. EtOAc (15 ml)
was added and the mixture washed with saturated aqueous sodium
hydrogen carbonate solution (15 ml) and then brine (15 ml). The
solvent was removed by evaporation and the residue purified by
column chromatography eluting with DCM and 2M methanolic ammonia
solution (100:0 increasing in polarity to 85:15) to give the title
compound 89 mg, (28%) as a solid product NMR: 1.75 (m, 2H), 2.76
(q, 2H), 3.14 (s, 3H), 3.22-3.30 (m, 2H), 4.01 (s, 3H), 7.25 (d,
1H), 7.34 (t, 1H), 7.70 (d, 2H), 7.77 (s, 1H), 7.83 (s, 1H), 7.91
(d, 2H), 8.47 (d, 1H), 9.92 (s, 1H); m/z: 403.
Examples 17-25
[0315] The following compounds were prepared by an analogous method
to that described in Example 15 using the appropriate
intermediates. TABLE-US-00002 Ex Compound NMR m/z 17
4-(1-Methylimidazol-5-yl)-2- 0.77(t, 3H), 1.35(m, 2H), 2.67(q, 2H),
4.01(s, 373 [4-(N-propylsulphamoyl) 3H), 7.25(d, 1H), 7.34(t, 1H),
7.69(d, anilino]pyrimidine 2H), 7.77(s, 1H), 7.83(s, 1H), 7.90(d,
2H), 8.47(d, 1H), 9.92(s, 1H) 18 2-{4-[N-(2,3- 2.53-2.64(m, 1H),
2.79-2.90(m, 1H), 3.25(t, 405 Dihydroxypropyl) 2H), 3.39-3.50(m,
1H), 4.02(s, 3H), 4.49(t, sulphamoyl]anilino}-4-(1- 1H), 4.71(d,
1H), 7.22-7.29(m, 2H), methylimidazol-5-yl) 7.70(d, 2H), 7.77(s,
1H), 7.83(s, 1H), 7.91(d, pyrimidine 2H), 8.47(d, 1H), 9.93(s, 1H)
19 2-(4-{N-[2-(2- 2.88(q, 2H), 3.24-3.48(m, 6H), 4.02(s, 419
Hydroxyethoxy) 3H), 4.51(t, 1H), 7.25(d, 1H), 7.42(t, 1H),
ethyl]sulphamoyl}anilino)-4-(1- 7.70(d, 2H), 7.77(s, 1H), 7.83(s,
1H), 7.90(d, methylimidazol-5-yl) 2H), 8.47(d, 1H), 9.92(s, 1H)
pyrimidine 20 2-{4-[N-(2-Furanylmethyl) 3.97(d, 2H), 4.02(s, 3H),
6.16(dd, 1H), 411 sulphamoyl]anilino}-4-(1- 6.30(dd, 1H), 7.25(d,
1H), 7.47-7.50(m, methylimidazol-5-yl) 1H), 7.68(d, 2H), 7.77(s,
1H), 7.83(s, 1H), pyrimidine 7.85-7.94(m, 3H), 8.48(d, 1H), 9.91(s,
1H) 21 2-{4-[N-(2-Hydroxyethyl) 2.77(q, 2H), 3.55(q, 2H), 4.02(s,
3H), 4.61(t, 375 sulphamoyl]anilino}-4-(1- 1H), 7.25(d, 1H),
7.33(t, 1H), 7.70(d, methylimidazol-5-yl) 2H), 7.77(s, 1H), 7.83(s,
1H), 7.90(d, 2H), pyrimidine 8.47(d, 1H), 9.91(s, 1H) 22
2-{4-[N-(Carbamoylmethyl) 3.29-3.37(m, 2H), 4.02(s, 3H), 7.06(br s,
388 sulphamoyl]anilino}-4-(1- 1H), 7.20(br s, 1H), 7.25(d, 1H),
7.58(t, methylimidazol-5-yl) 1H), 7.71(d, 2H), 7.77(s, 1H), 7.83(s,
1H), pyrimidine 7.90(d, 2H), 8.47(d, 1H), 9.93(s, 1H) 23
4-(1,2-Dimethylimidazol-5- 1.75(m, 2H), 2.37(s, 3H), 2.76(t, 2H),
3.14(s, 417 yl)-2-{4-[N-(3- 3H), 3.26(t, 2H), 3.96(s, 3H), 7.19(d,
methoxypropyl)sulphamoyl] 1H), 7.33(br s, 1H), 7.63(s, 1H), 7.68(d,
anilino}pyrimidine 2H), 7.92(d, 2H), 8.43(d, 1H), 9.91(s, 1H) 24
4-(1,2-Dimethylimidazol-5- 2.37(s, 3H), 3.94(s, 2H), 3.95(s, 3H),
7.04-7.12(m, 453 yl)-2-{4-[N-(4-fluorobenzyl) 2H), 7.20(d, 1H),
7.24-7.29(m, sulphamoyl]anilino} 2H), 7.63(s, 1H), 7.70(d, 2H),
7.88-7.95(m, pyrimidine 3H), 8.43(d, 1H), 9.91(s, 1H) 25
2-{4-[N-(Cyclopropylmethyl) 0.00-0.05(m, 2H), 0.27-0.33(m, 2H),
0.7-0.8(m, 399 sulphamoyl]anilino}-4-(1,2- 1H), 2.34(s, 3H),
2.59(t, 2H), 3.91(s, dimethylimidazol-5-yl) 3H), 7.15(d, 1H),
7.44(t, 1H), 7.60(s, pyrimidine 1H), 7.66(d, 2H), 7.87(d, 2H),
8.39(d, 1H), 9.86(s, 1H)
Example 26
4-(1,2-Dimethylimidazol-5-yl)-2-(4-{N-[3-(pyrrolidin-2-on-1-yl)propyl]sulp-
hamoyl}anilino)pyrimidine
[0316] Ethereal hydrogen chloride (1 ml of a 1M solution, 1.0 mmol)
was added to a solution of
4-{N-[3-(pyrrolidin-2-on-1-yl)propyl]sulphamoyl}aniline (Method 13,
300 mg, 1.0 mmol) in MeOH (minimum volume). The volatiles were
removed by evaporation and cyanamide (50 mg, 1.2 mmol) followed by
dimethylacetamide (0.5 ml) were added to the residue. The mixture
was heated to 100.degree. C. for 30 minutes.
5-(3-Dimethylaminoprop-2-enoyl)-1,2-dimethylimidazole (Method 1;
180 mg, 0.93 mmol) and sodium methoxide (110 mg, 2.0 mmol) were
added and the mixture heated at reflux for one hour. The mixture
was allowed to cool and was partitioned between EtOAc and aqueous
sodium hydrogen carbonate solution. The organic layer was
separated, washed with brine, dried (Na.sub.2SO.sub.4) and the
volatiles removed by evaporation. The residue was purified by
column chromatography eluting with DCM and 7M methanolic ammonia
solution (96:4) to give the title compound 220 mg, (50%). NMR:
1.48-1.58 (m, 2H), 1.79-1.89 (m, 2H), 2.14 (t, 2H), 2.37 (s, 3H),
2.68 (q, 2H), 3.10 (t, 2H), 3.21 (t, 2H), 3.95 (s, 3H), 7.19 (d,
1H), 7.34 (t, 1H), 7.63 (s, 1H) 7.69 (d, 2H), 7.92 (d, 2H) 8.43 (d,
1H), 9.92 (s, 1H); m/z: 470.
Example 27
[0317] The following compound was prepared by an analogous method
to that described in Example 26 using the appropriate intermediates
TABLE-US-00003 Ex Compound NMR, DMSO-d6, 300 MHz @ 303.1 k m/z 27
4-(1,2-Dimethyl- 1.45-1.56(m, 1H), 1.68-1.88(m, 3H), 2.37(s, 429
imidazol-5-yl)-2-{4-[N-(2- 3H), 2.75(t, 2H), 3.51-3.58(m, 1H),
3.63-3.70(m, tetrahydrofuranyl- 1H), 3.73-3.82(m, 1H), 3.95(s, 3H),
7.19(d, methyl)sulphamoyl] 1H), 7.46(t, 1H), 7.63(s, 1H), 7.70(d,
2H), 7.91(d, anilino}pyrimidine 2H), 8.43(d, 1H), 9.90(s, 1H)
Example 28
2-Anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine
[0318] 5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2-methylimidazole
(Method 16; 2.10 g, 10.1 mmol), phenylguanidine hydrogen carbonate
(2.2 g, 11.1 mmol) and sodium methoxide (1.2 g, 22.2 mmol) were
suspended in anhydrous DMA (15 ml) and the mixture heated at
110.degree. C. for 18 hours. The reaction mixture was allowed to
cool to ambient temperature and poured into water (50 ml). The
solution was extracted EtOAc (2.times.50 ml). The combined extracts
were washed with water (2.times.50 ml) and then brine (2.times.50
ml), dried and the volatiles removed by evaporation. The residue
was triturated with ether, collected by filtration and air dried to
give the title compound (1.48 g, 53%) as a reddish brown solid. NMR
1.17 (t, 3H), 2.38 (s, 3H), 4.52 (q, 2H), 6.93 (t, 1H), 7.08 (d,
1H), 7.27 (t, 2H), 7.60 (s, 1H), 7.62 (d, 2H), 8.35 (d, 1H), 9.35
(s, 1H); m/z 280.
Examples 29-33
[0319] The following compounds were synthesised in an analogous
method to Example 28. TABLE-US-00004 Ex Compound NMR m/z SM 29
2-Anilino-4-(1-methyl-2- 1.23(t, 3H), 2.90(q, 2H), 3.92(s, 280 Meth
ethylimidazol-5-yl)pyrimidine 3H), 6.92(t, 1H), 7.08(d, 1H),
7.25(t, 20 2H), 7.59(s, 1H), 7.70(d, 1H), 8.38(d, 1H), 9.42(s, 1H)
30 2-Anilino-4-[1-(2,2,2- 2.41(s, 3H), 5.76(q, 2H), 6.98(t, 334
Meth trifluoroethyl)-2- 1H), 7.13(d, 1H), 7.29(t, 3H), 7.60(d, 21
methylimidazol-5-yl]pyrimidine 2H), 7.71(s, 1H), 8.38(d, 1H),
8.56(s, 1H) 31.sup.1 2-Anilino-4-(1,2,4- 2.26(s, 3H), 2.32(s, 3H),
3.72(s, 279 Meth trimethylimidazol-5- 3H), 6.85(d, 1H), 6.94(dd,
1H), 24 yl)pyrimidine 7.24(dd, 1H), 7.73(d, 2H), 8.42(d, 1H),
9.45(s, 1H) 32.sup.2 2-Anilino-4-(1-isopropyl-2- 1.44(d, 6H),
2.51(s, 3H), 5.72(septuplet, 294 Meth
methylimidazol-5-yl)pyrimidine 1H), 6.99(t, 1H), 7.04(d, 19 1H),
7.30(t, 2H), 7.42(s, 1H), 7.67(d, 2H), 8.39(d, 1H), 9.42(s, 1H)
33.sup.3 2-Anilino-4-(1-methyl-2- 3.30(s, 3H) 3.99(s, 3H), 4.50(s,
296 Meth methoxymethylimidazol-5-yl) 2H), 6.94(t, 1H), 7.13(d, 1H),
7.28(t, 25 pyrimidine 2H), 7.65(s, 1H), 7.69(d, 2H), 8.41(d, 1H),
9.48(s, 1H) .sup.1Reaction heated at 150.degree. C. for 18 hours.
Water added, precipitated solid collected by filtration and
purified by flash chromatography on silica gel eluting with
DCM/MeOH (100:0 increasing in polarity to 95:5). .sup.2Solid
crystallised from EtOAc. .sup.3Purified by flash chromatography on
silica gel eluting with DCM/MeOH (100:0 increasing in polarity to
97:3).
Example 34
4-(1,2-Dimethylimidazol-5-yl)-2-(4-mesylaminoanilino)pyrimidine
[0320] Methanesulphonyl chloride (0.055 ml, 0.71 mmole) was added
to a solution of
4-(1,2-dimethylimidazol-5-yl)-2-(4-aminoanilino)pyrimidine (Example
165; 0.18 g, 0.64 mmole) and pyridine (0.052 ml, 0.64 mmole) in DCM
(2.0 mL) cooled at 4.degree. C. The mixture was allowed to warm to
ambient temperature. The mixture was partitioned between saturated
aqueous sodium hydrogen carbonate solution and EtOAc. The organic
layer was separated, the volatiles evaporated and the residue
purified by column chromatography on silica gel eluting with DCM/7M
methanolic ammonia (96:4) to give the title compound (0.15 g, 65%)
as a solid. NMR: 2.36 (s, 3H), 2.90 (s, 3H), 3.91 (s, 3H), 7.06 (d,
1H), 7.14 (d, 2H), 7.57 (s, 1H), 7.64 (d, 2H), 8.33 (d, 1H), 9.37
(br s, 1H), 9.42 (s, 1H); m/z 359.
Example 35
4-(1,2-Dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl
sulphamoyl]anilino}pyrimidine
[0321] Sodium t-butoxide (1.04 g, 10.8 mmol) was added to a
degassed solution of
2-amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 26; 567 mg,
3 mmol), N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 40;
1.54 g, 4.5 mmol), tris(dibenzylideneacetone) dipalladium (0) (72
mg, 0.15 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (102
mg, 0.15 mmol) in dioxane (36 ml) and the mixture heated at
80.degree. C. overnight. The reaction was cooled to room
temperature and MeOH (5 ml) was added and the mixture poured onto
an Isolute SCX-2 column, eluted first with MeOH (10.times.30 ml)
and the product was then eluted with 2% methanolic ammonia
(10.times.30 ml). The solvent was removed by evaporation and the
residue was dissolved in EtOAc (100 ml), washed with water
(3.times.100 ml) and then brine (100 ml), dried and the solvent
removed by evaporation to give the title compound (1.01 g, 84%) as
a foam. NMR 2.40 (s, 3H), 3.07 (q, 2H), 3.20 (s, 3H), 3.38 (t, 2H),
3.86 (s, 3H), 5.00 (t, 1H), 6.95 (d, 1H), 7.47 (s, 2H), 7.71 (m,
4H), 8.36 (d, 1H); m/z 403
Examples 36-72
[0322] The following compounds were synthesised in an analogous
method to Example 35. TABLE-US-00005 Ex Compound NMR m/z SM 36
4-(1,2-Dimethylimidazol-5- 1.40(s, 9H), 2.49(s, 3H), 3.96(s, 3H),
445 Meth yl)-2-[4-(N-t- 7.03(d, 1H), 7.38(s, 1H), 7.82(d, 54,
butoxycarbonylsulphamoyl) 2H), 7.96(d, 2H), 8.08(s, 1H), 8.43(d,
Meth anilino]pyrimidine 1H) 26 37 4-(1-Ethyl-2-methylimidazol-
1.25(t, 3H), 2.40(s, 3H), 3.05(q, 2H), 417 Meth 5-yl)-2-{4-[N-(2-
3.20(s, 3H), 3.36(t, 2H), 4.43(q, 2H), 40, methoxyethyl)sulphamoyl]
4.92(t, 1H), 6.95(d, 1H), 7.32(s, 1H), Meth anilino}pyrimidine
7.50(s, 1H), 7.72(m, 4H), 8.35(d, 27 1H) 38
4-(1,2-Dimethylimidazol-5- 1.20(s, 3H), 1.25(s, 3H), 2.40(s, 3H),
459 Meth yl)-2-{4-[N-(2,2-dimethyl- 2.91(m, 1H), 3.12(m, 1H),
3.60(m, 42, 1,3-dioxalon-4-ylmethyl) 1H), 3.86(s, 3H), 3.92(m, 1H),
4.13(m, Meth sulphamoyl]anilino} 1H), 4.83(t, 1H), 6.95(d, 1H), 26
pyrimidine 7.38(s, 1H), 7.49(s, 1H), 7.72(m, 4H), 8.35(d, 1H) 39
4-(1,2-Dimethylimidazol-5- 2.40(s, 3H), 3.12(q, 2H), 3.46(t, 2H),
479 Meth yl)-2-{4-[N-(2- 3.90(s, 3H), 4.37(s, 2H), 4.95(t, 1H), 43,
benzyloxyethyl)sulphamoyl] 6.95(d, 1H), 7.20(m, 5H), 7.40(s, Meth
anilino}pyrimidine 1H), 7.46(s, 1H), 7.73(m, 4H), 8.33(d, 26 1H) 40
4-(1,2-Dimethylimidazol-5- 2.40(s, 3H), 3.00(t, 2H), 3.28(s, 6H),
433 Meth yl)-2-{4-[N-(2,2-dimethoxyethyl) 3.89(s, 3H), 4.28(t, 1H),
4.75(t, 1H), 44, sulphamoyl]anilino} 6.95(d, 1H), 7.40(s, 1H),
7.48(s, Meth pyrimidine 1H), 7.76(m, 4H), 8.32(d, 1H) 26 41
4-(1-Ethyl-2-methylimidazol- 1.24(t, 3H), 1.50(m, 1H), 1.80(m, 441
Meth 5-yl)-2-(4-{N-[2-(2- 3H), 2.43(s, 3H), 2.80(t, 1H), 3.62(q,
45, tetrahydrofur-2- 1H), 3.74(m, 1H), 3.84,(m, 1H), 4.73(q, Meth
yl)methyl]sulphamoyl} 2H), 7.32(d, 1H), 7.56(t, 1H), 27
anilino)pyrimidine 7.78(d, 2H), 7.94(d, 2H), 8.50(d, 1H), 9.90(s,
1H) 42.sup.1 4-(1-Ethyl-2-methylimidazol- 1.18(t, 3H), 1.58(m, 2H),
2.40(s, 431 Meth 5-yl)-2-{4-[N-(3- 3H), 2.78(q, 2H), 3.16(s, 3H),
3.30(m, 46, methoxypropyl)sulphamoyl] 2H), 4.58(q, 2H), 7.20(d,
1H), Meth anilino}pyrimidine 7.36(t, 1H), 7.70(m, 3H), 7.90(d, 27
2H), 8.41(d, 1H), 9.80(s, 1H) 43.sup.1 4-(1-Ethyl-2-methylimidazol-
0.01(q, 2H), 0.40(q, 2H), 0.81(m, 413 Meth 5-yl)-2-{4- 1H), 1.24(t,
3H), 2.40(s, 3H), 2.78(t, 41, [N-(cyclopropylmethyl) 2H), 4.42(q,
2H), 4.56(t, 1H), 6.96(d, Meth sulphamoyl]anilino} 1H), 7.30(s,
1H), 7.50(s, 1H), 27 pyrimidine 7.68(d, 2H), 7.76(d, 2H), 8.36(d,
1H) 44 4-(1,2-Dimethylimidazol-5- 2.40(s, 3H), 2.78(s, 3H), 3.16(t,
2H), 417 Meth yl)-2-{4-[N-(2-methoxyethyl)- 3.22(s, 3H), 3.45(t,
3H), 3.89(s, 3H), 62, N-methylsulphamoyl] 6.95(d, 1H), 7.37(s, 1H),
7.46(s, Meth anilino}pyrimidine 1H), 7.70(m, 4H), 8.38(d, 1H) 26
45.sup.1 4-(1-Ethyl-2-methylimidazol- 1.24(t, 3H), 2.40(s, 3H),
2.78(s, 3H), 431 Meth 5-yl)-2-{4-[N-(2- 3.16(t, 2H), 3.23(s, 3H),
3.45(t, 3H), 62, methoxyethyl)-N-methylsulphamoyl] 4.43(q, 2H),
6.95(d, 1H), 7.26(s, Meth anilino} 1H), 7.46(s, 1H), 7.70(m, 4H),
8.38(d, 27 pyrimidine 1H) 46.sup.1 4-(1,2-Dimethylimidazol-5-
2.40(s, 3H), 2.98(s, 3H), 3.86(s, 3H), 344 Meth
yl)-2-(4-mesylanilino) 6.96(d, 1H), 7.40(s, 1H), 7.51(s, 65,
pyrimidine 1H), 7.80(m, 4H), 8.38(d, 1H) Meth 26 47
4-(1,2-Dimethylimidazol-5- 1.76(m, 2H), 2.40,(m, 6H), 2.46(s, 486
Meth yl)-2-{4-[N-(3- 3H), 2.73(s, 3H), 3.10(t, 3H), 7.71(m, 63
morpholinopropyl)-N- 4H), 3.97(s, 3H), 7.03(d, 1H),
methylsulphamoyl]anilino} 7.37(s, 1H), 7.53(s, 1H), 7.77(m,
pyrimidine 4H), 8.40(d, 1H) 48.sup.1 4-(1,2-Dimethylimidazol-5-
1.87(m, 2H), 2.16(s, 6H), 2.33(t, 415 Meth
yl)-2-{4-[3-(N,N-dimethyl- 2H), 2.50(s, 3H), 3.16(m, 2H), 3.96(s,
70, amino)propylsulphonyl] 3H), 7.02(d, 1H), 7.45(s, 1H), Meth
anilino}pyrimidine 7.57(s, 1H), 7.83(m, 4H), 8.41(d, 26 1H) 49
4-(1,2-Dimethylimidazol-5- 2.48(s, 3H), 2.57(m, 2H), 3.31(m, 426
Meth yl)-2-[4-(3,3,3- 2H), 3.96(s, 3H), 7.03(d, 1H), 7.56(s, 71,
trifluoropropylsulphonyl) 2H), 7.84(m, 4H), 8.40(d, 1H) Meth
anilino]pyrimidine 26 50.sup.1 4-(1,2-Dimethylimidazol-5- 0.80(t,
3H), 1.31(m, 2H), 1.51(m, 386 Meth yl)-2-(4-butylsulphonyl- 2H),
2.38(s, 3H), 3.19(m, 2H), 3.96(s, 72, anilino)pyrimidine 3H),
7.20(d, 1H), 7.61(s, 1H), Meth 7.76(d, 2H), 7.98(d, 2H), 8.43(d, 26
1H), 10.05(s, 1H) 51.sup.1 4-(1,2-Dimethylimidazol-5- 2.02(m, 2H),
2.48(s, 3H), 3.20(m, 402 Meth yl)-2-[4-(3-methoxypropylsulphonyl)
2H), 3.27(s, 3H), 3.45(t, 2H), 3.95(s, 74, anilino] 3H), 7.03(d,
1H), 7.56(s, 2H), 7.83(s, Meth pyrimidine 4H), 8.40(d, 1H) 26
52.sup.1 4-(1-Ethyl-2-methylimidazol- 1.34(t, 3H), 2.50(s, 3H),
3.17(q, 2H), 447 Meth 5-yl)-2-(4-{N- 3.31(s, 3H), 3.59(t, 2H),
4.53(m, 39, [2-(methoxy-methoxy)ethyl] 4H), 5.09(t, 1H), 7.03(d,
1H), 4.39(s, Meth sulphamoyl}anilino) 1H), 7.56(s, 1H), 7.80(m,
4H), 27 pyrimidine 8.39(d, 1H) 53.sup.1
4-(1-Ethyl-2-methylimidazol- 0.33(m, 2H), 0.45(m, 2H), 1.12(t, 399
Meth 5-yl)-2-[4-(N- 3H), 2.08(m, 1H), 2.40(s, 3H), 4.59(q, 47,
cyclopropylsulphamoyl) 2H), 7.16(d, 1H), 7.68(m, 3H), Meth
anilino]pyrimidine 7.86(d, 2H), 8.41(d, 1H), 9.80(s, 1H) 27
54.sup.2 4-(1-Ethyl-2-methylimidazol- 1.24(t, 3H), 2.23(s, 3H),
2.70(s, 3H), 470 Meth 5-yl)-2-{4-[N-(4- 4.10(d, 2H), 4.70(q, 2H),
7.12(s, 48, methylthiazol-2-ylmethyl) 1H), 7.38(d, 1H), 7.73(d,
2H), 7.86(d, Meth sulphamoyl]anilino} 2H), 8.40(m, 2H), 8.65(d,
1H), 27 pyrimidine 10.11(s, 1H) 55.sup.2
4-(1-Ethyl-2-methylimidazol- 1.24(t, 3H), 2.10(s, 3H), 2.68(s, 3H),
454 Meth 5-yl)-2-{4-[N-(3- 4.10(d, 2H), 4.70(q, 2H), 6.03(s, 49,
methylisoxazol-5- 1H), 7.37(d, 1H), 7.69(d, 2H), 7.84(d, Meth
ylmethyl)sulphamoyl] 2H), 8.20(t, 1H), 8.36(s, 1H), 8.63(d, 27
anilino}pyrimidine 1H), 10.09(s, 1H) 56.sup.2
4-(1-Ethyl-2-methylimidazol- 1.23(t, 3H), 2.70(s, 3H), 2.74(t, 2H),
459 Meth 5-yl)-2-{4-[N-(1,4- 3.10(m, 1H), 3.70(m, 6H), 4.70(q, 50,
dioxan-2-ylmethyl) 2H), 7.35(d, 1H), 7.59(t, 1H), 7.72(d, Meth
sulphamoyl]anilino} 2H), 7.86(d, 2H), 8.40(s, 1H), 27 pyrimidine
8.63(d, 1H), 10.09(brs, 1H) 57 5-Chloro-4-(1,2- 0.78(t, 3H),
1.35(m, 2H), 2.4(s, 3H), 419 Meth dimethylimidazol-5-yl)-2- 2.67(m,
2H), 3.8(s, 3H), 7.33(t, 1H), M-H- 111, [4-(N-propylsulphamoyl)
7.65(s, 1H), 7.72(d, 2H), 7.87(d, Meth anilino]pyrimidine 2H),
8.63(s, 1H), 10.14(s, 1H) 51 58 5-Chloro-4-(1,2-dimethylimidazol-
0.0(m, 2H), 0.27(m, 2H), 0.72(m, 431 Meth 5-yl)-2-{4- 1H), 2.35(s,
3H), 2.57(t, 2H), 3.73(s, M-H- 111, [N-(cyclopropylmethyl) 3H),
7.43(t, 1H), 7.6(s, 1H), 7.66(d, Meth sulphamoyl]anilino} 2H),
7.8(d, 2H), 8.55(s, 1H), 41 pyrimidine 10.08(s, 1H). 59
5-Chloro-4-(1,2- 1.57(m, 2H), 2.42(s, 3H), 2.75(m, 449 Meth
dimethylimidazol-5-yl)-2- 2H), 3.13(s, 3H), 3.25(m, 2H), 3.78(s,
M-H- 111, {4-[N-(3-methoxypropyl) 3H), 7.35(t, 1H), 7.63(s, 1H),
7.7(d, Meth sulphamoyl]anilino} 2H), 7.87(d, 2H), 8.6(s, 1H), 46
pyrimidine 10.15(s, 1H). 60 5-Chloro-4-(1,2- 1.07(s, 9H), 2.4(s,
3H), 3.78(s, 3H), 433 Meth dimethylimidazol-5-yl)-2- 7.27(s, 1H),
7.65(s, 1H), 7.73(d, M-H- 111, {4-[N-(t-butyl)sulphamoyl] 2H),
7.83(d, 2H), 8.6(s, 1H), Meth anilino}pyrimidine 10.12(s, 1H). 52
61.sup.3 4-[1-(2-Methoxyethyl)-2- 2.40(s, 3H), 2.89(s, 3H), 3.12(s,
3h), 447 Meth methylimidazol-5-yl]-2-{4- 3.18(s, 3H), 3.31(t, 2H),
3.52(t, 2H), 28, [N-(2-methoxyethyl) 4.77(t, 2H), 7.24(d, 1H),
7.50(brs, Meth sulphamoyl]anilino} 1H), 7.71(d, 3H), 7.88(d, 2H),
8.42(d, 40 pyrimidine 1H), 9.81(s, 1H) 62.sup.4
4-[1-(1-Butene-4-yl)-2- 2.29(q, 2H), 2.39(s, 3H), 2.88(brq, 443
Meth methylimidazol-5-yl]-2-{4- 2H), 3.18(s, 3H), 3.30(t, 2H),
4.63(t, 29, [N-(2-methoxyethyl) 2H), 4.84(d, 1H), 4.88(s, 1H),
5.62(m, Meth sulphamoyl]anilino} 1H), 7.22(d, 1H), 7.48(brt, 1H),
40 pyrimidine 7.67(s, 1H), 7.71(d, 2H), 7.87(d, 2H), 8.44(d, 1H),
9.82(s, 1H) 63.sup.5 2-Anilino-5-bromo-4-(1,2- 2.39(s, 3H), 3.70(s,
3H), 6.99(dd, 343 Meth dimethylimidazol-5-yl) 1H), 7.30(dd, 1H),
7.60(s, 1H), 7.64(d, 61 pyrimidine 2H), 8.60(s, 1H), 9.70(s, 1H)
64.sup.6 4-(1-Methyl-2- 1.41(t, 3H), 1.96(m, 4H), 2.77(q, 443 Meth
ethylimidazol-5-yl)-2-{4- 2H), 2.93(m, 1H), 3.16(m, 1H), 3.73(m,
30, [N-(tetrahydrofur-2- 2H), 3.96(s, 3H), 4.82(m, 1H), Meth
ylmethyl)sulphamoyl] 7.01(d, 1H), 7.38(s, 1H), 7.53(s, 45
anilino}pyrimidine 1H), 7.80(m, 4H), 8.39(d, 1H) 65.sup.6
4-(1-Methyl-2-ethyl- 1.39(t, 3H), 2.78(q, 2H), 3.13(q, 417 Meth
imidazol-5-yl)-2-{4-[N-(2- 2H), 3.28(s, 3H), 3.45(t, 2H), 3.95(s,
30, methoxyethyl)sulphamoyl] 3H), 4.92(t, 1H), 7.03(d, 1H), 7.40(s,
Meth anilino}pyrimidine 1H), 7.58(s, 1H), 7.80(m, 4H), 40 8.39(d,
1H) 66.sup.7 4-(1-Methyl-2-isopropyl- 1.40(t, 3H), 3.15(q, 2H),
3.30(s, 3H), 431 Meth imidazol-5-yl)-2-{4-[N-(2- 3.42(t, 2H),
3.96(s, 3H), 4.98(t, 1H), 31, methoxyethyl)sulphamoyl] 7.03(d, 1H),
7.49(s, 1H), 7.58(s, Meth anilino}pyrimidine 1H), 7.80(m, 4H),
8.40(d, 1H) 40 67.sup.7 4-(1-Methyl-2-isopropyl- 0.08(m, 2H),
0.39(m, 2H), 0.84(m, 427 Meth imidazol-5-yl)-2-{4- 1H), 1.30(d,
6H), 2.67(m, 2H), 3.20(m, 31, [N-(cyclopropylmethyl) 1H), 3.96(s,
3H), 7.27(d, 1H), Meth sulphamoyl]anilino} 7.50(t, 1H), 7.69(s,
1H), 7.75(d, 2H), 41 pyrimidine 7.97(d, 2H), 8.43(d, 1H), 9.93(s,
1H) 68.sup.7 4-(1-Methyl-2-isopropyl- 1.41(d, 6H), 1.90(m, 3H),
2.94(m, 457 Meth imidazol-5-yl)-2-{4- 1H), 3.15(m, 2H), 3.72(q,
1H), 3.80(q, 31, [N-(tetrahydrofur-2-ylmethyl) 1H), 3.95(m, 1H),
4.04(s, 3H), Meth sulphamoyl]anilino} 4.82(t, 1H), 7.08(d, 1H),
7.36(s, 1H), 45 pyrimidine 7.60(s, 1H), 7.82(m, 4H), 8.41(d, 2H)
69.sup.6 4-(1-Methyl-2- 0.10(m, 2H), 0.45(m, 2H), 0.91(m, 413 Meth
ethylimidazol-5-yl)-2-{4- 1H), 1.30(t, 3H), 2.82(m, 4H), 3.96(s,
30, [N-(cyclopropylmethyl) 3H), 4.76(m, 1H), 7.03(d, 1H), Meth
sulphamoyl]anilino} 7.46(s, 1H), 7.58(s, 1H), 7.82(m, 41 pyrimidine
4H), 8.40(d, 1H) 70.sup.7 4-(1-Methyl-2- 1.51(m, 1H), 1.78(m, 3H),
2.74(t, 483 Meth trifluoromethylimidazol-5- 2H), 3.56(m, 1H),
3.65(q, 1H), 3.76(m, 32, yl)-2-{4-[N-(tetrahydrofur- 1H), 4.16(s,
3H), 7.36(d, 1H), Meth 2-ylmethyl)sulphamoyl] 7.49(t, 1H), 7.73(d,
2H), 7.90(m, 45 anilino}pyrimidine 3H), 8.60(d, 1H), 10.10(s, 1H)
71 5-Chloro-4-(1,2- 1.23(s, 9H), 2.42(s, 3H), 2.85(s, 3H), 447 Meth
dimethylimidazol-5-yl)-2- 3.77(s, 3H), 7.65(s, 1H), 7.7(d, 2H),
M-H.sup.- 111, [4-(N-t-butyl-N-methyl 7.87(d, 2H), 8.62(s, 1H),
10.17(s, Meth sulphamoyl)anilino] 1H) 64 pyrimidine 72
4-(1-Ethyl-2- 1.20(t, 3H), 2.39(s, 3H), 3.40(m, 399 Meth
methylimidazol-5-yl)-2-[4-(N- 2H), 4.57(q, 2H), 5.00(d, 1H),
5.14(d, 27, allylsulphamoyl) 1H), 5.67(m, 1H), 7.21(d, 1H), Meth
anilino]pyrimidine 7.59(t, 1H), 7.68(s, 1H), 7.70(d, 2H), 53
7.89(d, 2H), 8.43(d, 1H), 9.82(s, 1H) .sup.1Purified by flash
chromatography on silica gel eluting with DCM/2% methanolic ammonia
(100:0 increasing in polarity to 95:5). .sup.2Purified by
preparative HPLC (gradient of H.sub.2O:CH.sub.3CN (5:95 increasing
in polarity to 95:5) containing 0.2% TFA over 8 min on a 21 .times.
100 mm RPB base deactivated C18 column). .sup.3Reaction mixture
evaporated before aqueous work-up with EtOAc extraction. The crude
product was purified by flash chromatography on silica gel eluting
with DCM/2% methanolic ammonia (100:0 increasing in polarity to
92:8). .sup.4Reaction mixture evaporated before aqueous work-up
with EtOAc extraction. The crude product was purified by flash
chromatography on silica gel eluting with DCM/MeOH (98:2 increasing
in polarity to 92:8). .sup.5Purified by flash chromatography
eluting with DCM/MeOH (100:0 increasing in polarity to 95:5).
.sup.6Purified by flash chromatography eluting with EtOAc/MeOH
(100:0 increasing in polarity to 80:20). .sup.7Purified by flash
chromatography eluting with EtOAc/MeOH (100:0 increasing in
polarity to 90:10).
Example 73
4-(1,2-Dimethylimidazol-5-yl)-2-(4-
{N-[2-(2-methoxyethoxy)ethyl]sulphamoyl}anilino)pyrimidine
hydrochloride
[0323] 1M Ethereal hydrogen chloride (4 ml) was added to solution
of
4-(1,2-dimethylimidazol-5-yl)-2-(4-(N-t-butoxycarbonyl)-N-[2-(2-methoxyet-
hoxy)ethyl]sulphamoyl) anilino)pyrimidine (Method 55; 77 mg, 0.14
mmol) in anhydrous dioxane (2 ml) and the mixture stirred at
ambient temperature for 5 days. The volatiles were removed by
evaporation and the residue triturated with ether, collected by
filtration, washed with ether (2.times.10 ml) and dried to give the
title compound (65 mg (96%) as a yellow solid. NMR 2.70 (s, 3H),
2.86 (m, 2H), 3.18 (s, 3H), 3.36 (m, 4H), 3.42 (m, 2H), 4.08 (s,
3H), 7.38 (d, 1H), 7.58 (s, 1H), 7.74 (d, 2H), 7.93 (d, 2H), 8.40
(s, 1H), 8.69 (d, 1H), 10.25 (s, 1H); m/z 447.
Examples 74-75
[0324] The following compounds were synthesised in an analogous
method to Example 73. TABLE-US-00006 Ex Compound NMR m/z SM 74
4-(1,2-Dimethylimidazol-5-yl)- 2.63(s, 3H), 2.84(m, 2H), 3.20(s,
491 Meth 2-[4-(N-{2-[2-(2- 3H), 3.40(m, 10H), 4.08(s, 3H), 56
methoxyethoxy)ethoxy]ethyl} 7.38(d, 1H), 7.48(m, 1H), 7.73(d,
sulphamoyl)anilino]pyrimidine 2H), 7.90(d, 2H), 8.38(s, 1H),
hydrochloride 8.66(d, 1H), 10.22(s, 1H) 75
4-(1,2-Dimethylimidazol-5-yl)- 2.68(s, 3H), 2.85(m, 2H), 3.20(s,
535 Meth 2-{4-[N-(2-{2-[2-(2- 3H), 3.40(m, 14H), 4.08(s, 3H), 57
methoxyethoxy)ethoxy]ethoxy} 7.32(d, 1H), 7.46(m, 1H), 7.73(d,
ethyl)sulphamoyl]anilino} 2H), 7.89(d, 2H), 8.40(s, 1H), pyrimidine
hydrochloride 8.62(d, 1H), 10.22(s, 1H)
Example 76
4-(1,2-Dimethylimidazol-5-yl)-2-{4-[N-(2-mesylethyl)sulphamoyl]anilino}pyr-
imidine
[0325] 4-Dimethylaminopyridine (3 mg, 0.025 mmol) and
3-methyoxypropylamine (200 .mu.l, 2 mmol) were added to a solution
of 4-(1,2-dimethylimidazol-5-yl)-2-(4-
(fluorosulphonyl)anilino)pyrimidine (Method 59; 87 mg, 0.25 mmol)
in NMR (1 mL) and the mixture heated at 100.degree. C. for 18
hours. The mixture was allowed to cool to ambient temperature and
the solvent removed by evaporation. The residue was purified by
preparative LCMS (constant flow of 5% v/v (35% NH.sub.3 in MeOH)
with a gradient of H.sub.2O:CH.sub.3CN (5:95 increasing in polarity
to 95:5) over 7.5 min) to give the title compound (90 mg, 81%) as a
solid. NMR 2.38 (s, 3H), 2.97 (s, 3H), 3.11 (m, 2H), 3.21 (m, 2H),
3.95 (s, 3H), 7.20 (d, 1H), 7.61 (s, 1H), 7.75 (m, 3H), 7.95 (d,
2H), 8.43 (d, 1H), 9.95 (s, 1H); m/z 451.
Examples 77-79
[0326] The following compounds were synthesised in an analogous
method to Example 76. TABLE-US-00007 Ex Compound NMR m/z 77
4-(1,2-Dimethylimidazol-5-yl)-2-{4- 1.58(m, 2H), 2.33(m, 9H),
3.02(t, 2H), 472 [N-(3-morpholinopropyl) 3.64(m, 5H), 3.90(s, 3H),
6.95(d, 1H), sulphamoyl]anilino}pyrimidine 7.45(m, 2H), 7.72(m,
4H), 8.35(d, 1H) 78 4-(1,2-Dimethylimidazol-5-yl)-2-(4- 2.01(s,
6H), 2.24(t, 2H), 2.40(s, 3H), 416 {N-[2-(N,N-dimethylamino)ethyl]
2.91(t, 2H), 3.93(s, 3H), 6.95(d, 1H),
sulphamoyl}anilino)pyrimidine 7.42(m, 2H), 7.72(m, 4H), 8.34(d, 1H)
79 4-(1,2-Dimethylimidazol-5-yl)-2-{4- 1.40(m, 6H), 2.13(m, 3H),
2.30(m, 456 [N-(2-piperidin-1-ylethyl) 6H), 2.89(t, 2H), 3.90(s,
3H), 6.95(d, sulphamoyl]anilino}pyrimidine 1H), 7.45(m, 2H),
7.72(m, 4H), 8.35(d, 1H)
Example 80
4-[1-(2-Methoxyethyl)-2-methylimidazol-5-yl]-2-{4-[N-(tetrahydrofur-2-ylme-
thyl) sulphamoyl]anilino}pyrimidine
[0327] A mixture of
4-[1-(2-methoxyethyl)-2-methylimidazol-5-yl]-2-N-(4-fluorosulphonylanilin-
o)pyrimidine (Method 60; 200 mg, 0.51 mmole) and polystyrene
supported dimethylaminopyridine (800 mg: 1.6 mmol/g resin) in
1-methyl-2-pyrrolidone (4 ml) was stirred for 10 minutes at ambient
temperature. Tetrahydrofurfurylamine (258 mg, 2.55 mmol) was added
and the reaction mixture heated at 90.degree. C. for 40 hours then
at 100.degree. C. for 48 hours. The volatiles were removed by
evaporation and the residue purified by column chromatography on
silica gel eluting with DCM/MeOH (99:1 increasing in polarity to
96:4) to give a purified product (120 mg) was triturated with
ether, collected by filtration and dried at 80.degree. C. under
vacuum to give the title compound (55 mg, 23%). NMR 1.52 (m, 1H),
1.70-1.88 (m, 3H), 2.39 (s, 3H), 2.75 (m, 2H), 3.10 (s, 3H), 3.49
(t, 2H), 3.55 (m, 1H), 3.67 (m, 1H), 3.78 (m, 1H), 4.74 (t, 2H),
7.23 (d, 1H), 7.49 (t, 1H), 7.70 (d, 3H), 7.85 (d, 2H), 8.42 (d,
1H), 9.79 (s, 1H); m/z 473.
Examples 81-82
[0328] The following compounds were synthesised in an analogous to
Example 80. TABLE-US-00008 Ex Compound NMR m/z 81.sup.1
4-[1-(2-Methoxyethyl)-2- 0.06(m, 2H), 0.34(m, 2H), 0.79(m, 1H), 443
methylimidazol-5-yl]-2-{4- 2.40(s, 3H), 2.62(t, 2H), 3.11(s, 3H),
[N-(cyclopropylmethyl) 3.50(t, 2H), 4.76(t, 2H), 7.24(d, 1H),
sulphamoyl]anilino}pyrimidine 7.50(t, 1H), 7.69(s, 1H), 7.70(d,
2H), 7.87(d, 2H), 8.42(d, 1H), 9.79(s, 1H) 82.sup.2
4-[1-(2-Methoxyethyl)-2- 1.60(m, 2H), 2.40(s, 3H), 2.77(brt, 2H),
461 methylimidazol-5-yl]-2-{4-[N-(3- 3.12(s, 3H), 3.15(s, 3H),
3.28(m, 2H), methoxypropyl)sulphamoyl] 3.52(t, 2H), 4.74(t, 2H),
7.24(d, 1H), anilino}pyrimidine 7.36(brs, 1H), 7.70(d, 3H), 7.88(d,
2H), 8.40(d, 1H), 9.80(s, 1H) .sup.1Purified by column
chromatography eluting with DCM/MeOH (98:2 increasing in polarity
to 90:10). .sup.2Purified by column chromatography eluting with
DCM/MeOH (98:2 increasing in polarity to 95:5).
Example 83
4-(1-Ethyl-2-methylimidazol-5-yl)-2-(4-(N-(Hydroxyethyl)sulphamoyl)anilino-
)pyrimidine
[0329] Chlorosulphonic acid (150 .mu.L, 2.16 mmol) was added
dropwise to solution of
2-anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine (Example 28;
150 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0.degree.
C. and the mixture stirred at 0.degree. C. for 10 minutes then
heated at 90.degree. C. for 90 minutes. The volatiles were removed
by evaporation and the residue was dried under high vacuum (<2
mmHg) for 1 hour. The resulting solid was placed under nitrogen and
a solution of ethanolamine (494 mg, 8.1 mmol) in MeOH (3 ml) added.
The mixture was stirred for 30 minutes and the volatiles were
evaporated in vacuo. Water (20 ml) was added and the precipitated
solid was collected by filtration, washed with water (2.times.10
ml) and ether (2.times.10 ml) and dried under vacuum at 60.degree.
C. to yield the title compound (177 mg, 81%) as a beige NMR 1.22
(t, 3H), 2.41 (s, 3H), 2.80 (s, 2H), 3.38 (q, 2H), 4.63 (m, 3H),
7.20 (d, 1H), (s, 1H), 7.77 (s, 1H), 7.82 (d, 2H), 7.91 (d, 2H),
8.34 (d, 1H), 9.85, (s, 1H); m/z 403
Examples 84-125
[0330] The following compounds were synthesised in an analogous
method to Example 83. TABLE-US-00009 Ex Compound NMR m/z SM 84
4-(1-Ethyl-2-methylimidazol- 0.76(s, 6H), 1.20(t, 3H), 2.40(s, 3H),
445 Ex 5-yl)-2-{4-[N-(3- 2.57(m, 2H), 3.06(d, 2H), 4.40(t, 1H), 28
hydroxy-2,2-dimethylpropyl) 4.55(q, 2H), 7.20(m, 2H), 7.68(m,
sulphamoyl] 3H), 7.84(d, 2H), 8.40(d, 1H), 9.80(s,
anilinopyrimidine 1H) 85 4-(1-Ethyl-2- 1.18(t, 3H), 1.50(m, 2H),
2.38(s, 3H), 417 Ex methylimidazol-5-yl)-2- 2.78(t, 2H), 3.38(q,
2H), 4.38(t, 1H), 28 {4-[N-(3-hydroxypropyl) 4.58(q, 2H), 7.20(d,
1H), 7.28(s, 1H), sulphamoyl]anilino} 7.68(m, 3H), 7.84(d, 2H),
8.41(d, 1H), pyrimidine 9.80(s, 1H) 86 4-(1,2-Dimethylimidazol-
2.38(s, 3H), 3.4(t, 2H), 3.96(s, 3H), 383 Ex 5 5-yl)-2-[4-(N-allyl-
5.0(d, 1H), 5.13(d, 1H), 5.65(m, 1H), (M-H)- sulphamoyl)anilino]
7.2(d, 1H), 7.55(t, 1H), 7.63(s, 1H), pyrimidine 7.68(d, 2H),
7.9(d, 2H), 8.43(d, 1H), 9.93(s, 1H) 87 4-(1,2-Dimethylimidazol-
2.50(s, 3H + DMSO peak), 3.02(s, 1H), 381 Ex 5
5-yl)-2-{4-[N-(1-propyn- 3.63(m, 2H), 4.03(s, 3H), 7.25(d, 1H),
(M-H).sup.- 3-yl) sulphamoyl]anilino} 7.72(d, 2H), 7.93(m, 3H),
8.0(d, 2H), pyrimidine 8.55(d, 1H), 10.07(s, 1H) 88
4-(1,2-Dimethylimidazol- 0.73(s, 6H), 2.38(s, 3H), 2.55(d, 2H), 429
Ex 5 5-yl)-2-{4-[N-(2,2- 3.07(d, 2H), 3.95(s, 3H), 4.4(t, 1H),
(M-H).sup.- dimethyl-3-hydroxypropyl) 7.15(s, 1H), 7.2(d, 1H),
7.63(s, 1H), sulphamoyl] 7.68(d, 2H), 7.9(d, 2H), 8.43(d, 1H),
anilino}pyrimidine 9.97(s, 1H) 89 4-(1,2-Dimethylimidazol- 1.5(m,
2H), 2.37(s, 3H), 2.76(m, 2H), 401 Ex 5
5-yl)-2-{4-[N-(3-hydroxypropyl) 3.33(m, 2H), 3.95(s, 3H), 4.36(t,
1H), (M-H).sup.- sulphamoyl] 7.2(d, 1H), 7.27(t, 1H), 7.63(s, 1H),
anilino}pyrimidine 7.67(d, 2H), 7.9(d, 2H), 8.43(d, 1H), 9.92(s,
1H) 90 4-(1,2-Dimethylimidazol- 0.97(t, 3H), 2.38(s, 3H), 2.77(m,
2H), 371 Ex 5 5-yl)-2-[4-(N-ethylsulphamoyl) 3.96(s, 3H), 7.2(d,
1H), 7.3(t, 1H), (M-H).sup.- anilino] 7.63(s, 1H), 7.68(d, 2H),
7.92(d, 2H), pyrimidine 8.43(d, 1H), 9.93(s, 1H) 91
4-(1,2-Dimethylimidazol- 2.37(s, 3H), 2.77(t, 2H), 3.33(m, 2H), 387
Ex 5 5-yl)-2-{4-[N-(2- 3.93(s, 3H), 4.62(t, 1H), 7.18(d, 1H),
(M-H).sup.- hydroxyethyl)sulphamoyl] 7.3(s, 1H), 7.63(s, 1H),
7.7(d, 2H), 7.9(d, anilino}pyrimidine 2H), 8.43(d, 1H), 9.93(s, 1H)
92 4-(1,2-Dimethylimidazol- 2.37(s, 3H), 2.9(m, 2H), 2.33(m, 4H),
431 Ex 5 5-yl)-2-(4-{N-[2-(2- 3.43(m, 2H), 3.96(s, 3H), 4.5(t, 1H),
(M-H).sup.- hydroxyethoxy) 7.2(d, 1H), 7.42(t, 1H), 7.63(s, 1H),
ethyl]sulphamoyl}anilino) 7.7(d, 2H), 7.92(d, 2H), 8.43(d, 1H),
pyrimidine 9.93(s, 1H) 93 4-(1,2-Dimethylimidazol- 2.4(s, 3H),
3.95(s, 3H), 4.07(s, 2H), 434 Ex 5 5-yl)-2-{4-[N-(pyrid-2- 7.2(m,
2H), 7.35(d, 1H), 7.63(s 1H), (M-H).sup.- ylmethyl)sulphamoyl]
7.7(m, 3H), 7.88(d, 2H), 8.0(s, 1H), anilino}pyrimidine 8.43(m,
2H), 9.93(s, 1H) 94 4-(1,2-Dimethylimidazol- 2.4(s, 3H), 3.96(s,
3H), 4.02(d, 2H), 434 Ex 5 5-yl)-2-{4-[N-(pyrid-3- 7.2(d, 1H),
7.27(m, 1H), 7.63(m, 2H), (M-H).sup.- ylmethyl)sulphamoyl] 7.7(d,
2H), 7.9(d, 2H), 8.03(t, 1H), anilino}pyrimidine 8.4(m, 3H),
9.93(s, 1H) 95 4-(1,2-Dimethylimidazol- 0.8(t, 3H), 1.2(m, 4H),
1.35(m, 2H), 413 Ex 5 5-yl)-2-[4-(N-pentylsulphamoyl) 2.38(s, 3H),
2.7(m, 2H), 3.95(s, 3H), (M-H).sup.- anilino] 7.2(d, 1H), 7.3(t,
1H), 7.63(s, 1H), pyrimidine 7.67(d, 2H), 7.92(d, 2H), 8.43(d, 1H),
9.93(s, 1H) 96 4-(1,2-Dimethylimidazol- 1.27(m, 6H), 2.36(s, 3H),
2.7(m, 2H), 429 Ex 5 5-yl)-2-{4-[N-(5-hydroxypentyl) 3.27(m, 2H),
3.96(s, 3H), 4.27(t, 1H), (M-H).sup.- sulphamoyl] 7.2(d, 1H),
7.3(t, 1H), 7.63(s, 1H), anilino}pyrimidine 7.67(d, 2H), 7.9(d,
2H), 8.43(d, 1H), 9.92(s, 1H) 97 4-(1,2-Dimethylimidazol- 1.03(t,
3H), 1.57(m, 2H), 2.37(s, 3H), 429 Ex 5 5-yl)-2-{4-[N-(3- 2.77(m,
2H), 3.27(m, 4H), 3.95(s, (M-H).sup.- ethoxypropyl)sulphamoyl] 3H),
7.2(d, 1H), 7.33(t, 1H), 7.63(s, anilino}pyrimidine 1H), 7.67(d,
2H), 7.93(d, 2H), 8.43(d, 1H), 9.93(s, 1H) 98
4-(1,2-Dimethylimidazol- 1.02(d, 3H), 2.4(s, 3H), 2.65(m, 2H), 401
Ex 5 5-yl)-2-(4-[N-(2-hydroxypropyl) 3.57(m, 1H), 3.98(s, 3H),
4.63(d, 1H), (M-H).sup.- sulphamoyl] 7.22(d, 1H), 7.32(t, 1H),
7.67(s, 1H), anilino}pyrimidine 7.7(d, 2H), 7.92(d, 2H), 8.43(d,
1H), 9.92(s, 1H) 99 4-(1,2-Dimethylimidazol- 1.0(d, 6H), 1.55(m,
2H), 2.38(s, 3H), 443 Ex 5 5-yl)-2-{4-[N-(3- 2.76(m, 2H), 3.27(m,
2H), 3.4(m, (M-H).sup.- isopropoxypropyl) 1H), 3.95(s, 3H), 7.18(d,
1H), 7.3(t, sulphamoyl]anilino} 1H), 7.63(s, 1H), 7.68(d, 2H),
7.92(d, pyrimidine 2H), 8.43(d, 1H), 9.93(s, 1H) 100
4-(1,2-Dimethylimidazol- 0.8(t, 3H), 1.22(m, 1H), 1.4(m, 1H), 415
Ex 5 5-yl)-2-{4-[N-(2- 2.37(s, 3H), 2.65(m, 2H), 3.27(m,
(M-H).sup.- hydroxybutyl)sulphamoyl] 1H), 3.95(s, 3H), 4.55(d, 1H),
7.2(d, anilino}pyrimidine 1H), 7.25(t, 1H), 7.63(s, 1H), 7.7(d,
2H), 7.92(d, 2H), 8.43(d, 1H), 9.92(s, 1H) 101
4-(1,2-Dimethylimidazol- 2.38(s, 3H), 2.83(t, 2H), 3.07(m, 2H), 448
Ex 5 5-yl)-2-{4-[N-(2-pyrid-2- 3.95(s, 3H), 7.18(m, 3H), 7.47(t,
1H), (M-H).sup.- ylethyl)sulphamoyl] 7.63(s 1H), 7.67(m, 3H),
7.9(d, 2H), anilino}pyrimidine 8.42(d, 2H), 9.93(s, 1H) 102
4-(1,2-Dimethylimidazol- 2.37(s, 3H), 2.7(t, 2H), 3.0(m, 2H), 448
Ex 5 5-yl)-2-{4-[N-(2-pyrid-4- 3.95(s, 3H), 7.17(m, 3H), 7.5(t,
1H), (M-H).sup.- ylethyl)sulphamoyl] 7.63(s 1H), 7.67(d, 2H),
7.9(d, 2H), anilino}pyrimidine 8.42(m, 3H), 9.93(s, 1H) 103
4-(1-Methyl-2-ethylimidazol- 0.30(m, 2H), 0.44(m, 2H), 1.23(t, 399
Ex 5-yl)-2-[4-(N- 3H), 2.06(m, 1H), 2.73(q, 2H), 3.95(s, 29
cyclopropylsulphamoyl) 3H), 7.20(d, 1H), 7.69(m, 4H), 7.90(d,
anilino]pyrimidine 2H), 8.43(d, 1H), 9.80(s, 1H) 104.sup.1
4-[1-(2,2,2- 0.02(m, 2H), 0.30(m, 2H), 0.78(m, 467 Ex
Trifluoroethyl)-2-methylimidazol- 1H), 2.40(s, 3H), 2.59(t, 2H),
5.76(q, 30 5-yl]-2-{4- 2H), 7.21(d, 1H), 7.46(t, 1H), 7.65(d,
[N-(cyclopropylmethyl) 2H), 7.73(s, 1H), 7.81(d, 2H), 8.42(d,
sulphamoyl]anilino} 1H), 9.93(s, 1H) pyrimidine 105.sup.1
4-[1-(2,2,2- 2.50(s, 3H), 3.13(m, 2H), 3.29(s, 3H), 471 Ex
Trifluoroethyl)-2-methylimidazol- 3.41(T, 2H), 5.05(brs, 1H),
5.38(q, 30 5-yl]-2-{4-[N-(2- 2H), 7.03(d, 1H), 7.48(s, 1H), 7.57(s,
methoxyethyl)sulphamoyl] 1H), 7.70(d, 2H), 7.81(d, 2H), 8.41(d,
anilino}pyrimidine 1H) 106.sup.1 4-[1-(2,2,2- 0.30(m, 2H), 0.47(m,
2H), 2.03(m, 453 Ex Trifluoroethyl)-2-methylimidazol- 1H), 2.40(s,
3H), 5.77(q, 2H), 7.20(d, 30 5-yl]-2-(4-(N- 1H), 7.73(m, 4H),
7.81(d, 2H), 8.42(d, cyclopropylsulphamoyl) 1H), 9.96(s, 1H)
anilino)pyrimidine 107.sup.5 4-(1-Isopropyl-2- 1.48(d, 6H), 2.51(s,
3H), 2.86(m, 2H), 431 Ex methylimidazol-5-yl)-2- 3.16(s, 3H),
3.29(t, 2H), 5.66(sept, 32 {4-[N-(2-methoxyethyl) 1H), 7.14(d, 1H),
7.46(s, 1H), 7.49(t, sulphamoyl]anilino} 1H), 7.69(d, 2H), 7.89(d,
2H), 8.45(d, pyrimidine 1H), 9.88(s, 1H) 108.sup.3
4-(1,2,4-Trimethylimidazol- 2.28(s, 3H), 2.35(s, 3H), 2.90(q, 2H),
416 Ex 5-yl)-2-{4-[N-(2- 3.18(s, 3H), 3.75(s, 3H), 6.98(d, 1H), 31
methoxyethyl)sulphamoyl] 7.44(t, 1H), 7.70(d, 2H), 7.95(d, 2H),
anilino}pyrimidine 8.52(d, 1H), 9.95(s, 1H) 109 5-Bromo-4-(1,2-
2.44(s, 3H), 3.75(s, 3H), 7.15(s, 2H), 424 Ex
dimethylimidazol-5-yl)- 7.65(s, 1H), 7.75(d, 2H), 7.85(d, 2H), 63
2-(4-sulphamoylanilino) 8.70(s, 1H), 10.15(s, 1H) pyrimidine 110
5-Bromo-4-(1,2- 0.78(t, 3H), 1.39(q, 2H), 2.41(s, 3H), 466 Ex
dimethylimidazol-5-yl)-2- 2.68(q, 2H), 3.75(s, 3H), 7.35(t, 1H), 63
[4-(N-propylsulphamoyl) 7.64(s, 1H), 7.70(d, 2H), 7.88(d, 2H),
anilino]pyrimidine 8.70(s, 1H) 111.sup.4 5-Bromo-4-(1,2- 1.58(q,
2H), 2.40(s, 3H), 2.76(q, 2H), 498 Ex dimethylimidazol-5-yl)-2-
3.14(s, 3H), 3.28(m, 2H), 3.73(s, 3H), 63 {4-[N-(3-methoxypropyl)
7.36(t, 1H), 7.64(s, 1H), 7.71(d, 2H), sulphamoyl]anilino} 7.87(d,
2H), 8.70(s, 1H) pyrimidine 112.sup.4 5-Bromo-4-(1,2- 2.38(s, 6H),
3.75(s, 3H), 7.10(m, 1H), 438 Ex dimethylimidazol-5-yl)-2- 7.62(s,
1H), 7.70(d, 2H), 7.87(d, 2H), 63 [4-(N-methylsulphamoyl) 8.70(s,
1H) anilino]pyrimidine 113.sup.4 5-Bromo-4-(1,2- 0.05(q, 2H),
0.31(q, 2H), 0.78(m, 1H), 476 Ex dimethylimidazol-5-yl)-2- 2.39(s,
3H), 2.60(t, 2H), 3.72(s, 3H), 63 {4-[N-(cyclopropylmethyl) 7.45(t,
1H), 7.60(s, 1H), 7.70(d, 2H), sulphamoyl]anilino} 7.82(d, 2H),
8.70(s, 1H) pyrimidine 114.sup.3 4-(1,2,4-Trimethylimidazol-
2.26(s, 3H), 2.34(s, 3H), 3.76(s, 3H), 358 Ex 5-yl)-2-(4- 6.95(s,
1H), 7.14(s, 2H), 7.72(d, 2H), 31 sulphamoylanilino) 7.90(s, 2H),
8.50(s, 1H), 9.90(s, 1H) pyrimidine 115.sup.3
4-(1,2,4-Trimethylimidazol- 2.23(s, 3H), 2.32(s, 3H), 2.38(d, 3H),
372 Ex 5-yl)-2-[4-(N- 3.75(s, 3H), 6.98(s, 1H), 7.18(m, 1H), 31
methylsulphamoyl) 7.67(d, 2H) 7.95(d, 2H), 8.50(d, 1H),
anilino]pyrimidine 9.98(s, 1H) 116.sup.5
4-(1,2,4-Trimethylimidazol- 1.45(q, 2H), 2.05(s, 3H), 2.12(t, 2H),
444 Ex 5-yl)-2-{4-[N-(3- 2.15(s, 3H), 2.35(s, 3H), 2.75(q, 2H), 31
N,N-dimethylamino- 3.72(s, 3H), 6.95(d, 1H), 7.32(t, 1H),
propyl)sulphamoyl] 7.68(d, 2H), 7.93(d, 2H), 8.50(d, 1H),
anilino}pyrimidine 9.95(s, 1H) 117.sup.3
4-(1,2,4-Trimethylimidazol- 1.08(s, 9H), 2.27(s, 3H), 2.34(s, 3H),
414 Ex 5-yl)-2-[4-(N-t- 3.72(s, 3H), 6.95(d, 1H), 7.25(s, 1H), 31
butylsulphamoyl) 7.70(d, 2H), 7.90(d, 2H), 8.50(d, 1H),
anilino]pyrimidine 9.90(s, 1H) 118.sup.3
4-(1,2,4-Trimethylimidazol- 0.71(t, 3H), 1.01(s, 3H), 1.21(q, 2H),
428 Ex 5-yl)-2-{4-[N-(1,1- 2.30(s, 3H), 2.40(s, 3H), 3.77(s, 3H),
31 dimethylpropyl) 7.0(d, 1H), 7.14(s, 1H), 7.70(d, 2H),
sulphamoyl]anilino} 7.89(d, 2H), 8.58(d, 1H), 9.98(s, 1H)
pyrimidine 119.sup.3 4-(1,2,4-Trimethylimidazol- 0.04(m, 2H),
0.15(m, 2H), 1.78(m, 398 Ex 5-yl)-2-[4-(N- 1H), 3.40(s, 3H),
6.64(d, 2H), 7.32(s, 31 cyclopropylsulphamoyl) 1H), 7.38(d, 2H),
7.62(d, 2H), 8.20(d, anilino]pyrimidine 1H), 9.63(s, 1H) 120
4-(1,2-Dimethylimidazol- 0.75-0.80(t, 3H), 1.29-1.41(m, 2H), 387 Ex
5 5-yl)-2-[4-(N- 2.37(s, 3H), 2.64-2.70(q, 2H), 3.95(s,
propylsulphamoyl) 3H), 7.18(d, 1H), 7.32(t, 1H), 7.62(s,
anilino]pyrimidine 1H), 7.68(d, 2H), 7.90(d, 2H), 8.42(d, 1H),
9.89(s, 1H) 121 4-(1,2-Dimethylimidazol- 0.00-0.06(m, 2H),
0.08-0.17(m, 2H), 385 Ex 5 5-yl)-2-[4-(N- 1.74-1.80(m, 1H), 2.05(s,
3H), 3.63(s, cyclopropylsulphamoyl) 3H), 6.87(d, 1H), 7.31(s, 1H),
7.33(brs, anilino]pyrimidine 1H), 7.38(d, 2H), 7.61(d, 2H), 8.11(d,
1H), 9.60(s, 1H) 122 4-(1,2-Dimethylimidazol- 1.4-1.50(m, 2H),
1.65-1.78(m, 2H), 399 Ex 5 5-yl)-2-[4-(N- 1.84-1.93(m, 2H), 2.37(s,
3H), 3.52-3.66(m, cyclobutylsulphamoyl) 1H), 3.94(s, 3H), 7.19(d,
1H), anilino]pyrimidine 7.63-7.71(m, 4H), 7.89(d, 2H), 8.43(d, 1H),
9.89(s, 1H) 123 4-(1,2-Dimethylimidazol- 2.38(s, 3H), 3.63(q, 2H),
3.95(s, 3H), 427 Ex 5 5-yl)-2-{4-[N-(2,2,2- 7.20(d, 1H), 7.63(s,
1H), 7.73(d, 2H), trifluoroethyl)sulphamoyl] 7.93(d, 2H), 8.35(brs,
1H), 8.43(d, anilino}pyrimidine 1H), 9.94(s, 1H) 124
4-(1,2-Dimethylimidazol- 2.36(s, 3H), 3.89(s, 3H), 7.19(d, 1H), 489
Ex 5 5-yl)-2-{4-[N-(3- 7.32-7.37(m, 3H), 7.44(d, 1H), 7.62(s,
trifluoromethylphenyl) 1H), 7.69(d, 2H), 7.87(d, 2H), 8.40(d,
sulphamoyl]anilino} 1H), 9.93(s, 1H), 10.50(brs, 1H) pyrimidine 125
4-(1-Ethyl-2- 9.81(s, 1H), 8.43(d, 1H), 7.91(d, 2H), 373 Ex
methylimidazol-5-yl)-2- 7.75-7.65(m, 3H), 7.27-7.18(m, 2H), 28
[4-(N-methylsulphamoyl) 4.60(q, 2H), 2.42-2.37(m, 6H), 1.19(t,
anilino]pyrimidine 3H) .sup.1Purified by flash chromatography
eluting with DCM/2% methanolic ammonia (100:0 increasing in
polarity to 95:5). .sup.2Purified by passing through an Isolute
amine column. .sup.3Purified by flash chromatography eluting with
DCM/MeOH (100:0 increasing in polarity to 95:5). .sup.4Purified by
flash chromatography eluting with DCM/MeOH (100:0 increasing in
polarity to 98:2). .sup.5Product isolated by aqueous work-up and
extraction with EtOAc. Extracts washed with 1M aqueous acetic acid
and aqueous sodium bicarbonate solution.
Example 126
4-(1-Ethyl-2-methylimidazol-5-yl)-2-(4-{N-[2-(2-hydroxyethoxy)ethyl]sulpha-
moyl}anilino) pyrimidine
[0331] Chlorosulphonic acid (150 .mu.l, 2.16 mmol) was added
dropwise to a solution of
2-anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine (Example 28;
150 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled to 0.degree.
C. and the mixture stirred for 10 minutes at 0.degree. C. then
heated at 90.degree. C. for 90 minutes. The volatiles were removed
by evaporation and the resultant solid placed under high vacuum
(<2 mmHg) for 1 hr. The resulting solid was placed under
nitrogen and a solution of 2-(2-aminoethyl)ethanol (114 mg, 1.08
mmol) and diethylmethylamine in MeOH (3 ml) was cautiously added.
The solution was stirred for 30 minutes and the volatiles were
evaporated. Water (20 ml) was added and the precipitated solid was
collected by filtration and washed with water (2.times.10 ml). The
residue was dissolved in MeOH (5 ml) and loaded on to an Isolute
amine column, eluted with MeOH (30 ml) and the fractions containing
product were evaporated to give the title compound (190 mg, 79%) as
a beige solid. NMR 1.18 (t, 3H), 2.39 (s, 3H), 2.89 (t, 2H), 3.15
(m, 7H), 4.38 (q, 2H), 7.21 (d, 1H), 7.71 (m, 3H), 7.89 (d, 2H),
8.41 (d, 1H), 9.82 (s, 1H); m/z 447.
Examples 127-144
[0332] The following compounds were synthesised in an analogous
method to Example 126. TABLE-US-00010 Ex Compound NMR m/z SM 127
4-(1-Ethyl-2-methylimidazol-5- 1.01(d, 6H), 1.20(t, 3H), 2.40(s,
475 Ex 28 yl)-2-{4-[N-(3-isopropoxy-2- 3H), 2.62(m, 1H), 2.81(m,
1H), hydroxypropyl)sulphamoyl] 3.23(d, 2H), 3.50(m, 2H), 4.48(q,
anilino}pyrimidine 2H), 4.76(s, 1H), 7.20(d, 1H), 7.70(m, 3H),
7.84(d, 2H), 8.40(d, 1H), 9.81(s, 1H) 128
4-(1-Ethyl-2-methylimidazol-5- 1.19(t, 3H), 2.40(s, 3H), 3.13(t,
470 Meth yl)-2-{4-[N-(2-isoxazol-3- 2H), 4.17(t, 2H), 4.54(q, 2H),
6.12(d, 85, yloxyethyl)sulphamoyl] 1H), 7.20(d, 1H), 7.70(m, 4H),
Ex 28 anilino}pyrimidine 7.86(d, 2H), 8.40(d, 1H), 8.60(d, 1H),
9.80(s, 1H) 129.sup.1 4-(1-Ethyl-2-methylimidazol-5- 1.19(t, 3H),
2.39(s, 3H), 3.13(q, 486 Meth yl)-2-{4-[N-(2-isothiazol-3- 2H),
4.26(t, 2H), 4.55(q, 2H), 6.67(d, 86, yloxyethyl)sulphamoyl] 1H),
7.20(d, 1H), 7.70(m, 4H), Ex 28 anilino}pyrimidine 7.84(d, 2H),
8.40(d, 1H), 8.81(d, 1H), 9.80(s, 1H) 130
4-(1-Ethyl-2-methylimidazol-5- 1.19(t, 3H), 2.39(s, 3H), 3.18(q,
487 Meth yl)-2-(4-{N-[2-(1,2,5-thiadiazol- 2H), 4.34(t, 2H),
4.56(q, 2H), 7.20(d, 87, 3-yloxy)ethyl]sulphamoyl} 1H), 7.70(m,
4H), 7.86(d, 2H), Ex 28 anilino)pyrimidine 8.25(s, 1H), 8.40(d,
1H), 9.80(s, 1H) 131.sup.1 4-(1-Ethyl-2-methylimidazol-5- 1.18(t,
3H), 1.80(m, 2H), 2.38(s, 484 Meth yl)-2-{4-[N-(3-isoxazol-3- 3H),
2.84(q, 2H), 4.16(t, 2H), 4.56(q, 88, yloxypropyl)sulphamoyl] 2H),
6.25(s, 1H), 7.20(d, 1H), Ex 28 anilino}pyrimidine 7.49(t, 1H),
7.68(m, 3H), 7.87(d, 2H), 8.40(d, 1H), 8.59(s, 1H), 9.80(s, 1H)
132.sup.1 4-(1-Ethyl-2-methylimidazol-5- 1.18(t, 3H), 1.80(m, 2H),
2.38(s, 500 Meth yl)-2-{4-[N-(3-isothiazol-3- 3H), 2.84(q, 2H),
4.26(t, 2H), 4.56(q, 89, yloxypropyl)sulphamoyl] 2H), 6.69(d, 1H),
7.20(d, 1H), Ex 28 anilino}pyrimidine 7.45(t, 1H), 7.68(m, 3H),
7.87(d, 2H), 8.40(d, 1H), 8.80(d, 1H), 9.80(s, 1H) 133.sup.1
4-(1-Ethyl-2-methylimidazol-5- 1.18(t, 3H), 1.85(m, 2H), 2.38(s,
501 Meth yl)-2-(4-{N-[3-(1,2,5-thiadiazol- 3H), 2.91(q, 2H),
4.36(t, 2H), 4.56(q, 90, 3-yloxy)propyl]sulphamoyl} 2H), 7.20(d,
1H), 7.45(t, 1H), Ex 28 anilino)pyrimidine 7.68(m, 3H), 7.87(d,
2H), 8.30(s, 1H), 8.40(d, 1H), 9.80(s, 1H) 134
4-(1-Methyl-2-ethylimidazol-5- 1.23(t, 3H), 1.45(m, 2H), 1.70(m,
413 Ex 29 yl)-2-[4-(N-cyclobutyl- 2H), 1.87(m, 2H), 2.93(q, 2H),
sulphamoyl)anilino]pyrimidine 3.58(m, 1H), 3.95(s, 3H), 7.20(d,
1H), 7.69(m, 4H), 7.90(d, 2H), 8.43(d, 1H), 9.86(s, 1H) 135.sup.1
4-[1-(2,2,2-Trifluoroethyl)-2- 1.45(m, 2H), 1.70(m, 2H), 1.87(m,
467 Ex 30 methylimidazol-5-yl]-2-[4-(N- 2H), 2.40(s, 3H), 3.58(m,
1H), cyclobutylsulphamoyl)anilino] 5.80(q, 2H), 7.23(d, 1H),
7.69(m, pyrimidine 4H), 7.90(d, 2H), 8.44(d, 1H), 9.96(s, 1H)
136.sup.2 4-(1-Isopropyl-2- 1.45(m, 8H), 1.72(m, 2H), 1.88(m, 427
Ex 32 methylimidazol-5-yl)-2-[4-(N- 2H), 3.30(s, 3H), 3.60(m, 1H),
cyclobutylsulphamoyl)anilino] 5.60(sept, 1H), 7.16(d, 1H), 7.48(s,
pyrimidine 1H), 7.68(d, 2H), 7.74(d, 1H), 7.88(d, 2H), 8.48(d, 1H),
9.90(s, 1H) 137.sup.3 4-(1-Isopropyl-2- 0.40(m, 2H), 0.50(m, 2H),
1.50(d, 413 Ex 32 methylimidazol-5-yl)-2-[4-(N- 6H), 2.12(m, 1H),
2.52(s, 3H), cyclopropylsulphamoyl)anilino] 5.70(m, 1H), 7.17(d,
1H), 7.48(s, pyrimidine 1H), 7.71(s, 1H), 7.75(d, 2H), 7.93(d, 2H),
8.49(d, 1H), 9.93(s, 1H) 138.sup.4 4-(1-Isopropyl-2- 0.09(m, 2H),
0.36(m, 2H), 0.81(m, 427 Ex 32 methylimidazol-5-yl)-2-{4- 1H),
1.49(d, 6H), 2.60(s, 3H), [N-(cyclopropylmethyl)sulphamoyl] 2.65(t,
2H), 5.70(m, 1H), 7.17(d, anilino}pyrimidine 1H), 7.48(s, 1H),
7.53(t, 1H), 7.72(d, 2H), 7.90(d, 2H), 8.48(d, 1H), 9.90(s, 1H)
139.sup.5 4-(1-Isopropyl-2- 1.46(d, 6H), 2.48(s, 3H), 4.04(d, 412
Ex 32 methylimidazol-5-yl)-2-{4- 2H), 5.66(sept, 1H), 7.15(d, 1H),
[N-(cyanomethyl)sulphamoyl] 7.46(s, 1H), 7.71(d, 2H), 7.92(d,
anilino}pyrimidine 2H), 8.32(t, 1H), 8.48(d, 1H), 9.95(s, 1H)
140.sup.6 4-(1-Isopropyl-2- 1.46(d, 6H), 3.29(s, 3H), 4.05(b 464 Ex
32 methylimidazol-5-yl)-2-{4- d, 2H), 5.67(sept, 1H), 7.13(d,
[N-(pyrid-2-ylmethyl)sulphamoyl] 1H), 7.21(m, 1H), 7.36(d, 1H),
anilino}pyrimidine 7.43(s, 1H), 7.69(m, 3H), 7.86(d, 2H), 8.02(b t,
1H), 8.42(d, 1H), 8.46(d, 1H), 9.88(s, 1H) 141
4-(1-Ethyl-2-methylimidazol-5- 1.20(t, 3H), 2.40(s, 6H), 4.11(s,
465 Ex 28 yl)-2-{4-[N-(5-methylpyrazin-2- 2H), 4.60(q, 2H), 7.24(d,
1H), ylmethyl)sulphamoyl]anilino} 7.68(m, 3H), 7.85(d, 2H), 8.10(s,
pyrimidine 1H) 8.36(s, 1H), 8.42(s, 1H) 8.45(d, 1H), 9.82(s, 1H)
142 4-(1-Methyl-2- 2.88(t, 2H), 3.17(s, 3H), 3.30(m, 433 Ex 33
methoxymethylimidazol-5-yl)-2- 5H), 4.05(s, 3H), 4.55(s, 2H),
7.28(d, {4-[N-(2-methoxyethyl) 1H), 7.49(t, 1H), 7.74(d, 3H),
sulphamoyl]anilino}pyrimidine 7.92(d, 2H), 8.50(d, 1H), 9.98(s, 1H)
143 4-(1,2-Dimethylimidazol-5-yl)- 1.81(m, 2H), 2.36(s, 3H),
2.87(q, 486 Ex 5, 2-{4-[N-(3-isothiazol-3- 2H), 3.96(s, 3H),
4.13(t, 2H), 6.68(d, Meth yloxypropyl)sulphamoyl] 1H), 7.20(d, 1H),
7.43(t, 1H), 89 anilino}pyrimidine 7.62(s, 1H), 7.68(d, 2H),
7.89(d, 2H), 8.42(d, 1H), 8.80(d, 1H), 9.89(s, 1H) 144
4-(1-Ethyl-2-methylimidazol-5- 1.20(t, 3H), 2.40(s, 3H), 3.05(s,
399 Ex 28 yl)-2-{4-[N-(2-propynyl) 1H), 3.65(s, 2H), 4.60(q, 2H),
sulphamoyl]anilino}pyrimidine 7.21(d, 1H), 7.68(s, 1H), 7.71(d,
2H), 7.90(d, 3H), 8.45(d, 1H), 9.85(s, 1H); m/z 397 .sup.1Purified
by flash chromatography eluting with DCM/2% methanolic ammonia
(100:0 increasing in polarity to 95:5). .sup.2Reacted with 4
equivalents of cyclobutylamine/12 equivalents of
dimethylethylamine. Purified by flash chromatography eluting with
DCM/MeOH (98:2 increasing in polarity to 95:5). .sup.3Reacted with
4 equivalents of cyclopropylamine/12 equivalents of
dimethylethylamine. Purified by flash chromatography eluting with
DCM/MeOH (98:2 increasing in polarity to 94:6). .sup.4Reacted with
4 equivalents of cyclopropylmethylamine/12 equivalents of
dimethylethylamine. Purified by flash chromatography eluting with
DCM/MeOH (98:2 increasing in polarity to 94:6). .sup.5Reacted with
5.75 equivalents of aminoacetonitrile/9 equivalents of
dimethylethylamine. Product extracted from aqueous sodium
bicarbonate solution with DCM. .sup.6Reacted with 4 equivalents of
2-aminomethylpyridine/9 equivalents of dimethylethylamine. Purified
by flash chromatography eluting with DGM/MeOH (98:2 increasing in
polarity to 90:10).
Example 145
5-Bromo-4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]a-
nilino}pyrimidine
[0333] Bromine (8 .mu.l, 0.14 mmol) was added to a solution of
4-(1,2-dimethylimidazol-5-yl)-2-{-[N-(2-methoxyethyl)sulphamoyl]anilino}p-
yrimidine (Example 35; 52 mg, 0.133 mmol) in glacial acetic acid (2
ml) heated at 60.degree. C. The mixture was heated at 60.degree. C.
for 4 hours, then the solvent was removed by evaporated. The
residue was dissolved in DCM (20 ml), washed with saturated aqueous
sodium hydrogen carbonate solution (20 ml), dried (Chemelut column
1005) and purified by flash chromatography eluting with DCM/2%
methanolic ammonia (100:0 increasing in polarity to 97:3) to yield
the title compound (37 mg, 60%) as a white foam NMR 2.40 (s, 3H),
3.06 (q, 2H), 3.20 (s, 3H), 3.36 (t, 2H), 3.68 (s, 3H), 5.00 (t,
1H), 7.56 (s, 1H), 7.67 (d, 2H), 7.73 (d, 2H), 7.80 (s, 1H), 8.53
(s, 1H); m/z 483.
Examples 146-148
[0334] The following compounds were synthesised in an analogous
method to Example 145. TABLE-US-00011 Ex Compound NMR m/z SM
146.sup. 5-Bromo-4-(1-ethyl-2- 1.25(t, 3H), 2.50(s, 3H), 3.15(q,
497 Ex methylimidazol-5-yl)-2-{4-[N- 2H), 3.26(s, 3H), 3.42(t, 2H),
4.33(q, 2H), 37 (2-methoxyethyl)sulphamoyl] 4.92(t, 1H), 7.40(s,
1H), anilino}pyrimidine 7.71(d, 2H), 7.82(m, 3H), 8.61(s, 1H)
147.sup.1 5-Bromo-4-[1-(2-methoxyethyl)- 2.42(s, 3H), 2.89(m, 2H),
3.02(s, 525 Ex 2-methylimidazol-5-yl]-2-{4-[N- 3H), 3.16(s, 3H),
3.29(m, 2H), 3.36(t, 2H), 61 (2-methoxyethyl)sulphamoyl] 4.51(t,
2H), 7.49(t, 1H), anilino}pyrimidine 7.58(s, 1H), 7.72(d, 2H),
7.85(d, 2H), 8.74(s, 1H), 10.15(s, 1H) 148.sup.2
5-Bromo-4-[1-(2-methoxyethyl)- 1.59(quin, 2H), 2.44(s, 3H), 2.78(q,
539 Ex 2-methylimidazol-5-yl]-2-{4-[N- 2H), 3.05(s, 3H), 3.17(s,
3H), 3.28(t, 2H), 82 (3-methoxypropyl)sulphamoyl] 3.39(t, 2H),
4.55(t, 2H), anilino}pyrimidine 7.39(t, 1H), 7.61(s, 1H), 7.73(d,
2H), 7.88(d, 2H), 8.77(s, 1H), 10.19(s, 1H) .sup.1Extracted into
EtOAc. Purified by column chromatography eluting with DCM/MeOH
(96:4 increasing in polarity to 90:10). .sup.2Extracted into EtOAc.
Purified by column chromatography eluting with DCM/2% methanolic
ammonia (98:2 increasing in polarity to 94:6).
Example 149
5-Chloro-4-(1-ethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulpham-
oyl]anilino}pyrimidine
[0335] N-Chlorosuccinimide (80 mg, 0.6 mmol) was added to a
solution of
4-(1-ethyl-2-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}py-
rimidine (Example 37; 208 mg, 0.5 mmol) in glacial acetic acid (5
ml) and the mixture heated at 60.degree. C. for 3 hours. The
solvent was evaporated and the residue dissolved in DCM (30 ml),
washed with saturated aqueous sodium hydrogen carbonate solution
(20 ml), the aqueous layer was extracted with DCM (20 ml). The DCM
extracts were combined, dried (Chemelut column 1005) and the
solvent evaporated. The residue was purified by flash
chromatography on silica gel eluting with DCM/2% methanolic ammonia
(100:0 increasing in polarity to 97:3) to give the title compound
(110 mg, 44%) as a white foam. NMR 1.24 (t, 3H), 2.45 (s, 3H), 3.09
(q, 2H), 3.28 (s, 3H), 3.40 (t, 2H), 4.32 (t, 2H), 4.92 (t, 1H),
7.40 (s, 1H), 7.72 (d, 2H), 7.83 (d, 2H), 7.88 (s, 1H), 8.49 (s,
1H); m/z 451.
Examples 150-153
[0336] The following compounds were synthesised in an analogous
method to Example 149. TABLE-US-00012 Ex Compound NMR m/z SM
150.sup. 5-Chloro-4-(1,2- 2.50(s, 3H), 3.15(q, 2H), 3.26(s, 437 Ex
dimethylimidazol-5-yl)-2-{4-[N- 3H), 3.42(t, 2H), 3.78(s, 3H),
4.92(t, 1H), 35 (2-methoxyethyl)sulphamoyl] 7.43(s, 1H), 7.71(d,
2H), anilino}pyrimidine 8.01(d, 3H), 8.07(s, 1H), 8.61(s, 1H)
151.sup.1 5-Chloro-4-(1-ethyl-2- 1.24(t, 3H), 1.50(m, 1H), 1.84(m,
477 Ex methylimidazol-5-yl)-2-{4-[N- 3H), 2.48(s, 3H), 2.90(m, 1H),
3.12(m, 1H), 41 (tetrahydrofur-2-ylmethyl) 3.73(m, 2H), 3.94(m,
1H), sulphamoyl]anilino}pyrimidine 4.37, (q, 2H), 4.83(t, 1H),
7.36(s, 1H), 7.70(d, 2H), 7.81(d, 2H), 7.89(s, 1H), 8.44(s, 1H)
152.sup.1 5-Chloro-4-(1-ethyl-2- 0.60(m, 4H), 1.25(t, 3H), 2.31(m,
433 Ex methylimidazol-5-yl)-2-[4-(N- 1H), 2.53(s, 3H), 4.39(q, 2H),
4.96(brs, 1H), 53 cyclopropylsulphamoyl)anilino] 7.37(s, 1H),
7.71(d, 2H), pyrimidine 7.85(m, 3H), 8.45(s, 1H) 153.sup.1
5-Chloro-4-[1-(2-methoxyethyl)- 2.44(s, 3H), 2.87(q, 2H), 3.03(s,
481 Ex 2-methylimidazol-5-yl]-2-{4-[N- 3H), 3.15(s, 3H), 3.29(m,
2H), 3.38(m, 2H), 61 (2-methoxyethyl)sulphamoyl] 4.60(m, 2H),
7.50(br t, anilino}pyrimidine 1H), 7.64(s, 1H), 7.72(d, 2H),
7.83(d, 2H), 8.63(s, 1H), 10.10(s, 1H) .sup.1Purified by column
chromatography eluting with DCM/MeOH (98:2 increasing in polarity
to 96:4).
Example 154
4-(1,2-Dimethylimidazol-5-yl)-2-{4-[N-(2,3-dihydroxypropyl)sulphamoyl]anil-
ino}pyrimidine
[0337] Water (0.5 ml) followed by TFA (2.5 ml) was added to a
solution of
4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2,2-dimethyl-1,3-dioxalon-4-ylmeth-
yl)sulphamoyl]anilino}pyrimidine (Example 38, 119 mg, 0.26 mmol) in
DCM (2 ml) and the mixture stirred at ambient temperature for 1
hour. The solvent was evaporated and 1M ethereal hydrogen chloride
(5 ml) and ether (20 ml) added to the residue. The resulting
precipitate was collected by filtration and dried under vacuum. The
solid was suspended in MeOH (2 ml) and 1M aqueous lithium hydroxide
solution (2 ml) was added and the mixture stirred for 1 hour at
ambient temperature. The reaction mixture was poured onto an
Isolute SCX-2 column, washed with MeOH (10.times.15 ml) and the
product eluted with 2% methanolic ammonia (5.times.15 ml). The
solvent was removed by evaporation to give the title compound (66
mg, 61%) as a white solid. NMR 2.38 (s, 3H), 2.60 (m, 1H), 2.83 (m,
1H), 3.25 (m, 2H), 3.43 (m, 1H), 3.95 (s, 3H), 4.48 (t, 1H), 4.70
(d, 1H), 7.20 (m, 2H), 7.62 (s, 1H), 7.69 (d, 2H), 7.90 (d, 2H),
8.41 (d, 1H), 9.90 (s, 1H); m/z 419.
Example 155
5-Chloro-4-(1,2-dimethylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine
[0338] A mixture of
5-chloro-4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(t-butyl)sulphamoyl]anilin-
o}pyrimidine (Example 60; 116 mg, 0.267 mmol), trifluoroacetic acid
(2.7 ml), water (0.3 ml) and anisole (145 .mu.l, 1.34 mmol) was
stirred at ambient temperature for 72 hours. The mixture was then
concentrated by evaporation and the residue treated with water and
ether. The precipitated solid was collected by filtration, washed
with water and ether, and dried to give the title compound (87 mg,
86%) as a white solid. NMR: 2.4 (s, 3H), 3.78 (s, 3H), 7.15 (s,
2H), 7.65 (s, 1H), 7.73 (d, 2H), 7.83 (d, 2H), 8.6 (s, 1H), 10.11
(s, 1H); m/z 378 (M-H).sup.-.
Example 156
[0339] The following compounds were synthesised in an analogous
method to Example 155. TABLE-US-00013 Ex Compound NMR m/z SM 156
5-Chloro-4-(1,2- 2.38(d, 3H), 391 Ex dimethylimidazol- 2.43(s, 3H),
(M-H).sup.- 71 5-yl)-2-[4-(N- 3.78(s, 3H), methylsulphamoyl)
7.2(1H, q), anilino] 7.67(m, 3H), pyrimidine 7.87(d, 2H), 8.63(s,
1H), 10.17(s, 1H)
Example 157
5-Bromo-4-(1-methylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine
[0340] Bromine (75.5 mg, 0.47 mmol) was added to a solution of
4(1-methylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine (Example
15; 0.14 g, 0.42 mmol) and sodium acetate (41.7mg, 0.5 mmol) in
acetic acid (4 ml) and the mixture stirred for 1 hour. The
volatiles were evaporated and the residue partitioned between EtOAc
and saturated aqueous potassium hydrogen carbonate solution. The
organic phase was separated and dried. The residue was pre-absorbed
on to silica gel and purified by column chromatography on silica
gel eluting with DCM/2% methanolic ammonia (9:1) to give the title
compound (91 mg, 52%). NMR 10.14 (s, 1H), 8.75 (s, 1H), 7.90-7.69
(m, 4H), 7.17 (s, 2H), 3.84 (s, 3H); m/z 409.
Example 158
2-(3-Chloroanilino)-4-[1-(2-acetamidoethyl)imidazol-5-yl]pyrimidine
[0341] Acetic anhydride (0.58 .mu.l, 1.0 mmol) was added to
solution of
2-(3-chloroanilino)-4-[1-(2-aminoethyl)imidazol-5-yl]pyrimidine
(Example 13; 0.30 g, 0.63 mmol) in pyridine (2 ml) at 0.degree. C.
The mixture was allowed to warm to ambient temperature and stirred
for 2 hours. 7M Methanolic ammonia (0.5 ml) was added and the
mixture diluted with EtOAc (10 ml). The precipitate was removed by
filtration and the filtrate pre-absorbed on to silica gel and
purified by column chromatography on silica gel eluting with DCMI
2% methanolic ammonia (11:1) to give the title compound (88 mg,
39%) as a white solid. NMR 9.68 (s, 1H), 8.43 (d, 1H), 8.03-7.96
(m, 2H), 7.81 (s, 1H), 7.79 (s, 1H), 7.60 (dd, 1H), 7.33 (t, 1H),
7.12 (d, 1H), 6.98 (dd, 1H), 4.56-4.46 (m, 2H), 3.44-3.37 (m, 2H),
1.80 (s, 3H); m/z 357.
Examples 159
[0342] The following compound was synthesised in an analogous
method to Example 158 using the appropriate sulphonyl chloride in
place of acetic anhydride. TABLE-US-00014 Ex Compound NMR m/z SM
159 2-(3- 9.41(s, 1H), 8.43(d, 1H), 7.93(m, 393, Ex Chloroanilino)-
1H), 7.83(s, 2H), 7.57(dd, 1H), 395 13 4-[1-(2-mesyl- 7.33(t, 1H),
7.24(d, 1H), aminoethyl) 7.22-7.17(m, 1H), imidazol-5- 7.00(dd,
1H), 4.64-4.57(m, 2H), yl]pyrimidine 3.29-3.22(m, 2H), 2.78(s,
3H)
Example 160
4-(1,2-Dimethylimidazol-5-yl)-2-[4-(N-methylsulphamoyl)anilino]pyrimidine
[0343] N-Methyl-4-aminobenzenesulphonamide (Method 110; 250 mg, 1.3
mmol) was dissolved in MeOH (3 ml) and 1M HCl in ether (1.3 ml, 1.3
mmol) added. Cyanamide (68 mg, 1.6 mmol) was added along with DMA
(0.5 ml). The mixture was heated to 100.degree. C. for 30 min. To
this was added
5-(3-dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole (Method
15; 230 mg, 1.2 mmol) and sodium methoxide (150 mg, 2.6 mmol) and
heated to 180.degree. C. for 1 hr. The reaction mixture was poured
into sat. sodium hydrogen carbonate solution and the resultant
solid collected. The solid was triturated with hot DMF and
filtered. The filtrate was evaporated in vacuo and purified by
flash chromatography on silica gel eluting with DCM/2% methanolic
ammonia (100:0 increasing in polarity to 85:15) to yield a white
solid which was digested with acetonitrile to yield the title
compound as a solid (84 mg, 20%). NMR: 2.38 (d, 6H), 3.95 (s, 3H),
7.19 (d, 2H), 7.63 (s, 1H), 7.68 (d, 2H), 7.93 (d, 2H), 8.43 (d,
1H), 9.91 (s, 1H); m/z 359.
Examples 161-164
[0344] The following compounds were synthesised in an analogous
method to Example 160. TABLE-US-00015 Ex Compound NMR m/z SM 161
4-(1,2-Dimethylimidazol-5-yl)- 2.36(s, 3H), 2.41(d, 3H), 3.88(s,
403 Meth 2-[2-methoxy-4-(N- 3H), 3.90(s, 3H), 7.20(d, 1H), 15
methylsulphamoyl)-5- 7.30(br q, 1H), 7.37(s, 1H), 7.64(s, 1H),
methylanilino]pyrimidine 8.16(s, 1H), 8.27(s, 1H), 8.40(d, 1H) 162
4-(1,2-Dimethylimidazol-5-yl)- 1.91(s, 3H), 2.02(s, 3H), 2.37(s,
440 Meth 2-{4-[N-(4,5-dimethyloxazol-2- 3H), 3.94(s, 3H), 7.16(d,
1H), 15 yl)sulphamoyl]anilino} 7.62(s, 1H), 7.75(d, 2H), 7.83(d,
pyrimidine 2H), 8.41(d, 1H), 9.82(s, 1H) 163
4-(1,2-Dimethylimidazol-5-yl)- 2.36(s, 3H), 2.76(d, 3H), 3.95(s,
323 Meth 2-[4-(N-methylcarbamoyl) 3H), 7.14(d, 1H), 7.61(s, 1H), 15
anilino]pyrimidine 7.77(s, 4H), 8.20(brq, 1H), 8.40(d, 1H), 9.71(s,
1H) 164 4-(1,2-Dimethylimidazol-5-yl)- 2.00(s, 3H), 2.35(s, 3H),
3.90(s, 323 Meth 2-(4-acetamidoanilino) 3H), 7.02(d, 1H), 7.47(d,
2H), 15 pyrimidine 7.57(m, 3H), 8.31(d, 1H), 9.33(s, 1H), 9.77(s,
1H)
Example 165
4-(1,2-Dimethylimidazol-5-yl)-2-(4-aminoanilino)pyrimidine
[0345] Sodium hydroxide (1.2 g, 3.0 mmole) was added to a solution
of 4-(1,2-dimethyl-imidazol-5-yl)-2-(4acetamidoanilino)pyrimidine
(Example 164; 1.25 g, 3.88 mmole) in isopropanol (12 mL) and water
(0.5 mL) and the mixture heated under reflux for 90 minutes. The
mixture was allowed to cool and was partitioned between saturated
aqueous sodium hydrogen carbonate solution and EtOAc. The organic
layer was separated and the volatiles evaporated. The residue was
purified by column chromatography on silica gel eluting with DCM/7M
methanolic ammonia (96:4) to give the title compound (0.75 g, 69%)
as a brown solid NMR: 2.33 (s, 3H), 3.85 (s, 3H), 4.75 (brs, 2H),
6.51 (d, 2H), 6.92 (d, 1H), 7.22 (d, 2H), 7.51 (s, 1H), 8.22 (d,
1H), 8.90 (s, 1H); m/z 281.
Preparation of Starting Materials:-
[0346] The starting materials for the examples above are either
commercially available or are readily prepared by standard methods
from known materials. For example, the following reactions are an
illustration, but not a limitation, of some of the starting
materials used in the above reactions.
Method 1
5-(3-Dimethylaminoprop-2-enoyl)-1,2-dimethylimidazole
[0347] 5-(3-Dimethylaminoprop-2-enoyl)-2-methylimidazole (350 mg,
1.95 mmol) was suspended in DMFDMA (14 ml) and the mixture stirred
and heated at 100.degree. C. for 56 hours. The excess DMFDMA was
removed by evaporation and the residue purified by chromatography
eluting with DCM/MeOH (94:6) to give the title compound 111 mg,
(29%) as a solid. NMR (CDCl.sub.3): 2.40 (s, 3H), 3.00 (s, 6H),
3.88 (s, 3H), 5.50 (d, 1H), 7.47 (s, 1H), 7.65 (d, 1H); m/z:
194.
Method 2
2-(3-Chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine
[0348] 4-3-Dimethylaminoprop-2-en-1-oyl)-1-triphenylmethylimidazole
(Method 3) was treated with 3-chlorophenylguanidine under
conditions analogous to those described in Example 7 to give the
title compound; m/z: 514.
Method 3
4-(3-Dimethylaminoprop-2-en-1-oyl)-1-triphenylmethylimidazole
[0349] A suspension of 4-acetyl-1-triphenylmethylimidazole (Method
6; 11.9 g, 33.9 mmol) in DMFDMA (30 ml) was heated at reflux for 24
hours. The solution was allowed to cool and the precipitate
collected by filtration to give the title compound 10.7 g, (78%).
M/z: 408.
Methods 4-5
[0350] The following compounds were prepared by the procedure of
Method 3. TABLE-US-00016 Meth Compound M/z 4
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-methylimidazole 180 5
1-Benzyl-5-(3-dimethylaminoprop-2-en-1-oyl)-2- 270
methylimidazole
Method 6 4-Acetyl-1-triphenylmethylimidazole
[0351] A solution of 4-(1-hydroxyethyl)-1-triphenylmethylimidazole
(Method 10; 30.5 g, 86 mmol) in dioxane (500 ml) was heated to
100.degree. C. Manganese dioxide (63.6 g, 0.73 mol) was added in
portions so that a gentle reflux was maintained. The mixture was
allowed to cool slightly and the inorganic solids were removed by
filtration. The volatiles were removed from the filtrate by
evaporation to give the title compound 30.3 g, (99%) as a solid
product. NMR: 2.55 (s, 3H), 7.04-7.40 (m, 15H), 7.43 (s, 1H), 7.57
(s, 1H).
Methods 7-8
[0352] The following compounds were prepared by the procedure of
Method 6. TABLE-US-00017 Meth Compound DATA 7
5-Acetyl-1-methylimidazole M/z: 125 8 5-Acetyl-1-benzyl-2- NMR:
2.38(s, 3H), 2.44(s, 3H), methylimidazole 5.60(s, 2H), 6.99(d, 2H),
7.22-7.31(m, 3H), 7.77(s, 1H)
Method 9 5-(1-Hydroxyethyl)-1-methylimidazole
[0353] Methyl magnesium bromide (100 ml of a 3M solution in diethyl
ether, 0.30 mol) was added dropwise to a solution of
5-formyl-1-methylimidazole (14.5 g, 0.13 mol) in THF (750 ml)
cooled to -20.degree. C. such that the reaction temperature was
kept below 3.degree. C. The mixture was allowed to warm to ambient
temperature and water (150 ml) was carefully added. The aqueous
mixture was continuously extracted with EtOAc. The EtOAc extract
was dried, and the volatiles removed by evaporation to give the
title compound 14.4 g, (88%) as a solid product. NMR: 1.41 (d, 3H),
4.65-4.77 (m, 1H), 4.96-5.11 (m, 1H), 6.72 (s, 1H), 7.47 (s,
1H).
Methods 10-11
[0354] The following compounds were prepared by the procedure of
Method 9. TABLE-US-00018 Meth Compound DATA 10
4-(1-Hydroxyethyl)-1- NMR: 1.28(d, 3H), 4.58(m, 1H),
triphenylmethylimidazole 4.83(d, 1H), 6.65(s, 1H), 7.03-7.10(m,
6H), 7.23(d, 1H), 7.33-7.43(m, 9H) 11 1-Benzyl-5-(1-hydroxyethyl)-
M/z: 217 2-methylimidazole
Method 12 1-Benzyl-5-formyl-2-methylimidazole
[0355] Benzyl bromide (21.4 ml, 0.18 mol) was added carefully to a
mixture of 4-formyl-2-methylimidazole (18.1 g, 0.16 mol) and
potassium carbonate (45.0 g, 0.33 mol) in DMF (100 ml) at 0.degree.
C. and the reaction mixture allowed to warm to ambient temperature.
The mixture was then partitioned between EtOAc and saturated
aqueous sodium hydrogen carbonate solution, the organic phase
separated and dried. The volatiles were removed by evaporation to
give the title compound as crude mixture of regioisomers 32.0 g,
(99%). M/z: 201.
Method 13
4-{N-[3-(Pyrrolidin-2-on-1-yl)propyl]sulphamoyl}aniline.
[0356] Sulphanilyl fluoride (6.5 g, 37.1 mmol),
3-(pyrrolidin-2-on-1-yl)propylamine (5.79 g, 40.8 mmol) and
triethylamine (5.69 ml, 40.8 mmol) in n-butanol (15 ml) was heated
at reflux for 10 hours. The mixture was allowed to cool, silica was
added and the volatiles were evaporated. The residue was purified
by chromatography eluting with DCM/MeOH (100:0) increasing in
polarity to (90:10) to give the title compound m/z: 297.
Method 14
[0357] The following compound was prepared using the procedure of
Method 13. TABLE-US-00019 Meth Compound m/z 14
4-[N-(2-Tetrahydrofuranylmethyl)sulphamoyl]aniline 257
Method 15
5-(3-Dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole
[0358] 2-Methyl-4-acetylimidazole (129 g, 1.04 mol) was dissolved
in a mixture of DMF (900 ml) and DMF.DMA (1.51) and the mixture
heated under reflux, under an atmosphere of nitrogen, for 18 hours.
The reaction mixture was allowed to cool to ambient temperature the
product crystallised. The solid product was collected by
filtration, washed with DMF.DMA and then ether and dried under
vacuum at 40.degree. C. to give the title compound (115 g, 57%) as
a pale brown crystalline solid. NMR 2.13 (s, 3H), 2.95 (s, 6H),
3.78 (s, 3H), 5.56 (d, 1H), 7.50 (d, 1H), 7.53 (s, 1H); m/z
194.
Methods 16-25
[0359] The following compounds were synthesised in an analogous
method to Method 15. TABLE-US-00020 Ex Compound NMR m/z SM 16.sup.1
5-(3-Dimethylaminoprop-2-en- 1.17(t, 3H), 2.16(s, 3H), 2.95(s, 208
Meth 1-oyl)-1-ethyl-2- 6H), 4.27(q, 2H), 5.57(d, 1H), 35
methylimidazole 7.50(d, 1H), 7.53(s, 1H) 17.sup.2
5-(3-Dimethylaminoprop-2-en- 2.29(s, 3H), 2.95(brs, 6H), 3.15(s,
238 Meth 1-oyl)-1-(2-methoxyethyl)-2- 3H), 3.52(t, 2H), 4.41(t,
2H), 5.58(d, 1H), 36 methylimidazole 7.51(d, 1H), 7.58(s, 1H)
18.sup.3 1-(1-Butene-4-yl)-5-(3- (CDCl.sub.3) 2.41(s, 3H), 2.49(q,
2H), 234 Meth dimethylaminoprop-2-en-1-oyl)- 2.99(brs, 6H), 4.39(t,
2H), 5.02(s, 37 2-methylimidazole 1H), 5.07(d, 1H), 5.52(d, 1H),
5.79(m, 1H), 7.49(s, 1H), 7.66(d, 1H) 19.sup.7
5-(3-Dimethylaminoprop-2-en- 1.43(d, 6H), 2.40(s, 3H), 2.95(brs,
6H), 222 Meth 1-oyl)-1-(isopropyl)-2- 3.31(s, 3H), 5.22(sept, 101
methylimidazole 1H), 5.54(d, 1H), 7.48(s, 1H), 7.52(d, 1H) 20.sup.1
5-(3-Dimethylaminoprop-2-en- 1.20(t, 3H), 2.62(q, 2H), 2.95(s, 208
Meth 1-oyl)-1-methyl-2- 6H), 3.78(s, 3H), 5.56(d, 1H), 96
ethylimidazole 7.51(m, 2H) 21.sup.1 5-(3-Dimethylaminoprop-2-en-
2.34(s, 3H), 2.85(s, 3H), 3.10(s, 262 Meth
1-oyl)-1-(2,2,2-trifluoroethyl)-2- 3H), 5.46(q, 2H), 5.57(d, 1H),
109 methylimidazole 7.56(d, 1H), 7.62(s, 1H) 22.sup.5
5-(3-Dimethylaminoprop-2-en- 1.20(d, 6H), 3.05(m, 1H), 3.80(s, 222
Meth 1-oyl)-1-methyl-2- 3H), 5.53(d, 1H), 7.50(m, 2H) 98
isopropylimidazole 23.sup.6 5-(3-Dimethylaminoprop-2-en- 2.95(s,
3H), 3.15(s, 3H), 4.11(s, 248 Meth 1-oyl)-1-methyl-2- 3H), 5.49(d,
1H), 7.53(s, 1H), 92 trifluoromethylimidazole 7.73(d, 1H) 24.sup.4
5-(3-dimethylaminoprop-2-en-1- 2.21(s, 3H), 2.22(s, 3H), 2.90(s,
207 Meth oyl)-1,2,4-trimethylimidazole 3H), 3.05(s, 3H), 3.58(s,
3H), 5.28(d, 1H), 107 7.51(d, 1H) 25.sup.5
5-(3-Dimethylaminoprop-2-en- 2.87(s, 3H), 3.05(s, 3H), 3.20(s, 224
Meth 1-oyl)-1-methyl-2- 3H), 3.83(s, 3H), 4.45(s, 2H), 5.58(d, 1H),
93 methoxymethyllimidazole 7.55(d, 1H), 7.59(s, 1H) .sup.1Only
DMF.DMA used as solvent. .sup.2Reaction was worked up by
evaporation. The resulting gum suspended in ether (60 ml), the
insolubles were removed by filtration and the filtrate was
evaporated to give the product as a solid. .sup.3Reaction heated 96
hours. Reaction evaporated and residue purified by flash
chromatography on silica gel eluting with DCM/MeOH (100:0
increasing in polarity to 95:5). .sup.4Reaction was heated under
reflux in neat DMF.DMA for 72 hrs. Reaction mixture was evaporated
and the residue triturated with ether and the solid product
collected filtration. .sup.5Purified by flash chromatography on
silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing
in polarity to 95:5). .sup.6Purified by flash chromatography on
silica gel eluting with EtOAc/MeOH (100:0 increasing in polarity to
70:30). .sup.7Purified by flash chromatography on silica gel
eluting with DCM/MeOH (98:2 increasing in polarity to 92.5:7.5)
Method 26 2-Amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine
[0360] 5-(3-Dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole
(Method 15; 2.8 g, 14.5 mmol) and guanidine hydrochloride (3.5 g,
36.3 mmol) were suspended in 1-butanol (30 ml). Sodium methoxide
(3.1 g, 58 mmol) was added in one portion and the mixture heated
under reflux, under an atmosphere of nitrogen, for 18 hours. The
reaction mixture was allowed to cool to ambient temperature and was
pre-absorbed on to silica gel and purified by column chromatography
on silica gel eluting with DCM/2% methanolic ammonia (100:0
increasing in polarity to 95:5) to give the title compound (2.3 g,
84%). NMR 2.16 (s, 3H), 3.93 (s, 3H), 6.52 (s, 2H), 6.80 (d, 1H),
7.47 (s, 1H), 8.17 (d, 1H); m/z 190.
Methods 27-32
[0361] The following compounds were synthesised in an analogous
method to Method 26. TABLE-US-00021 Ex Compound NMR m/z SM 27
2-Amino-4-(1-ethyl-2- 1.24(t, 3H), 2.40(s, 3H), 4.40(q, 204 Meth
methylimidazol-5-yl)pyrimidine 2H), 4.88(s, 2H), 6.78(d, 1H), 16
7.41(s, 1H), 8.14(d, 1H) 28.sup.1 2-Amino-4-[1-(2-methoxyethyl)-
2.35(s, 3H), 3.14(s, 3H), 3.58(t, 234 Meth 2-methylimidazol-5- 2H),
4.64(t, 2H), 6.49(brs, 2H), 17 yl]pyrimidine 6.83(d, 1H), 7.51(s,
1H), 8.11(d, 1H) 29.sup.2 2-Amino-4-[1-(1-buten-4-yl)-2- 2.50(s,
5H), 4.54(t, 2H), 4.94(d, 230 Meth methylimidazol-5-yl]pyrimidine
1H), 4.99(d, 1H), 5.80(m, 1H), 18 6.49(brs, 2H), 6.84(d, 1H),
7.51(s, 1H), 8.13(d, 1H) 30.sup.3 2-Amino-4-(1-methyl-2- 1.38(t,
3H), 2.76(d, 2H), 3.94(s, 204 Meth ethylimidazol-5-yl)pyrimidine
3H), 5.00(s, 2H), 6.83(d, 1H), 20 7.51(s, 1H), 8.12(d, 1H) 31.sup.3
2-Amino-4-(1-methyl-2- 1.40(d, 6H), 3.13(m, 1H), 3.98(s, 218 Meth
isopropylimidazol-5-yl) 3H), 5.00(s, 2H), 6.83(d, 1H), 22
pyrimidine 7.50(s, 1H), 8.22(d, 1H) 32.sup.4 2-Amino-4-(1-methyl-2-
4.16(s, 3H), 5.13(s, 2H), 6.87(d, 244 Meth
trifluoromethylimidazol-5-yl) 1H), 7.53(s, 1H), 8.35(d, 1H) 23
pyrimidine .sup.1Reaction refluxed for 2 hrs 40 mins. Reaction
mixture was evaporated, water added and the mixture was extracted
with EtOAc. The extract was washed with brine, dried and
evaporated. .sup.2Reaction evaporated under vacuum. Added water and
extracted into EtOAc. Extract washed with brine, dried and
evaporated. .sup.3Purified by column chromatography on silica gel
eluting with EtOAc/MeOH (100:0 increasing in polarity to 50:50).
.sup.4Purified by column chromatography on silica gel eluting with
EtOAc/MeOH (100:0 increasing in polarity to 70:30).
Method 33
1-(Triphenylmethyl)-2-methyl-4-(2-hydroxyethyl)imidazole
[0362] Triphenylmethyl chloride (24.5 g, 88 mmol) in DMF (100 ml)
was added dropwise over 1 hr to a solution of
2-methyl-4-(2-hydroxyethyl)imidazole (10 g, 80 mmol) and
triethylamine in DMF (100 ml). The reaction mixture was stirred at
ambient temperature for 18 hours and then the volatiles were
removed by evaporation. The resultant solid was triturated with
water (3.times.500 ml) and ether (200 ml), collected by filtration
and dried under vacuum at 60.degree. C. to give the title compound
(23.7 g, 80%) as a pale yellow solid. NMR 1.43 (d, 3H), 1.62 (s,
3H), 2.53 (s, 1H), 4.80 (q, 1H), 6.59 (s, 1H), 7.13 (m, 6H), 7.37
(m, 9H); m/z 369.
Method 34
1-(Triphenylmethyl)-2-methyl-4-acetylimidazole
[0363] 1-(Triphenylmethyl)-2-methyl-4-(2-hydroxyethyl)imidazole
(Method 33; 23.7 g, 64 mmol) was suspended in chloroform (180 ml)
under nitrogen. Activated manganese(IV)oxide (27.8 g, 320 mol) was
added in one portion and the mixture heated at reflux for 3 hours.
The reaction mixture was allowed to cool then filtered through a
pad of diatomaceous earth and the pad washed thoroughly with
chloroform. The filtrate was evaporated to give the title compound
(23.4 g, 100%) as a pale yellow powder. NMR 1.71 (s, 3H), 2.53 (s,
3H), 7.13 (m, 6H), 7.37 (m, 9H), 7.52 (s, 1H); m/z 367.
Method 35
1-Ethyl-2-methyl-5-acetylimidazole
[0364] Ethyl triflate (11 ml, 83.2 mmol) was added dropwise over 15
minutes to a solution of
1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 23.4 g,
64 mmol) in DCM (300 ml) and the mixture stirred for 5 hours at
ambient temperature. The solution was diluted with DCM (100 ml) and
extracted with 1M aqueous citric acid solution (5.times.75 ml). The
aqueous extracts were combined, basified with solid sodium hydrogen
carbonate and the extracted with DCM (5.times.75 ml). The organic
extracts were combined, dried and evaporated to give the title
compound (8.59 g, 88%) as a pale yellow oil. NMR 1.32 (t, 3H), 2.41
(s, 6H), 4.29 (q, 2H), 7.68 (s, 1H); m/z 153.
Method 36
1-(2-Methoxyethyl)-2-methyl-5-acetylimidazole
[0365] A solution of 2-methoxyethyl triflate (prepared on a 6 mmole
scale from 2-methoxyethanol and trifluoromethanesulphonic anhydride
by the method published in Synthesis 1982 85) in DCM (20 ml) was
added dropwise to a solution of
1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 1.5 g, 4
mmol) in DCM (5 ml) and the mixture was stirred for 40 hours at
ambient temperature. The volatiles were removed by evaporation to
give a solid (2.4 g) which was purified by flash chromatography on
silica gel eluting with DCM/MeOH (100:0 increasing in polarity to
95:5) to yield the title compound (660 mg, 88%) as a solid. NMR
(CDCl.sub.3) 1.31 (s, 3H), 1.49 (s, 3H), 2.02 (s, 3H), 2.43 (m,
2H), 3.31 (m, 2H), 6.87 (s, 1H); m/z 183.
Method 37
1-(1-Buten-4-yl)-2-methyl-5-acetylimidazole
[0366] The title compound was synthesised in an analogous method to
Method 36, using the triflate derived from cyclopropanemethanol.
The title compound was obtained as an oil after flash
chromatography on silica gel eluting with DCM/MeOH (100:0
increasing in polarity to 96:4). NMR (CDCl.sub.3) 2.43 (m, 8H),
4.32 (t, 2H), 5.02 (m, 1H), 5.08 (s, 1H), 5.74 (m, 1H), 7.69 (s,
1H); m/z 179.
Method 38
{N-[2-(Methoxymethoxyethyl)ethyl]carbomoyloxymethyl}phenyl
[0367] Chloromethyl methyl ether (5 ml, 65 mmol) added cautiously
to a solution of [N-(2-hydroxyethyl)carbamoyloxymethyl]phenyl (6.45
g, 33 mmol) and diisopropylethylamine (12 ml, 70 mmol) in DCM (50
ml) and the reaction was stirred at ambient temperature for 4
hours. The volatiles were removed by evaporation and the residue
dissolved in EtOAc (100 ml), washed 1M aqueous citric acid solution
(2.times.50 ml), saturated aqueous sodium hydrogen carbonate
solution (50 ml), and then brine (50 ml), dried and evaporated to
give the title compound (7.64 g, 97%) as a colourless oil. NMR 3.34
(s, 3H), 3.42 (q, 2H), 3.61 (t, 2H), 4.60 (s, 3H), 5.14 (m, 3H),
7.34 (m, 5H); m/z 262 (M+Na).sup.+.
Method 39
N-[2-(Methoxymethoxy)ethyl]-4-iodobenzenesulphonamide
[0368] A suspension of
{N-[2-(methoxymethoxy)ethyl)]carbamoyloxymethyl}phenyl (Method 38,
2.4 g, 10 mmol) and 10% palladium on carbon (300 mg) in THF (20 ml)
was stirred under an atmosphere of hydrogen at ambient temperature
for 18 hours. The catalyst was removed by filtration and the
filtrate was placed under nitrogen. Triethylamine (1 ml, 7.5 mmol)
and 4-iodophenylsulphonyl chloride (1.82 g, 6 mmol) were added and
the mixture was stirred at ambient temperature for 2 hours. The
reaction mixture was poured into a mixture of EtOAc (30 ml) and 1M
aqueous citric acid solution (30 ml). The phases were separated and
the aqueous phase washed with EtOAc (30 ml). The organic extracts
were combined, washed 1M aqueous citric acid solution (2.times.30
ml), brine (30 ml), dried and the volatiles removed by evaporation
to yield the title compound (2.18 g, 98%) as a waxy solid. NMR 3.15
(q, 2H), 3.31 (s, 3H), 3.59 (t, 2H), 4.53 (s, 2H), 4.96 (t, 1H),
7.58 (d, 2H), 7.90 (d, 2H); m/z 370 (M-H).sup.-.
Method 40
N-(2-Methoxyethyl)-4-iodobenzenesulphonamide
[0369] A solution of 4-iodophenylsulphonyl chloride (3.64 g, 12
mmol) in DCM (30 ml) was added dropwise to a solution of
2-methoxyethylamine (1.3 ml, 15 mmol) and triethylamine (2 ml, 15
mmol) in DCM (60 ml) cooled by an ice bath to 0.degree. C. The
mixture was then allowed to warm to ambient temperature and stirred
for 1 hour. The solvent was removed by evaporation and the
resulting oil dissolved EtOAc (100 ml) and washed with 1N aqueous
citric acid solution (2.times.100 ml), brine (100 ml) and dried.
The volatiles were removed by evaporation to give the title
compound (4.1 g, 100%) as a clear oil. NMR 3.12 (2H, q), 3.28 (3H,
s), 3.44 (2H, t), 4.90 (1H, t), 7.57 (2H, d), 7.81 (2H, d); m/z:
342.
Methods 41-53
[0370] The following compounds were synthesised in an analogous
method to Method 40. TABLE-US-00022 Ex Compound NMR m/z 41
N-(Cyclopropylmethyl)-4- 0.01(m, 2H), 0.32(m, 2H), 0.76(m, 1H), 336
iodobenzenesulphonamide 2.60(t, 2H), 7.47(d, 2H), 7.72(t, 3H),
7.91(d, 2H) 42 N-(2,2-Dimethyl-1,3- 1.20(s, 3H), 1.25(s, 3H),
2.91(m, 1H), 3.12(m, 1H), 396 dioxolan-4-ylmethyl)-4- 3.60(m, 1H),
3.92(m, 1H), 4.13(m, 1H), iodobenzenesulphonamde 4.71(t, 1H),
7.52(d, 2H), 7.80(d, 2H) 43.sup.1 N-(2-Benzyloxyethyl)-4- 3.12(q,
2H), 3.42(m, 2H), 4.35(s, 2H), 4.80(m, 1H), 418
iodobenzenesulphonamide 7.25(m, 5H), 7.48(d, 2H), 7.79(d, 2H) 44
N-(2,2-Dimethoxyethyl)-4- 3.00(t, 2H), 3.28(s, 6H), 4.24(t, 1H),
4.64(t, 370 iodobenzenesulphonamide 1H), 7.51(d, 2H), 7.80(d, 2H)
45 N-(Tetrahydrofur-2- 1.50(m, 1H), 1.80(m, 3H), 2.81(m, 1H), 368
ylmethyl)-4- 3.10(m, 1H), 3.65(m, 2H), 3.84(m, 1H),
iodobenzenesulphonamide 4.89(t, 1H), 7.49(d, 2H), 7.80(d, 2H) 46
N-(3-Methoxypropyl)-4- 1.68(m, 2H), 3.02(q, 2H), 3.21(s, 3H),
3.38(t, 2H), 356 iodobenzenesulphonamide 5.10(s, 1H), 7.51(d, 2H),
7.80(d, 2H) 47 N-(Cyclopropyl)-4- 0.60(4H, d), 2.27(1H, m),
4.85(1H, s), 322 iodobenzenesulphonamide 7.60(2H, d), 7.90(2H, d)
(M-H).sup.- 48 N-(4-Methylthiazol-2- 2.22(s, 3H), 4.26(d, 2H),
7.11(s, 1H), 7.53(d, 2H), 395 ylmethyl)-4- 7.94(d, 2H), 8.60(t, 1H)
iodobenzenesulphonamide 49 N-(3-Methylisoxazol-5- 2.11(s, 3H),
4.16(d, 2H), 6.02(s, 1H), 7.48(d, 2H), 377 ylmethyl)-4- 7.93(d,
2H), 8.43(t, 1H) (M-H).sup.- iodobenzenesulphonamide 50
N-(1,4-Dioxan-2-ylmethyl)- 2.82(m, 1H), 3.02(m, 1H), 3.60(m, 7H),
382 4-iodobenzene 4.83(t, 1H), 7.51(d, 2H), 7.83(d, 2H) (M-H).sup.-
sulphonamide 51.sup.2 N-Propyl-4- 0.9(t, 3H), 1.5(q, 2H), 2.93(q,
2H), 4.45(t, 324 iodobenzenesulphonamide 1H), 7.57(d, 2H), 7.87(d,
2H) (M-H).sup.- 52.sup.2 N-(t-Butyl)-4- 1.07(s, 9H), 7.55(m, 3H),
7.93(d, 2H) 338 iodobenzenesulphonamide (M-H).sup.- 53 N-Allyl-4-
3.20(t, 2H), 5.00(d, 1H), 5.10(d, 1H), 5.66(m, 1H), 322
iodobenzenesulphonamide 7.52(d, 2H), 7.85(t, 1H) 7.96(d, 2H)
.sup.1Starting material prepared according to JACS 1966; vol 88,
2302. .sup.2Triethylamine was replaced by excess of the reacting
amine.
Method 54 N-t-Butoxycarbonyl-4-iodobenzenesulphonamide
[0371] A solution of di-t-butyl dicarbonate (10 g, 46 mmol) in DCM
(80 ml) was added dropwise over 15 min to a stirred solution of
4-iodobenzenesulphonamide (11.3 g, 40 mmol),
4-dimethylaminopyridine (488 mg, 4 mmol) and triethylamine (6.2 ml,
44 mmol) in DCM (50 ml). The reaction was stirred at ambient
temperature for 2 hours and the solvent was then removed by
evaporation. The residue was dissolved in EtOAc (240 ml), washed 1M
aqueous citric acid solution (2.times.160 ml), brine (160 ml),
dried and the solvent removed by evaporation to yield an orange
solid. The crude product was recrystallized from EtOAc/isohexane,
collected by filtration, washed twice with isohexane and dried to
give the title compound (10.25 g, 67%) as off white crystals. NMR
1.40 (s, 9H), 7.71 (d, 2H), 7.90 (d, 2H); m/z 382 (M-H).sup.-.
Method 55
4(1,2-Dimethylimidazol-5-yl)-2-(4-{N-(t-butoxycarbonyl-N-[2-(2-methoxyet-
hoxy)ethyl]sulphamoyl}anilino)pyrimidine
[0372] 2-(2-Methoxyethoxy)ethanol (50 .mu.l, 0.4 mmol) followed by
diisopropyl azodicarboxylate (0.1 ml, 0.4 mmol) was added to a
stirred solution of
4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(t-butoxycarbonyl)sulphamoyl]anilin-
o}pyrimidine (Example 36; 90 mg, 0.2 mmol) and triphenylphosphine
(105 mg, 0.4 mmol) in anhydrous THF (4 ml) under nitrogen at
0.degree. C. The reaction was allowed to warm to ambient
temperature and stirred for 1 hour. The mixture was poured directly
on to an Isolute SCX-2 column, eluted first with MeOH (8.times.15
ml) and then the product was eluted with 2% methanolic ammonia
(6.times.15 ml). The solvent was evaporated and the residue
dissolved in EtOAc (25 ml), washed with saturated aqueous sodium
hydrogen carbonate solution (2.times.25 ml), dried and the solvent
evaporated to give the title compound (77 mg, 71%) as a yellow oil.
NMR 1.38 (s, 9H), 2.49 (s, 3H), 3.38 (s, 3H), 3.56 (m, 2), 3.68 (m,
2H), 3.76 (t, 2), 3.96 (s, 3H), 4.06 (t, 2H), 7.03 (d, 1H), 7.49
(s, 1H), 7.58 (s, 1H), 7.78 (d, 2H), 7.93 (d, 2H), 8.40 (d, 1H);
m/z 547.
Methods 56-57
[0373] The following compounds were synthesised in an analogous
method to Method 55. TABLE-US-00023 Ex Compound NMR m/z SM 56
4-(1,2-Dimethylimidazol-5-yl)- 1.38(s, 9H), 2.48(s, 3H), 3.37(s,
3H), 591 Ex 2-[4-(N-(t-butoxycarbonyl)-N- 3.56(m, 2H), 3.65(m, 8H),
3.79(t, 36 {2-[2-(2-methoxyethoxy) 2H), 3.96(s, 3H), 4.04(t, 2H),
7.01(d, ethoxy]ethyl}sulphamoyl) 1H), 7.41(s, 1H), 7.56(s, 1H),
anilino]pyrimidine 7.79(d, 2H), 7.92(d, 2H), 8.40(d, 1H) 57
4-(1,2-Dimethylimidazol-5-yl)- 1.38(s, 9H), 2.48(s, 3H), 3.37(s,
3H), 635 Ex 2-{4-[N-(t-butoxycarbonyl)-N- 3.56(m, 2H), 3.65(m,
12H), 3.79(t, 36 (2-{2-[2-(2-methoxyethoxy) 2H), 3.96(s, 3H),
4.04(t, 2H), 7.01(d, ethoxy]ethoxy}ethyl) 1H), 7.41(s, 1H), 7.56(s,
1H), sulphamoyl]anilino}pyrimidine 7.79(d, 2H), 7.92(d, 2H),
8.40(d, 1H)
Method 58 4-Iodobenzenesulphonyl fluoride
[0374] 18-Crown-6 (0.5 g) and potassium fluoride (11.6 g, 200 mmol)
were added to a solution of iodobenzenesulphonyl chloride (30.3 g,
100 mmol) in acetonitrile (100 ml) and the suspension was stirred
for 18 hours at ambient temperature. The insolubles were removed by
filtration and the solvent removed from the filtrate by
evaporation. The residue was dissolved in EtOAc (300 ml), washed
with water (2.times.150 ml), brine (100 ml), dried and the solvent
evaporated to give the title compound (27.54 g, 96%) as a white
solid. NMR 7.70 (d, 2H), 8.01 (d, 2H); m/z 286.
Method 59
4-(1,2-Dimethylimidazol-5-yl)-2-[4(fluorosulphonyl)anilino]pyrimidine
[0375] Caesium carbonate (2.3 g, 7.2 mmol) was added to a degassed
solution of 2-amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method
26; 756 mg, 4 mmol), 4-iodosulphonyl fluoride (Method 58; 1.50 g,
5.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (92 mg, 0.18
mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (124 mg, 0.18
mmol) in dioxane (36 ml) under nitrogen. The mixture was heated at
80.degree. C. for 18 hours and then allowed to cool to ambient
temperature. The mixture was poured into water (50 ml) and
extracted with DCM (2.times.50 ml). The organic extracts were
combined, washed with brine (50 ml), dried and the solvent
evaporated. The residue was pre-absorbed on to silica gel and
purified by column chromatography on silica gel eluting with DCM/2%
methanolic ammonia (100:0 increasing in polarity to 97:3) to give
the title compound (984 mg, 71%) as a pale yellow solid. NMR 2.38
(s, 3H), 3.96 (s, 3H), 7.28 (d, 1H), 7.65 (s, 1H), 8.00 (d, 2H),
8.13 (s, 2H), 8.47 (d, 1H), 10.32 (s, 1H); m/z 348.
Method 60
4-[1-(2-Methoxyethyl)-2-methylimidazol-5-yl]-2-N-(4-fluorosulphonylanili-
no)pyrimidine
[0376] The title compound was synthesised from Method 28 in an
analogous method to Method 59 except that the reaction was
evaporated before aqueous work-up and extraction was with EtOAc.
The crude product purified by column chromatography on silica gel
eluting with DCM/MeOH (98:2 increasing in polarity to 96:4). NMR:
(CDCl.sub.3) 2.52 (s, 3H), 3.27 (s, 3H), 3.61 (t, 2H), 4.68 (t,
2H), 7.11 (d, 1H), 7.52 (s, 1H), 7.61 (s, 1H), 7.89 (d, 2H), 7.96
(d, 2H), 8.41 (d, 1H); m/z 392.
Method 61
2-Amino-5-bromo-4-(1,2-dimethylimidazol-5-yl)pyrimidine
[0377] The title compounds was synthesised from Method 26 in an
analogous method to Example 145 except that the reaction was heated
at 60.degree. C. for 1.5 hrs, diluted with water and basified 2M
aqueous sodium hydroxide solution. The resultant solid was
collected by filtration and dried in vac oven at 60.degree. C. NMR:
2.38 (s, 3H), 3.72 (s, 3H), 6.84 (s, 2H), 7.55 (s, 1H), 8.38 (s,
1H); m/z 269.
Method 62
N-(2-Methoxyethyl)-N-methyl-4-iodobenzenesulphonamide
[0378] Sodium hydride (144 mg, 3.6 mmol) was added in portions to a
solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method
40, 1 g, 3 mmol) in THF (10 ml) and the mixture stirred at ambient
temperature for 15 minutes. Iodomethane (230 .mu.l, 3.6 mmol) was
added and the reaction stirred for 18 hours. Water (30 ml) was
added cautiously and the mixture extracted with ether (40 ml). The
combined organics were washed with brine (50 ml), dried and the
volatiles evaporated. The residue was purified by flash
chromatography on silica gel eluting with iso-hexane/EtOAc (100:0
increasing in polarity to 10:1) to give the title compound (730 mg,
69%) as a clear oil. NMR 2.78 (s, 3H), 3.16 (t, 2H), 3.22 (s, 3H),
3.45 (t, 3), 7.42 (d, 2H), 7.80 (d, 2H); m/z 356.
Methods 63-64
[0379] The following compounds were synthesised in an analogous
method to Method 62. TABLE-US-00024 Ex Compound NMR m/z SM 63
N-(3-Morpholinopropyl)-N- 1.77(m, 2H), 425 Meth
methyl-4-iodobenzene 2.41(m, 6H), 66 sulphonamide 2.75(s, 3H),
3.11(t, 2H), 3.69(m, 4H), 7.48(d, 2H), 7.87(d, 2H) 64
N-(t-Butyl)-N-methyl-4- (CDCl.sub.3): 1.35(s, 9H), n/a Meth
iodobenzenesulphonamide 2.96(s, 3H), 7.53(d, 2H), 52 7.83(d,
2H)
Method 65 4-Mesylbromobenzene
[0380] To a solution of 4-bromothioanisole (22.3 g, 11 mmol) in DCM
(250 ml) was added m-chloroperoxybenzoic acid (40 g, 23 mmol) in 10
g portions. The precipitate was removed by filtration and washed
with DCM. The filtrate was evaporated in vacuo and the resultant
solid recrystallized from EtOH (c.a. 180 ml) to yield the title
compound as colourless crystals 11.7 g (45%). Mp 103-106.degree.
C.
Method 66
N-(3-Morpholinopropyl)-4-iodobenzenesulphonamide
[0381] 4-Iodophenylsulphonyl chloride (3.03 g, 10 mmol) in DCM (30
ml) was added dropwise over 15 minutes to a solution of
4-(3-aminopropyl)morpholine (1.75 ml, 12 mmol) and triethylamine
(1.7 ml, 12 mmol) in DCM (50 ml) cooled in an ice bath. The mixture
was allowed to warm to ambient temperature and stirred for 15
minutes. Water (50 ml) was added and the phases separate. The
organic layer was washed with water (50 ml) and brine (50 ml),
dried (Chemelut column 1010) and evaporated to give the title
compound (4.10 g, 100%) as a beige solid. NMR 1.70 (m, 2H), 2.43
(m, 6H), 3.14 (t, 2H), 3.71 (m, 4H), 7.08 (s, 1H), 7.58 (d(,2H),
7.85 (d, 2H); m/z 411.
Method 67
1-[3-(N,N-Dimethylamino)propylthiol]-4-bromobenzene
[0382] 3-(Dimethylamino)propyl chloride hydrochloride (3.48 g, 22
mmol) was added in portions to a suspension of 4-bromothiophenol
(3.78 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in DMF
(40 ml) and the reaction mixture heated to 60.degree. C. for 15
minutes. The mixture was allowed to cool to ambient temperature and
poured into water (100 ml) and extracted with EtOAc (2.times.100
ml). The extracts were combined, washed with brine (3.times.100
ml), dried (Chemelut column 1010) and evaporated to give the title
compound (5.25 g, 96%) as a pale yellow oil. NMR 1.76 (m, 2H), 2.20
(s, 6H), 2.35 (t, 2H), 2.93 (t, 2H), 7.18 (d, 2H), 7.38 (d, 2H);
m/z 276.
Method 68
1-(3,3,3-Trifluoropropylthio)-4-bromobenzene
[0383] 3-Bromo-1,1,1-trifluoropropane (640 .mu.L, 6 mmol) was added
to a mixture of 4-bromothiophenol (945 mg, 5 mmol) and potassium
carbonate (760 mg, 5.5 mmol) in DMF (5 ml) and the reaction mixture
heated at 40.degree. C. for 1 hour. The mixture was allowed to cool
to ambient temperature and poured into water (50 ml) and extracted
with EtOAc (2.times.30 ml). The extracts were combined, washed with
brine (3.times.30 ml), dried (Chemelut column 1010) and evaporated
to give the title compound (1.36 g, 95%) as a pale yellow oil. NMR
2.56 (m, 2H), 3.13 (t, 2H), 7.31 (d, 2H), 7.51 (d, 2H); m/z 285
(M.sup.+).
Method 69
1-(1-Butylthio)-4-bromobenzene
[0384] The title compounds was synthesised in an analogous method
to Method 68. NMR 0.85 (t, 3H), 1.38 (m, 2H), 1.51 (m, 2H), 2.96
(t, 2H), 7.23 (d, 2H), 7.46 (d, 2H); m/z 244 (M.sup.+).
Method 70
1-[3-(N,N-Dimethylamino)propylsulphonyl]-4-bromobenzene
[0385] Oxone (14 g, 23 mmol) was added to a solution of
1-[3-(N,N-dimethylamino)propylthio]-4-bromobenzene (Method 67; 5.24
g, 19.1 mmol) in MeOH (150 ml) and water (30 ml) and the mixture
was stirred at ambient temperature for 90 minutes. The reaction
mixture was poured onto an Isolute SCX-2 column, washed MeOH
(6.times.40 ml) and the product eluted with 2% methanolic ammonia
(10.times.40 ml). The solvent was evaporated and residue purified
by flash chromatography on silica gel eluting with DCM/2%
methanolic ammonia (100:0 increasing in polarity to 94:6) to yield
the title compound (4.68 g, 80%) as a pale yellow oil. NMR 1.62 (m,
2H), 2.03 (s, 6H), 2.19 (t, 2H) 3.32 (m, 2H), 7.81 (m, 4H); m/z
306.
Method 71
1-(3,3,3-Trifluoropropylsulphonyl)-4-bromobenzene
[0386] Oxone (3.7 g, 6 mmol) was added to a solution of
1-(3,3,3-trifluoropropylthio)-4-bromobenzene (Method 68 1.36, 4.75
mmol) in MeOH (25 ml) and water (5 ml) and the mixture was stirred
at ambient temperature for 18 hours. The MeOH evaporated and water
(20 ml) added and the mixture extracted with DCM. The extracts were
dried (Chemelut column CE1005) and solvent removed by evaporation
to give the title compound (1.43 g, 95%) as a white solid. NMR 2.62
(m, 2H), 3.67 (m, 2H), 7.86 (s, 4H); m/z 316 (M.sup.+).
Method 72
1-(1-Butylsulphonyl)-4-bromobenzene
[0387] The title compound was synthesised from Method 69 in an
analogous method to Method 71. NMR: 0.80 (t, 3H), 1.31 (m, 2H),
1.47 (m, 2H), 3.29 (t, 2H), 7.78 (d, 2H), 7.86 (d, 2H); m/z 276
M.sup.+).
Method 73
3-Methoxy-1-propanol methanesulphonate
[0388] Methanesulphonyl chloride (1.75 ml, 22 mmol) was added to a
solution of 3-methoxy-1-propanol (1.81 g, 20 mmol) and
triethylamine (3.35 ml, 24 mmol) in DCM (40 ml) cooled in an ice
bath and the mixture stirred at ambient temperature for 18 hours.
DCM (25 ml) and water (50 ml) were added and the phases separated
and the aqueous layer was extracted with DCM (25 ml). The extracts
were combined, washed with water (50 ml) and brine (50 ml), dried
(Chemelut column CE1010) and evaporated to give the title compound
3.25 g (97%) as a pale yellow oil. NMR 2.00 (m, 2H), 3.01 (s, 3H),
3.35 (s, 3H), 3.49 (t, 2H), 4.38 (t, 2H).
Method 74
1-(3-Methoxypropylsulphonyl)-4-bromobenzene
[0389] Potassium carbonate (2.8 g, 20 mmol) was added to a solution
of 3-methoxypropan-1-yl methansulphonate (Method 73; 3.25 g, 19.3
mmol) and 4-bromothiophenol (3.48 g, 18.4 mmol) in DMF (30 ml) and
the mixture heated at 40.degree. C. for 4 hours. The mixture was
allowed to cool to ambient temperature, poured into water (100 ml)
and extracted with EtOAc (2.times.50 ml). The extracts were
combined, washed with saturated aqueous sodium hydrogen carbonate
solution (50 ml) and brine (2.times.50 ml), dried (Chemelut column
CE1010) and the volatiles removed by evaporation. The residue was
dissolved in MeOH (150 ml) and water (30 ml) and oxone (13.4 g,
21.6 mmol) was added in portions. The mixture was stirred at
ambient temperature for 18 hours. The MeOH was evaporated, water
(50 ml) added and the solution extracted with DCM (3.times.50 ml).
The extracts were combined, washed with brine (50 ml), dried
(Chemelut column CE1010), and evaporated. The residue was purified
by flash chromatography on silica gel eluting with iso-hexane:EtOAc
(100:0 increasing in polarity to 90:10) to give the title compound
(3.32 g, 62%) as a colourless oil. NMR 1.95 (m, 2H), 3.19 (m, 2H),
3.26 (s, 3H), 3.41 (t, 2H), 7.70 (d, 2H), 7.78 (d, 2H).
Method 75
3-Hydroxyisoxazole
[0390] Hydroxylamine hydrochloride (35 g, 0.5 mol) was added to a
solution of sodium hydroxide (58 g, 1.45 mol) in water (580 ml).
MeOH (600 ml) followed by ethyl propiolate (38 ml, 0.37 mol) in
portions was then added and the resulting solution stirred at
ambient temperature for 6 days. The mixture was acidified to pH2
with concentrated hydrochloric acid and then saturated with sodium
chloride. The solution was extracted with DCM (8.times.500 ml), the
extracts combined, dried and the solvent evaporated. The solid
residue was washed with hot iso-hexane (3.times.300 ml) and the
final suspension was allowed to cool and the resulting solid was
collected by filtration, dried under vacuum to give the title
compound (11.16 g, 35%) as a white solid crystallised. NMR 6.04 (s,
1H), 8.43 (s, 1H), 11.16 (s, 1H). m/z 85 (M.sup.+).
Method 76
3-Oxo-2,3-dihydroisothiazole
[0391] Glycinamide.HCl (1 mol) was suspended in DMF (500 ml) and
SO.sub.2Cl.sub.2 (300 ml) was added dropwise over 1.5 hours with
cooling keeping the reaction temperature between 5-10.degree. C.
The reaction was stirred at 10-15.degree. C. for 6 hours when water
(500 ml) was added cautiously. The solid was removed by filtration
and the filtrate extracted with ether (21). The Ethereal solution
was washed brine (200 ml) and evaporated in vacuo to yield a pale
yellow solid (132 g)--A. The aqueous layer was extracted with DCM
(2.times.600 ml). The DCM portions were combined and washed with
ether and water. The organic layer was washed brine and evaporated
in vacuo to yield a cream solid (18 g)--B. A & B were combined,
dissolved in ether, dried and charcoal was added. The solution was
filtered and the filtrate evaporated in vacuo to yield a pale
yellow solid (104.3 g). This solid was triturated with isohexane to
yield the title compound (91.3 g, 90%). Mpt: 102-5.degree. C.
Method 77
Ethynylcarbamoyl
[0392] To liquid ammonia (300 ml) was added methyl propiolate (52.4
g, 0.62 mol) over 2 hours keeping the temperature at -70.degree. C.
The ammonia was left to evaporate and the reaction mixture
evaporated in vacuo to yield the title compound (43 g) which was
used without any further purification. Mpt: 54-55.degree. C.
Method 78
3-Oxo-2,3-dihydro-1,2,5-thiadiazole
[0393] To a stirred solution of ethynylcarbamoyl (Method 77; 43 g,
0.62 mol) in water (310 ml) cooled in ice bath was added ammonium
thiosulphate (92.35 g, 0.62 mol) in one portion. The reaction was
allowed to warm to room temperature over 5 hours. To the reaction
mixture was added a solution of iodine (79.2 g, 0.3 mol) in MeOH
(11) rapidly over 10 minutes to yield a dark solution. Ammonium
thiosulphate was added until a yellow solution was obtained. The
solvent was evaporated to approximately 400 ml and extracted ether
(3.times.300 ml). The ethereal solution was washed brine (100 ml),
passed through phase separation paper and evaporated in vacuo to
yield the title compound as a pale orange solid (32.8 g, 52%). Mpt:
70-71.degree. C.
Method 79
3-[2-(t-Butoxycarbonylamino)ethoxy]isoxazole
[0394] Diisopropyl azodicarboxylate (1.1 ml, 5.5 mmol) was added
dropwise to a solution of 2-(t-butoxycarbonylamino)ethanol (850
.mu.l, 5.5 mmol), 3-hydroxyisoxazole (Method 75; 425 mg, 5 mmol)
and triphenylphosphine (1.44 g, 5.5 mmol) in THF (20 ml) and the
mixture was stirred at ambient temperature for 18 hours. The
solvent was evaporated and the residue purified by flash
chromatography on silica gel eluting with iso-hexane: EtOAc (100:0
increasing in polarity to 4:1) to give the title compound (506 mg,
44%) as a white solid. NMR (1.43 (s, 9H), 3.56 (m, 2H), 4.32 (m,
2H), 4.90 (s, 1H), 5.98 (s, 1H), 8.16 (s, 1H); m/z 229.
Methods 80-84
[0395] The following compounds were synthesised in an analogous
method to Method 79 using the appropriate amine and heterocycle as
starting materials. TABLE-US-00025 Ex Compound NMR m/z SM 80
3-[2-(t-Butoxycarbonylamino) 1.38(s, 9H), 3.30(m, 2H), 4.24(t, 2H),
245 Meth ethoxy]isothiazole 6.71(d, 1H), 6.93(m, 1H), 8.81(4, 1H)
76 81 3-[2-(t-Butoxycarbonylamino) 1.38(s, 9H), 3.31(m, 2H),
4.16(t, 2H), 246 Meth ethoxy]-1,2,5-thiadiazole 6.96(m, 1H),
8.35(s, 1H) 78 82 3-[3-(t-Butoxycarbonylamino) 1.36(s, 9H), 1.80(m,
2H), 3.04(q, 2H), 243 Meth propoxy]isoxazole 4.17(t, 2H), 6.24(s,
1H), 6.83(m, 1H), 75 8.61(s, 1H) 83 3-[3-(t-Butoxycarbonylamino)
1.36(s, 9H), 1.80(m, 2H), 3.04(q, 2H), 259 Meth propoxy]isothiazole
4.17(t, 2H), 6.71(d, 1H), 6.80(m, 1H), 76 8.82(d, 1H) 84
3-[3-(t-Butoxycarbonylamino) 1.36(s, 9H), 1.80(m, 2H), 3.04(q, 2H),
260 Meth propoxy]-1,2,5-thiadiazole 4.17(t, 2H), 6.80(m, 1H),
8.36(s, 1H) 78
Method 85 3-(2-Aminoethoxy)isoxazole hydrochloride
[0396] 4M Hydrogen chloride in dioxane (10 ml) was added to a
solution of 3-[2-(t-butoxycarbonylamino)ethoxy]isoxazole (Method
79; 500 mg, 2.2 mmol) in dioxane (10 ml) and the mixture was
stirred at ambient temperature for 3 days. The resulting solid was
collected by filtration, washed with ether and dried to give the
title compound (298 mg, 83%) as a white solid NMR 3.20 (m, 2H),
4.39 (t, 2H), 6.13 (s, 1H), 8.30 (s, 3H), 8.69 (s, 1H); m/z
129.
Methods 86-90
[0397] The following compounds were synthesised in an analogous
method to Method 85. TABLE-US-00026 Ex Compound NMR m/z SM 86
3-(2-Aminoethoxy) 3.19(m, 2H), 4.46(t, 2H), 6.76(d, 1H), 145 Meth
isothiazole hydrochloride 7.28(s, 1H), 8.40(s, 3H), 8.87(d, 1H) 80
87 3-(2-Aminoethoxy)-1,2,5- 3.20(m, 2H), 4.58(t, 2H), 8.36(m, 4H)
146 Meth thiadiazole hydrochloride 81 88 3-(3-Aminopropoxy) 2.02(m,
2H), 2.83(m, 2H), 4.24(t, 2H), 143 Meth isoxazole hydrochloride
6.29(s, 1H), 8.20(s, 3H), 8.61(s, 1H) 82 89 3-(3-Aminopropoxy)
2.02(m, 2H), 2.83(m, 2H), 4.36(t, 2H), 159 Meth isothiazole
hydrochloride 6.78(d, 1H), 8.10(s, 3H), 8.81(d, 1H) 83 90
3-(3-Aminopropoxy)-1,2,5- 2.02(m, 2H), 2.83(m, 2H), 4.43(t, 2H),
160 Meth thiadiazole hydrochloride 8.10(s, 3H), 8.39(s, 1H) 84
Methods 91-94
[0398] The following compounds were synthesised by the procedure as
described in JOC 1987, 2714-2716. TABLE-US-00027 Method Compound 91
5-Methyl-4-(methylamino)isoxazole hydrochloride 92
5-Acetyl-2-(trifluoromethyl)imidazole 93
5-Acetyl-2-(methoxymethyl)imidazole 94
N-(5-Methyl-4-isoxazolyl)-2,2,2-trifluoroacetamide
Methods 95-109
[0399] The following compounds were prepared using procedures
analogous to those described in JOC 1987, 2714-2726. TABLE-US-00028
Ex Compound NMR m/z SM 95 5-Methyl-4-(N-methyl-N- 1.09(t, 3H),
2.08(q, 169 Meth 91 propionylamino)isoxazole 2H), 2.38(s, 3H),
3.16(s, 3H), 8.16(s, 1H) 96 1-Methyl-2-ethyl-5- 1.36(t, 3H),
2.41(s, 153 Meth 95 acetylimidazole 3H), 2.72(q, 2H), 3.82(s, 3H),
7.72(s, 1H) 97 5-Methyl-4-(N-methyl-N- 1.03(d, 6H), 2.36(s, 183
Meth 91 isobutyrylamino)isoxazole 3H), 2.48(m, 1H), 3.16(s, 3H),
8.20(s, 1H) 98 1-Methyl-2-isopropyl-5- 1.36(d, 6H), 2.42(s, 167
Meth 97 acetylimidazole 3H), 3.10(m, 1H), 3.84(s, 3H), 7.75(s, 1H)
99 4-(Isopropylamino)-5- CDCl.sub.3 1.12(d, 6H), 141 4-amino-5-
methylisoxazole 2.30(s, 3H), 3.21(1H, methylisoxazole septuplet),
8.01(s, 1H) 100 5-Methyl-4-(N- CDCl.sub.3 1.02(brs, 6H), 183 Meth
99 isopropylacetamido)isoxazole 1.80(s, 3H), 2.38(s, 3H), 4.99(1H,
septuplet), 8.09(s, 1H) 101 5-Acetyl-1-isopropyl-2- 1.40(d, 6H),
2.38(s, 167 Meth 100 methylimidazole 3H), 2.42(s, 3H), 5.08(brm,
1H), 7.81(s, 1H) 102 3,5-Dimethyl-4-amino- 2.04(s, 3H), 2.19(s, 112
isoxazole 3H), 3.78(s, 2H) 103 N-(2,2,2-Trifluoroethyl)-5- (CDCl3)
2.32(s, 3H), 181 Meth 94 methyl-4-aminoisoxazole 2.80(s, 1H),
3.52(q, 2H), 8.06(s, 1H) 104 3,5-Dimethyl-4- 2.08(s, 3H), 2.23(s,
140 Meth 102 formamidoisoxazole 3H), 8.10(s, 1H), 9.50(s, 1H) 105
3,5-Dimethyl-4- 2.08(s, 3H), 2.30(s, n/a Meth 104
methylaminoisoxazole 3H), 2.60(d, 3H), 3.84(s, 1H) 106
3,5-Dimethyl-4-(N- 1.75(s, 3H), 2.16(s, 168 Meth 105
methylacetamido)isoxazole 3H), 2.30(s, 3H), 3.00(s, 3H) 107
1,2,4-Trimethyl-5-acetyl- 2.26(s, 3H), 2.38(s, 152 Meth 106
imidazole 6H), 3.65(s, 3H) 108 N-(2,2,2-Trifluoroethyl)-N-(5-
1.82(s, 3H), 2.37(s, 223 Meth 103 methyl-4-isoxazolyl) acetamide
3H, 4.36(q 2H), 8.62(s, 1H) 109 1-(2,2,2-Trifluoroethyl)-2- 2.38(s,
6H), 5.31(q, 207 Meth 108 methyl-5-acetylimidazole 2H), 7.96(s,
1H)
Method 110 N-Methyl-4-aminobenzenesulphonamide
[0400] 4-Aminobenzenesulphonylfluoride (200 mg, 1.14 mmol) was
dissolved in a solution of methylamine in EtOH (3 mL, excess) and
heated to 80.degree. C. for 45 minutes, then cooled to room
temperature and left to stir overnight. The solvent was evaporated
in vacuo and azeotroped with ether to yield the title compound as a
solid (160 mg, 75%). NMR: 2.12 (s, 3H), 5.85 (s, 2H), 6.59 (d, 2H),
7.37 (d, 2H); m/z 187.
Method 111
2-Amino-4-(1,2-dimethylimidazol-5-yl)-5-chloropyrimidine
[0401] 2-Amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 26;
378 mg, 2 mmol) and N-chlorosuccinimide (267 mg, 2 mmol) were
dissolved in glacial acetic acid (7 ml) under an atmosphere of
nitrogen. The reaction mixture was heated at 65.degree. C. for 18
hours when further N-chlorosuccinimide (89 mg, 0.66 mmol) was added
and the reaction heated at 65.degree. C. for an additional 2 hours.
The volatiles were removed by evaporation and the residue dissolved
in water (10 ml). The solution was adjusted to pH 11-12 by addition
of 40% aqueous sodium hydroxide solution. The precipitated solid
was collected by filtration and washed sparingly with water, dried
under vacuum at 60.degree. C. to give the title compound (344 mg,
77%) as a yellow solid. NMR 2.35 (s, 3H), 3.75 (s, 3H), 4.83 (s,
2H), 7.53 (s, 1H), 8.27 (s, 1H); m/z 224.
Example 166
[0402] The following illustrate representative pharmaceutical
dosage forms containing the compound of formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof (hereafter compound X), for therapeutic or prophylactic use
in humans: TABLE-US-00029 (a): Tablet I mg/tablet Compound X 100
Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch
paste(5% w/v paste) 2.25 Magnesium stearate 3.0
[0403] TABLE-US-00030 (b): Tablet II mg/tablet Compound X 50
Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0
Polyvinylpyrrolidone(5% w/v paste) 2.25 Magnesium stearate 3.0
[0404] TABLE-US-00031 (c): Tablet III mg/tablet Compound X 1.0
Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste
(5% w/v paste) 0.75 Magnesium stearate 1.0
[0405] TABLE-US-00032 (d): Capsule mg/capsule Compound X 10 Lactose
Ph.Eur 488.5 Magnesium stearate 1.5
[0406] TABLE-US-00033 (e): Injection I (50 mg/ml) Compound X 5.0%
w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid
(to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for
injection to 100%
[0407] TABLE-US-00034 (f): Injection II 10 mg/ml Compound X 1.0%
w/v Sodium phosphate BP 3.6% w/v 0.1M Sodium hydroxide solution
15.0% v/v Water for injection to 100%
[0408] TABLE-US-00035 (g): Injection III (1 mg/ml, buffered to pH6)
Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38%
w/v Polyethylene glycol 400 3.5% w/v Water for injection to
100%
Note
[0409] The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art. The tablets
(a)-(c) may be enteric coated by conventional means, for example to
provide a coating of cellulose acetate phthalate.
* * * * *