U.S. patent application number 11/625406 was filed with the patent office on 2007-06-14 for imidazole derivatives as raf kinase inhibitors.
Invention is credited to David Kenneth DEAN, Andrew Kenneth Takle, David Matthew Wilson.
Application Number | 20070135433 11/625406 |
Document ID | / |
Family ID | 27447885 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135433 |
Kind Code |
A1 |
DEAN; David Kenneth ; et
al. |
June 14, 2007 |
IMIDAZOLE DERIVATIVES AS RAF KINASE INHIBITORS
Abstract
Novel compounds and their use as pharmaceuticals particularly as
Raf kinase inhibitors for the treatment of neurotraumatic diseases,
cancer, chronic neurodegeneration, pain, migraine and cardiac
hypertrophy.
Inventors: |
DEAN; David Kenneth;
(Harlow, GB) ; Takle; Andrew Kenneth; (Harlow,
GB) ; Wilson; David Matthew; (Harlow, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Family ID: |
27447885 |
Appl. No.: |
11/625406 |
Filed: |
January 22, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10380891 |
Mar 20, 2003 |
7199137 |
|
|
PCT/GB01/04195 |
Sep 19, 2001 |
|
|
|
11625406 |
Jan 22, 2007 |
|
|
|
Current U.S.
Class: |
514/235.5 ;
514/241; 514/252.05; 514/252.19; 514/256; 544/112; 544/122;
544/239; 544/295; 544/331 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 401/04 20130101; A61P 35/00 20180101; A61P 25/28 20180101;
C07D 401/14 20130101; A61P 29/00 20180101; A61P 25/06 20180101;
A61K 49/0021 20130101; A61P 43/00 20180101; A61P 9/10 20180101;
C07D 405/14 20130101; A61P 25/04 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/235.5 ;
514/241; 514/252.05; 514/252.19; 514/256; 544/112; 544/122;
544/295; 544/239; 544/331 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/506 20060101 A61K031/506; A61K 31/501
20060101 A61K031/501; A61K 31/497 20060101 A61K031/497; C07D 413/14
20060101 C07D413/14; C07D 403/14 20060101 C07D403/14 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 21, 2000 |
GB |
0023196.9 |
Sep 21, 2000 |
GB |
0023208.2 |
Sep 21, 2000 |
GB |
0023197.7 |
Sep 21, 2000 |
GB |
0023193.6 |
Claims
1. A compound of formula (I): ##STR31## wherein X is O, CH.sub.2,
CO, S or NH, or the moiety X--R.sup.1 is hydrogen; Y.sub.1 and
Y.sub.2 are independently N or CH; R.sup.1 is hydrogen,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl, aryl, arylC.sub.1-6alkyl,
heterocyclyl, heterocyclylC.sub.1-6alkyl, heteroaryl, or
heteroarylC.sub.1-6alkyl, any of which may be optionally
substituted; in addition when X is CH.sub.2 then R.sup.1 may be
hydroxy or C.sub.1-6alkoxy which may be optionally substituted;
R.sup.2 is a substituted C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, C.sub.5-7cycloalkenyl aryl, wherein the
substituent is selected from aryl, heteroaryl, heterocyclyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, arylC.sub.1-6alkoxy, aryl
C.sub.1-6alkylthio, amino, mono- or di-C.sub.1-6alkylamino,
aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy and esters
thereof, amide, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, C.sub.1-6acyloxy, hydroxy, and
halogen or any combinations thereof but must include a heterocyclyl
or heteroaryl group, or R.sup.2 is a heterocyclyl, or heteroaryl,
either of which may be optionally substituted; Ar is a group of the
formula a) or b): ##STR32## wherein A represents a fused 5- to
7-membered ring optionally containing up to two heteroatoms
selected from O, S and NR.sup.5, wherein R.sup.5 is hydrogen or
C.sub.1-6alkyl, which ring is optionally substituted by up to 2
substituents selected from halogen, C.sub.1-6alkyl, hydroxy,
C.sub.1-6alkoxy or keto; R.sup.3 and R.sup.4 are independently
selected from hydrogen, halogen, C.sub.1-6alkyl, aryl, aryl
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl,
haloC.sub.1-6alkyl, arylC.sub.1-6alkoxy, hydroxy, nitro, cyano,
azido, amino, mono- and di-N--C.sub.1-6alkylamino, acylamino,
arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters,
carbamoyl, mono- and di-N--C.sub.1-6alkylcarbamoyl,
C.sub.1-6alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino,
C.sub.1-6alkylguanidino, amidino, C.sub.1-6alkylamidino,
sulphonylamino, aminosulphonyl, C.sub.1-6alkylthio,
C.sub.1-6alkylsulphinyl or C.sub.1-6alkylsulphonyl; R.sup.15 is O
or N--OH; one of X.sub.1 and X.sub.2 is N and the other is NR.sup.6
wherein R.sup.6 is hydrogen or C.sub.1-6alkyl; or a
pharmaceutically acceptable salt thereof.
2. A compound of formula (I) according to claim 1 wherein X is NH
or X--R.sup.1 is hydrogen.
3. A compound of formula (I) according to claim 1 wherein R.sup.15
is N--OH
4. A compound of formula (I) according to claim 1 wherein R.sup.2
is i) --CR.sup.7R.sup.8--CH.sub.2-Z, --CH.sub.2-Z and heterocyclyl,
wherein R.sup.7 and R.sup.8 independently represent hydrogen or
optionally substituted C.sub.1-6alkyl, or R.sup.7 and R.sup.8
together with the carbon atom to which they are attached form an
optionally substituted C.sub.3-7cycloalkyl or C.sub.5-7cycloalkenyl
ring; and Z is NR.sup.9R.sup.10, NR.sup.9C(Q)NR.sup.9R.sup.10,
NR.sup.9COOR.sup.10, NR.sup.9SO.sub.2R.sup.10, NR.sup.9C(Q)R.sup.10
or heterocyclyl wherein R.sup.9 and R.sup.10 are independently
selected from heterocyclyl, heterocyclylC.sub.1-6alkyl, heteroaryl
and heteroarylC.sub.1-6alkyl, any of which may be optionally
substituted or together form a heterocyclic group, when present as
NR.sup.9R.sup.10; Q is O or S, preferably O; and when R.sup.2 or Z
is heterocyclyl, e.g. piperidyl, piperazine or morpholine, the
heterocyclyl group is optionally substituted; or ii) optionally
substituted pyridyl, pyrimidyl and furanyl.
5. A compound of formula (I) according to claim 1 wherein R.sup.3
is hydrogen.
6. A compound of formula (I) according to claim 1 wherein R.sup.4
is hydrogen.
7. A compound of formula (I) according to claim 1 wherein R.sup.6
is hydrogen.
8. A compound of formula (I) according to claim 1 which is selected
from: 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
{2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-meth-
yl-propyl}-amide;
5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime;
5-[2-(1-{1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-mathanoyl}-piperidin-4-yl-
)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one oxime;
5-[2-(1-Furan-3-ylmethyl-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-
-indan-1-one oxime;
5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl-
}-indan-1-one oxime; 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic
acid
[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-am-
ide;
5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-o-
ne oxime
5-(2-Morpholin-4-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-
-1-one oxime;
5-(5-Pyridin-4-yl-2-(2,3,5,6-tetrahydro-[1,2']bipyrazin-4-ylmethyl)-1H-im-
idazol-4-yl]-indan-1-one oxime;
5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one
oxime;
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imida-
zol-4-yl 1-indan-1-one;
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl-
}1-indan-1-one oxime;
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one;
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-one
oxime; and pharmaceutically acceptable salts thereof.
9. A pharmaceutical composition comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
10. (canceled)
11. (canceled)
12. (canceled)
13. A method of therapeutic treatment of any disease state in a
human, or other mammal, which is exacerbated or caused by a
neurotraumatic event which method comprises administering to a
human or other mammal a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof.
14. A method of therapeutic treatment of ischemic stroke which
method comprises administering to a human or other mammal a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
15. A method of therapeutic treatment of cancer which method
comprises administering to a human or other mammal a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
16. A method of therapeutic treatment of chronic neurogeneration,
pain, migraine and cardiac hypertrophy which method comprises
administering to a human or other mammal a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
17. A method of therapeutic treatment of any disease state in a
human, or other mammal, which is exacerbated or caused by a
neurotraumatic event which method comprises administering to a
human or other mammal a therapeutically effective amount of a
compound of formula (Ia) ##STR33## wherein X is O, CH.sub.2, CO, S
or NH, or the moiety X--R.sup.1 is hydrogen; Y.sub.1 and Y.sub.2
are CH; R.sup.1 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
aryl, or arylC.sub.1-6alkyl, any of which may be optionally
substituted; in addition, when X is CH.sub.2 then R.sup.1 may be
hydroxy or C.sub.1-6alkoxy which may be optionally substituted;
R.sup.2 is H, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, C.sub.5-7cycloalkenyl, or aryl, any of which
may be optionally substituted; Ar is a group of the formula a) or
b): ##STR34## wherein A represents a fused 5-membered carbocyclic
ring which ring is optionally substituted by up to 2 substituents
selected from halogen, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy and
keto; R.sup.3 and R.sup.4 are independently selected from hydrogen,
halogen, C.sub.1-6alkyl, aryl, aryl C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, haloC.sub.1-6alkyl,
arylC.sub.1-6alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and
di-N--C.sub.1-6alkylamino, acylamino, arylcarbonylamino, acyloxy,
carboxy, carboxy salts, carbamoyl, mono- and
di-N--C.sub.1-6alkylcarbamoyl, C.sub.1-6alkoxycarbonyl,
aryloxycarbonyl, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, sulphonylamino, aminosulphonyl,
C.sub.1-6alkylthio, C.sub.1-6alkylsulphinyl and
C.sub.1-6alkylsulphonyl; R.sup.15 is O or N--OH; one of X.sub.1 and
X.sub.2 is N and the other is NR.sup.6 wherein R.sup.6 is hydrogen
or C.sub.1-6alkyl; wherein the optional substituents for alkyl,
alkoxy, alkenyl, cycloalkyl and cycloalkenyl groups are selected
from aryl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
arylC.sub.1-6alkoxy, aryl C.sub.1-6alkylthio, amino, mono- or
di-C.sub.1-6alkylamino, aminosulphonyl, cycloalkyl, cycloalkenyl,
carboxy, amide, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, C.sub.1-6acyloxy, hydroxy, halogen,
cyano and any combinations thereof; wherein the aryl groups may be
optionally substituted by a substituent selected from halogen,
hydroxy, C.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkyl, haloC.sub.1-6alkyl,
arylC.sub.1-6alkoxy, nitro, cyano, azido, amino, mono- and
di-N--C.sub.1-6alkylamino, acylamino, arylcarbonylamino, acyloxy,
carboxy, carboxy salts, carbamoyl, mono- and
di-N--C.sub.1-6alkylcarbamoyl, C.sub.1-6alkoxycarbonyl,
aryloxycarbonyl, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, urea, carbamate, acyl,
sulphonylamino, aminosulphonyl, C.sub.1-6alkylthio,
C.sub.1-6alkylsulphinyl, C.sub.1-6alkylsulphonyl, and any
combination thereof; or a pharmaceutically acceptable salt
thereof.
18. A method of therapeutic treatment of ischemic stroke which
method comprises administering to a human or other mammal a
therapeutically effective amount of a compound of formula (Ia) as
defined in claim 17 or a pharmaceutically acceptable salt
thereof.
19. A method of therapeutic treatment of cancer which method
comprises administering to a human or other mammal a
therapeutically effective amount of a compound of formula (Ia) as
defined in claim 17 or a pharmaceutically acceptable salt
thereof.
20. A method of therapeutic treatment of chronic neurogeneration,
pain, migraine and cardiac hypertrophy which method comprises
administering to a human or other mammal a therapeutically
effective amount of a compound of formula (Ia) as defined in claim
17 or a pharmaceutically acceptable salt thereof.
Description
[0001] This invention relates to novel compounds and their use as
pharmaceuticals particularly as Raf kinase inhibitors for the
treatment of neurotraumatic diseases, cancer, chronic
neurodegeneration, pain, migraine and cardiac hypertrophy.
[0002] Raf protein kinases are key components of signal
transduction pathways by which specific extracellular stimuli
elicit precise cellular responses in mammalian cells. Activated
cell surface receptors activate ras/rap proteins at the inner
aspect of the plasma-membrane which in turn recruit and activate
Raf proteins. Activated Raf proteins phosphorylate and activate the
intracellular protein kinases MEK1 and MEK2. In turn, activated
MEKs catalyse phosphorylation and activation of p42/p44
mitogen-activated protein kinase (MAPK). A variety of cytoplasmic
and nuclear substrates of activated MAPK are known which directly
or indirectly contribute to the cellular response to environmental
change. Three distinct genes have been identified in mammals that
encode Raf proteins; A-Raf, B-Raf and C-Raf (also known as Raf-1)
and isoformic variants that result from differential splicing of
mRNA are known.
[0003] Inhibitors of Raf kinases have been suggested for use in
disruption of tumor cell growth and hence in the treatment of
cancers, e.g. histiocytic lymphoma, lung adenocarcinoma, small cell
lung cancer and pancreatic and breast carcinoma; also in the
treatment and/or prophylaxis of disorders associated with neuronal
degeneration resulting from ischemic events, including cerebral
ischemia after cardiac arrest, stroke and multi-infarct dementia
and also after cerebral ischemic events such as those resulting
from head injury, surgery and/or during childbirth; also in chronic
neurodegeneration such as Alzheimer's disease and Parkinson's
disease; also in the treatment of pain, migraine and cardiac
hypertrophy.
[0004] We have now found a group of novel compounds that are
inhibitors of Raf kinases, in particular inhibitors of B-Raf
kinase.
[0005] According to the invention there is provided a compound of
formula (I): ##STR1## wherein
[0006] X is O, CH.sub.2, CO, S or NH, or the moiety X--R.sup.1 is
hydrogen;
[0007] Y.sub.1 and Y.sub.2 are independently N or CH;
[0008] R.sup.1 is hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
aryl, arylC.sub.1-6alkyl, heterocyclyl, heterocyclylC.sub.1-6alkyl,
heteroaryl, or heteroarylC.sub.1-6alkyl, any of which may be
optionally substituted; in addition when X is CH.sub.2 then R.sup.1
may be hydroxy or C.sub.1-6alkoxy which may be optionally
substituted;
[0009] R.sup.2 is H, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, C.sub.5-7cycloalkenyl, heterocyclyl, aryl or
heteroaryl, any of which may be optionally substituted;
[0010] Ar is a group of the formula a) or b): ##STR2##
[0011] wherein A represents a fused 5- to 7-membered ring
optionally containing up to two heteroatoms selected from O, S and
NR.sup.5, wherein R.sup.5 is hydrogen or C.sub.1-6alkyl, which ring
is optionally substituted by up to 2 substituents selected from
halogen, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy or keto;
[0012] R.sup.3 and R.sup.4 are independently selected from
hydrogen, halogen, C.sub.1-6alkyl, aryl, aryl C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkoxyC.sub.1-6alkyl, haloC.sub.1-6alkyl,
arylC.sub.1-6alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and
di-N--C.sub.1-6alkylamino, acylamino, arylcarbonylamino, acyloxy,
carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and
di-N--C.sub.1-6alkylcarbamoyl, C.sub.1-6alkoxycarbonyl,
aryloxycarbonyl, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, sulphonylamino, aminosulphonyl,
C.sub.1-6alkylthio, C.sub.1-6alkylsulphinyl or
C.sub.1-6alkylsulphonyl;
[0013] R.sup.15 is O or N--OH;
[0014] one of X.sub.1 and X.sub.2 is N and the other is NR.sup.6
wherein R.sup.6 is hydrogen or C.sub.1-6alkyl;
[0015] or a pharmaceutically acceptable salt thereof
[0016] As used herein, the double bond indicated by the dotted
lines of formula (I), represent the possible tautomeric ring forms
of the compounds falling within the scope of this invention. It
will be understood that the double bond is to the unsubstituted
nitrogen.
[0017] The oxime moiety can be positioned on any of carbon atoms of
the non-aromatic ring in groups a) and b).
[0018] Alkyl and alkenyl groups referred to herein, individually or
as part of larger groups e.g. alkoxy, may be straight or branched
groups containing up to six carbon atoms.
[0019] Cycloalkyl and cycloalkenyl groups referred to herein
include groups having from three to seven and five to seven ring
carbon atoms respectively.
[0020] Optional substituents for alkyl, alkenyl, cycloalkyl and
cycloalkenyl groups include aryl, heteroaryl, heterocyclyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, arylC.sub.1-6alkoxy, aryl
C.sub.1-6alkylthio, amino, mono- or di-C.sub.1-6alkylamino,
aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy and esters
thereof, amide, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, C.sub.1-6acyloxy, hydroxy, and
halogen or any combinations thereof. A further substituent can be
cyano.
[0021] Preferably the optional substituent contains a
water-solubilising group; suitable solubilising moieties will be
apparent to those skilled in the art and include hydroxy and amino
group. Even more preferably the optional substituent includes
amino, mono or di-C.sub.1-6alkyl, amino, amino containing
heterocyclyl or hydroxy or any combination thereof.
[0022] When used herein, the term "aryl" means single and fused
rings suitably containing from 4 to 7, preferably 5 or 6, ring
atoms in each ring, which rings, may each be unsubstituted or
substituted by, for example, up to three substituents. A fused ring
system may include aliphatic rings and need include only one
aromatic ring. Suitable aryl groups include phenyl and naphthyl
such as 1-naphthyl or 2-naphthyl.
[0023] When used herein the term "heterocyclyl" suitably includes,
unless otherwise defined, non-aromatic, saturated or unsaturated,
single and fused, rings suitably containing up to four heteroatoms
in either or both rings, each of which is selected from O, N and S,
which rings, may be unsubstituted or substituted by, for example,
up to three substituents. Each heterocyclic ring suitably has from
4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring
system may include carbocyclic rings and need include only one
heterocyclic ring. Examples of heterocyclyl groups include
pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,
imidazolidine and pyrazolidine. Prefered examples of heterocyclyl
groups include pyrrolidine, piperidine, piperazine, morpholine,
imidazolidine and pyrazolidine.
[0024] When used herein, the term "heteroaryl" suitably includes,
unless otherwise defined, mono- and bicyclic heteroaromatic ring
systems comprising up to four, preferably 1 or 2, heteroatoms each
selected from O, N and S. Each ring may have from 4 to 7,
preferably 5 or 6, ring atoms. A bicyclic heteroaromatic ring
system may include a carbocyclic ring. Examples of heteroaryl
groups include pyrrole, quinoline, isoquinoline, pyridine,
pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole and
benzimidazole.
[0025] Suitably aryl, heterocyclyl and heteroaryl groups may be
optionally substituted by preferably up to three substituents.
Suitable substituents include halogen, hydroxy, C.sub.1-6alkyl,
aryl, arylC.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxyC.sub.1-6alkyl, haloC.sub.1-6alkyl,
arylC.sub.1-6alkoxy, nitro, cyano, azido, amino, mono- and
di-N--C.sub.1-6alkylamino, acylamino, arylcarbonylamino, acyloxy,
carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and
di-N--C.sub.1-6alkylcarbamoyl, C.sub.1-6alkoxycarbonyl,
aryloxycarbonyl, ureido, guanidino, C.sub.1-6alkylguanidino,
amidino, C.sub.1-6alkylamidino, urea, carbamate, acyl,
sulphonylamino, aminosulphonyl, C.sub.1-6alkylthio,
C.sub.1-6alkylsulphinyl, C.sub.1-6alkylsulphonyl, heterocyclyl,
heteroaryl, heterocyclylC.sub.1-6alkyl and heteroaryl
C.sub.1-6alkyl, or any combination thereof. In addition two ring
carbon atoms may be linked to form a bicyclic system.
[0026] When used herein halogen means fluoro, chloro, bromo or
iodo.
[0027] In the compounds of formula (I):
[0028] X is preferably O, CH.sub.2, S or NH, or the moiety
X--R.sup.1 is hydrogen.
[0029] More preferably X is CH.sub.2 or NH or X--R.sup.1 is
hydrogen, most preferably X is NH or X--R.sup.1 is hydrogen.
[0030] Preferably Y.sub.1 is CH and Y.sub.2 is N or CH.
[0031] Preferably R.sup.15 is N--OH.
[0032] Alternatively, R.sup.1 is hydrogen, C.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclyl, heterocyclylC.sub.1-6alkyl,
heteroaryl, or heteroarylC.sub.1-6alkyl, any of which may be
optionally substituted; in addition when X is CH.sub.2 then R.sup.1
may be hydroxy or C.sub.1-6alkoxy which may be optionally
substituted.
[0033] R.sup.2 can be C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, C.sub.5-7cycloalkenyl or heterocyclyl, any of
which may be optionally substituted. Alternatively R.sup.2 is aryl
or heteroaryl, either of which may be optionally substituted.
[0034] Preferably Ar is a group Ar is a group of the formula a) or
b): ##STR3##
[0035] R.sup.4 is as defined for compounds of formula (I), n is 1,
2 or 3 and R.sup.15 is O or N--OH.
[0036] More preferably Ar is a group of formula a) or b)
##STR4##
[0037] wherein R.sup.4 is as defined for compounds of formula (I),
and n is 1, 2 or 3.
[0038] n is preferably 1.
[0039] Ar is preferably an indone group
[0040] Suitable optional substituents for the group R.sup.2 include
one or more groups selected from the group consisting of aryl,
heteroaryl, heterocyclyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
arylC.sub.1-6alkoxy, arylC.sub.1-6alkylthio, amino, mono- or
di-C.sub.1-6alkylamino, aminosulphonyl, cycloalkyl, cycloalkenyl,
carboxy and esters thereof, amide, ureido, guanidino,
C.sub.1-6alkylguanidino, amidino, C.sub.1-6alkylamidino,
C.sub.1-6acyloxy, hydroxy, and halogen or any combinations thereof.
Alternatively the substituent can be C.sub.1-6alkylaryl
[0041] R.sup.2 is preferably a group that contains a solubilising
moiety, suitable solubilising moieties will be apparent to those
skilled in the art and include basic groups. Particular
solubilising groups that can be mentioned include amine and hydroxy
groups. For example, amino, mono- or di-C.sub.1-6alkylamino, amine
containing heterocyclyl or hydroxy groups or any combination
thereof.
[0042] Specific R.sup.2 groups that may be mentioned include
--CR.sup.7R.sup.8--CH.sub.2-Z, --CH.sub.2-Z and heterocyclyl,
wherein R.sup.7 and R.sup.8 independently represent optionally
substituted C.sub.1-6alkyl, or R.sup.7 and R.sup.8 together with
the carbon atom to which they are attached form an optionally
substituted C.sub.3-7cycloalkyl or C.sub.5-7cycloalkenyl ring; and
Z is NR.sup.9R.sup.10, NR.sup.9C(Q)NR.sup.9R.sup.10,
NR.sup.9COOR.sup.10, NR.sup.9SO.sub.2R.sup.10, NR.sup.9C(Q)R.sup.10
or heterocyclyl wherein R.sup.9 and R.sup.10 are independently
selected from hydrogen, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
heterocyclyl, heterocyclylC.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl,
heteroaryl and heteroarylC.sub.1-6alkyl, any of which may be
optionally substituted or together form a heterocyclic group, when
present as NR.sup.9R.sup.10; Q is O or S, preferably O; and when
R.sup.2 or Z is heterocyclyl, e.g. piperidyl, piperazine or
morpholine, the heterocyclyl group is optionally substituted.
[0043] Specific R.sup.2 groups that may be mentioned include
optionally substituted phenyl, pyridyl, pyrimidyl and furanyl.
[0044] Further specific R.sup.2 groups which may be mentioned
included phenyl substituted by a group
--O--(CH.sub.2).sub.m--NR.sup.18R.sup.19 or
--(CH.sub.2).sub.m--NR.sup.18R.sup.19, wherein m is an integer from
1 to 6, e.g. 2 or 3, and R.sup.18 and R.sup.19 independently
represent hydrogen, C.sub.1-6alkyl, or R.sup.18 and R.sup.19
together with the nitrogen atom to which they are attached form an
optionally substituted 5- to 7-membered ring optionally containing
an additional heteroatom selected from NR.sup.20 and O, wherein
R.sup.20 is hydrogen or C.sub.1-6alkyl, e.g. morpholinyl.
[0045] Alternatively R.sup.7 or R.sup.8 can be hydrogen.
[0046] R.sup.3 is preferably hydrogen.
[0047] R.sup.4 is preferably hydrogen.
[0048] R.sup.6 is preferably hydrogen.
[0049] The compounds of formula (I) preferably have a molecular
weight of less than 800.
[0050] It will be understood that the invention includes
pharmaceutically acceptable derivatives of compounds of formula (I)
and that these are included within the scope of the invention.
[0051] Particular compounds according to the invention include
those mentioned in the examples and their pharmaceutically
acceptable salts. As used herein "pharmaceutically acceptable
derivatives" includes any pharmaceutically acceptable salt, ester
or salt of such ester of a compound of formula (I) which, upon
administration to the recipient, is capable of providing (directly
or indirectly) a compound of formula (I) or an active metabolite or
residue thereof.
[0052] Preferably the derivative is a salt
[0053] Particular compounds according to the invention include
those mentioned in the examples and their pharmaceutically
acceptable salts.
[0054] It will be appreciated that for use in medicine the salts of
the compounds of formula (I) should be pharmaceutically acceptable.
Suitable pharmaceutically acceptable salts will be apparent to
those skilled in the art and include those described in J. Pharm.
Sci., 1977, 66, 1-19, such as acid addition salts formed with
inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric
or phosphoric acid; and organic acids e.g. succinic, maleic,
acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic,
methanesulfonic or naphthalenesulfonic acid. Other salts e.g.
oxalates, may be used, for example in the isolation of compounds of
formula (I) and are included within the scope of this
invention.
[0055] The compounds of this invention may be in crystalline or
non-crystalline form, and, if crystalline, may optionally be
hydrated or solvated. This invention includes within its scope
stoichiometric hydrates as well as compounds containing variable
amounts of water.
[0056] The invention extends to all isomeric forms including
stereoisomers and geometric isomers of the compounds of formula (I)
including enantiomers and mixtures thereof e.g. racemates. The
different isomeric forms may be separated or resolved one from the
other by conventional methods, or any given isomer may be obtained
by conventional synthetic methods or by stereospecific or
asymmetric syntheses.
[0057] Since the compounds of formula (I) are intended for use in
pharmaceutical compositions it will readily be understood that they
are each preferably provided in substantially pure form, for
example at least 60% pure, more suitably at least 75% pure and
preferably at least 85%, especially at least 98% pure (% are on a
weight for weight basis). Impure preparations of the compounds may
be used for preparing the more pure forms used in the
pharmaceutical compositions.
[0058] Compounds of formula (I) are imidazole derivatives which may
be readily prepared using procedures well-known to those skilled in
the art, and described in, for instance, Comprehensive Heterocyclic
Chemistry, Editors Katritzky and Rees, Pergamon Press, 1984, 5,
457-497, from starting materials which are either commercially
available or can be prepared from such by analogy with well-known
processes.
[0059] Examples of processes for preparing compounds of this
invention are as outlined in schemes 1 and 2. The schemes
illustrate the production of compounds in which --X--R.sup.1,
R.sup.3 and R.sup.4 are hydrogen, X.sub.1 is NH, Y.sub.1 and
Y.sub.2 are CH and Ar is a group of formula a) wherein n is 1,
however the processes are applicable for the production of all the
compounds of formula (I). In the first such process (scheme 1),
.alpha.-diketones are prepared by reaction of the anion of an
O-protected derivative of 4-pyridine-methanol, with a suitably
protected fused bicyclic aryl-aldehyde wherein PG is an oxime
protecting group e.g. .dbd.N--OR.sup.11 wherein R.sup.11 is
optionally substituted C.sub.1-6 alkyl, e.g. methyl, optionally
substituted aryl or silyl, or PG is a ketone protecting group.
O-deprotection followed by oxidation of the intermediate diol
affords the aforementioned .alpha.-diketones. Reacting the diketone
with a suitable aldehyde and ammonium acetate in a solvent e.g.
acetic acid, methoxy.sup.tbutylether, or methanol, allows access to
the imidazole nucleus. Thereafter, the group R.sup.2 may be
converted into another group R.sup.2, using conventional functional
group interconversion procedures, and the group PG converted into
an oximino group (.dbd.N--OH). ##STR5##
[0060] The second such process (scheme 2) is analogous to that
described by Liverton et al (J. Med. Chem., 1999, 42, 2180). In
this approach, 2-bromo-1-pyridine-4-yl-ethanone is reacted with a
suitable amidine to form the central imidazole nucleus. Protection
of the labile imidazole hydrogen (typical protecting groups, PG,'
are 2-trimethylsilyl-ethoxymethyl-, SEM, and methoxymethyl-, MOM)
then allows metallation of the imidazole ring. Introduction of the
remaining substituent can then be achieved by a transition metal
catalysed cross-coupling of the metallated imidazole with a
suitably protected, fused bicyclic aromatic system substituted with
a halogen or sulphonate ester, wherein PG is .dbd.O or a protecting
group as defined for Scheme 1 above. Such transition metal coupling
procedures are well known to those skilled in the art and described
in, for instance, D. W. Knight in Comprehensive Organic Synthesis,
volume 4, page 481, editors B. M. Trost and I. Fleming, Pergamon
Press, 1991. Thereafter, the group R.sup.2 may be converted into
another group R.sup.2, using conventional functional group
interconversion procedures, the protecting group PG' removed and
the group PG converted into an oximino group (.dbd.N--OH). It will
also be appreciated that the cross-coupling procedure could be
reversed such that a halogenated imidazole is coupled with a
suitably protected, metallated fused bicyclic aromatic system
##STR6##
[0061] Compounds of formula (I) wherein R.sup.6 is C.sub.1-6 alkyl
may be produced by alkylation of a compound of formula (II),
following removal of the protecting group PG', by a process
analogous to that described by Liverton et al (J. Med. Chem., 1999,
42, 2180). The resulting isomers may be separated by
chromatographic techniques.
[0062] During the synthesis of the compounds of formula (I) labile
functional groups in the intermediate compounds, e.g. hydroxy,
carboxy and amino groups, may be protected. A comprehensive
discussion of the ways in which various labile functional groups
may be protected and methods for cleaving the resulting protected
derivatives is given in for example Protective Groups in Organic
Chemistry, T. W. Greene and P. G. M. Wuts, (Wiley-Interscience, New
York, 2nd edition, 1991).
[0063] The compounds of formula (I) may be prepared singly or as
compound libraries comprising at least 2, for example 5 to 1,000
compounds, and more preferably 10 to 100 compounds of formula (I).
Libraries of compounds of formula (I) may be prepared by a
combinatorial `split and mix` approach or by multiple parallel
synthesis using either solution phase or solid phase chemistry, by
procedures known to those skilled in the art.
[0064] Thus according to a further aspect of the invention there is
provided a compound library comprising at least 2 compounds of
formula (I), or pharmaceutically acceptable salts thereof.
[0065] Pharmaceutically acceptable salts may be prepared
conventionally by reaction with the appropriate acid or acid
derivative.
[0066] Various of the intermediates used in the production of the
compounds of formula (I) are novel thus according to a further
aspect of the invention there is provided a compound of formula
(II), (III) or (IV), wherein PG represents .dbd.O or a protecting
group and PG' represents a protecting group. Suitable protecting
groups include those described above.
[0067] As indicated above the compounds of formula (I) and their
pharmaceutically acceptable derivatives are useful for the
treatment and/or prophylaxis of disorders in which Raf kinases, in
particular B-Raf kinase, are implicated.
[0068] According to a further aspect of the invention there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable derivatives thereof as an inhibitor of B-Raf kinase.
[0069] As indicated above the compounds of formula (I) and their
pharmaceutically acceptable derivatives are useful for the
treatment and/or prophylaxis of disorders associated with neuronal
degeneration resulting from ischemic events, as well as chronic
neurodegeneration, pain, migraine and cardiac hypertrophy.
[0070] According to a further aspect of the invention there is
provided a method of treatment or prophylaxis of a neurotraumatic
disease, in a mammal in need thereof, which comprises administering
to said mammal an effective amount of a compound of formula (I) or
a pharmaceutically acceptable derivative thereof.
[0071] According to a further aspect of the invention there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable derivative thereof in the manufacture of a medicament
for the prophylactic or therapeutic treatment of any disease state
in a human, or other mammal, which is exacerbated or caused by a
neurotraumatic event.
[0072] Neurotraumatic diseases/events as defined herein include
both open or penetrating head trauma, such as caused by surgery, or
a closed head trauma injury, such as caused by an injury to the
head region. Also included within this definition is ischemic
stroke, particularly to the brain area, transient ischemic attacks
following coronary by-pass and cognitive decline following other
transient ischemic conditions.
[0073] Ischemic stroke may be defined as a focal neurologic
disorder that results from insufficient blood supply to a
particular brain area, usually as a consequence of an embolus,
thrombi, or local atheromatous closure of the blood vessel. Roles
for stress stimuli (such as anoxia), redox injury, excessive
neuronal excitatory stimulation and inflammatory cytokines in this
area has been emerging and the present invention provides a means
for the potential treatment of these injuries. Relatively little
treatment, for an acute injury such as these has been
available.
[0074] The compounds of the invention may also be used in the
treatment or prophylaxis of cancers.
[0075] According to a further aspect of the invention there is
provided a method of treatment or prophylaxis of a cancer, in a
mammal in need thereof, which comprises administering to said
mammal an effective amount of a compound of formula (I) or a
pharmaceutically acceptable derivative thereof.
[0076] According to a further aspect of the invention there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable derivative thereof in the manufacture of a medicament
for the prophylactic or therapeutic treatment of cancer.
[0077] According to a further aspect of the invention there is
provided a method of treatment or prophylaxis of a chronic
neurogeneration, pain, migraine and cardiac hypertrophy, in a
mammal in need thereof, which comprises administering to said
mammal an effective amount of a compound of formula (I) or a
pharmaceutically acceptable derivative thereof.
[0078] According to a further aspect of the invention there is
provided the use of a compound of formula (I) or a pharmaceutically
acceptable derivative thereof in the manufacture of a medicament
for the prophylactic or therapeutic treatment of chronic
neurogeneration, pain, migraine and cardiac hypertrophy.
[0079] In order to use the compounds of formula (I) in therapy,
they will normally be formulated into a pharmaceutical composition
in accordance with standard pharmaceutical practice.
[0080] According to a further aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (I) or a pharmaceutically acceptable derivative thereof and
a pharmaceutically acceptable carrier.
[0081] The compounds of formula (I) may conveniently be
administered by any of the routes conventionally used for drug
administration, for instance, parenterally, orally, topically or by
inhalation. The compounds of formula (I) may be administered in
conventional dosage forms prepared by combining it with standard
pharmaceutical carriers according to conventional procedures. The
compounds of formula (I) may also be administered in conventional
dosages in combination with a known, second therapeutically active
compound. These procedures may involve mixing, granulating and
compressing or dissolving the ingredients as appropriate to the
desired preparation. It will be appreciated that the form and
character of the pharmaceutically acceptable carrier is dictated by
the amount of compound of formula (I) with which it is to be
combined, the route of administration and other well-known
variables. The carrier(s) must be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and
not deleterious to the recipient thereof.
[0082] The pharmaceutical carrier employed may be, for example,
either a solid or liquid. Exemplary of solid carriers are lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, stearic acid and the like. Exemplary of liquid carriers
are syrup, peanut oil, olive oil, water and the like. Similarly,
the carrier or diluent may include time delay material well known
to the art, such as glyceryl mono-stearate or glyceryl distearate
alone or with a wax.
[0083] A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation can be tableted,
placed in a hard gelatin capsule in powder or pellet form or in the
form of a troche or lozenge. The amount of solid carrier will vary
widely but preferably will be from about 25 mg to about 1 g. When a
liquid carrier is used, the preparation will be in the form of a
syrup, emulsion, soft gelatin capsule, sterile injectable liquid
such as an ampoule or nonaqueous liquid suspension.
[0084] The compounds of formula (I) are preferably administered
parenterally, that is by intravenous, intramuscular, subcutaneous,
sublinqual, intranasal, intrarectal, intravaginal or
intraperitoneal administration. The intravenous form of parenteral
administration is generally preferred. The compounds may be
administered as a bolus or continuous infusion e.g. for 6 hours up
to 3 days. Appropriate dosage forms for such administration may be
prepared by conventional techniques.
[0085] The compounds of formula (I) may also be administered
orally. Appropriate dosage forms for such administration may be
prepared by conventional techniques.
[0086] The compounds of formula (I) may also be administered by
inhalation, that is by intranasal and oral inhalation
administration. Appropriate dosage forms for such administration,
such as aerosol formulations, may be prepared by conventional
techniques.
[0087] The compounds of formula (I) may also be administered
topically, that is by non-systemic administration. This includes
the application of the inhibitors externally to the epidermis or
the buccal cavity and the instillation of such a compound into the
ear, eye and nose, such that the compound does not significantly
enter the blood stream.
[0088] For all methods of use disclosed herein the daily oral
dosage regimen will preferably be from about 0.1 to about 200 mg/kg
of total body weight, preferably from about 0.2 to 30 mg/kg, more
preferably from about 0.5 to 15 mg/kg. The daily parenteral dosage
regimen about 0.1 to about 200 mg/kg of total body weight,
preferably from about 0.2 to about 30 mg/kg, and more preferably
from about 0.5 to 15 mg/kg. The daily topical dosage regimen will
preferably be from 0.1 mg to 150 mg, administered one to four,
preferably two or three times daily. The daily inhalation dosage
regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg
per day. It will also be recognized by one of skill in the art that
the optimal quantity and spacing of individual dosages of the
inhibitors will be determined by the nature and extent of the
condition being treated, the form, route and site of
administration, and the particular patient being treated, and that
such optimums can be determined by conventional techniques. It will
also be appreciated by one of skill in the art that the optimal
course of treatment, i.e., the number of doses of the inhibitors
given per day for a defined number of days, can be ascertained by
those skilled in the art using conventional course of treatment
determination tests. In the case of pharmaceutically acceptable
salts the above figures are calculated as the parent compound of
formula (I).
[0089] No toxicological effects are indicated/expected when a
compound of formula (I) is administered in the above mentioned
dosage range.
[0090] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0091] The following Examples illustrate the preparation of
pharmacologically active compounds of the invention.
[0092] The abbreviations used herein are as follows:
[0093] THF means tetrahydrofuran
[0094] DMF means N,N-Dimethylforamide
[0095] TBAF means tetrabutylammonium fluoride
[0096] DMSO means dimethylsulfoxide
[0097] LDA means lithium diisopropyl amide
EXAMPLE 1
5-[2-(2-Amino-1,1-dimethyl-ethyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-
-one oxime
[0098] ##STR7##
Step 1: 5-Bromo-indan-1-one O-methyl-oxime
[0099] To a solution of 5-bromo-indanone (100 g, 0.474 mol) in
ethanol (650 ml) under argon was added methoxylamine hydrochloride
(198 g, 2.38 mol) and pyridine (125 ml). The mixture was refluxed
for 2.5 hours, cooled to room temperature and poured into saturated
aqueous sodium hydrogen carbonate solution. The mixture was then
extracted with ethyl acetate and the organic phase dried
(Na.sub.2SO.sub.4) and then concentrated in vacuo. The crude
material was recrystallised from isopropanol to furnish the title
compound, (110 g, 97%), as a brown solid; .sup.1H NMR (CDCl.sub.3)
7.52 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3,
1 Hz), 3.97 (3H, s), 2.99 (2H, m), 2.99 (2H, m), 2.85 (2H, m).
Step 2: 1-Methoxyimino-indan-5-carbaldehyde
[0100] To a solution of the product of Step 1 (112 g, 0.46 mol) in
THF (1500 ml) at -60.degree. C. under argon, was added n-BuLi (325
ml, 0.52 mol) over 1 hour. After stirring at -60.degree. C. for 1
hour a solution of DMF (39.7 ml) in THF (50 ml) was added dropwise
over 1 hour. The reaction was stirred at -60.degree. C. for 1 hour
before being allowed to warm to room temperature. After 1 hour the
reaction was quenched with saturated aqueous sodium hydrogen
carbonate solution and extracted into ethyl acetate. The organic
phase was then dried (Na.sub.2SO.sub.4), concentrated in vacuo and
the residue purified by silica gel chromatography, to give the
title compound (57 g, 65%) as a yellow solid; .sup.1H NMR
(CDCl.sub.3) 10.0 (1H, s), 7.83-7.73 (3H, m), 4.02 (3H, s), 3.10
(2H, m), 2.92 (2H, m).
Step 3:
5-(1,2-Dihydroxy-2-pyridin-4-yl-ethyl)-indan-1-one-O-methyl-oxime
[0101] To a solution of
4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine [T. F. Gallagher
et al, Bioorg. Med. Chem., 1997, 5, 49] (71.5 g, 0.32 mol) in THF
(800 ml) at -50.degree. C. under argon was added LDA (162 ml, 2M in
heptane/THF/ethylbenzene, 0.324 mol) over 1 hour. The mixture was
stirred at -40.degree. C. for a further 1 hour before a solution of
the product of Step 2 (55 g, 0.29 mol) in THF (600 ml) was added
over 1 hour. The reaction was then allowed to warm to room
temperature overnight before being quenched by the addition of
saturated aqueous sodium hydrogen carbonate solution and then
extracted into ethyl acetate. The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give a brown oil
(125 g).
[0102] The oil was then dissolved in THF (1500 ml), treated with
TBAF (356 ml, 0.356 mol) and stirred for 1 hour. The reaction
mixture was then evaporated and the residue partitioned between
water and ethyl acetate. The organic phase was then dried
(Na.sub.2SO.sub.4) and concentrated to give the title compound (57
g, 64%) as a pale yellow solid which was used without further
purification. .sup.1H NMR (CDCl.sub.3) 8.38 (2H, m), 7.57 (1H, m),
7.12-6.99 (4H, m), 4.88 (1H, m), 4.66 (1H, m), 3.96 (3H, s), 2.93
(2H, m), 2.85 (2H, m).
Step 4:
1-(1-Methoxyimino-indan-5-yl)-2-pyridin-4-yl-ethane-1,2-dione
[0103] To a mixture of DMSO (43 ml, 0.56 mol) and dichloromethane
(800 ml) at -70.degree. C. under argon, was added oxalyl chloride
(71.4 g) and then a solution of the product of Step 3 (55 g, 0.185
mol) in a mixture of dichloromethane/DMSO (1000 ml/60 ml) over 2
hours at -60.degree. C. After stirring for 2 hours at -60.degree.
C., triethylamine (154 ml) was added dropwise and the mixture then
allowed to warm to room temperature overnight. The reaction mixture
was then quenched with water, the organic phase separated then
washed with water, dried (Na.sub.2SO.sub.4) and concentrated to
yield the title compound (51 g, 94%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3) 8.87 (2H, d), 7.89-7.77 (5H, m), 4.03 (3H, s), 3.09
(2H, m), 2.93 (2H, m).
Step 5:
{2-[4-(1-Methoxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-yl]-
-2-methyl-propyl}-carbamic acid tert-butyl ester
[0104] A mixture of the product of Step 4 (1.02 g, 3.47 mmol),
(2,2-dimethyl-3-oxo-propyl)-carbamic acid tert-butyl ester (0.84 g,
4.16 mmol) [Y. Guindon et al, J. Am. Chem. Soc., 1997, 119, 9289]
and ammonium acetate (1.34 g, 17.4 mmol) in MeOH (15 ml) and
tert-butyl methyl ether (30 ml) was stirred at room temperature for
2 hours. The reaction was then poured into water and extracted with
ethyl acetate. The organic extract was then dried (MgSO.sub.4),
concentrated in vacuo and the crude material purified by silica gel
chromatography eluting with ethyl acetate to give the title
compound (0.450 g, 27%) as a colourless solid; MS(AP+) m/e 477
[M+H].sup.+
Step 6:
5-[2-(2-Amino-1,1-dimethyl-ethyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-
-indan-1-one
[0105] A mixture of the product of Step 5 (0.400 g, 0.839 mmol) and
5M HCl (2 ml) in dioxan (4 ml) was heated to 100.degree. C. for 1
hour. Acetone (10 drops) was then added and the heating continued
for a further 1 hour before the mixture was cooled to room
temperature and reduced in vacuo. The residue was purified by
silica gel chromatography, eluting with a 2:18:80 mixture of 0.88
ammonia solution:methanol:ethyl acetate to give the title compound
(0.18 g, 62%) as a yellow solid; MS(AP+) m/e 348 [M+H].sup.+.
Step 7:
5-[2-(2-Amino-1,1-dimethyl-ethyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-
-indan-1-one oxime
[0106] To a solution of the product of Step 6 (0.12 g, 0.350 mmol)
in ethanol (5 ml) at 80.degree. C. was added aqueous hydroxylamine
(0.07 g, 1.04 mmol, 50% in water). After 30 min the mixture was
cooled to room temperature and concentrated in vacuo to give the
title compound, (0.124 g, 100%) as a yellow solid; MS(AP+) m/e 362
[M+H].sup.+.
EXAMPLE 2
N-{2-[5-(1-Hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-met-
hyl-propyl}-methanesulfonamide
[0107] ##STR8##
Step 1:
N-{2-Methyl-2-[5-(1-oxo-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-y-
l]-propyl}-methanesulfonamide
[0108] A mixture of the product of Example 1, Step 6 (0.1 g, 0.29
mmol ) and methane sulphonyl chloride (0.023 ml, 0.3 mmol) in
dichloromethane (3 ml) was stirred at room temperature for 2 hours.
The reaction was then poured into ethyl acetate, washed with water
and aqueous sodium hydrogen carbonate solution, dried (MgSO.sub.4)
and concentrated in vacuo. The crude residue was then purified by
silica gel chromatography eluting with a 1:9:90 mixture of 0.88
ammonia solution:methanol:dichloromethane to give the title
compound (0.075 g, 61%) as a yellow solid; MS(AP+) m/e 425
[M+H].sup.+.
Step 2:
N-{2-[5-(1-Hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-y-
l]-2-methyl-propyl}-methanesulfonamide
[0109] The title compound (0.06 g, 90%) was prepared from the
product of Step 1 as described in Example 1 Step 7; MS(AP+) m/e
440[M+H].sup.+.
EXAMPLE 3
1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
{2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-meth-
yl-propyl}-amide
[0110] ##STR9##
Step 1: 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
{2-methyl-2-[5-(1-oxo-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-propyl-
}-amide
[0111] A mixture of the product of Example 1, Step 6 (0.1 g, 0.29
mmol), 1-hydroxybenzo-triazole (0.06 g, 0.44 mmol) and polymer
bound 1,3-dicyclohexylcarbodiimide (0.4 g, 0.6 mmol, 1.52 mmol/g)
in a 1:1 mixture of dichloromethane and DMF (4 ml) was stirred at
room temperature for 30 min. A solution of
1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO
97/25309] (0.098 g, 0.44 mmol) in DMF (2 ml) was then added and the
mixture stirred at room temperature overnight. The reaction mixture
was then filtered, the solvent removed in vacuo and the crude
residue purified by silica gel chromatography eluting with a 1:9:90
mixture of 0.88 ammonia solution:methanol:dichloromethane to give
the title compound (0.12 g, 80%) as a yellow oil; MS(AP+) m/e 516
[M+H].sup.+.
Step 2: 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
{2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-meth-
yl-propyl}-amide
[0112] The title compound (0.07 g, 70%) was prepared from the
product of Step 1 as described in Example 1 Step 7; MS(AP+) m/e
531[M+H].sup.+.
EXAMPLE 4
5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0113] ##STR10##
Step 1.
4-[4-(1-Methoxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-yl]--
piperidine-1-carboxylic acid tert-butyl ester
[0114] The title compound (0.765 g, 79%) was prepared from the
product of Example 1 Step 4 and 4-formyl-piperidine-1-carboxylic
acid tert-butyl ester (S. I. Klein et al; J. Med. Chem., 1998, 41,
2492) as described in Example 1 Step 5; MS(AP+) m/e 488
[M+H].sup.+.
Step 2.
5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
[0115] The title compound (0.55 g, 90%) was prepared from the
product of Step 1 as described in Example 1 Step 6; MS(AP+) m/e 359
[M+H].sup.+.
Step 3.
5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0116] The title compound (0.35 g, 90%) was prepared from the
product of Step 2 as described in Example 1 Step 7 followed by
purification by silica gel chromatography eluting with 0.88 ammonia
solution:methanol:dichloromethane mixtures. MS(AP+) m/e 374
[M+H].sup.+.
EXAMPLE 5
5-[2-(1-{1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-mathanoyl}-piperidin-4-yl)-
-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one oxime
[0117] ##STR11##
[0118] The title compound (0.028 g, 28%) was prepared from the
product of Example 4 and
1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO
97/25309] as described in Example 3 Step 1; MS(AP+) m/e 543
[M+H].sup.+.
EXAMPLE 6
5-[2-(1-Furan-3-ylmethyl-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]--
indan-1-one oxime
[0119] ##STR12##
[0120] A mixture of the product of Example 4 (0.093 g, 0.25 mmol),
3-furaldehyde (0.024 g, 0.25 mmol) and polymer bound
trimethylammonium cyanoborohydride (0.125 g, 0.5 mmol, 4 mmol/g) in
methanol (3 ml) containing acetic acid (0.1 ml) was stirred at room
temperature for 24 hours. The reaction mixture was poured onto the
top of an SCX column eluting with 0.880 ammonia solution:methanol
mixtures (0-10%), the product was then purified further by silica
gel chromatography eluting with a 1:9:90 mixture of 0.880 ammonia
solution:ethanol:dichloromethane to give the title compound (0.070
g, 62%) as a solid; MS(AP+) m/e 454 [M+H].sup.+.
EXAMPLE 7
5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-
-indan-1-one oxime
[0121] ##STR13##
Step 1. 1-(2-Methoxy-ethyl)-piperidine-4-carbaldehyde
[0122] To a solution of 1-(2-methoxy-ethyl)-piperidine-4-carboxylic
acid ethyl ester [WO97/25309] (2.0 g, 9.3 mmol) in toluene (40 ml)
at -78.degree. C. was added diisobutylaluminum hydride (10.2 ml, 1M
solution in tetrahydrofuran, 10.2 mmol) over 1 hour. After 1 hour
the reaction mixture was quenched with methanol (5 ml) and
saturated ammonium acetate solution (5 ml). The mixture was stirred
at room temperature for 1 hour and then filtered. The filtrate was
concentrated to give the title compound as a yellow oil (1.1 g,
69%); MS(AP+) m/e 172 [M+H].sup.+.
Step 2.
5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidaz-
ol-4-yl}-indan-1-one O-methyl-oxime
[0123] The title compound (0.27 g, 32%) was prepared from the
product of Step 1 and the product of Example 1 Step 4 as described
in Example 1 Step 5; MS(AP+) m/e 446 [M+H].sup.+.
Step 3.
5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidaz-
ol-4-yl}-indan-1-one
[0124] The title compound (0.193 g, 93%) was prepared from the
product of Step 2 as described in Example 1 Step 6; MS(AP+) m/e 417
[M+H].sup.+.
Step 4.
5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidaz-
ol-4-yl}-indan-1-one oxime
[0125] The title compound (0.105 g, 68%) was prepared from the
product of Step 3 as described in Example 4 Step 3; MS(AP+) m/e 432
[M+H].sup.+.
EXAMPLE 8
5-(2-Aminomethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0126] ##STR14##
Step 1.
[4-(1-Methoxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-ylmeth-
yl]-carbamic acid tert-butyl ester
[0127] The title compound (1.04 g, 70%) was prepared from the
product of Example 1 Step 4 and (2-oxo-ethyl)-carbamic acid
tert-butyl ester as described in Example 1 Step 5; MS(AP+) m/e 434
[M+H].sup.+.
Step 2.
5-(2-Aminomethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
[0128] The title compound (0.21 g, 30%) was prepared from the
product of Step 1 as described in Example 1 Step 6; MS(AP+) m/e 305
[M+H].sup.+.
Step 3.
5-(2-Aminomethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0129] The title compound (0.064 g, 80%) was prepared from the
product of Step 2 as described in Example 4 Step 3; MS(AP+) m/e 320
[M+H].sup.+.
EXAMPLE 9
1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-am-
ide
[0130] ##STR15##
Step 1. 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
[4-(1-oxo-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-amide
[0131] The title compound (0.095 g, 67%) was prepared from the
product of Example 8 Step 2 and
1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO
97/25309] as described in Example 3 Step 1; MS(AP+) m/e 474
[M+H].sup.+.
Step 2. 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid
[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-am-
ide
[0132] The title compound (0.041 g, 42%) was prepared from the
product of Step 1 as described in Example 4 Step 3; MS(AP+) m/e 531
[M+H].sup.+.
EXAMPLE 10
5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0133] ##STR16##
Step 1.
5-[2-(1,1-Dimethoxy-methyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-
-1-one O-methyl oxime
[0134] The title compound (1.05 g, 79%) was prepared from the
product of Example 1 Step 4 and dimethoxy-acetaldehyde (45%
solution in tert-butyl methyl ether) as described in Example 1 Step
5; MS(AP+) m/e 379 [M+H].sup.+.
Step 2.
4-(1-oxo-indan-5-yl)-5-pyridin-4-yl-1H-imidazole-2-carbaldehyde
[0135] The title compound (0.92 g, 90%) was prepared from the
product of Step 1 as described in Example 1 Step 6; MS(AP+) m/e 303
[M+H].sup.+.
Step 3.
5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-
-one
[0136] The title compound (0.11 g, 44%) was prepared from the
product of Step 2 and piperidine as described in Example 6; MS(AP+)
m/e 373 [M+H].sup.+.
Step 4.
5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-
-one oxime
[0137] The title compound (0.55 g, 53%) was prepared from the
product of Step 3 as described in Example 4 Step 3; MS(AP+) m/e 387
[M+H].sup.+.
EXAMPLE 11
5-(2-morpholin-4-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0138] ##STR17##
[0139] The title compound (0.034 g, 13%) was prepared from the
product of Example 10 Step 2 and morpholine according to the
procedures described in Example 10 Steps 3 and 4; MS(AP+) m/e 390
[M+H].sup.+.
EXAMPLE 12
5-(5-Pyridin-4-yl-2-(2,3,5,6-tetrahydro-[1,2']bipyrazin-4-ylmethyl)-1H-imi-
dazol-4-yl]-indan-1-one oxime
[0140] ##STR18##
[0141] The title compound (0.038 g, 17%) was prepared from the
product of Example 10 Step 2 and
3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl according to the procedures
described in Example 10 Steps 3 and 4; MS(AP+) m/e 467
[M+H].sup.+.
EXAMPLE 13
5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one
oxime
[0142] ##STR19##
Step 1.
4-[4-(1-Oxo-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-methyl]pipera-
zine-1-carboxylic acid tert-butyl ester
[0143] The title compound (0.35 g, 74%) was prepared from the
product of Example 10 Step 2 and piperazine-1-carboxylic acid
tert-butyl ester as described in Example 6; MS(AP+) m/e 474
[M+H].sup.+.
Step 2.
5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-
-one
[0144] A solution of the product of Step 1 (0.350 g, 0.74 mmol) in
dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was stirred
at room temperature for 3 hours. The solution was concentrated and
the residue co-evaporated with dichloromethane. The residue was
dissolved in water (10 ml) and the solution was neutralised with
sodium carbonate solution. The solvent was evaporated in vacuo and
the resulting solid was dried over phosphorus pentoxide to give
title compound which was used in the next step; MS(AP+) m/e 374
[M+H].sup.+.
Step 3.
5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-
-one oxime
[0145] The title compound (0.105 g, 37%) was prepared from the
product of Step 2 as described in Example 4 Step 3; MS(AP+) m/e 389
[M+H].sup.+.
EXAMPLE 14
5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-y-
l}-indan-1-one
[0146] ##STR20##
Step 1: 5-Bromo-indan-1-one O-methyl-oxime
[0147] To a solution of 5-bromo-indanone (100 g, 0.474 mol) in
ethanol (650 ml) under argon was added methoxylamine hydrochloride
(198 g, 2.38 mol) and pyridine (125 ml). The mixture was refluxed
for 2.5 hours, cooled to room temperature and poured into saturated
aqueous sodium hydrogen carbonate solution. The mixture was then
extracted with ethyl acetate and the organic phase dried (sodium
sulphate) and then concentrated in vacuo. The crude material was
recrystallised from isopropanol to furnish the title compound, (110
g, 97%), as a brown solid; .sup.1H NMR (CDCl.sub.3) 7.52 (1H, d, J
8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1 Hz), 3.97
(3H, s), 2.99 (2H, m), 2.99 (2H, m), 2.85 (2H, m).
Step 2: 1-Methoxyimino-indan-5-carbaldehyde
[0148] To a solution of the product of Step 1 (112 g, 0.46 mol) in
THF (1500 ml) at -60.degree. C. under argon, was added n-BuLi (325
ml, 0.52 mol) over 1 hour. After stirring at -60.degree. C. for 1
hour a solution of DMF (39.7 ml) in THF (50 ml) was added dropwise
over 1 hour. The reaction was stirred at -60.degree. C. for 1 hour
before being allowed to warm to room temperature. After 1 hour the
reaction was quenched with saturated aqueous sodium hydrogen
carbonate solution and extracted into ethyl acetate. The organic
phase was then dried (sodium sulphate), concentrated in vacuo and
the residue purified by silica gel chromatography, to give the
title compound (57 g, 65%) as a yellow solid; .sup.1H NMR
(CDCl.sub.3) 10.0 (1H, s), 7.83-7.73 (3H, m), 4.02 (3H, s), 3.10
(2H, m), 2.92 (2H, m).
Step 3:
5-(1,2-Dihydroxy-2-pyridin-4-yl-ethyl)-indan-1-one-O-methyl-oxime
[0149] To a solution of
4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine [T. F. Gallagher
et al; Bioorg. Med. Chem., 1997, 5, 49] (71.5 g, 0.32 mol) in THF
(800 ml) at -50.degree. C. under argon was added LDA (162 ml, 2M in
heptane/THF/ethylbenzene, 0.324 mol) over 1 hour. The mixture was
stirred at -40.degree. C. for a further 1 hour before a solution of
the product of Step 2 (55 g, 0.29 mol) in THF (600 ml) was added
over 1 hour. The reaction was then allowed to warm to room
temperature overnight before being quenched by the addition of
saturated aqueous sodium hydrogen carbonate solution and then
extracted into ethyl acetate. The organic phase was dried (sodium
sulphate) and concentrated in vacuo to give a brown oil (125
g).
[0150] The oil was then dissolved in THF (1500 ml), treated with
TBAF (356 ml, 0.356 mol) and stirred for 1 hour. The reaction
mixture was then evaporated and the residue partitioned between
water and ethyl acetate. The organic phase was then dried (sodium
sulphate) and concentrated to give the title compound (57 g, 64%)
as a pale yellow solid which was used without further purification.
.sup.1H NMR (CDCl.sub.3) 8.38 (2H, m), 7.57 (1H, m), 7.12-6.99 (4H,
m), 4.88 (1H, m), 4.66 (1H, m), 3.96 (3H, s), 2.93 (2H, m), 2.85
(2H, m).
Step 4:
1-(1-Methoxyimino-indan-5-yl)-2-pyridin-4-yl-ethane-1,2-dione
[0151] To a mixture of DMSO (43 ml, 0.56 mol) and dichloromethane
(800 ml) at -70.degree. C. under argon, was added oxalyl chloride
(43.2 g) and then a solution of the product of Step 3 (55 g, 0.185
mol) in a mixture of dichloromethane/DMSO (1000 ml/60 ml) over 2
hours at -60.degree. C. After stirring for 2 hours at -60.degree.
C., triethylamine (154 ml) was added dropwise and the mixture then
allowed to warm to room temperature overnight. The reaction mixture
was then quenched with water, the organic phase separated then
washed with water, dried (sodium sulphate) and concentrated to
yield the title compound (51 g, 94%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3) 8.87 (2H, d), 7.89-7.77 (5H, m), 4.03 (3H, s), 3.09
(2H, m), 2.93 (2H, m).
Step 5:
5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-phenyl-1H-imidazol-4-
-yl}-indan-1-one O-methyl-oxime
[0152] A mixture of the product of Step 4 (0.3 g, 1.02 mmol),
4-(3-dimethylamino-propyloxy)-benzaldehyde (0.27 ml, 1.33 mmol) and
ammonium acetate (0.785 g, 10.2 mmol) in acetic acid (10 ml) was
heated to 100.degree. C. for 1 hour. The reaction was then cooled
to room temperature, poured into ice/0.880 ammonia solution and
extracted with ethyl acetate. The organic extract was then dried
(magnesium sulphate), concentrated in vacuo and the crude material
purified by silica gel chromatography eluting with a 1:9:90 mixture
of 0.88 ammonia solution:methanol:ethyl acetate to give the title
compound (0.08 g, 16%) as a yellow solid; MS(AP+) m/e 483
[M+H].sup.+.
Step 6:
5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imid-
azol-4-yl}-indan-1-one
[0153] A mixture of the product of Step 5 (0.07 g, 0.146 mmol) and
5M HCl (4 ml) in dioxan (3 ml) was heated to 100.degree. C. for 1
hour. Acetone (3 ml) was then added and the heating continued for a
further 1.5 hours before the mixture was cooled to room
temperature, neutralised with 1 M sodium hydroxide solution and
extracted with ethyl acetate. The organic extract was then washed
with water, dried (magnesium sulphate), concentrated in vacuo and
the crude material purified by silica gel chromatography, eluting
with a 2:18:80 mixture of 0.88 ammonia solution:methanol:ethyl
acetate to give the title compound (0.035 g, 53%) as a yellow
solid; MS(AP+) m/e 453 [M+H].sup.+.
EXAMPLE 15
5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-y-
l}-indan-1-one oxime
[0154] ##STR21##
Step 1:
5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imid-
azol-4-yl}-indan-1-one oxime
[0155] To a solution of the product of Example 14, Step 6 (0.07 g,
0.155 mmol) in ethanol (3 ml) at 80.degree. C. was added aqueous
hydroxylamine (1.5 ml, 50% in water). After 30 minutes the mixture
was cooled to room temperature and concentrated in vacuo to give
the title compound, (0.072 g, 100%) as a yellow solid; MS(AP+) m/e
468 [M+H].sup.+.
EXAMPLE 16
5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}--
1-indanone
[0156] ##STR22##
Step 1:
5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazo-
l-4-yl}-indan-1-one-O-methyl-oxime
[0157] The title compound (0.19 g, 30%) was prepared from the
product of Example 14 Step 4 and
4-(2-dimethylamino-ethoxy)-benzaldehyde [WO 99/19293] as described
in Example 14 Step 5; MS(AP+) m/e 468 [M+H].sup.+.
Step 2:
5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazo-
l-4-yl}-1-indanone
[0158] The title compound (0.313 g, 56%) was prepared from the
product of Step 1 as described in Example 14 Step 6; MS(AP+) m/e
439 [M+H].sup.+.
EXAMPLE 17
5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}--
indan-1-one oxime
[0159] ##STR23##
Step 1
5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-
-4-yl}-indan-1-one oxime
[0160] The title compound (0.321 g, 100%) was prepared from the
product of Example 16 Step 2 as described in Example 15 Step 1;
MS(AP+) m/e 454 [M+H].sup.+.
EXAMPLE 18
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-
-indan-1-one
[0161] ##STR24##
Step 1:
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidaz-
ol-4-yl}-indan-1-one-O-methyl-oxime
[0162] The title compound (0.15 g, 20%) was prepared from the
product of Example 14 Step 4 and
4-(2-morpholin-4-yl-ethoxy)-benzaldehyde [WO 96/28448] as described
in Example 14 Step 5; MS(AP+) m/e 510 [M+H].sup.+
Step 2:
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidaz-
ol-4-yl}-indan-1-one
[0163] The title compound (0.048 g, 36%) was prepared from the
product of Step 1 as described in Example 14 Step 6; MS(AP+) m/e
481 [M+H].sup.+.
EXAMPLE 19
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-
-indan-1-one oxime
[0164] ##STR25##
Step 1:
5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidaz-
ol-4-yl}-indan-1-one oxime
[0165] The title compound (0.048 g, 97%) was prepared from the
product of Example 18 Step 2 as described in Example 15 Step 1;
MS(AP+) m/e 496 [M+H].sup.+.
EXAMPLE 20
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one
[0166] ##STR26##
Step 1:
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one-O-m-
ethyl-oxime
[0167] The title compound (0.11 g, 28%) was prepared from the
product of Example 14 Step 4 and pyridine-3-carbaldehyde as
described in Example 14 Step 5; MS(AP+) m/e 382 [M+H].sup.+.
Step 2:
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one
[0168] The title compound (0.025 g, 25%) was prepared from the
product of Step 1 as described in Example 14 Step 6; MS(AP+) m/e
353 [M+H].sup.+.
EXAMPLE 21
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-one
oxime
[0169] ##STR27##
Step 1:
5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-one
oxime
[0170] The title compound (0.075 g, 76%) was prepared from the
product of Example 20 Step 2 as described in Example 15 Step 1;
MS(AP+) m/e 368[M+H].sup.+.
EXAMPLE 22
5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
[0171] ##STR28##
Step 1:
4-[2-Phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]--
pyridine
[0172] 4-(2-Phenyl-1H-imidazol-4-yl)-pyridine [N. J. Liverton et.
al., J. Med. Chem., 1999, 42, 2180] (17.8 g, 80.5 mmol) was
dissolved in DMF (150 ml) and cooled to 0.degree. C. The solution
was then treated with sodium hydride (3.54 g, 60% dispersion, 88.6
mmol), and stirred for 25 minutes maintaining the temperature of
0.degree. C.
[0173] 2-(Trimethylsilyl)ethoxymethyl chloride (14.77 g, 88.6 mmol)
was then added dropwise over 5 minutes and the mixture warmed to
room temperature overnight. The reaction was then poured into a
saturated solution of sodium hydrogen carbonate and extracted
several times with diethyl ether. The combined ether extracts were
then dried (sodium sulphate), concentrated in vacuo and the residue
purified by silica gel chromatography, eluting with ethyl acetate
to give the title compound as a pale yellow solid (16.8 g, 59%);
MS(AP+) m/e 353 [M+H].sup.+.
Step 2:
4-[5-Bromo-2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazo-
l-4-yl]-pyridine
[0174] To a solution of the product of Step 1 (15 g, 42.6 mmol) in
dichloromethane (300 ml) at room temperature was added bromine
(6.81 g, 2.38 ml, 46.5 mmol) followed by a saturated solution of
sodium carbonate (150 ml). The mixture was stirred for 40 minutes
before being separated and the organic layer washed successively
with water and brine. The organic layer was then dried (magnesium
sulphate) and concentrated in vacuo to give the title compound (18.
1 g, 99%) as a brown viscous oil which was used without further
purification; MS(AP+) m/e 431/433 [M+H].sup.+.
Step 3:
4-[2-Phenyl-5-tributylstannanyl-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H -imidazol-4-yl]-pyridine
[0175] To a solution of the product of Step 2 (13.4 g, 31.2 mmol)
in THF (200 ml) at -78.degree. C. was added dropwise .sup.tBuLi (22
ml, 1.7M, 38 mmol). After 25 minutes tributyltin chloride (12.37 g,
10.3 ml, 38 mmol) was added dropwise and the mixture was then
allowed to reach room temperature overnight. The reaction was then
poured into a saturated solution of sodium hydrogen carbonate and
washed several times with diethyl ether. The combined organic
layers were dried (magnesium sulphate), concentrated in vacuo and
the residue purified by silica gel chromatography, eluting with a
0.5:4.5:45:50 mixture of 0.88 ammonia
solution:methanol:hexane:diethyl ether to give the title compound
(18.5 g, 93%) as a brown viscous oil; MS(AP+) m/e
641/643/644[M+H].sup.+.
Step 4:
5-[2-Phenyl-5-pyridin-4-yl-3-(2-trimethylsilanyl-ethoxymethyl)-1H--
imidazol-4-yl]-indan-1-one
[0176] Palladium acetate (0.025 g, 0.11 mmol) and
triphenylphosphine (0.06 g, 0.22 mmol) were suspended in toluene (1
ml). 5-bromoindanone (240 mg, 11 mmol) was then added and the
mixture heated to 100.degree. C. for 5 min. The solution was then
treated with a solution of the product of Step 3 (0.6 g, 0.94 mmol)
in toluene (1 ml) and stirred for 18 hours at 100.degree. C. After
cooling the solvent was removed in vacuo and the residue purified
by silica gel chromatography, eluting with ethyl acetate to afford
the title compound (0.25 g, 55%) as a yellow solid; MS(AP+) m/e 482
[M+H].sup.+.
Step 5:
5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
[0177] The product of Step 4 (0.32 g, 0.66 mmol) was dissolved in
ethanol (4 ml), 5M aqueous hydrochloric acid solution (3 ml) added
and the mixture heated to reflux for 30 min. On cooling, the
solvent was removed in vacuo to afford the title compound as a
yellow solid (0.27 g, 96%); MS(AP+) m/e 352 [M+H].sup.+.
EXAMPLE 23
5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime
[0178] ##STR29##
Step 1: 5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one
oxime
[0179] A solution of the product of Example 22 Step 5 (0.06 g, 0.17
mmol) and hydroxylamine hydrochloride (0.035 g, 0.5 mmol) in 40%
aqueous sodium hydroxide (2 ml) and ethanol (3 ml) was heated to
reflux for 30 min. On cooling the mixture was neutralised with
aqueous 2M hydrochloric acid and extracted into ethyl acetate. The
organic layer was washed with brine, dried (magnesium sulphate) and
concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with a 1:9:90 mixture of 0.88 ammonia
solution:methanol:dichloromethane to give the title compound (0.05
g, 80%) as a yellow solid; MS(AP+) m/e 367 [M+H].sup.+.
BIOLOGICAL EXAMPLES
[0180] The activity of compounds of formula (I) as B-Raf inhibitors
may be determined by the following in vitro assays:
Fluorescence Anisotropy Kinase Binding Assay
[0181] The kinase enzyme, fluorescent ligand and a variable
concentration of test compound are incubated together to reach
thermodynamic equilibrium under conditions such that in the absence
of test compound the fluorescent ligand is significantly (>50%)
enzyme bound and in the presence of a sufficient concentration
(>10.times.K.sub.i) of a potent inhibitor the anisotropy of the
unbound fluorescent ligand is measurably different from the bound
value.
[0182] The concentration of kinase enzyme should preferably be
>1.times.K.sub.f. The concentration of fluorescent ligand
required will depend on the instrumentation used, and the
fluorescent and physicochemical properties. The concentration used
must be lower than the concentration of kinase enzyme, and
preferably less than half the kinase enzyme concentration. A
typical protocol is:
[0183] All components dissolved in Buffer of composition 50 mM
HEPES, pH 7.5, 1 mM CHAPS, 10 mM MgCL.sub.2.
[0184] B-Raf Enzyme concentration: 1 nM
[0185] Fluorescent ligand concentration: 0.5 nM
[0186] Test compound concentration: 0.1 nM-100 uM
[0187] Components incubated in 10 ul final volume in LJL HE 384
type B black microtitre plate until equilibrium reached (Over 3 h,
up to 30 h)
[0188] Fluorescence anisotropy read in LJL Acquest. [0189]
Definitions: K.sub.i=dissociation constant for inhibitor binding
[0190] K.sub.f=dissociation constant for fluorescent ligand
binding
[0191] The fluorescent ligand is the following compound:
##STR30##
[0192] which is derived from
5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chloropheno-
l and rhodamine green.
[0193] Raf Kinase Assay
[0194] Activity of human recombinant B-Raf protein was assessed in
vitro by assay of the incorporation of radiolabelled phosphate to
recombinant MAP kinase (MEK), a known physiologic substrate of
B-Raf. Catalytically active human recombinant B-Raf protein was
obtained by purification from sf9 insect cells infected with a
human B-Raf recombinant baculovirus expression vector. To ensure
that all substrate phosphorylation resulted from B-Raf activity, a
catalytically inactive form of MEK was utilised. This protein was
purified from bacterial cells expression mutant inactive MEK as a
fusion protein with glutathione-S-transferase (GST-kdMEK).
[0195] Method: Standard assay conditions of B-Raf catalytic
activity utilised 3 ug of GST-kdMEK, 10 uM ATP and 2 uCi
.sup.33P-ATP, 50 mM MOPS, 0.1 mM EDTA, 0.1M sucrose, 10 mM
MgCl.sub.2 plus 0.1% dimethylsulphoxide (containing compound where
appropriate) in a total reaction volume of 30 ul. Reactions were
incubated at 25.degree. C. for 90 minutes and reactions terminated
by addition of EDTA to a final concentration of 50 uM. 10 ul of
reaction was spotted to P30 phosphocellulose paper and air dried.
Following four washes in ice cold 10% trichloroacetic acid, 0.5%
phosphoric acid, papers were air dried prior to addition of liquid
scintillant and measurement of radioactvity in a scintillation
counter.
[0196] Results: The compounds of the examples were found to be
effective in inhibiting B-Raf mediated phosphorylation of GST-kdMEK
substrate having IC.sub.50's of <3 .mu.M.
[0197] The activity of compounds as Raf inhibitors may also be
determined by the assays described in WO 99/10325; McDonald, O. B.,
Chen, W. J., Ellis, B., Hoffman, C., Overton, L., Rink, M., Smith,
A., Marshall, C. J. and Wood, E. R. (1999) A scintillation
proximity assay for the Raf/MEK/ERK kinase cascade: high throughput
screening and identification of selective enzyme inhibitors, Anal.
Biochem. 268: 318-329 and AACR meeting New Orleans 1998 Poster
3793.
[0198] The neuroprotective properties of B-Raf inhibitors may be
determined by the following in vitro assay:
[0199] Neuroprotective Properties of B-Raf Inhibitors in Rat
Hippocampal Slice Cultures
[0200] Organotypic cultures provide an intermediate between
dissociated neuronal cell cultures and in-vivo models of oxygen and
glucose deprivation (OGD). The majority of glial-neuronal
interactions and neuronal circuitry are maintained in cultured
hippocampal slices, so facilitating investigation of the patterns
of death among differing cell types in a model that resembles the
in vivo situation. These cultures allow the study of delayed
cellular damage and death 24 hours, or more, post-insult and permit
assessment of the consequences of long-term alterations in culture
conditions. A number of laboratories have reported delayed neuronal
damage in response to OGD in organotypic cultures of the
hippocampus (Vornov et al, Stroke, 1994, 25, 57-465; Newell et al.,
Brain Res., 1995, 676, 38-44). Several classes of compounds have
been shown to protect in this model, including EAA antagonists
(Strasser et al., Brain Res., 1995, 687, 167-174), Na channel
blockers (Tasker et al., J. Neurosci., 1992, 12, 98-4308) and Ca
channel blockers (Pringle et al., Stroke, 1996, 7, 2124-2130). To
date, relatively little is known of the roles of intracellular
kinase mediated signalling pathways in neuronal cell death in this
model.
[0201] Method: Organotypic hippocampal slice cultures were prepared
using the method of Stoppini et al., J. Neurosci. Methods, 1995,
37, 173-182. Briefly, 400 micron sections prepared from hippocampi
of 7-8 day postnatal Sprague Dawley rats are cultured on semiporous
membranes for 9-12 days. OGD is then induced by incubation in serum
and glucose-free medium in an anaerobic chamber for 45 minutes.
Cultures are then returned to the air/CO.sub.2 incubator for 23
hours before analysis. Propidium iodide (PI) is used as an
indicator of cell death. PI is non toxic to neurones and has been
used in many studies to ascertain cell viability. In damaged
neurons PI enters and binds to nucleic acids. Bound PI shows
increased emission at 635 nm when excited at 540 nm. One PI
fluorescence image and one white light image are taken and the
proportion of cell death analysed. The area of region CA1 is
defined from the white light image and superimposed over the PI
image. The PI signal is thresholded and area of PI damage expressed
as a percentage of the CA1 area. Correlation between PI
fluorescence and histologically confirmed cell death has been
validated previously by Nissl-staining using cresyl fast violet
(Newell et al., J. Neurosci., 1995, 15, 7702-771 1).
[0202] Throughout the specification and the claims which follow,
unless the context requires otherwise, the word `comprise`, and
variations such as `comprises` and `comprising`, will be understood
to imply the inclusion of a stated integer or step or group of
integers but not to the exclusion of any other integer or step or
group of integers or steps.
[0203] The application of which this description and claims forms
part may be used as a basis for priority in respect of any
subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described
herein. They may take the form of composition, process, or use
claims and may include by way of example and without limitation the
following claims.
* * * * *