U.S. patent application number 12/140510 was filed with the patent office on 2009-06-11 for new compounds.
Invention is credited to Stefan Berg, Sven Hellberg, Martin Nylof, Yafeng Xue.
Application Number | 20090149460 12/140510 |
Document ID | / |
Family ID | 20287447 |
Filed Date | 2009-06-11 |
United States Patent
Application |
20090149460 |
Kind Code |
A1 |
Berg; Stefan ; et
al. |
June 11, 2009 |
New Compounds
Abstract
The present invention provides new compounds of formula Ia and
Ib: ##STR00001## as well as a process for their preparation and new
intermediates used therein, pharmaceutical formulations containing
said therapeutically active compounds and to the use of said active
compounds in therapy.
Inventors: |
Berg; Stefan; (Sodertalje,
SE) ; Hellberg; Sven; (Sodertalje, SE) ;
Nylof; Martin; (Sodertalje, SE) ; Xue; Yafeng;
(Molndal, SE) |
Correspondence
Address: |
ASTRA ZENECA PHARMACEUTICALS LP;GLOBAL INTELLECTUAL PROPERTY
1800 CONCORD PIKE
WILMINGTON
DE
19850-5437
US
|
Family ID: |
20287447 |
Appl. No.: |
12/140510 |
Filed: |
June 17, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10509268 |
Sep 27, 2004 |
7399780 |
|
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12140510 |
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Current U.S.
Class: |
514/235.2 ;
514/339; 544/144; 546/277.7 |
Current CPC
Class: |
A61P 31/18 20180101;
A61P 25/00 20180101; A61P 43/00 20180101; A61P 31/00 20180101; A61P
9/00 20180101; A61P 25/16 20180101; C07D 401/14 20130101; A61P
15/18 20180101; A61P 17/00 20180101; A61P 25/24 20180101; A61P
15/16 20180101; A61P 17/14 20180101; A61P 25/18 20180101; C07D
401/04 20130101; A61P 3/10 20180101; A61P 21/00 20180101; A61P
17/04 20180101; A61P 9/10 20180101; A61P 15/00 20180101; A61P 3/00
20180101; A61P 25/28 20180101; A61P 29/00 20180101; A61P 21/02
20180101; C07D 413/14 20130101; C07D 417/14 20130101; C07D 405/14
20130101; C07D 403/04 20130101; A61P 25/14 20180101 |
Class at
Publication: |
514/235.2 ;
546/277.7; 544/144; 514/339 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 401/04 20060101 C07D401/04; C07D 413/04 20060101
C07D413/04; A61P 9/10 20060101 A61P009/10; A61P 25/28 20060101
A61P025/28; A61K 31/4439 20060101 A61K031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2002 |
SE |
0200979-3 |
Claims
1-41. (canceled)
42. A method of prevention and/or treatment of conditions
associated with glycogen synthase kinase-3, comprising
administering to a mammal, including man in need of such prevention
and/or treatment, a therapeutically effective amount of a compound
of formula Ia ##STR00031## wherein the compound is in the form of a
base or a pharmaceutically acceptable salt thereof, and wherein: P
is a 6-membered ring containing one nitrogen; R.sup.1 is hydrogen;
R.sup.2 is C.sub.0-6alkylcyano; R.sup.3 is
C.sub.0-6alkylNR.sup.4R.sup.5; m is 1; n is 1; R.sup.4 is selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, C.sub.1-6alkylNR.sup.14R.sup.15, and a 5-
or 6-membered heterocyclic group containing one or two heteroatoms
independently selected from N, O, and S, wherein the heterocyclic
group is optionally substituted by a group Y; R.sup.5 is selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, and C.sub.1-6alkylNR.sup.14R.sup.15; or
R.sup.4 and R.sup.5 together with the N to which they are attached
may form a 6-membered heterocyclic group containing one nitrogen
and one oxygen; and wherein any C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, and C.sub.0-6alkylheteroaryl group defined
under R.sup.2 to R.sup.5 is optionally substituted by one or more
groups Z; R.sup.14 and R.sup.15 are independently selected from
hydrogen, C.sub.1-6alkyl, and C.sub.0-6alkylC.sub.3-6cycloalkyl,
wherein R.sup.14 and R.sup.15 optionally together form a 5- or
6-membered heterocyclic group containing one or more heteroatoms
independently selected from N, O, and S, wherein the heterocyclic
group is optionally substituted by a group Y; Z is independently
selected from the group consisting of oxo, halogen, nitro, CN,
OR.sup.16, C.sub.1-6alkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.16R.sup.17, NR.sup.16R.sup.17,
CONR.sup.16R.sup.17NR.sup.16(CO)R.sup.17, O(CO)C.sub.1-6alkyl,
(CO)OC.sub.1-6alkyl, COR.sup.16, (SO.sub.2)NR.sup.16R.sup.17,
SO.sub.2R.sup.16, SOR.sup.16, (CO)C.sub.1-6alkylNR.sup.16R.sup.17,
(SO.sub.2)C.sub.1-6alkylNR.sup.16R.sup.17, phenyl, heteroaryl, and
a 5- or 6-membered heterocyclic group containing one or two
heteroatoms independently selected from N, O, and S, wherein the
phenyl, heteroaryl, and heterocyclic groups are optionally
substituted by a group Y; Y is selected from the group consisting
of oxo, halogen, nitro, CN, OR.sup.16, C.sub.1-6alkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.16R.sup.17, NR.sup.16R.sup.17,
CONR.sup.16R.sup.17, NR.sup.16(CO)R.sup.17, O(CO)C.sub.1-6alkyl,
(CO)OC.sub.1-6alkyl, COR.sup.16, (SO.sub.2)NR.sup.16R.sup.17,
SO.sub.2R.sup.16, SOR.sup.16, (CO)C.sub.1-6alkylNR.sup.16R.sup.17
(SO.sub.2)C.sub.1-6alkylNR.sup.16R.sup.17, phenyl,
C.sub.0-6alkylaryl, and heteroaryl, wherein the phenyl,
C.sub.0-6alkylaryl, and heteroaryl groups are optionally
substituted with one or more substituents selected from the group
consisting of halogen, nitro, CN, OR.sup.16, C.sub.1-6alkyl,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy, and trifluoromethoxy; R.sup.16 and R.sup.17 are
independently selected from hydrogen and C.sub.1-6alkyl, and
wherein R.sup.16 and R.sup.17 optionally together form a 5- or
6-membered heterocyclic group containing one or more heteroatoms
independently selected from N, O, and S.
43. A method according to claim 42 wherein in said compound of
formula Ia, R.sup.5 is C.sub.1-6ylNR.sup.14R.sup.15, and R.sup.4 is
selected from hydrogen, C.sub.1-6alkyl; or R.sup.4 and R.sup.5
together with the N to which they are attached form a 6-membered
heterocyclic group containing one or more heteroatoms selected
independently from N and O, wherein said heterocyclic group may
optionally be substituted by a group Y; and wherein R.sup.14 and
R.sup.15 may together form a 5-membered heterocyclic group
containing one or more heteroatoms, selected independently from N,
and O Y is selected from C.sub.1-6alkyl, C.sub.0-6alkylaryl,
NR.sup.16R.sup.17, phenyl, wherein the phenyl may be optionally
substituted with nitro and trifluoromethyl; wherein R.sup.16 and
R.sup.17 may together form a 5-membered heterocyclic group
containing one N heteroatom, in the form of a base or a
pharmaceutically acceptable salt thereof.
44. A method according to claim 42 wherein in said compound of
formula Ia, P is pyridyl; R.sup.2 is CN; R.sup.3 is
C.sub.0-6alkylNR.sup.4R.sup.5; wherein R.sup.4 and R.sup.5 may
together form a 5- or 6-membered heterocyclic group containing one
or more heteroatoms selected independently from N and O, in the
form of a base or a pharmaceutically acceptable salt thereof.
45. A method according to claim 42 wherein in said compound of
formula Ia, R.sup.4 and R.sup.5 together form a 6-membered
heterocyclic group containing one or more heteroatoms selected
independently from N and O, in the form of a base or a
pharmaceutically acceptable salt thereof.
46. A method according to claim 42 wherein in said compound of
formula Ia is a compound selected from:
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole--
5-carbonitrile;
2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbon-
itrile;
3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hyd-
roxy-1H-indole-5-carbonitrile;
2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5--
carbonitrile;
3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitril-
e;
2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonit-
rile;
3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol,
or
2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonit-
rile; or a pharmaceutically acceptable salt thereof.
47. A method according to claim 42 wherein in said compound of
formula Ia is a compound selected from:
2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole--
5-carbonitrile;
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5--
carbonitrile;
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole--
5-carbonitrile;
2-Hydroxy-3-{5-(pyrrolidin-1-ylmethyl)pyridin-2-yl}-1H-indole-5-carbonitr-
ile;
2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-i-
ndole-5-carbonitrile;
2-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H--
indole-5-carbonitrile;
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;
6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2--
ol; 6-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;
5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;
3-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carboni-
trile;
3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-i-
ndole-5-carbonitrile;
2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indo-
le-5-carbonitrile;
3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-
-carbonitrile;
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol;
5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;
3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-i-
ndol-2-ol;
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-
-indol-2-ol;
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide-
;
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)n-
icotinamide;
5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H--
indol-2-ol;
3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-
-indol-2-ol;
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)py-
ridine-3-sulfonamide;
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thia-
zol-4-yl)-1H-indol-2-ol;
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol;
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3--
sulfonamide;
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitri-
le;
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carboni-
trile;
5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol,
or
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indo-
le-6-carbonitrile; or a pharmaceutically acceptable salt
thereof.
48. A method of prevention and/or treatment according to claims 42
wherein said condition associated with glycogen synthase kinase-3
is selected from: dementia, Alzheimer's Disease, Parkinson's
Disease, Frontotemporal dementia Parkinson's Type, Parkinson
dementia complex of Guam, HIV dementia, diseases with associated
neurofibrillar tangle pathologies and dementia pugilistica.
49. A method according to claim 48, wherein the condition is
Alzheimer's Disease.
50. A method of prevention and/or treatment according to claim 42
wherein said condition is selected from: amyotrophic lateral
sclerosis, corticobasal degeneration, Down syndrome, Huntington's
Disease, postencephalitic parkinsonism, progressive supranuclear
palsy, Pick's Disease, Niemann-Pick's Disease, stroke, head trauma
and other chronic neurodegenerative diseases, Bipolar Disease,
affective disorders, depression, schizophrenia or cognitive
disorders.
51. A method of prevention and/or treatment according to claim 42
wherein said condition is selected from: predemented states, Mild
Cognitive Impairment, Age-Associated Memory Impairment, Age-Related
Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive
decline, mild neurocognitive decline, Late-Life Forgetfulness,
memory impairment and cognitive impairment, vascular dementia,
dementia with Lewy bodies or Frontotemporal dementia.
52. A method according to claim 50 wherein the condition is Bipolar
Disease.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new compounds of formula Ia
and Ib, as a free base or a pharmaceutically acceptable salt
thereof, to pharmaceutical formulations containing said compounds
and to the use of said compounds in therapy. The present invention
further relates to a process for the preparation of compounds of
formula Ia and Ib and to new intermediates used therein.
BACKGROUND OF THE INVENTION
[0002] Glycogen synthase kinase 3 (GSK3) is a serine/threonine
protein kinase composed of two isoforms (.alpha. and .beta.), which
are encoded by distinct genes but are highly homologous within the
catalytic domain. GSK3 is highly expressed in the central and
peripheral nervous system. GSK3 phosphorylates several substrates
including tau, .beta.-catenin, glycogen synthase, pyruvate
dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin
and growth factors activate protein kinase B, which phosphorylates
GSK3 on serine 9 residue and inactivates it.
Alzheimer's Disease (AD) dementias, and taupathies.
[0003] AD is characterized by cognitive decline, cholinergic
dysfunction and neuronal death, neurofibrillary tangles and senile
plaques consisting of amyloid-.beta. deposits. The sequence of
these events in AD is unclear, but are believed to be related.
Glycogen synthase kinase 3.beta. (GSK3.beta.) or Tau (.tau.)
phosphorylating kinase selectively phosphorylates the microtubule
associated protein .tau. in neurons at sites that are
hyperphosphorylated in AD brains. Hyperphosphorylated protein z has
lower affinity for microtubules and accumulates as paired helical
filaments, which are the main components that constitute
neurofibrillary tangles and neuropil threads in AD brains. This
results in depolymerization of microtubules, which leads to dying
back of axons and neuritic dystrophy. Neurofibrillary tangles are
consistently found in diseases such as AD, amyotrophic lateral
sclerosis, parkinsonism-dementia of Gaum, corticobasal
degeneration, dementia pugilistica and head trauma, Down's
syndrome, postencephalatic parkinsonism, progressive supranuclear
palsy, Niemann-Pick's Disease and Pick's Disease. Addition of
amyloid-O to primary hippocampal cultures results in
hyperphosphorylation of .tau. and a paired helical filaments-like
state via induction of GSK3.beta. activity, followed by disruption
of axonal transport and neuronal death (Imahori and Uchida., J.
Biochem 121:179-188, 1997). GSK3.beta. preferentially labels
neurofibrillary tangles and has been shown to be active in
pre-tangle neurons in AD brains. GSK3 protein levels are also
increased by 50% in brain tissue from AD patients. Furthermore,
GSK3.beta. phosphorylates pyruvate dehydrogenase, a key enzyme in
the glycolytic pathway and prevents the conversion of pyruvate to
acetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A is
critical for the synthesis of acetylcholine, a neurotransmitter
with cognitive functions. Thus, GSK3.beta. inhibition may have
beneficial effects in progression as well as the cognitive deficits
associated with Alzheimer's disease and other above-referred to
diseases.
Chronic and Acute Neurodegenerative Diseases.
[0004] Growth factor mediated activation of the PI3K/Akt pathway
has been shown to play a key role in neuronal survival. The
activation of this pathway results in GSK3.beta. inhibition. Recent
studies (Bhat et. al., PNAS 97:11074-11079 (2000)) indicate that
GSK3.beta. activity is increased in cellular and animal models of
neurodegeneration such as cerebral ischemia or after growth factor
deprivation. For example, the active site phosphorylation was
increased in neurons vulnerable to apoptosis, a type of cell death
commonly thought to occur in chronic and acute degenerative
diseases such as Alzheimer's Disease, Parkinson's Disease,
amyotrophic lateral sclerosis, Huntington's Disease and HIV
dementia, ischemic stroke and head trauma. Lithium was
neuroprotective in inhibiting apoptosis in cells and in the brain
at doses that resulted in the inhibition of GSK3.beta.. Thus
GSK3.beta. inhibitors could be useful in attenuating the course of
neurodegenerative diseases.
Bipolar Disorders (BD)
[0005] Bipolar Disorders are characterised by manic episodes and
depressive episodes. Lithium has been used to treat BD based on its
mood stabilising effects. The disadvantage of lithium is the narrow
therapeutic window and the danger of overdosing that can lead to
lithium intoxication. The recent discovery that lithium inhibits
GSK3 at therapeutic concentrations has raised the possibility that
this enzyme represents a key target of lithium's action in the
brain (Stambolic et al., Curr. Biol. 6:1664-1668, 1996; Klein and
Melton; PNAS 93:8455-8459, 1996). Inhibition of GSK3.beta. may
therefore be of therapeutic relevance in the treatment of BD as
well as in AD patients that have affective disorders.
Schizophrenia
[0006] GSK3 is involved in signal transduction cascades of multiple
cellular processes, particularly during neural development.
Kozlovsky et al (Am J Psychiatry 2000 May; 157(5):831-3) found that
GSK3.beta. levels were 41% lower in the schizophrenic patients than
in comparison subjects. This study indicates that schizophrenia
involves neurodevelopmental pathology and that abnormal GSK3
regulation could play a role in schizophrenia. Furthermore, reduced
.beta.-catenin levels have been reported in patients exhibiting
schizophrenia (Cotter et al., Neuroreport 9:1379-1383 (1998)).
Diabetes
[0007] Insulin stimulates glycogen synthesis in skeletal muscles
via the dephosphorylation and thus activation of glycogen synthase.
Under resting conditions, GSK3 phosphorylates and inactivates
glycogen synthase via dephosphorylation. GSK3 is also
over-expressed in muscles from Type II diabetic patients (Nikoulina
et al., Diabetes 2000 February; 49(2):263-71). Inhibition of GSK3
increases the activity of glycogen synthase thereby decreasing
glucose levels by its conversion to glycogen. GSK3 inhibition may
therefore be of therapeutic relevance in the treatment of Type I
and Type II diabetes and diabetic neuropathy.
Hair Loss
[0008] GSK3 phosphorylates and degrades .beta.-catenin.
.beta.-catenin is an effector of the pathway for keratonin
synthesis. .beta.-catenin stabilisation may be lead to increase
hair development. Mice expressing a stabilised .beta.-catenin by
mutation of sites phosphorylated by GSK3 undergo a process
resembling de novo hair morphogenesis (Gat et al., Cell 1998 Nov.
25; 95 (5):605-14)). The new follicles formed sebaceous glands and
dermal papilla, normally established only in embryogenesis. Thus
GSK3 inhibition may offer treatment for baldness.
Oral Contraceptives
[0009] Vijajaraghavan et al. (Biol Reprod 2000 June; 62
(6):1647-54) reported that GSK3 is high in motile versus immotile
sperm. Immunocytochemistry revealed that GSK3 is present in the
flagellum and the anterior portion of the sperm head. These data
suggest that GSK3 could be a key element underlying motility
initiation in the epididymis and regulation of mature sperm
function. Inhibitors of GSK3 could be useful as contraceptives for
males.
DISCLOSURE OF THE INVENTION
[0010] The object of the present invention is to provide compounds
having an inhibiting effect on GSK3 as well as having a good
bioavailability.
[0011] Accordingly, the present invention provides compounds of
formula Ia and Ib:
##STR00002##
wherein: P represents a 5- or 6-membered heteroaromatic ring
containing one or two heteroatoms selected independently from N, O
and S of which at least one atom is nitrogen; R.sup.1 is hydrogen;
R.sup.2 and R.sup.3 are independently selected from halogen, nitro,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, CHO, C.sub.0-6alkylOR.sup.4,
OC.sub.1-6alkylOR.sup.4, C.sub.0-6alkylSR.sup.4,
OC.sub.1-6alkylSR.sup.4, (CO)R.sup.4, (CO)OR.sup.4, O(CO)R.sup.4,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, OC.sub.1-6alkylcyano,
C.sub.0-6alkylcyano, C.sub.1-6alkylCO.sub.2R.sup.4,
OC.sub.1-6alkylCO.sub.2R.sup.4, O(CO)OR.sup.4,
OC.sub.1-6alkylCOR.sup.4, C.sub.1-6alkylCOR.sup.4,
NR.sup.4OR.sup.5, C.sub.0-6alkylNR.sup.4R.sup.5,
OC.sub.1-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylCONR.sup.4R.sup.5,
OC.sub.1-6alkylCONR.sup.4R.sup.5,
OC.sub.1-6alkylNR.sup.4(CO)R.sup.5,
C.sub.0-6alkylNR.sup.4(CO)R.sup.5,
C.sub.0-6alkylNR.sup.4(CO)NR.sup.4R.sup.5, O(CO)NR.sup.4R.sup.5,
NR.sup.4(CO)OR.sup.5, C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
OC.sub.1-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4(SO.sub.2)R.sup.5,
OC.sub.1-6alkylNR.sup.4(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)NR.sup.4R.sup.5,
OC.sub.1-6alkyl(SO)NR.sup.4R.sup.5, SO.sub.3R.sup.4,
C.sub.0-6alkylNR.sup.4(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4(SO)R.sup.5,
OC.sub.0-6alkylNR.sup.4(SO)R.sup.5, OC.sub.0-6alkylSO.sub.2R.sup.4,
C.sub.0-6alkylSO.sub.2R.sup.4, C.sub.0-6alkylSOR.sup.4,
OC.sub.1-6alkylSOR.sup.4 and a group X.sup.1R.sup.6, wherein
X.sup.1 is a direct bond, O, CONR.sup.7R.sup.8,
SO.sub.2NR.sup.9R.sup.10, SO.sub.2R.sup.1 or NR.sup.12R.sup.13; and
wherein R.sup.6 is linked to
R.sup.8, R.sup.10, R.sup.11 and R.sup.13;
[0012] R.sup.7, R.sup.9 and R.sup.12 each independently are
hydrogen or C.sub.1-6alkyl; R.sup.8, R.sup.10, R.sup.11 and
R.sup.13 are C.sub.1-6alkyl; R.sup.6 is phenyl or a 5-, 6- or
7-membered heterocyclic group containing one or two heteroatoms,
selected independently from N, O and S, which heterocyclic group
may be saturated or unsaturated or said phenyl or 5-, 6- or
7-membered heterocyclic group may optionally be fused with a 5- or
6-membered saturated or unsaturated ring containing atoms selected
independently from C, N, O and S and which phenyl or heterocyclic
group may be substituted with one or two substituents selected from
W; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; R.sup.4 is selected
from hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, C.sub.1-6alkylNR.sup.14R.sup.15 and a 5-
or 6-membered heterocyclic group containing one or two heteroatoms,
selected independently from N, O and S, wherein said heterocyclic
group may optionally be substituted by a group Y; R.sup.5 is
selected from hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl and
C.sub.1-6alkylNR.sup.14R.sup.15 and; wherein R.sup.4 and R.sup.5
may together form a 4-, 5-, 6- or 7-membered heterocyclic group
containing one or more heteroatoms selected independently from N, O
and S, wherein said heterocyclic group may optionally be
substituted is by a group Y; and wherein any C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl; and
C.sub.0-6alkylheteroaryl defined under R.sup.2 to R.sup.5 may be
substituted by one or more group Z; R.sup.14 and R.sup.15 are
independently selected from hydrogen, C.sub.1-6alkyl and
C.sub.0-6alkylC.sub.3-6cycloalkyl and wherein R.sup.14 and R.sup.15
may together form a 5- or 6-membered heterocyclic group containing
one or more heteroatoms, selected independently from N, O and S,
wherein said heterocyclic group may optionally be substituted by a
group Y; W and Z are independently selected from oxo, halogen,
nitro, CN, OR.sup.16, C.sub.1-6alkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.16R.sup.17, NR.sup.16R.sup.17,
CONR.sup.16R.sup.17NR.sup.16(CO)R.sup.17, O(CO)C.sub.1-6alkyl,
(CO)OC.sub.1-6alkyl, COR.sup.16, (SO.sub.2)NR.sup.16R.sup.17,
SO.sub.2R.sup.16, SOR.sup.16, (CO)C.sub.1-6alkylNR.sup.16R.sup.17,
(SO.sub.2)C.sub.1-6alkylNR.sup.16R.sup.17, a 5- or 6-membered
heterocyclic group containing one or two heteroatoms, selected
independently from N, O and S, phenyl and heteroaryl, which
heterocyclic group, phenyl or heteroaryl may optionally be
substituted by a group Y; Y is selected from oxo, halogen, nitro,
CN, OR.sup.16, C.sub.1-6alkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.16R.sup.17, NR.sup.16R.sup.17,
CONR.sup.16R.sup.17, NR.sup.16(CO)R.sup.17, O(CO)C.sub.1-6alkyl,
(CO)OC.sub.1-6alkyl, COR.sup.16, (SO.sub.2)NR.sup.16R.sup.17,
SO.sub.2R.sup.16, SOR.sup.16, (CO)C.sub.1-6alkylNR.sup.16R.sup.71
(SO.sub.2)C.sub.1-16alkylNR.sup.16R.sup.17, phenyl,
C.sub.0-6alkylaryl and heteroaryl wherein the phenyl,
C.sub.0-6alkylaryl and heteroaryl group may be optionally
substituted with halogen, nitro, CN, OR.sup.16, C.sub.1-6alkyl,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy and trifluoromethoxy; R.sup.16 and R.sup.17 are
independently selected from hydrogen and C.sub.1-6alkyl and wherein
R.sup.16, and R.sup.17 may together form a 5- or 6-membered
heterocyclic group containing one or more heteroatoms, selected
independently from N, O and S; as a free base or a pharmaceutically
acceptable salt thereof.
[0013] In one aspect of the invention there is provided compounds
of Formula Ia and Ib wherein P is a 6-membered heteroaromatic ring
containing one or two nitrogen atoms.
[0014] In a first embodiment of this aspect of the invention there
is provided compounds of Formula Ia and Ib, wherein P is
pyridine.
[0015] In another embodiment of this aspect of the invention there
is provided compounds of is Formula Ia and Ib, wherein P is
pyrimidine.
[0016] In another aspect of the invention there is provided
compounds of Formula Ia.
[0017] In yet another aspect of the invention there is provided
compounds of Formula Ia and Ib wherein R.sup.2 and R.sup.3 are
independently selected from: halogen, nitro,
C.sub.0-6alkylheteroaryl, trifluoromethyl, C.sub.0-6alkylcyano,
C.sub.0-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylCONR.sup.4R.sup.5,
OC.sub.1-6alkylNR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5, and a group
X.sup.1R.sup.6, wherein X.sup.1 is a direct bond; R.sup.6 is a
5-membered heterocyclic group containing one or two heteroatoms,
selected independently from N, O and S, and which heterocyclic
group may be substituted with one or two substituents W, preferably
C.sub.1-6alkyl; m is 0, 1, 2; and n is 1 or 2.
[0018] In yet another aspect of the invention there is provided
compounds of Formula Ia and Ib wherein R.sup.4 is independently
selected from hydrogen, C.sub.1-6alkyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, C.sub.1-6alkylNR.sup.14R.sup.15 and a 5-
or 6-membered heterocyclic group containing one or two heteroatoms,
selected independently from N, O and S, wherein said heterocyclic
group may optionally be substituted by a group Y; R.sup.5 is
selected from hydrogen, C.sub.1-6alkyl; wherein R.sup.4 and R.sup.5
may together form a 4-, 5-, 6- or 7-membered heterocyclic group
containing one or more heteroatoms selected independently from N, O
and S, wherein said heterocyclic group may optionally be
substituted by a group Y; and wherein any C.sub.1-6alkyl,
C.sub.0-6alkylaryl defined under R.sup.2 to R.sup.5 may be
substituted by one or more group Z; R.sup.14 and R.sup.15 are
independently C.sub.1-6alkyl and wherein R.sup.14 and R.sup.15 may
together form a 5- or 6-membered heterocyclic group containing one
or more heteroatoms, selected independently from N, O and S; Z is
independently selected from, halogen, C.sub.1-6alkyl, CN,
NR.sup.16R.sup.17; Y is selected from C.sub.1-6alkyl,
C.sub.0-6alkylaryl, NR.sup.16R.sup.17, phenyl, wherein the phenyl
may be optionally substituted with nitro and trifluoromethyl;
R.sup.16 and R.sup.17 are C.sub.1-6alkyl and wherein R.sup.16 and
R.sup.17 may together form a 5- or 6-membered heterocyclic group
containing one or more heteroatoms, selected independently from N,
O and S.
[0019] In yet another aspect of the invention there is provided
compounds of Formula Ia and Ib wherein P is pyridine; R.sup.1 is
hydrogen; R.sup.2 is CN; R.sup.3 is C.sub.0-6alkylNR.sup.4R.sup.5;
wherein R.sup.4 and R.sup.5 may together form a 4-, 5-, 6- or
7-membered heterocyclic group containing one or more heteroatoms
selected independently from N, O and S.
[0020] Yet another aspect of the invention relates to compounds
selected from: [0021]
2-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]isonicotina-
mide; [0022]
2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole--
5-carbonitrile hydrochloride; [0023]
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole--
5-carbonitrile; [0024]
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitri-
le hydrochloride; [0025]
2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbon-
itrile; [0026]
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5--
carbonitrile hydrochloride; [0027]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-methylni-
cotinamide hydrochloride; [0028]
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole--
5-carbonitrile hydrochloride; [0029]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3--
sulfonamide hydrochloride; [0030]
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitri-
le; [0031]
2-Hydroxy-3-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-
-carbonitrile hydrochloride; [0032]
2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indol-
e-5-carbonitrile hydrochloride; [0033]
2-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H--
indole-5-carbonitrile hydrochloride; [0034]
3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H-
-indole-5-carbonitrile; [0035]
2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5--
carbonitrile; [0036]
2-Hydroxy-3-{5-[(4-phenylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5--
carbonitrile; [0037]
3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitril-
e; [0038]
2-Hydroxy-3-[5-({4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin--
1-yl}methyl)pyridin-2-yl]-1H-indole-5-carbonitrile; [0039]
3-(5-{[(2-Cyanoethyl)(ethyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indol-
e-5-carbonitrile; [0040]
3-(5-{[(4-Chlorobenzyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-in-
dole-5-carbonitrile; [0041]
3-(5-{[(2-Furylmethyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-ind-
ole-5-carbonitrile; [0042]
2-Hydroxy-3-(5-{[methyl(phenyl)amino]methyl}pyridin-2-yl)-1H-indole-5-car-
bonitrile; [0043]
2-Hydroxy-3-{5-[(3-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5--
carbonitrile; [0044]
3-(5-{[Cyclohexyl(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-
-carbonitrile; [0045]
2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitri-
le; [0046]
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-
-ol hydrochloride; [0047]
6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2--
ol hydrochloride; [0048]
3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol;
[0049]
6-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
hydrochloride; [0050]
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitri-
le hydrochloride; [0051]
5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
hydrochloride; [0052]
5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
hydrochloride; [0053]
3-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carboni-
trile hydrochloride; [0054]
3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole--
5-carbonitrile hydrochloride; [0055]
2-Hydroxy-3-(5-{[4-(3-methylbutyl)piperazin-1-yl]sulfonyl}pyridin-2-yl)-1-
H-indole-5-carbonitrile hydrochloride; [0056]
2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indo-
le-5-carbonitrile hydrochloride; [0057]
3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-
-carbonitrile hydrochloride; [0058]
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol;
[0059]
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-o-
l hydrochloride; [0060]
5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
hydrochloride; [0061]
3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-i-
ndol-2-ol hydrochloride; [0062]
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-o-
l hydrochloride; [0063]
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole--
6-carbonitrile hydrochloride; [0064]
N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nic-
otinamide hydrochloride; [0065]
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide
hydrochloride; [0066]
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)ni-
cotinamide hydrochloride; [0067]
5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H--
indol-2-ol hydrochloride; [0068]
3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-
-indol-2-ol hydrochloride; [0069]
N-[2-(Dimethylamino)-1-methylethyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)ni-
cotinamide hydrochloride; [0070]
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-pyrollindin-1-ylethyl)nicotinami-
de fumarate; [0071]
3-{5-[(4-Methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-5-nitro-1H-indol-2-o-
l fumarate; [0072]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)nicotinamid-
e fumarate; [0073]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)py-
ridine-3-sulfonamide hydrochloride; [0074]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]pyridine-3--
sulfonamide fumarate; [0075]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpyr-
idine-3-sulfonamide fumarate; [0076]
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyr-
idine-3-sulfonamide fumarate; [0077]
2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]pyridin-2-yl}-1H-ind-
ole-5-carbonitrile fumarate; [0078]
2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonit-
rile; [0079]
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thia-
zol-4-yl)-1H-indol-2-ol hydrochloride; [0080]
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-thiazol-4-yl)-
-1H-indol-2-ol fumarate; [0081]
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-oxazol-5-yl)--
1H-indol-2-ol; [0082]
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol
hydrochloride.
[0083] Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
[0084] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined`, `defined hereinbefore` or `defined above` the said group
encompasses the first occurring and broadest definition as well as
each and all of the other definitions for that group.
[0085] For the avoidance of doubt it is to be understood that in
this specification `C.sub.0-6` means a carbon group having 0, 1, 2,
3, 4, 5 or 6 carbon atoms.
[0086] For the avoidance of doubt it is to be understood that in
this specification `C.sub.1-6` means a carbon group having 1, 2, 3,
4, 5 or 6 carbon atoms.
[0087] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl groups and
may be, but is not limited to, methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl,
neo-pentyl, n-hexyl or i-hexyl, t-hexyl.
[0088] In this specification, unless stated otherwise, the term
"cycloalkyl" refers to an optionally substituted, saturated cyclic
hydrocarbon ring system. The term "C.sub.3-6cycloalkyl" may be, but
is not limited to, cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl.
[0089] In this specification, unless stated otherwise, the term
"alkylaryl", includes both substituted and unsubstituted alkylaryl
groups, which may be substituted on the alkyl and/or the aryl and
may be, but are not limited to, C.sub.1-6alkylaryl, benzyl or
ethylphenyl.
[0090] In this specification, unless stated otherwise, the term
"heteroaryl" may be a monocyclic heteroaromatic, or a bicyclic
fused-ring heteroaromatic group. Examples of said heteroaryl
include, but are not limited to, pyridyl, pyrrolyl, furyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, benzofuryl,
indolyl, isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, tetrazolyl and triazolyl.
[0091] In this specification, unless stated otherwise, the term
"alkenyl" includes both straight and branched chain alkenyl groups
but references to individual alkenyl groups such as 2-butenyl are
specific for the straight chain version only. The term
C.sub.2-C.sub.6 alkenyl having 2 to 6 carbon atoms and one or two
double bonds, and may be, but is not limited to, vinyl, allyl,
propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl,
i-pentenyl or hexenyl.
[0092] In this specification, unless stated otherwise, the term
"alkynyl" includes both straight and branched chain alkynyl groups
but references to individual alkynyl groups such as 2-butynyl are
specific for the straight chain version only. The term
C.sub.2-C.sub.6 alkynyl having 2 to 6 carbon atoms and one or two
triple bonds, and may be, but is not limited to, etynyl, propargyl,
butynyl, i-butynyl, pentynyl, i-pentynyl or hexynyl.
[0093] In this specification, unless stated otherwise, the term "5-
or 6-membered heteroaromatic ring containing one or two heteroatoms
selected independently from N, O and S of which at least one atom
is selected from nitrogen" includes, but is not limited to,
isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl,
imidazolyl.
[0094] In this specification, unless stated otherwise, the terms
"5- or 6-membered heterocyclic group containing one or more
heteroatoms, selected independently from N, O and S" or "5-, 6- or
7-membered heterocyclic group containing one or two heteroatoms,
selected independently from N, O and S, which heterocyclic group
may be saturated or unsaturated" or "4-, 5-, 6- or 7-membered
heterocyclic group containing one or more heteroatoms selected
independently from N, O and S" may be, but are not limited to,
azepanyl, azitidinyl, imidazolidinyl, imidazolinyl, morpholinyl,
piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl,
furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,
imidazolyl.
[0095] In this specification, unless stated otherwise, the term "5-
or 6-membered saturated or unsaturated ring containing atoms
selected independently from C, N, O and S", includes both aromatic,
heteroaromatic rings and heterocyclic rings that are saturated or
unsaturated. Examples of such heterocyclic rings may be, but are
not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,
thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl,
morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,
pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
thiomorpholinyl, phenyl, cyclohexyl or cyclopentyl.
[0096] In this specification, unless stated otherwise, the term
"6-membered heteroaromatic ring containing one or two nitrogen
atoms" includes, but is not limited to, pyrazinyl, pyridazinyl,
pyridyl or pyrimidyl.
[0097] In this specification, unless stated otherwise, the term
"5-membered heterocyclic group containing one or two heteroatoms
atoms, selected independently from N, O and S" includes, but is not
limited to, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thienyl,
furyl, imidazolyl, isothiazolyl or isoxazolyl.
[0098] In the case where a subscript is the integer 0 (zero) the
group to which the subscript refers to, indicates that the group is
absent, i.e. there is a direct bond between the groups.
[0099] In this specification, unless stated otherwise, the term
halogen may be fluorine, chlorine, bromine or iodine.
[0100] The present invention relates to the use of compounds of
formula Ia and Ib as hereinbefore defined as well as to the salts
thereof. Salts for use in pharmaceutical compositions will be
pharmaceutically acceptable salts, but other salts may be useful in
the production of the compounds of formula Ia and Ib.
[0101] Both organic and inorganic acids can be employed to form
non-toxic pharmaceutically acceptable salts of the compounds of
this invention. Pharmaceutically acceptable salts include, but are
not limited to hydrochloride, and fumarate. These salts are readily
prepared by methods known in the art.
[0102] Some compounds of formula Ia and Ib 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,
diastereoisomeric and geometric isomers.
[0103] Within the present invention it is to be understood that a
compound of formula Ia or a salt thereof may exhibit the phenomenon
of tautomerism as shown in FIG. 1. It is to be understood that the
invention encompasses any tautomeric form of compounds of formula
Ia and is not to be limited merely to any one tautomeric form
utilized within the formula drawings:
##STR00003##
wherein P, R.sup.1, R.sup.2, R.sup.3, m and n are as defined
above.
[0104] An object of the invention is to provide compounds of
formula Ia or Ib for therapeutic use, especially compounds that are
useful for the prevention and/or treatment of conditions associated
with glycogen synthase kinase-3 (GSK3) in mammals including man.
Particularly, compounds of formula Ia or Ib exhibiting a selective
affinity for GSK-3.
Pharmaceutical Compositions
[0105] According to one aspect of the present invention there is
provided a pharmaceutical composition comprising a compound of
formula Ia or Ib, as a free base or a pharmaceutically acceptable
salt thereof, for use in the prevention and/or treatment of
conditions associated with glycogen synthase kinase-3.
[0106] The composition may be in a form suitable for oral
administration, for example as a tablet, for parenteral injection
as a sterile solution or suspension. In general the above
compositions may be prepared in a conventional manner using
pharmaceutically carriers or diluents. Suitable daily doses of the
compounds of formula Ia or Ib in the treatment of a mammal,
including man, are approximately 0.01 to 250 mg/kg bodyweight at
peroral administration and about 0.001 to 250 mg/kg bodyweight at
parenteral administration. The typical daily dose of the active
ingredients varies within a wide range and will depend on various
factors such as the relevant indication, the route of
administration, the age, weight and sex of the patient and may be
determined by a physician.
[0107] A compound of formula Ia or Ib, or a pharmaceutically
acceptable salt thereof, can be used on its own but will usually be
administered in the form of a pharmaceutical composition in which
the formula Ia or Ib compound/salt (active ingredient) is in
association with a pharmaceutically acceptable diluent or carrier.
Dependent on the mode of administration, the pharmaceutical
composition may comprise from 0.05 to 99% w (percent by weight),
for example from 0.10 to 50% w, of active ingredient, all
percentages by weight being based on total composition.
[0108] A diluent or carrier includes water, aqueous polyethylene
glycol, magnesium carbonate, magnesium stearate, talc, a sugar
(such as lactose), pectin, dextrin, starch, tragacanth,
microcrystalline cellulose, methylcellulose, sodium carboxymethyl
cellulose or cocoa butter.
[0109] A composition of the invention can be in tablet or
injectable form. The tablet may additionally comprise a
disintegrant and/or may be coated (for example with an enteric
coating or coated with a coating agent such as hydroxypropyl
methylcellulose).
[0110] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula I, or a pharmaceutically acceptable
salt thereof, a hereinbefore defined, with a pharmaceutically
acceptable diluent or carrier.
[0111] An example of a pharmaceutical composition of the invention
is an injectable solution containing a compound of the invention,
or a pharmaceutically acceptable salt thereof, as hereinbefore
defined, and sterile water, and, if necessary, either sodium
hydroxide or hydrochloric acid to bring the pH of the final
composition to about pH 5, and optionally a surfactant to aid
dissolution.
[0112] Liquid solution comprising a compound of formula Ia or Ib,
or a salt thereof, dissolved in water.
TABLE-US-00001 Solution mg/mL Active Compound 5.0% w/v Pure water
To 100%
Medical Use
[0113] Surprisingly, it has been found that the compounds defined
in the present invention, as a free base or a pharmaceutically
acceptable salt thereof, are well suited for inhibiting glycogen
synthase kinase-3 (GSK3). Accordingly, the compounds of the present
invention are expected to be useful in the prevention and/or
treatment of conditions associated with glycogen synthase kinase-3
activity, i.e. the compounds may be used to produce an inhibitory
effect of GSK-3 in mammals, including man, in need of such
prevention and/or treatment.
[0114] GSK-3 is highly expressed in the central and peripheral
nervous system and in other tissues. Thus, it is expected that
compounds of the invention are well suited for the prevention
and/or treatment of conditions associated with glycogen synthase
kinase-3 in the central and peripheral nervous system. In
particular, the compounds of the invention are expected to be
suitable for prevention and/or treatment of conditions associated
with especially, dementia, Alzheimer's Disease, Parkinson's
Disease, Frontotemporal dementia Parkinson's Type, Parkinson
dementia complex of Guam, HIV dementia, diseases with associated
neurofibrillar tangle pathologies and dementia pugilistica.
[0115] Other conditions are selected from the group consisting of
amyotrophic lateral sclerosis, corticobasal degeneration, Down
syndrome, Huntington's Disease, postencephelatic parkinsonism,
progressive supranuclear palsy, Pick's Disease, Niemann-Pick's
Disease, stroke, head trauma and other chronic neurodegenerative
diseases, Bipolar Disease, affective disorders, depression,
schizophrenia, cognitive disorders, hair loss and contraceptive
medication.
[0116] Further conditions are selected from the group consisting
predemented states, Mild Cognitive Impairment, Age-Associated
Memory Impairment, Age-Related Cognitive Decline, Cognitive
Impairement No Dementia, mild cognitive decline, mild
neurocognitive decline, Late-Life Forgetfulness, memory impairment
and cognitive impairment, vascular dementia, dementia with Lewy
bodies and androgenetic alopecia.
One embodiment of the invention relates to the prevention and/or
treatment of dementia and Alzheimer's Disease.
[0117] The dose required for the therapeutic or preventive
treatment of a particular disease will necessarily be varied
depending on the host treated, the route of administration and the
severity of the illness being treated.
[0118] The present invention relates also to the use of a compound
of formula Ia or Ib as defined hereinbefore, in the manufacture of
a medicament for the prevention and/or treatment of conditions
associated with glycogen synthase kinase-3.
[0119] In the context of the present specification, the term
"therapy" also includes "prevention" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0120] The invention also provides for a method of treatment and/or
prevention of conditions associated with glycogen synthase kinase-3
comprising administering to a mammal, including man in need of such
treatment and/or prevention a therapeutically effective amount of a
compound of formula Ia or Ib, as hereinbefore defined.
Non-Medical Use
[0121] In addition to their use in therapeutic medicine, the
compounds of formula Ia or Ib as a free base or a pharmaceutically
acceptable salt thereof, are also useful as pharmacological tools
is in the development and standardisation of in vitro and in vivo
test systems for the evaluation of the effects of inhibitors of
GSK3 related activity in laboratory animals such as cats, dogs,
rabbits, monkeys, rats and mice, as part of the search for new
therapeutics agents.
Methods of Preparation
[0122] The present invention also relates to processes for
preparing the compound of formula Ia or Ib. Throughout the
following description of such processes it is understood that,
where appropriate, suitable protecting groups will be added to, and
subsequently removed from the various reactants and intermediates
in a manner that will be readily understood by one skilled in the
art of organic synthesis. Conventional procedures for using such
protecting groups as well as examples of suitable protecting groups
are for example described in "Protective Groups in Organic
Synthesis", T. W. Greene, P. G. M Wutz, Wiley-Interscience, New
York, 1999.
Preparation of Intermediates
[0123] The process, wherein halo is halogen, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, X.sup.1, n and m, unless otherwise specified, are
as defined hereinbefore, comprises,
(i) halogenation of a compound of formula II,
##STR00004##
wherein R.sup.2 is halogen, to obtain a compound of formula III,
wherein halo is halogen e.g. bromine, chlorine or iodine, may be
performed by an aromatic electrophilic substitution using a
suitable halogenation agent such as Br.sub.2, Cl.sub.2, I.sub.2,
ICl, SO.sub.2Cl.sub.2 or another suitable halogenation agent such
as N-bromosuccinimid in an appropriate solvent such as
acetonitrile, acetic acid, HCl/ethanol or water, with or without a
suitable base e.g. an alkali metal acetate such as sodium acetate,
at a reaction temperature between -20.degree. C. and room
temperature. (ii) conversion of a compound of formula IV, wherein
halo is a halogen, e.g. bromine or iodine, to obtain a compound of
formula V, wherein X.sup.1 is a direct bond and R.sup.6 is as
defined above,
##STR00005##
that may be carried out by reaction with a suitable tin reagent
such as a trialkyltin-R.sup.6 reagent e.g. tributyltin-R.sup.6 in
the presence of a suitable catalyst such as
bis(triphenylphosphine)palladium(II) chloride,
tetrakis(triphenylphosphine)palladium(0) or
bis(triphenylphosphine)palladium(II) acetate in a suitable solvent
such as tetrahydrofuran, acetonitrile, toluene or
N,N-dimethylformamide and at a temperature range between 25.degree.
C. and reflux. The reaction may be aided by the presence of
tetraethyl ammonium chloride. (iii) reduction of a compound of
formula VI to obtain a compound of formula VII,
##STR00006##
that may be carried out in a suitable solvent such as toluene,
tetrahydrofuran, diethyl ether or a mixture of tetrahydrofuran and
an alcohol such as methanol or ethanol in the presence of a
suitable reducing reagent such as lithium borohydride or sodium
borohydride and at a reaction temperature between 0.degree. C. and
reflux. (iv) oxidation of a compound of formula VII to obtain a
compound of formula VIII,
##STR00007##
that may be carried out in a suitable solvent such as chloroform,
tetrahydrofuran or pyridine in the presence of a suitable oxidizing
reagent such as chromium (VI) oxide or manganese (IV) oxide and at
a reaction temperature between 0.degree. C. and +100.degree. C. (v)
conversion of a compound of formula VIII to obtain a compound of
formula IX,
##STR00008##
that may be carried out in a suitable solvent such as an alcohol
e.g. methanol in the presence of a suitable reagent such as
tosylmethyl isocyanide and a suitable base such as potassium
carbonate or sodium carbonate and at a reaction temperature between
0.degree. C. and reflux. (vi) conversion of a compound of formula X
to obtain a compound of formula XI,
##STR00009##
that may be carried out in a suitable solvent such as carbon
disulfide in the presence of suitable reagents such as aluminum
trichloride and chloroacetyl chloride and at a reaction temperature
between 0.degree. C. and reflux. (vii) Conversion of a compound of
formula XI to obtain a compound of formula XII,
##STR00010##
that may be carried out in a suitable solvent such as toluene,
dioxane or tetrahydrofuran in the presence of a suitable reagent
such as thioformamide and a suitable base such as a trialkylamine
e.g triethylamine, or potassium carbonate and at a reaction
temperature between +25.degree. C. and reflux. (viii) conversion of
a compound of formula XI to obtain a compound of formula XIII,
##STR00011##
that may be carried out in a suitable solvent such as acetic acid
in the presence of a suitable reagent such as thioacetamide and at
a reaction temperature between +25.degree. C. and reflux. (ix)
conversion of a compound of formula XIV, wherein halo is halogen
e.g. fluorine, chlorine or bromine, to a compound of formula XV may
be carried out by
##STR00012##
activation of the acid function in a compound of formula XIV, with
a) a halogenation reagent such as thionyl chloride or oxalyl
chloride in a suitable solvent such as methylene chloride,
chloroform or toluene or using the reagent neat and the reaction
may occur at a temperature between 0.degree. C. and +80.degree. C.,
followed by the reaction with the appropriate amine
R.sup.4R.sup.5NH in a suitable solvent such as methylene chloride,
chloroform, toluene or acetonitrile with or without a suitable base
such as an alkali metal, an alkaline earth metal carbonate or
hydroxide such as sodium carbonate, potassium carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide or an alkylamine
base such as triethylamine and the reaction may occur at a
temperature between -20.degree. C. and +80.degree. C., or b) a
suitable coupling reagent such as 1,3-diisopropylcarbodiimide,
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,
1,3-dicyclohexylcarbodiimide,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate,
O-(benzotriazol-1-yl)-N,N,N,N'-tetramethyluronium
hexafluorophosphate, 1,1'-carbonyldiimidazole or
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate where the reaction may be aided by the addition
of 1-hydroxybenzotriazole hydrate and in a suitable solvent such as
methylene chloride, N,N-dimethylformamide or tetrahydrofuran and
the reaction may occur at a temperature between +20.degree. C. and
+130.degree. C., followed by addition of the appropriate amine
R.sup.4R.sup.5NH and at a reaction temperature between +20.degree.
C. and +130.degree. C. (x) conversion of a compound of formula XVI,
wherein halo is halogen e.g. fluorine, chlorine or bromine, to a
compound of formula XV may be carried out by
##STR00013##
the reaction with the appropriate amine R.sup.4R.sup.5NH in a
suitable solvent such as methylene chloride, chloroform, toluene or
acetonitrile with or without a suitable base such as sodium
carbonate, potassium carbonate, calcium carbonate, sodium hydroxide
or potassium hydroxide or an alkylamine base such as triethylamine,
the reaction may occur at a temperature between -20.degree. C. and
+80.degree. C. (xi) Conversion of a compound of formula XVII,
wherein halo is halogen e.g. fluorine, chlorine or bromine, to a
compound of formula XVIII may be carried out by
##STR00014##
activation of the sulfonic acid function in the compound of formula
XVII with a suitable halogenating reagent such as thionyl chloride
or phosphorus oxychloride in a suitable solvent such as methylene
chloride, chloroform, acetonitrile or toluene, and sulfolane may be
added as a co-solvent to facilitate the reaction. A catalytic
amount of N,N-dimethylacetamide may speed up the reaction and the
reaction may occur at a temperature between 0.degree. C. and
+120.degree. C., followed by the reaction with the appropriate
substituted amine R.sup.4R.sup.5NH in a suitable solvent such as
methylene chloride, chloroform, toluene or acetonitrile with or
without a suitable base such as sodium carbonate, potassium
carbonate, calcium carbonate, sodium hydroxide or potassium
hydroxide or an alkylamine base such as triethylamine and the
reaction may occur at a temperature between -20.degree. C. and
+80.degree. C. (xii) conversion of a compound of formula XIX,
wherein halo is halogen e.g. fluorine, chlorine or bromine and
R.sup.3 is hydrogen or a halogen e.g. fluorine, chlorine or
bromine, to a compound of formula XVIIIa may be carried out by
##STR00015##
the reaction with the appropriate amine R.sup.4R.sup.5NH in a
suitable solvent such as methylene chloride, chloroform, toluene or
acetonitrile with or without a suitable base such as sodium
carbonate, potassium carbonate, calcium carbonate, sodium hydroxide
or potassium hydroxide or an alkylamine base such as triethylamine
and the reaction may occur at a temperature between -20.degree. C.
and +80.degree. C. (xiii) reaction of a compound of formula XX,
wherein halo is halogen, to a compound of formula XXI may be
carried out by
##STR00016##
the reaction with an appropriate amine R.sup.4R.sup.5NH in a
suitable solvent such as methylene chloride, chloroform,
acetonitrile or N,N-dimethylformamide with or without a suitable
base such as sodium carbonate, potassium carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide or an alkylamine
base such as triethylamine and the reaction may occur at a
temperature between 0.degree. C. and +120.degree. C. (xiv) reaction
of a compound of formula XXII, wherein halo is halogen e.g.
fluorine chlorine, bromine, to a compound of formula XXIII may be
carried out by
##STR00017##
the reaction with an appropriate reagent R.sup.4OH in a suitable
solvent such as acetonitrile, methylene chloride, chloroform,
toluene or N,N-dimethylformamide in the presence of a suitable base
such as sodium carbonate, potassium carbonate, calcium carbonate,
sodium hydroxide, potassium hydroxide or sodium hydride or an
alkylamine base such as triethylamine and the reaction may occur at
a temperature between 0.degree. C. and +80.degree. C. (xv)
Conversion of a compound of formula XXIV, wherein halo is halogen
e.g. fluorine, chlorine, bromine, to a compound of formula XXV may
be carried out by
##STR00018##
reacting a compound of formula XXIV with an appropriate amine
R.sup.4R.sup.5NH in a suitable solvent such as methylene chloride,
chloroform, acetonitrile or N,N-dimethylformamide with or without a
suitable base such as sodium carbonate, potassium carbonate,
calcium carbonate, sodium hydroxide or potassium hydroxide or, an
alkylamine base such as triethylamine or, a macroporous polystyrene
anion-exchange resin such as MP-Carbonate or, a cross linked
polystyrene-co-divinylbenzene such as PS-diisopropylethylamine and
the reaction may occur at a temperature between 0.degree. C. and
+120.degree. C. (xvi) reacting a compound of formula XXVI, wherein
R.sup.4 is C.sub.1-6alkyl and halo is a halogen, e.g. fluorine,
chlorine or bromine, with a compound of formula C (wherein R.sup.2
and m are as defined above e.g. compounds of formula III, V, IX,
XII or XIII) to form a compound of formula XXVII,
##STR00019##
may be carried out in an appropriate solvent such as an ether e.g.
tetrahydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such
as toluene or a dipolar aprotic solvent such as
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulphoxide and the reaction may
occur at a temperature between +10.degree. C. and +150.degree.
C.
[0124] The reaction is advantageously effected in the presence of a
base. A suitable base may be an organic amine base such as
pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,
triethylamine, morpholine, N-methylmorpholine,
diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or an alkali
metal or an alkaline earth metal carbonate or hydroxide such as
sodium carbonate, potassium carbonate, calcium carbonate, sodium
hydroxide or potassium hydroxide. Alternatively, such a base may be
an alkali metal hydride such as sodium hydride, or an alkali metal
or alkaline earth metal amide such as sodium amide, sodium
bis(trimethylsilyl)amide, potassium amide or potassium
bis(trimethylsilyl)amide.
##STR00020##
(xvii) reacting a compound of formula XXV, wherein halo is a
halogen, e.g. fluorine, chlorine or bromine, with a compound of
formula C (wherein R.sup.2 and m are as defined above e.g.
compounds of formula III, V, IX, XII or XIII), to form a compound
of formula XXVIII, may be carried out in an appropriate solvent
such as an ether e.g. tetrahydrofuran or 1,4-dioxan, an aromatic
hydrocarbon solvent such as toluene or a dipolar aprotic solvent
such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulphoxide and the reaction may
occur at a temperature between +10.degree. C. and +150.degree.
C.
[0125] The reaction is advantageously effected in the presence of a
base. A suitable base may be an organic amine base such as
pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,
triethylamine, morpholine, N-methylmorpholine,
diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or an alkali
metal or an alkaline earth metal carbonate or hydroxide such as
sodium carbonate, potassium carbonate, calcium carbonate, sodium
hydroxide or potassium hydroxide. Alternatively, such a base may be
an alkali metal hydride such as sodium hydride, or an alkali metal
or alkaline earth metal amide such as sodium amide, sodium
bis(trimethylsilyl)amide, potassium amide or potassium
bis(trimethylsilyl)amide.
Methods of Preparation of End products
[0126] Another object of the invention are processes a, b, c, d and
e for the preparation of compounds of general formula Ia and Ib,
wherein halo is halogen, P, R.sup.1, R.sup.2, R.sup.3R.sup.4,
R.sup.5, m and n, unless otherwise specified, are defined as
hereinbefore, and salts thereof.
These processes comprise; a) reacting a compound of formula B (XV,
XVIII, XVIIIa, XXI, XXIII), wherein L.sup.1 is a leaving group such
as halogen, e.g. fluorine, chlorine or bromine, with a compound of
formula C (e.g. compounds of formula III, V, IX, XII, XIII);
wherein R.sup.1, R.sup.2 and m are as defined as hereinbefore to
form a compound of formula Ia;
##STR00021##
The reaction of process a may be carried out in an appropriate
solvent such as an ether e.g. tetrahydrofuran or 1,4-dioxan, an
aromatic hydrocarbon solvent such as toluene or a dipolar aprotic
solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulphoxide and the reaction may
occur at a temperature between +10.degree. C. and +150.degree.
C.
[0127] The reaction is advantageously effected in the presence of a
base. A suitable base may be an organic amine base such as
pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,
triethylamine, morpholine, N-methylmorpholine,
diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or an alkali
metal or an alkaline earth metal carbonate or hydroxide such as
sodium carbonate, potassium carbonate, calcium carbonate, sodium
hydroxide or potassium hydroxide. Alternatively, such a base may be
an alkali metal hydride such as sodium hydride, or an alkali metal
or alkaline earth metal amide such as sodium amide, sodium
bis(trimethylsilyl)amide, potassium amide or potassium
bis(trimethylsilyl)amide.
[0128] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide such as
hydrogen chloride or, a carboxylic acid such as fumaric acid in a
suitable solvent such as tetrahydrofuran, diethyl ether, methanol,
ethanol, chloroform or methylene chloride or mixtures thereof, the
reaction may occur between -30.degree. C. to +50.degree. C.
b) reacting a compound of formula XXV, wherein halo is halogen,
e.g. fluorine, chlorine or bromine, with a compound of formula C
(e.g. compounds of formula III, V, IX, XII, XIII); wherein R.sup.1,
R.sup.2 and m are as defined as hereinbefore); to form a compound
of formula Ia;
##STR00022##
The reaction of process b may be carried out in an appropriate
solvent such as an ether e.g. tetrahydrofuran or 1,4-dioxan, an
aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic
solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulphoxide, the reaction may
occur at a temperature between +10.degree. C. and +150.degree.
C.
[0129] The reaction is advantageously effected in the presence of a
base. Such a base may be an organic amine base such as pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
morpholine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene,
tetramethylguanidine or an alkali metal or an alkaline earth metal
carbonate or hydroxide such as sodium carbonate, potassium
carbonate, calcium carbonate, sodium hydroxide or potassium
hydroxide. Alternatively, such a base may be an alkali metal
hydride such as sodium hydride, an alkali metal or an alkaline
earth metal amide such as sodium amide, sodium
bis(trimethylsilyl)amide, potassium amide or potassium
bis(trimethylsilyl)amide.
[0130] The N-oxide may be removed by using a suitable reagent such
as phosphorus trichloride in a suitable solvent such as methylene
chloride, chloroform, toluene or ethyl acetate and the reaction may
occur at a temperature between 0.degree. C. and +100.degree. C.
[0131] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide such as
hydrogen chloride, or a carboxylic acid such as fumaric acid in a
suitable solvent such as tetrahydrofuran, diethyl ether, methanol,
ethanol, chloroform or methylene chloride or mixtures thereof, the
reaction may occur between -30.degree. C. to +50.degree. C.
c) reacting a compound of formula XXVII, wherein R.sup.4 is
C.sub.1-6alkyl, with the appropriate amine HNR.sup.4R.sup.5, to
form a compound of formula Ia;
##STR00023##
The reaction of process c may be carried out by: i) the reaction of
the compound of formula XXVII with the appropriate amine
R.sup.4R.sup.5NH in a suitable solvent such as benzene, methylene
chloride, chloroform, toluene or acetonitrile in the presence of a
suitable reagent such as trimethyl aluminum and at a reaction
temperature between 0.degree. C. and reflux or, ii) the reaction of
the compound of formula XXVII with the appropriate amine
R.sup.4R.sup.5NH neat or in a suitable solvent such as methylene
chloride, chloroform, toluene or acetonitrile with or without a
suitable base such as an alkali metal, an alkaline earth metal
carbonate or hydroxide such as sodium carbonate, potassium
carbonate, calcium carbonate, sodium hydroxide or potassium
hydroxide or an alkyl aminebase such as triethylamine, the reaction
may occur at a temperature between -20.degree. C. and +150.degree.
C.
[0132] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide such as
hydrogen chloride, or a carboxylic acid such as fumaric acid in a
suitable solvent such as tetrahydrofuran, diethyl ether, methanol,
ethanol, chloroform or methylene chloride or mixtures thereof, the
reaction may occur between -30.degree. C. to +50.degree. C.
d) reduction of the N-oxide in the compound of formula XXVIII to
form a compound of formula Ia;
##STR00024##
The N-oxide may be reduced by using a suitable reagent such as
phosphorus trichloride in a suitable solvent such as methylene
chloride, chloroform, toluene or ethyl acetate and the reaction may
occur at a temperature between 0.degree. C. and +100.degree. C.
[0133] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide such as
hydrogen chloride, or a carboxylic acid such as fumaric acid in a
suitable solvent such as tetrahydrofuran, diethyl ether, methanol,
ethanol, chloroform or methylene chloride or mixtures thereof, the
reaction may occur between -30.degree. C. to +50.degree. C.
e) fluorinating a compound of formula Ia to form a compound of
formula Ib;
##STR00025##
The reaction of process e may be carried out in an appropriate
solvent such as an ether e.g. tetrahydrofuran or 1,4-dioxan or
mixtures thereof in the presence of a suitable fluorinating reagent
such as 1-fluoro-2,4,6-trimethylpyridinium triflate and a suitable
base such as n-butyllithium or sodium bis(trimethylsilyl)amide and
at a reaction temperature between -40.degree. C. and +80.degree.
C.
[0134] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide such as
hydrogen chloride, or a carboxylic acid such as fumaric acid in a
suitable solvent such as tetrahydrofuran, diethyl ether, methanol,
ethanol, chloroform or methylene chloride or mixtures thereof, the
reaction may occur between -30.degree. C. to +50.degree. C.
Intermediates
[0135] The present invention further relates to new intermediates
and the use of these intermediates in the preparation of compounds
of formula Ia and Ib as defined hereinbefore.
[0136] In one aspect of the invention the intermediate is a
compound according to formula XXV
##STR00026##
wherein halo is halogen; R.sup.3 is selected from halogen, nitro,
C.sub.1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylCONR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4R.sup.5 and a group X.sup.1R.sup.6, wherein X
is a direct bond, O, CONR.sup.7R.sup.8, SO.sub.2NR.sup.9R.sup.10,
SO.sub.2R.sup.11 or NR.sup.12R.sup.13; R.sup.7, R.sup.9 and
R.sup.12 each independently are hydrogen or C.sub.1-3alkyl;
R.sup.8, R.sup.10, R.sup.11 and R.sup.13 are C.sub.0-4alkyl;
R.sup.6 is phenyl or a 5-, 6- or 7-membered heterocyclic group
containing one or two heteroatoms, selected independently from N, O
and S, which heterocyclic group may be saturated or unsaturated or
said phenyl or 5-, 6- or 7-membered heterocyclic group may
optionally be fused with a 5- or 6-membered saturated or
unsaturated ring containing atoms selected independently from C, N,
O and S and which phenyl or heterocyclic group may be substituted
with one or two substituents selected from W; and R.sup.6 is linked
to R.sup.8, R.sup.10, R.sup.11 and R.sup.13.
[0137] In one embodiment of this aspect there are provided
compounds according to formula XXV wherein R.sup.3 is
C.sub.0-6alkylNR.sup.4R.sup.5; and n is 1.
[0138] In another aspect there are provided compounds, said
compounds being: [0139]
1-[(6-Chloropyridin-3-yl)methyl]-4-methylpiperazine; [0140]
2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide; [0141]
2-Chloro-5-(pyrrolidin-1-ylmethyl)pyridine 1-oxide; [0142]
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-methyl-1,4-diazepane;
[0143] 2-Chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridine
1-oxide; [0144]
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N,N-dimethylpyrrolidin-3--
amine; [0145] 2-Chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine
1-oxide; [0146]
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-phenylpiperazine; [0147]
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-[2-nitro-4-(trifluorome-
thyl)phenyl]piperazine; [0148]
3-[[(6-Chloro-1-oxidopyridin-3-yl)methyl](ethyl)amino]propanenitrile;
[0149]
N-(4-Chlorobenzyl)-N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-meth-
ylamine; [0150]
N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-(2-furylmethyl)-N-methylamine;
[0151]
N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-methyl-N-phenylamine;
[0152] 5-(Azetidin-1-ylmethyl)-2-chloropyridine 1-oxide; [0153]
2-Chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide; [0154]
N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-cyclohexyl-N-methylamine;
[0155] 2-Chloro-5-(piperidin-1-ylmethyl)pyridine 1-oxide; as a free
base or a salt thereof.
[0156] In another aspect of the invention the intermediate is a
compound according to formula B (XV, XVIII, XVIIIa XXI, XXIII)
##STR00027##
wherein P represents a 5- or 6-membered heteroaromatic ring
containing one or two heteroatoms selected independently from N, O
and S of which at least one atom is selected from nitrogen and
L.sup.1 is a leaving group such as a halogen e.g. fluorine,
chlorine or bromine; wherein R.sup.3 is selected from halogen,
nitro, C.sub.1-6alkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylCONR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4R.sup.5 and a group X.sup.1R.sup.6, wherein
X.sup.1 is a direct bond, O, CONR.sup.7R.sup.8,
SO.sub.2NR.sup.9R.sup.10, SO.sub.2R.sup.11 or NR.sup.12R.sup.13;
R.sup.7, R.sup.9 and R.sup.12 each independently are hydrogen or
C.sub.1-3alkyl; R.sup.8, R.sup.10, R.sup.11 and R.sup.13 are
C.sub.0-4alkyl; R.sup.6 is phenyl or a 5-, 6- or 7-membered
heterocyclic group containing one or two heteroatoms, selected
independently from N, O and S, which heterocyclic group may be
saturated or unsaturated or said phenyl or 5-, 6- or 7-membered
heterocyclic group may optionally be fused with a 5- or 6-membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O and S and which phenyl or heterocyclic
group may be substituted with one or two substituents selected from
W; and R.sup.6 is linked to R.sup.8, R.sup.10, R.sup.11 and
R.sup.13.
[0157] In one embodiment of this aspect there are provided
compounds according to formula B (XV, XVIII, XVIIIa XXI, XXIII)
wherein P is a pyridine or pyrimidine ring and L.sup.1 is a leaving
group such as a halogen e.g. chlorine; wherein R.sup.3 is selected
from C.sub.0-6alkylCONR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5 and
C.sub.0-6alkylNR.sup.4R.sup.5; n is 1.
[0158] In another aspect there are provided compounds, said
compounds being: [0159]
2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide; [0160]
1-(2-Chloroisonicotinoyl)-4-methylpiperazine; [0161]
6-Chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide; [0162]
4-{2-[(6-Chloropyrimidin-4-yl)oxy]ethyl}morpholine; [0163]
1-Benzyl-4-[(6-chloropyridine-3-yl)sulfonyl]piperazine; [0164]
1-[(6-Chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine;
[0165] 1-[(6-Chloropyridin-3-yl)sulfonyl]-4-isopropylpiperazine;
[0166] 1-[(6-Chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine; [0167]
1-[(5-Bromo-6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine;
[0168]
6-Chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;
[0169] 6-Chloro-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide;
[0170]
6-Chloro-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide;
[0171]
6-Chloro-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide;
[0172] 1-[(6-Chloropyridin-3-yl)sulfonyl]-4-methyl-1,4-diazepane;
[0173] 4-[(6-Chloropyridin-3-yl)sulfonyl]morpholine; as a free base
or a salt thereof.
[0174] In yet another aspect of the invention the intermediate is a
compound according to formula C (III, V, IX, XII, XIII)
##STR00028##
wherein R.sup.1 is hydrogen; R.sup.2 is selected from halogen,
nitro, C.sub.1-6alkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylCONR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4R.sup.5 and a group X.sup.1R.sup.6, wherein
X.sup.1 is a direct bond, O, CONR.sup.7R.sup.8,
SO.sub.2NR.sup.9R.sup.10, SO.sub.2R.sup.11 or NR.sup.12R.sup.13;
R.sup.7, R.sup.9 and R.sup.12 each independently are hydrogen or
C.sub.1-3alkyl; R.sup.8, R.sup.10, R.sup.11 and R.sup.13 are
C.sub.0-4alkyl; R.sup.6 is phenyl or a 5-, 6- or 7-membered
heterocyclic group containing one or two heteroatoms, selected
independently from N, O and S, which heterocyclic group may be
saturated or unsaturated or said phenyl or 5-, 6- or 7-membered
heterocyclic group may optionally be fused with a 5- or 6-membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O and S and which phenyl or heterocyclic
group may be substituted with one or two substituents selected from
W; and R.sup.6 is linked to R.sup.8, R.sup.10, R.sup.11 and
R.sup.13.
[0175] In one embodiment of this aspect there are provided
compounds according to formula C (III, V, IX, XII, XIII) wherein
R.sup.1 is hydrogen; R.sup.2 is selected from halogen and a group
X.sup.1R.sup.6, wherein X.sup.1 is a direct bond; R.sup.6 is a 5-
or 6-membered heterocyclic group containing one or two heteroatoms,
selected independently from N, O and S; m is 1 or 2.
[0176] In another aspect there are provided compounds, said
compounds being: [0177] 5,6-Dibromo-1,3-dihydroindol-2-one; [0178]
55-Pyridin-3-yl-1,3-dihydro-2H-indol-2-one; [0179]
5-Thien-2-yl-1,3-dihydro-2H-indol-2-one; [0180]
5-(2-Furyl)-1,3-dihydro-2H-indol-2-one; [0181]
5-(1,3-Oxazol-5-yl)-1,3-dihydro-2H-indol-2-one; [0182]
5-(1,3-Thiazol-4-yl)-1,3-dihydro-2H-indol-2-one; [0183]
5-(2-Methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one; as a free
base or a salt thereof.
[0184] In yet another aspect of the invention the intermediate is a
compound according to formula XXVII
##STR00029##
wherein R.sup.1 is hydrogen; R.sup.2 is selected from halogen,
nitro, C.sub.1-6alkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylCONR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4R.sup.5 and a group X.sup.1R.sup.6, wherein X
is a direct bond, O, CONR.sup.7R.sup.8, SO.sub.2NR.sup.9R.sup.10,
SO.sub.2R.sup.11 or NR.sup.12R.sup.13; R.sup.7, R.sup.9 and
R.sup.12 each independently are hydrogen or C.sub.1-3alkyl;
R.sup.8, R.sup.10, R.sup.11 and R.sup.13 are C.sub.0-4alkyl;
R.sup.6 is phenyl or a 5-, 6- or 7-membered heterocyclic group
containing one or two heteroatoms, selected independently from N, O
and S, which heterocyclic group may be saturated or unsaturated or
said phenyl or 5-, 6- or 7-membered heterocyclic group may
optionally be fused with a 5- or 6-membered saturated or
unsaturated ring containing atoms selected independently from C, N,
O and S and which phenyl or heterocyclic group may be substituted
with one or two substituents selected from W; and R.sup.6 is linked
to R.sup.8, R.sup.10, R.sup.11 and R.sup.13.
[0185] In one embodiment of this aspect there are provided
compounds according to formula XXVII, wherein R.sup.1 is hydrogen;
R.sup.2 is selected from nitro and cyano; m is 1.
[0186] In another aspect there are provided compounds, said
compounds being: [0187] Ethyl
6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate; [0188] Ethyl
6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate; as a free base or a
salt thereof.
[0189] In yet another aspect of the invention the intermediate is a
compound according to formula XXVIII
##STR00030##
wherein R.sup.1 is hydrogen; R.sup.2 is selected from halogen,
nitro, C.sub.1-6alkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
OC.sub.1-6alkylNR.sup.4R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylCONR.sup.4R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.4R.sup.5,
C.sub.0-6alkylNR.sup.4R.sup.5 and a group X.sup.1R.sup.6, wherein
X.sup.1 is a direct bond, O, CONR.sup.7R.sup.8,
SO.sub.2NR.sup.9R.sup.10, SO.sub.2R.sup.11 or NR.sup.12R.sup.13;
R.sup.7, R.sup.9 and R.sup.12 each independently are hydrogen or
C.sub.1-3alkyl; R.sup.8, R.sup.10, R.sup.11 and R.sup.13 are
C.sub.0-4alkyl; R.sup.6 is phenyl or a 5-, 6- or 7-membered
heterocyclic group containing one or two heteroatoms, selected
independently from N, O and S, which heterocyclic group may be
saturated or unsaturated or said phenyl or 5-, 6- or 7-membered
heterocyclic group may optionally be fused with a 5- or 6-membered
saturated or unsaturated ring containing atoms selected
independently from C, N, O and S and which phenyl or heterocyclic
group may be substituted with one or two substituents selected from
W; and R.sup.6 is linked to R.sup.8, R.sup.10, R.sup.11 and
R.sup.13.
[0190] In one embodiment of this aspect there are provided
compounds according to formula XXVIII, wherein R.sup.1 is hydrogen;
R.sup.2 is a group X.sup.1R.sup.6, wherein X.sup.1 is a direct
bond; R.sup.6 is a 5- or 6-membered heterocyclic group containing
one or two heteroatoms, selected independently from N, O and S; m
is 1
[0191] In yet another aspect there are provided compounds, said
compounds being: [0192]
3-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol--
2-ol; [0193]
3-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2--
ol; [0194]
5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-1H-
-indol-2-ol; as a free base or a salt thereof.
[0195] In yet another aspect there are provided compounds, said
compounds being: [0196]
5-(Hydroxymethyl)-1,3-dihydro-2H-indol-2-one; [0197]
2-Oxoindoline-5-carbaldehyde; [0198]
5-(Chloroacetyl)-1,3-dihydro-2H-indol-2-one; as a free base or a
salt thereof.
[0199] A further aspect of the invention relates to use of the
compounds according to any one of formulas XXV; B (XV, XVIII,
XVIIIa XXI, XXIII); C (III, V, IX, XII, XIII); XXVII; XXVIII; in
the preparation of a compound of formula Ia or Ib.
WORKING EXAMPLES
[0200] The invention will now be illustrated in the following
non-limiting Examples and unless stated otherwise:
(i) temperatures are given in degrees Celsius (.degree. C.);
operations were carried out at room temperature, i.e. at a
temperature in the range of 18 to 25.degree. C.; (ii) 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; (iii) when given, NMR data
is in the form of delta values, given in parts per million (ppm)
relative to the solvent or relative to tetramethylsilane (TMS) as
an internal standard; (iv) chemical symbols have their usual
meanings; SI units and symbols are used; (v) solvent ratios are
given in volume:volume (v/v) terms; and (vi) mass spectra: where
indicated, ionization was effected by chemical ionization (CI),
electron impact (EI), fast atom bombardment (FAB) or electrospray
(ESP) unless otherwise indicated; values for m/z are given;
generally, only ions which indicate the parent mass are
reported.
Example 1
2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide
[0201] To a solution of 2-chloroisonicotinic acid (0.50 g, 3.17
mmol) in N,N-dimethylformamide (20 mL) was added
1,1'-carbonyldiimidazole (0.565 g, 3.49 mmol). The solution was
heated at 70.degree. C. for 30 min. The reaction mixture was cooled
to room temperature and N,N-dimethylethane-1,2-diamine (0.31 g,
3.49 mmol) was added. The solution was stirred at room temperature
overnight. The solvent was evaporated in vacuo and the residue was
purified on a silica gel column using chloroform/methanol/conc.
NH.sub.3(aq), (90:10:1), as the eluent to afford 40 mg (5.7% yield)
of the title compound as a colorless oil: .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 8.51 (d, J=5 Hz, 1H), 7.68 (s, 1H), 7.56 (dd, J=5,
1 Hz, 1H), 6.92-7.08 (br s, 1H), 3.58-3.48 (m, 2H), 2.59-2.52 (m,
2H), 2.28 (s, 6H); MS (TSP) m/z 228 (M.sup.++1).
Example 2
1-(2-Chloroisonicotinoyl)-4-methylpiperazine
[0202] The title compound was prepared as described for Example 1
using 2-chloroisonicotinic acid and 1-methylpiperazine. The crude
product was purified on a silica gel column using
chloroform/methanol/conc. NH.sub.3(aq), (100:10:1), as the eluent
to give the title compound as a colorless oil. Yield: 68%: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.51 (d, J=5 Hz, 1H), 7.57 (s,
1H), 7.43 (dd, J=5, 1 Hz, 1H), 3.66-3.58 (m, 2H), 3.28-3.21 (m,
2H), 2.41-2.34 (m, 2H), 2.30-2.24 (m, 2H), 2.20 (s, 3H); MS (TSP)
m/z 240 (M.sup.++1).
Example 3
6-Chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide
[0203] To a solution of N,N,'N-trimethylethylenediamine (1.0 g, 10
mmol) and triethylamine (2.0 g, 20 mmol) in methylene chloride (25
mL) was added 6-chloronicotinyl chloride (1.7 g, 10 mmol) in
methylene chloride (50 mL) at room temperature. After 2 h at room
temperature, the solvent was removed in vacuo and the residue was
partitioned between a 2 M aqueous NaOH solution and methylene
chloride. The combined extracts were dried (Na.sub.2SO.sub.4) and
the solvent was removed in vacuo to afford 2.6 g of a crude
product. The residue was purified on a silica gel column using
acetonitrile/triethylamine, (90:10), as the eluent to afford 2.1 g
(87% yield) of the title compound as an bright yellow oil: .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 8.62 (d, J=2 Hz, 1H), 8.06 (dd, J=8,
2 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 3.70 (s, 1H), 3.41 (s, 1H), 3.12
(d, J=19 Hz, 3H), 2.64 (s, 1H), 2.51 (s, 1H), 2.37 (s, 3H), 2.13
(s, 3H); MS (TSP) m/z 242 (M.sup.++1).
Example 4
4-{2-[(6-Chloropyrimidin-4-yl)oxy]ethyl}morpholine
[0204] To a solution of N-(2-hydroxyethyl)morpholine (1.09 g, 8.27
mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (364
mg, 9.10 mmol, 60% dispersion in oil) in portions. The mixture was
stirred at room temperature for 1 h and at 45.degree. C. for 1.5 h.
The greenish solution was added dropwise over 5 min to a solution
of 4,6-dichloropyrimidine (3.0 g, 20.1 mmol) in
N,N-dimethylformamide (5 mL). The solvent was removed in vacuo, and
the residue was partitioned between water and ethyl acetate. The
organic layer was dried (Na.sub.2SO.sub.4) and the solvent was
removed in vacuo. The crude product was purified on a silica gel
column using ethyl acetate as the eluent affording 1.17 g (58%
yield) of the title compound as a yellow oil: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.57 (s, 1H), 6.80 (s, 1H), 4.53 (t,
J=6 Hz, 2H), 3.72 (t, J=5 Hz, 4H), 2.77 (t, J=6 Hz, 2H), 2.55 (t,
J=4 Hz, 4H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 170.0,
160.7, 158.1, 108.0, 66.9, 64.6, 57.1, 53.9; MS (ESP) m/z 244
(M.sup.++1).
Example 5
1-[(6-Chloropyridin-3-yl)methyl]-4-methylpiperazine
[0205] To a suspension of 2-chloro-5-(chloromethyl)pyridine (971
mg, 5.99 mmol) in acetonitrile (50 mL) was added a solution of
N-methylpiperazine (1.20 g, 12.0 mmol) in acetonitrile (3 mL)
followed by potassium carbonate (0.83 g, 5.99 mmol). The obtained
yellow solution was heated is at reflux for 40 min. The mixture was
allowed to cool for 10 min and the solvent was removed in vacuo.
The residue was partitioned between water, NaCl (s), and ethyl
acetate. The aqueous layer was extracted with another portion of
ethyl acetate. The combined organic layers were dried
(Na.sub.2SO.sub.4) and the solvent was removed in vacuo affording
1.0 g (74% yield) of the title compound as a yellow oil: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.31 (d, J=2 Hz, 1H), 7.65 (dd,
J=8, 2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 3.49 (s, 2H), 2.46 (br s,
8H), 2.28 (s, 3H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
150.2, 150.1, 139.5, 132.8, 124.0, 59.2, 55.0, 53.0, 46.0; MS (ESP)
m/z 226 (M.sup.++1).
Example 6
2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide
[0206] A mixture of 2-chloro-5-(chloromethyl)pyridine 1-oxide (1.16
g, 6.52 mmol; described in: Tilley, J. W. et al, J. Heterocyclic
Chem. 1979, 16, 333), morpholine (1.14 g, 13.0 mmol), and potassium
carbonate (0.90 g, 6.52 mmol) in acetonitrile (30 mL) was stirred
at room temperature for 72 h. The solvent was removed in vacuo and
the residue was purified on a silica gel column using
chloroform/ethanol, (9:1), as the eluent affording 1.21 g (81%
yield) of the title compound as a colorless solid: mp 72-74.degree.
C.; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.34 (s, 1H), 7.39
(d, J=8 Hz, 1H), 7.16 (dd, J=8.2 Hz, 1H), 3.65 (t, J=5 Hz, 4H),
3.40 (s, 2H), 2.40 (t, J=4 Hz, 4H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 140.4 (br), 135.9, 126.6, 126.6, 66.8, 59.2, 53.4; MS
(ESP) m/z 229 (M.sup.++1).
Example 7
6-Chloro-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide
[0207] The title compound was prepared as described for Example 3
using 2-pyrrolidin-1-yl-ethylamine and 6-chloropyridine-3-sulfonyl
chloride (described in: Naegeli, C. et al. Helv. Chim. Actal. 1938,
21, 1746-1750). Purification on a silica gel column using ethyl
acetate/triethylamine, (9:1), as the eluent gave the title
compound. Yield: 58%: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.79 (d, J=2 Hz, 1H), 8.05 (dd, J=8, 3 Hz, 1H), 7.42 (d, J=9 Hz,
1H), 3.00 (app. t, J=6 Hz, 2H), 2.50 (app. t, J=6 Hz, 2H), 2.33 (m,
4H), 1.67 (m, 4H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
155.7, 148.8, 137.8, 136.1, 125.0, 54.1, 53.9, 41.6, 23.9; MS (TSP)
m/z 290 (M.sup.++1).
Example 8
2-Chloro-5-(pyrrolidin-1-ylmethyl)pyridine 1-oxide
[0208] To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide
(477 mg, 2.68 mmol; described in: Tilley, J. W. et al, J.
Heterocyclic Chem. 1979, 16, 333) in acetonitrile (10 mL) was added
pyrrolidine (381 mg, 5.36 mmol), and the reaction mixture was
stirred at room temperature overnight. The solvent was evaporated,
and the residue was dissolved in 2 M HCl(aq) and washed with ethyl
acetate. The aqueous layer was alkalized to pH 8 with NaHCO.sub.3
(s), and the mixture was extracted four times with ethyl acetate.
The combined organic layers were dried (Na.sub.2SO.sub.4), and the
solvent was evaporated to give 0.43 g (75% yield) of the title
compound as a red oil: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.37 (d, J=1 Hz, 1H), 7.44 (d, J=8 Hz, 1H), 7.23 (dd, J=8, 2 Hz,
1H), 3.57 (s, 2H), 2.51 (m, 4H), 1.80 (m, 4H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 140.1, 139.9, 137.2, 126.4, 126.4,
56.4, 54.0, 23.5; MS (ES) m/z 213 (M.sup.++1).
Example 9
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-methyl-1,4-diazepane
[0209] To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide
(940 mg, 5.28 mmol; described in: Tilley, J. W. et al, J.
Heterocyclic Chem. 1979, 16, 333) in acetonitrile (30 mL) were
added N-methylhomopiperazine (1.21 g, 10.6 mmol), and
K.sub.2CO.sub.3 (730 mg, 5.28 mmol). The reaction mixture was
stirred at room temperature for 3.5 days. The solvent was removed
in vacuo, and the residue was partitioned between brine and ethyl
acetate. The aqueous layer was extracted with another two portions
of ethyl acetate and one portion of tetrahydrofuran. The combined
organic layers were dried (Na.sub.2SO.sub.4), and evaporated to
give 0.86 g (64% yield) of the title compound as an orange oil:
.sup.1H NMR (acetone-d6, 400 MHz) .delta. 8.30 (dd, J=2 Hz, 1H),
7.60 (d, J=8 Hz, 1H), 7.29 (dd, J=8, 2 Hz, 1H), 3.65 (s, 2H),
2.74-2.69 (m, 4H), 2.62-2.54 (m, 4H), 2.29 (s, 3H), 1.81-1.75 (m,
2H); MS (ES) m/z 256 (M.sup.++1).
[0210] The following Examples, 10-11, were prepared as described
for Example 9:
Example 10
2-Chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridine
1-oxide
[0211] Starting material: 4-(1-pyrrolidinyl)piperidine. Yield: 93%:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.33 (d, J=1 Hz, 1H),
7.41 (d, J=8 Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 3.41 (s, 2H),
2.83-2.78 (m, 2H), 2.58-2.53 (m, 4H), 2.15-2.00 (m, 3H), 1.88-1.83
(m, 2H), 1.81-1.75 (m, 4H), 1.61-1.53 (m, 2H); MS (ES) m/z 296
(M.sup.++1).
Example 11
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N,N-dimethylpyrrolidin-3-amine
[0212] Starting material: 3-(dimethylamino)pyrrolidine. Yield: 67%:
.sup.1H NMR (aceton-d6, 400 MHz) .delta. 8.28 (d, J=1 Hz, 1H), 7.60
(d, J=8 Hz, 1H), 7.27 (dd, J=8, 2 Hz, 1H), 3.66-3.53 (m, 2H),
2.76-2.63 (m, 2H), 2.58-2.50 (m, 1H), 2.43-2.35 (m, 1H), 2.24-2.21
(m, 1H), 2.12 (s, 6H), 1.96-1.89 (m, 1H), 1.74-1.64 (m, 1H); MS
(ES) m/z 256 (M.sup.++1).
Example 12
2-Chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide
[0213] To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide
(222 mg, 1.25 mmol; described in: Tilley, J. W. et al, J.
Heterocyclic Chem. 1979, 16, 333) in tetrahydrofuran (2 mL) were
added a solution of 4-methylpiperidine (247 mg, 2.49 mmol) in
tetrahydrofuran (1.5 mL), a catalytic amount of potassium iodide,
and MP-Carbonate (2.55 mmol/g, 1.47 g, 3.74 mmol). The mixture was
gently stirred at room temperature for one week. The mixture was
filtered (20 .mu.m polyethylene filter), and the beads were washed
with several portions of methylene chloride. The filtrate was
washed with NaHCO.sub.3 (aq. sat.), dried (Na.sub.2SO.sub.4), and
the solvent was evaporated to give a crude product which was
purified by column chromatography using chloroform/ethanol, (95:5),
as the eluent to give 168 mg (56% yield) of the title compound as a
yellow oil: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.37 (d, J=1
Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 3.41 (s,
2H), 2.80-2.75 (m, 2H), 2.00 (dt, J=12, 2 Hz, 2H), 1.63-1.58 (m,
2H), 1.45-1.30 (m, 1H), 1.22 (m, 2H), 0.92 (d, J=6 Hz, 3H); MS (ES)
m/z 241 (M.sup.++1).
Example 13
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-phenylpiperazine
[0214] PS-Diisopropylethylamine (3.54 mmol/g, 0.4 g, 1.40 mmol) was
washed with tetrahydrofuran and 2-chloro-5-(chloromethyl)pyridine
1-oxide (100 mg, 0.56 mmol; described in: Tilley, J. W. et al, J.
Heterocyclic Chem. 1979, 16, 333) was added followed by
tetrahydrofuran (1 mL). A solution of 1-phenylpiperazine (182 mg,
1.12 mmol) in tetrahydrofuran (1 mL) and a catalytic amount of
potassium iodide were added, and the mixture was gently stirred
(100 r/min) at room temperature for one week. PS-Isocyanate (1.76
mmol/g, 0.80 g, 1.40 mmol) was washed with tetrahydrofuran and
added to the mixture followed by additional tetrahydrofuran (1 mL).
The suspension was gently stirred (100 r/min) at room temperature
for 19 h. The suspension was filtered (20 .mu.m polyethylene
filter), and the resins were washed with methylene chloride,
tetrahydrofuran, and ethanol. Volatiles were removed in vacuo, and
the residue was suspended in a 1:1-mixture of tetrahydrofuran and
ethanol (8 mL) followed by the addition of
N-ethyl-N,N-diisopropylamine (50 .mu.L, 0.28 mmol). The mixture was
added to PS-Thiophenol (1.35 mmol/g, 0.21 g, 0.28 mmol), and
MP-Carbonate (3.20 mmol/g, 90 mg, 0.28 mmol), both pre-swelled in
tetrahydrofuran. The mixture was stirred (100 r/min) at room
temperature overnight followed by filtration. The resins were
washed with methylene chloride, tetrahydrofuran, and ethanol, and
the filtrate was concentrated in vacuo to give 141 mg (83% yield)
of the title compound: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.42 (s, 1H), 7.45 (d, J=8 Hz, 1H), 7.30-7.26 (m, 2H), 7.25-7.21
(m, 1 H), 6.95-6.90 (m, 2H), 6.89-6.85 (m, 1H), 3.51 (s, 2H),
3.22-3.18 (m, 4H), 2.65-2.60 (m, 4H); MS (ES) m/z 304
(M.sup.++1).
[0215] The following Examples, 14-19, were prepared as described
for Example 13:
Example 14
1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)phe-
nyl]piperazine
[0216] Starting material:
1-[2-nitro-4-(trifluoromethyl)phenyl]piperazine. Yield: 100%:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.43 (d, J=1 Hz, 1H),
8.06 (d, J=2 Hz, 1H), 7.68 (dd, J=9, 2 Hz, 1H), 7.45 (d, J=8 Hz,
1H), 7.19 (dd, J=8, 2 Hz, 1H), 7.16 (d, J=9 Hz, 1H), 3.54 (s, 2H),
3.18 (t, J=5 Hz, 4H), 2.64 (t, J=5 Hz, 4H); MS (ES) m/z 417
(M.sup.++1).
Example 15
3-[[(6-Chloro-1-oxidopyridin-3-yl)methyl](ethyl)amino]propanenitrile
[0217] Starting material: 3-(ethylamino)propionitrile. Yield: 82%:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.35 (d, J=1 Hz, 1H),
7.46 (d, J=8 Hz, 1H), 7.32 (dd, J=9, 1 Hz, 1H), 3.60 (s, 2H), 2.82
(t, J=7 Hz, 2H), 2.60 (q, J=7 Hz, 2H), 2.47 (t, J=7 Hz, 2H), 1.07
(t, J=7 Hz, 3H); MS (ES) m/z 240 (M.sup.++1).
Example 16
N-(4-Chlorobenzyl)-N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methylamine
[0218] Starting material: p-chloro-N-methylbenzylamine. Yield:
100%: .sup.1H NMR (CDCl.sub.3/DMSO-d6, 7:1, 400 MHz) .delta. 8.39
(s, 1H), 7.46 (dd, J=8, 1 Hz, 1H), 7.34-7.26 (m, 4H), 7.24-7.20 (m,
1H), 3.54 (d, J=2 Hz, 2H), 3.45 (s, 2H), 2.20 (d, J=2 Hz, 3H); MS
(ES) m/z 297 (M.sup.++1).
Example 17
N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-(2-furylmethyl)-N-methylamine
[0219] Starting material: N-methylfurfurylamine. Yield: 71%:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.37 (d, J=1 Hz, 1H),
7.43 (d, J=8 Hz, 1H), 7.39 (dd, J=2, 1 Hz, 1H), 7.22 (dd, J=8, 2
Hz, 1H), 6.34 (dd, J=3, 2 Hz, 1H), 6.22-6.20 (m, 1H), 3.61 (s, 2H),
3.46 (s, 2H), 2.26 (s, 3H); MS (ES) m/z 253 (M.sup.++1).
Example 18
N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-methyl-N-phenylamine
[0220] Starting material: N-methylaniline. Yield: 100%: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.26 (d, J=1 Hz, 1H), 7.42 (d, J=8
Hz, 1H), 7.26-7.20 (m, 2H), 7.10-7.06 (m, 1H), 6.81-6.75 (m, 1H),
6.71-6.67 (m, 2H), 4.45 (s, 2H), 3.02 (s, 3H); MS (ES) m/z 249
(M.sup.++1).
Example 19
5-(Azetidin-1-ylmethyl)-2-chloropyridine 1-oxide
[0221] Starting material: azetidine. Yield: 100%: MS (ES) m/z 199
(M.sup.++1).
Example 20
2-Chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide
[0222] PS-Diisopropylethylamine (3.54 mmol/g, 0.4 g, 1.40 mmol) was
washed with tetrahydrofuran and 2-chloro-5-(chloromethyl)pyridine
1-oxide (100 mg, 0.56 mmol; described in: Tilley, J. W. et al, J.
Heterocyclic Chem. 1979, 16, 333) was added followed by
tetrahydrofuran (1 mL). A solution of 3-methylpiperidine in
tetrahydrofuran (1.5 mL) and a catalytic amount of potassium iodide
were added, and the mixture was gently stirred (80 r/min) at room
temperature for 5 days. PS-Isocyanate (1.10 mmol/g, 1.27 g, 1.40
mmol) was washed with tetrahydrofuran and added to the mixture
followed by additional tetrahydrofuran (2 mL). The suspension was
gently stirred (80 r/min) at room temperature overnight.
N-Ethyl-N,N-diisopropylamine (50 .mu.L, 0.28 mmol) and MP-Carbonate
(2.55 mmol/g, 0.66 g, 1.68 mmol) were added, and the contents were
mixed and gently stirred for 24 h. The mixture was filtered (20
.mu.m polyethylene filter), and the resins were washed with
methylene chloride. Volatiles were removed in vacuo to give 138 mg
(99% yield) of the title compound: MS (ES) m/z 241 (M.sup.++1).
[0223] The following Examples, 21-22, were prepared as described
for Example 20:
Example 21
N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-cyclohexyl-N-methylamine
[0224] Starting material: N-methylcyclohexylamine. Yield: 96%: MS
(ES) m/z 255 (M.sup.++1).
Example 22
2-Chloro-5-(piperidin-1-ylmethyl)pyridine 1-oxide
[0225] Starting material: piperidine: MS (ES) m/z 227
(M.sup.++1)
Example 23
6-Dibromo-1,3-dihydroindol-2-one
[0226] 6-Bromooxindole (0.168 g, 0.8 mmol) was dissolved in acetic
acid (4 mL) and stirred for 5 min at room temperature.
N-Bromosuccinimide (0.14 g, 0.8 mmol) was added and the yellow
reaction mixture was stirred for 3 h at ambient temperature. The
mixture was poured onto ice and the resulting precipitate was
collected by filtration and dried in vacuo to give 0.192 g (83%
yield) of the title compound as a white solid: .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.61 (s, 1H), 7.60 (s, 1H), 7.14 (s,
1H), 3.52 (s, 2H).
Example 24
1-Benzyl-4-[(6-chloropyridine-3-yl)sulfonyl]piperazine
[0227] To a solution of benzylpiperazine (0.45 mL, 2.59 mmol) in
methylene chloride (15 mL), cooled on an ice-bath, was
6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described
in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750)
dissolved in methylene chloride (10 mL) added slowly. The reaction
was stirred for 30 min and the formed white precipitation was
filtered and washed with methylene chloride and water affording,
after drying, 0.68 g (82% yield) of the title compound: .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 8.70 (d, J=3 Hz, 1H), 8.14 (dd, J=8, 3
Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.50-7.43 (m, 2H), 7.38-7.30 (m,
3H), 4.23 (br s, 2H), 3.79-3.63 (m, 2H), 3.45-3.18 (m, 2H),
3.11-2.96 (m, 2H), 2.96-2.81 (m, 2H); MS (ES) m/z 352
(M.sup.++1).
Example 25
1-[(6-Chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine
[0228] To a solution of 1-(3-methylbutyl)piperazine (0.41 g, 2.60
mmol; described in: Yamane, T. et al. Chem. Pharm. Bull. 1993, 41,
148-155) in methylene chloride (15 mL) cooled on an ice-bath was
6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described
in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750)
dissolved in methylene chloride (10 mL) added slowly. The reaction
was stirred for 30 min and a 5% HCl(aq) solution (30 mL) was added
and the phases were separated. The aqueous layer was alkalyzed with
a saturated aqueous NaHCO.sub.3 solution until pH 9 and the mixture
was extracted with methylene chloride. The organic layers were
combined, dried (Na.sub.2SO.sub.4) and the solvent was removed in
vacuo affording 650 mg (83% yield) of the title compound as a white
solid: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.75 (d, J=2 Hz,
1H), 7.97 (dd, J=8, 2 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 3.33-3.05 (m,
4H), 2.86-2.29 (m, 6H), 1.66-1.50 (m, 1H), 1.5-1.28 (m, 2H), 0.88
(d, J=7 Hz, 6H); MS (ES) m/z 332 (M.sup.++1).
Example 26
1-[(6-Chloropyridin-3-yl)sulfonyl]-4-isopropylpiperazine
[0229] The title compound was prepared as described for Example 25
using N-isopropylpiperazine and 6-chloropyridine-3-sulfonyl
chloride (described in: Naegeli, C. et al. Helv. Chim. Actal. 1938,
21, 1746-1750). Yield: 89%: .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.73 (d, J=3 Hz, 1H), 7.96 (dd, J=8, 3 Hz, 1H), 7.48 (d,
J=8 Hz, 1H), 3.12-3.01 (m, 4H), 2.76-2.63 (m, 1H), 2.63-2.54 (m,
4H), 0.99 (d, J=7 Hz, 6H); .sup.13C NMR (CDCl.sub.3, 100 MHz)
.delta. 156.1, 149.3, 138.2, 131.7, 125.0, 54.8, 48.0, 46.7, 18.7;
MS (ES) m/z 304 (M.sup.++1).
Example 27
1-[(6-Chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine
[0230] The title compound was prepared as described for Example 25
using N-ethylpiperazine and 6-chloropyridine-3-sulfonyl chloride
(described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21,
1746-1750). Yield: 83%: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.75 (d, J=3 Hz, 1H), 7.97 (dd, J=8, 3 Hz, 1H), 7.50 (d, J=8 Hz,
1H), 3.16-3.06 (m, 4H), 2.60-2.46 (m, 4H), 2.42 (q, J=7 Hz, 2H),
1.04 (t, J=7 Hz, 3H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
155.8, 148.9, 137.8, 131.3, 124.7, 51.9, 51.6, 46.0, 11.9; MS (ES)
m/z 290 (M.sup.++1).
Example 28
1-[(5-Bromo-6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine
[0231] The title compound was prepared as described for Example 3
using 1-methylpiperazine and 5-bromo-6-chloropyridine-3-sulfonyl
chloride. Yield: 91%: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.59 (d, J=2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 3.08-3.01 (m, 4H), 2.43
(t, J=5 Hz, 4H), 2.22 (s, 3H); .sup.13C NMR (CDCl.sub.3, 100 MHz)
.delta. 155.5, 146.8, 141.2, 132.7, 121.4, 54.2, 46.3, 46.1.
Example 29
6-Chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide
[0232] To a solution of 6-chloropyridine-3-sulfonylchloride (636
mg, 3 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal.
1938, 21, 1746-1750) in methylene chloride (10 mL) was added
methyl-(2-pyrrolidin-1-ylethyl)amine (384 mg, 3 mmol; described in:
J. Amer. Chem. Soc. 1955, 77, 3632-3634) dissolved in methylene
chloride (10 mL) dropwise. The reaction mixture was stirred over
night at room temperature followed by the extraction with aqueous
HCl (3%). The acidic water layer was alkalized with an aqueous
saturated solution of NaHCO.sub.3 and extracted with methylene
chloride. The organic phase was dried (Na.sub.2SO.sub.4) and
evaporated in vacuo to give 0.75 gram (80% yield) of the title
compound: MS (ES) m/z 304 (M.sup.++1).
Example 30
6-Chloro-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide
[0233] The title compound was prepared as described for Example 29
using 6-chloropyridine-3-sulfonylchloride and
N,N-dimethylethane-1,2-diamine. Yield: 72%: MS (ES) m/z 264
(M.sup.++1).
Example 31
6-Chloro-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide
[0234] To a solution of N'-ethyl-N,N-dimethylethane-1,2-diamine
(0.62 mL, 4.4 mmol) in methylene chloride (10 mL) was added
6-chloropyridine-3-sulfonylchloride (0.85 g, 4 mmol; described in:
Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750)
dissolved in methylene chloride (10 mL) dropwise. The reaction
mixture was stirred for 30 min at room temperature followed by the
extraction with aqueous HCl (5%). The acidic water layer was
alkalized with an aqueous saturated solution of NaHCO.sub.3 and
extracted with methylene chloride. The organic phase was dried
(Na.sub.2SO.sub.4) and evaporated in vacuo to give 0.7 gram (60%
yield) of the title compound: MS (ES) m/z 292 (M.sup.++1).
Example 32
6-Chloro-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide
[0235] The title compound was prepared as described for Example 31
using (1-ethylpyrrolidin-2-yl)methylamine. Yield: 58%: MS (ES) m/z
304 (M.sup.++1).
Example 33
1-[(6-Chloropyridin-3-yl)sulfonyl]-4-methyl-1,4-diazepane
[0236] The title compound was prepared as described for Example 31
using 1-methylhomopiperazine. Yield: 60%: MS (ES) m/z 290
(M.sup.++1).
Example 34
4-[(6-Chloropyridin-3-yl)sulfonyl]morpholine
[0237] The title compound was prepared as described for Example 31
using morpholine. The crude product was purified on a silica gel
column using heptane/ethyl acetate, (1:1), as the eluent: Yield:
60%: MS (ES) m/z 263 (M.sup.++1).
Example 35
Ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate
[0238] To a cooled solution of 5-nitrooxindol (5.27 g, 29.6 mmol)
in N,N-dimethylamide (50 mL) was added sodium hydride (1.4 g, 35
mmol) during 5 min at 0.degree. C. After 10 min at 0.degree. C.,
6-chloronicotinic acid ethyl ester (5.0 g, 26.9 mmol) was added
dropwise and the reaction was heated to 135.degree. C. for 45 min.
The mixture was diluted with water (200 mL) and saturated
NH.sub.4Cl(aq) (100 mL). The formed precipitate was filtrated and
washed with water, methanol, ethyl acetate and diethyl ether. The
residual green yellow solid was dried to give 4.1 g (47% yield) of
the title compound: .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 14.57
(s, 1H), 11.24 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 8.10 (d, J=9
Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.03 (d, J=9
Hz, 1H), 4.31 (q, J=7 Hz, 2H), 1.32 (t, J=7 Hz, 3H).
Example 36
Ethyl 6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate
[0239] To a solution of 5-cyanooxindole (360 mg, 2.27 mmol) in
N,N-dimethylformamide (5 mL) was added sodium hydride (106 mg, 4.41
mmol). The greenish reaction mixture was stirred for 50 min
whereafter 6-chloronicotinic acid ethyl ester (350 mg, 1.89 mmol)
dissolved in N,N-dimethylformamide (5 mL) was added. The reaction
mixture was heated at 110.degree. C. for 30 min and water (50 mL)
and saturated NH.sub.4Cl(aq) (20 mL) was added, followed by
extraction with ethyl acetate. The phases were separated and the
organic phase contained the title compound as a precipitation that
was filtered off. The solvent was concentrated in vacuo and
additional product precipitated that was filtered to give 200 mg
(34% yield) of the title compound in total: .sup.1H NMR (DMSO-d6,
300 MHz) .delta. 14.50 (br s, 1H), 11.00 (s, 1H), 8.73 (s, 1H),
7.95 (s, 2H), 7.80 (s, 1H), 7.48 (s, 1H), 6.95 (d, J=7 Hz, 1H),
4.50-4.15 (m, 2H), 1.32 (t, J=7 Hz, 3H).
Example 37
5-Pyridin-3-yl-1,3-dihydro-2H-indol-2-one
[0240] A mixture of 5-bromooxindole (0.95 g, 4.48 mmol),
3-(tri-n-butylstannyl)pyridine (1.65 g, 4.48 mmol), tetraethyl
ammonium chloride (2.23 g, 13.4 mmol) and bis(triphenylphospine
palladium (II) chloride (0.16 g, 0.22 mmol) in acetonitrile (20 mL)
was heated at reflux over night. After cooling to ambient
temperature the mixture was diluted with chloroform (100 mL) and a
potassium fluoride solution (10%, 250 mL) was added. The mixture
was filtered through Celite and the layers were separated. The
organic layer was dried (Na.sub.2SO.sub.4) and the solvent was
removed in vacuo. The residue was purified on a silica gel column
using chloroform/ethanol, (50:1), as the eluent affording 165 mg
(18% yield) of the title compound as a white solid: .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 9.64 (br s, 1H), 7.97 (d, J=2 Hz, 1H),
7.66 (dd, J=5, 1 Hz, 1H), 7.21-7.10 (m, 1H), 6.73 (s, 1H),
6.73-6.65 (m, 1H), 6.65-6.54 (m, 1H), 6.08 (d, J=8 Hz, 1H), 2.69
(s, 2H); MS (ES) m/z 211 (M.sup.++1).
Example 38
5-Thien-2-yl-1,3-dihydro-2H-indol-2-one
[0241] The title compound was prepared as described for Example 37
using 5-bromooxindole and tri-n-butyl(2-thienyl)tin: MS (ES) m/z
216 (M.sup.++1).
Example 39
5-(2-Furyl)-1,3-dihydro-2H-indol-2-one
[0242] The title compound was prepared as described for Example 37
using 5-bromooxindole and tri-n-butyl(2-furyl)tin: MS (ES) m/z 200
(M.sup.++1).
Example 40
5-(Hydroxymethyl)-1,3-dihydro-2H-indol-2-one
[0243] To an ice-cooled mixture of methyl
2-oxoindoline-5-carboxylate (0.5 gram, 2.6 mmol) in a
tetrahydrofuran/ethanol mixture (15:0.3 mL) was added lithium
borohydride (115 mg, 5.2 mmol) in one portion. After 30 min,
another portion of lithium borohydride (100 mg, 4.5 mmol) was added
and the reaction solution was stirred for 4 h at room temperature.
A third portion of lithium borohydride (200 mg, 9.2 mmol) and
ethanol (0.3 mL) were added and the reaction solution was stirred
for 14 h at room temperature. The reaction was quenched with water
(10 mL) and an aqueous saturated ammonium chloride solution (30 mL)
and extracted with ethyl acetate. The combined organic phases were
dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The crude product
was purified on a silica gel column using methylene
chloride/methanol, (10:1) as the eluent to give 140 mg (33% yield)
of the title compound: .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.3
(br s, 1H), 7.14 (s, 1H), 7.09 (d, J=8 Hz, 1H), 6.74 (d, J=8 Hz,
1H), 5.03 (t, J=6 Hz, 1H), 4.41 (7, J=6 Hz, 2H), 3.44 (s, 2H).
Example 41
2-Oxoindoline-5-carbaldehyde
[0244] Chromium (VI) oxide (240 mg, 2.4 mmol) was added to
ice-cooled pyridine (3 mL). To the formed yellow suspension was
added additional pyridine (2 mL) and
5-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (130 mg, 0.8 mmol)
dissolved in pyridine (3 mL). The reaction was quenched after 15
min by the addition of water (50 mL) and extracted with ethyl
acetate. The organic phases were dried (Na.sub.2SO.sub.4) and
evaporated in vacuo. The crude product was purified on a silica gel
column using methylene chloride/methanol, (10:1), as the eluent to
give 60 mg (46% yield) of the title compound.
Example 42
5-(1,3-Oxazol-5-yl)-1,3-dihydro-2H-indol-2-one
[0245] A mixture of 2-oxoindoline-5-carbaldehyde (60 mg, 0.38
mmol), tosylmethyl isocyanide (145 mg, 0.75 mmol) and potassium
carbonate (103 mg, 0.75 mmol) in methanol (20 mL) was heated at
reflux for 2 h. The mixture was concentrated in vacuo and diluted
with an aqueous saturated solution of sodium hydrogencarbonate and
extracted with methylene chloride. The combined organic layers were
dried (Na.sub.2SO.sub.4) and evaporated in vacuo. The crude product
was purified on a silica gel column using heptane/ethyl acetate,
(1:4), as the eluent to give 40 mg (53% yield) of the title
compound: .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.54 (br s, 1H),
8.36 (br s, 1H), 7.64-7.44 (m, 3H), 6.89 (d, J=8 Hz, 1H), 3.54 (br
s, 2H).
Example 43
5-(Chloroacetyl)-1,3-dihydro-2H-indol-2-one
[0246] To a mixture of aluminum trichloride (17 gram, 128 mmol) and
chloroacethyl chloride (3 gram, 2.65 mmol) in carbon disulfide (40
mL) was oxindole (2.73 gram, 20.5 mmol) added and the mixture was
stirred at reflux for 3.5 h. The mixture was cooled to room
temperature and carefully quenched with cooled water (50 mL). The
quenched reaction mixture was stirred for 2 h and the formed
precipitate was filtered and washed two times with water. The solid
was dried to give 2.3 gram (53% yield) of the title compound:
.sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.82 (br s, 1H), 7.87 (d,
J=8 Hz, 1H), 7.82 (s, 1H), 6.92 (d, J=8 Hz, 1H), 5.08 (s, 2H), 3.57
(s, 2H).
Example 44
5-(1,3-Thiazol-4-yl)-1,3-dihydro-2H-indol-2-one
[0247] A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one
(630 mg, 3 mmol), thioformamide (30 mL, 30 mmol; described in: J.
Med. Chem. 1995, 858-868) and triethylamine (0.42 mL, 3 mmol) in
dioxane was heated at 110.degree. C. for 3 h. Additional
thioformamide (10 mL, 10 mmol) was added and the reaction was
stirred at 110.degree. C. for 2 h.
[0248] This batch was combined with an new batch starting from 230
mg of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one and the combined
reaction mixtures was concentrated to approximately 10 mL and an
aqueous saturated sodium hydrogencarbonate solution (50 mL) was
added and the solution was extracted with ethyl acetate. The
combined organic layers were dried (Na.sub.2SO.sub.4) and
evaporated in vacuo. The crude product was purified on a silica gel
column using heptane/ethyl acetate, (1:2), as the eluent to give
400 mg (35% yield) of the title compound: .sup.1H NMR (DMSO-d6, 300
MHz) .delta. 10.47 (s, 1H), 9.15 (s, 1H), 7.97 (s, 1H), 7.83 (br s,
2H), 6.87 (d, J=8 Hz, 1H), 3.54 (s, 2H); MS (ES) m/z 217
(M.sup.++1).
Example 45
5-(2-Methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one
[0249] A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one
(1.5 g, 7.15 mmol) and thioacetamide (540 mg, 7.15 mmol) in acetic
acid (18 mL) was heated at 80.degree. C. for 3 h. The mixture was
cooled to room temperature and the formed precipitate was filtered
and washed with ethyl acetate two times and diethyl ether two times
and the solid was dried under vacuo to give 1.5 gram (91% yield) of
the title compound: .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.49
(s, 1H), 7.90-7.70 (m, 3H), 6.85-6.75 (m, 1H), 3.55 (s, 2H), 2.70
(s, 3H).
Example 46
3-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-
-ol
[0250] To a suspension of sodium hydride (0.05 g, 1.2 mmol, 60%
dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide
(3 mL) was added a solution of
5-pyridin-3-yl-1,3-dihydro-2H-indol-2-one (0.19 g, 0.90 mmol) in
N,N-dimethylformamide (4 mL). The mixture was stirred for 20 min
under nitrogen atmosphere.
2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (0.14 g, 0.60
mmol), dissolved in N,N-dimethylformamide (3 mL) was added dropwise
and the mixture was stirred at room temperature for 2 h and then
heated at 130.degree. C. for 1.5 h. The solvent was evaporated in
vacuo and the residue was partitioned between 2 M HCl and ethyl
acetate and the phases were separated. The aqueous layer was
alkalized by addition of NaHCO.sub.3 (s) and extracted with ethyl
acetate. The organic layer was dried (Na.sub.2SO.sub.4) and the
solvent was removed in vacuo affording 200 mg of the title compound
as a yellow solid: MS (ES) m/z 403 (M.sup.++1).
Example 47
3-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2-o-
l
[0251] The title compound was prepared as described for Example 46
using 5-thien-2-yl-1,3-dihydro-2H-indol-2-one: MS (ES) m/z 408
(M.sup.++1).
Example 48
5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-1H-indol-2-ol
[0252] The title compound was prepared as described for Example 46
using 5-(2-furyl)-1,3-dihydro-2H-indol-2-one: MS (ES) m/z 392
(M.sup.++1).
Example 49
2-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]isonicotinam-
ide
[0253] To a suspension of sodium hydride (0.15 g, 3.70 mmol, 60%
dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide
(3 mL) was added a solution of 5-cyanooxindole (0.29 g, 1.84 mmol)
in N,N-dimethylformamide (4 mL). The mixture was stirred for 30 min
under a nitrogen atmosphere.
2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide (0.21 g, 0.92
mmol) dissolved in N,N-dimethylformamide (4 mL) was added dropwise
and the mixture was stirred at room temperature for 30 min and then
heated at 150.degree. C. for 45 min. The solvent was evaporated in
vacuo and the residue was partitioned between ethyl acetate and
water. A 2 M aqueous HCl solution was added until pH 2 and the
mixture was extracted with ethyl acetate. To the aqueous layer, a
45% aqueous NaOH solution was added until pH 11 and the suspension
was extracted with ethyl acetate. The aqueous layer was
concentrated in vacuo and the crude product was purified by
preparative HPLC (column: Xterra, 19.times.300 mm, eluent: 0.05 M
NH.sub.4OAc buffert/acetonitrile, 9:1 to 3:7) to give 15 mg (5%
yield) of the title compound as a red solid: .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 14.88 (br s, 1H), 11.03 (br s, 1H),
9.10 (br s, 1H), 8.28 (d, J=6 Hz, 1H), 8.04-7.96 (m, 1H), 7.95-7.83
(m, 1H), 7.42-7.34 (m, 1H), 7.13-7.02 (m, 2H), 3.62-3.50 (m, 2H),
2.86-2.69 (m, 2H), 2.58-2.29 (m, 6H); MS (TSP) m/z 350
(M.sup.++1).
Example 50
2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-
-carbonitrile Hydrochloride
[0254] The reaction was performed as described in Example 49 using
5-cyanooxindole and 1-(2-chloroisonicotinoyl)-4-methylpiperazine.
The crude product was purified on a silica gel column using
chloroform/ethanol/conc. NH.sub.3(aq), (100:10:1), as the eluent.
The base (20 mg) was dissolved in chloroform and a solution of HCl
in diethyl ether was added until acidic pH. The formed
precipitation was filtered and washed with diethyl ether. Drying in
vacuo afforded 10 mg the title compound as a red solid. Yield: 2%:
.sup.1H NMR (D.sub.2O, 400 MHz) .delta. 7.82-7.77 (m, 1H),
7.18-7.11 (m, 1H), 7.09-7.05 (m, 1H), 7.04-6.98 (m, 1H), 6.78-6.71
(m, 1H), 6.67-6.61 (m, 1H), 4.05-3.94 (m, 1H), 3.93-3.82 (m, 1H),
3.67-3.48 (m, 2H), 3.48-3.37 (m, 1H), 3.35-3.04 (m, 3H), 2.92-2.80
(m, 3H); MS (TSP) m/s 362 (M.sup.++1).
Example 51
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-
-carbonitrile
[0255] A mixture of 5-cyanooxindole (213 mg, 1.35 mmol) and sodium
hydride (72 mg, 1.80 mmol, 60% dispersion in oil) in
N,N-dimethylformamide (4 mL) was stirred at room temperature for 10
min. A solution of
1-[(6-chloropyridin-3-yl)carbonyl]-4-methylpiperazine (216 mg,
0.901 mmol; described in: Thunus, L. Ann. Pharm. Fr. 1977, 35(5-6),
197-203) in N,N-dimethylformamide (2 mL) was added dropwise. The
reaction was stirred at room temperature for 3 h, then at
50.degree. C. for 2.5 h. The solvent was removed in vacuo, and the
residue was partitioned between chloroform and water. The phases
were separated and the pH of the water phases was adjusted to 8
with a 2 M aqueous solution of HCl. The aqueous layer was extracted
with ethyl acetate and the organic layers were dried
(Na.sub.2SO.sub.4), combined, and the solvent was removed in vacuo
affording an orange semi-solid. The material was purified on a
silica gel column using chloroform/methanol, (8:2), as the eluent
affording 24 mg (7% yield) of the title compound as a yellow solid:
mp decomposes >295.degree. C.; .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.95 (s, 1H), 7.91 (s, 1H), 7.74 (dd, J=9, 2 Hz, 1H), 7.69
(s, 1H), 7.48 (d, J=9 Hz, 1H), 7.36 (dd, J=8, 1 Hz, 1H), 7.06 (d,
J=8 Hz, 1H), 3.69 (br s, 4H); 2.48 (br s, 4H), 2.36 (s, 3H); MS
(TSP) m/z 362 (M.sup.++1).
Example 52
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitril-
e hydrochloride
[0256] To a suspension of 5-cyanooxindole (720 mg, 4.55 mmol) in
N,N-dimethylformamide (5 mL) was added sodium hydride (248 mg, 6.2
mmol, 60% dispersion in oil). After 15 min, was added
4-[(6-chloropyridin-3-yl)methyl]morpholine (323 mg, 1.52 mmol;
described in: Maienfisch, P. et al. J. Med. Chem. 2000, 43, 5003)
to the solution. The reaction mixture was heated at reflux for 1 h.
The solvent was removed in vacuo, and the residue was partitioned
between ethyl acetate and water. A 2 M aqueous HCl solution was
added to the ethyl acetate and water mixture until slightly acidic
pH, and then NaHCO.sub.3 (s) was added until saturation. The
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried (Na.sub.2SO.sub.4) and the solvent was
removed in vacuo. The crude product was dissolved in a mixture of
methanol and ethyl acetate and was cooled on ice. A solution of HCl
in diethyl ether was added until acidic pH. Approximately half of
the solvent volume was removed in vacuo. The precipitated
hydrochloride salt was filtered, washed with ethyl acetate, and
dried in vacuo. The salt was converted back to the base by
partitioning between ethyl acetate and an aqueous saturated
NaHCO.sub.3 solution. The obtained material (142 mg) was purified
on a silica gel column using chloroform/ethanol, (9:1), as the
eluent affording 34 mg (7% yield) of the title compound as the base
as a yellow solid: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 14.96
(br s, 1H), 8.83 (br s, 1H), 7.79 (dd, J=9, 1 Hz, 1H), 7.69 (s,
1H), 7.63 (s, 1H), 7.50 (d, J=9 Hz, 1H), 7.29-7.26 (m, 1H), 7.06
(d, J=8 Hz, 1H), 3.75-3.72 (m, 4H), 3.44 (s, 2H), 2.50-2.49 (m,
4H).
[0257] The base was dissolved in a mixture of methanol,
dichloromethane, and ethyl acetate (15 mL total volume) and cooled
on ice. A solution of HCl in diethyl ether (1 M) was added until
acidic pH. Approximately half of the solvent volume was removed in
vacuo, and ethyl acetate was added. The precipitated hydrochloride
salt was filtered, washed with ethyl acetate, and dried in vacuo at
40.degree. C. affording 33 mg (87% yield from the base) as a yellow
solid: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 14.75 (br s,
1H), 11.36 (br s, 1H), 10.98 (s, 1H), 8.30 (s, 1H), 8.07-8.02 (m,
2H), 7.90 (d, J=9 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz,
1H), 4.29 (s, 2H), 3.98-3.94 (m, 2H), 3.82-3.75 (m, 2H), 3.37-3.32
(m, 2H), 3.11-3.08 (m, 2H); .sup.13C NMR (DMSO-d6, 100 MHz) .delta.
168.9, 148.4, 142.6, 139.7, 137.4, 124.8, 124.8, 120.8, 119.4,
118.4, 113.1, 108.9, 101.5, 85.6, 63.0, 55.5, 50.2; MS (TSP) m/z
335 (M.sup.++1).
Example 53
2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carboni-
trile
[0258] To a solution of 5-cyanooxindole (411 mg, 2.60 mmol) in
N,N-dimethylformamide (4 mL) was added sodium hydride (181 mg, 4.52
mmol, 60% dispersion in oil). After 10 min, a solution of
4-{2-[(6-chloropyrimidin-4-yl)oxy]ethyl}morpholine (367 mg, 1.51
mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. The
mixture was stirred at room temperature for 3 h. The solvent was
removed in vacuo, and the residue was suspended in a 2 M aqueous
HCl solution and washed twice with ethyl acetate. The aqueous layer
was alkalized to pH 8 by adding a 45% aqueous NaOH solution. The
obtained suspension was extracted twice with ethyl acetate. The
combined phases were washed with brine, dried (Na.sub.2SO.sub.4)
and the solvent was removed in vacuo. The crude product was
purified on a silica gel column using chloroform/ethanol, (9:1), to
chloroform/methanol, (8:2), as the eluent affording 172 mg (31%
yield) of the title compound as a yellow solid: .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.89 (br s, 1H), 8.62 (s, 1H), 8.02 (s,
1H), 7.30 (d, J=7 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 6.83 (br s, 1H),
4.52 (t, J=5 Hz, 2H), 3.60 (t, J=4 Hz, 4H), 2.77 (m, 2H), 2.54 (m,
4H); MS (TSP) m/z 366 (M.sup.++1).
Example 54
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-c-
arbonitrile Hydrochloride
[0259] A mixture of 5-cyanooxindole (694 mg, 4.39 mmol) and sodium
hydride (234 mg, 5.85 mmol, 60% dispersion in oil) in
N,N-dimethylformamide (2.5 mL) was stirred at room temperature for
15 min. To the greenish solution was added a solution of
1-[(6-chloropyridin-3-yl)methyl]-4-methylpiperazine (330 mg, 1.46
mmol) in N,N-dimethylformamide (1.2 mL) and the mixture was heated
at 150.degree. C. for 30 min. The mixture was allowed to cool and
the solvent was removed in vacuo. The residue was suspended in a 2
M aqueous HCl solution and washed twice with ethyl acetate. The
aqueous layer was alkalized with NaHCO.sub.3 (s) until saturation
followed by three extractions with ethyl acetate. The organic
layers were combined, dried (Na.sub.2SO.sub.4), and the solvent was
removed in vacuo. The obtained material was purified twice by
column chromatography on silica using chloroform/methanol/conc.
NH.sub.3(aq), (90:10:0.5), as the eluent affording 56 mg of an oil.
38 mg of the oil was purified by preparative HPLC (column: Xterra,
19.times.300 mm, eluent: 0.05 M NH.sub.4OAc buffert/acetonitrile,
9:1-3:7) affording 29 mg (6% yield) of the title compound as a
yellow solid: mp decomposes>240.degree. C.; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.74 (s, 1H), 7.78 (d, J=9 Hz, 1H),
7.70 (s, 1H), 7.64 (s, 1H), 7.50 (d, J=9 Hz, 1H), 7.29 (m, 1H),
7.06 (d, J=8 Hz, 1H), 3.44 (s, 2H), 2.52 (br s, 8H), 2.31 (s, 3H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 169.1, 149.6, 141.7,
136.1, 134.2, 125.4, 124.7, 123.6, 121.0, 119.7, 118.4, 109.3,
103.2, 85.4, 59.0, 55.0, 52.9, 45.9.
[0260] 10 mg of the solid was dissolved in a mixture of ethyl
acetate, methylene chloride, and a small volume of methanol (10 mL
total volume). The solution was cooled on ice and HCl in diethyl
ether (1 M) was added until acidic pH. Approximately 2/3 of the
solvent volume was removed in vacuo and ethyl acetate was added.
The precipitated hydrochloride salt was filtered, washed with ethyl
acetate and dried in vacuo affording 12 mg of the title compound as
an orange solid: .sup.1H NMR (D.sub.2O, 400 MHz) .delta. 7.78 (s,
1H), 7.68-7.65 (m, 1H), 7.47 (s, 1H), 7.34-7.31 (m, 1H), 7.14-7.11
(m, 1H), 6.93-6.6.90 (m, 1H), 3.62-3.48 (m, 10H), 2.77 (s, 3H); MS
(TSP) m/z 348 (M.sup.++1).
Example 55
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-methylnic-
otinamide hydrochloride
[0261] A mixture of sodium hydride (330 mg, 8.2 mmol, 60%
dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide
(2 mL) was added to 5-cyanooxindole (980 mg, 6.2 mmol) in
N,N-dimethylformamide (4 mL). The formed brown mixture was stirred
at room temperature for 20 min and
6-chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (500 mg,
2.1 mmol) in N,N-dimethylformamide (3 mL) was added. The obtained
red solution was heated at 150.degree. C. for 30 min and was then
allowed to reach room temperature overnight. The solvent was
removed in vacuo and the residue was partitioned between a 2 M
aqueous HCl solution and ethyl acetate. The mixture was alkalized
to pH 8 by adding NaHCO.sub.3 (s) and extracted with ethyl acetate.
The combined extracts were dried (Na.sub.2SO.sub.4) and the solvent
was removed in vacuo to afford 450 mg of a crude product. The
residue was purified on a silica gel column using chloroform
methanol/conc. NH.sub.3(aq), (80:19:1), as the eluent. Fractions
containing product were collected, evaporated in vacuo and dried at
25.degree. C. in vacuo to afford 70 mg. The residue was purified by
preparative HPLC (column: Xterra, 19.times.300 mm, eluent: 0.05 M
NH.sub.4OAc buffert/acetonitrile, 9:1-3:7). Fractions containing
product were collected, evaporated in vacuo and dried at 25.degree.
C. in vacuo to afford 35 mg (4.6% yield) of the title compound as
the base: .sup.1H NMR (D.sub.2O, 400 MHz) .delta. 7.89 (s, 1H),
7.59 (d, J=9 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J=8 Hz, 1H), 6.84 (d,
J=9 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 3.76 (s, 2H), 3.30 (s, 2H), 3.07
(s, 3H), 2.84 (s, 6H).
[0262] 10 mg of the base was dissolved in diethyl ether and treated
with 5 M HCl in diethyl ether. The hydrochloride salt was dried at
25.degree. C. in vacuo to afford 6 mg of the title compound as an
orange powder: MS (ESP) m/z 364 (M.sup.++1).
Example 56
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-
-carbonitrile Hydrochloride
[0263] The reaction was performed as described in Example 55 using
1-(6-chloropyridine-3-sulfonyl)-4-methylpiperazine (described in:
Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203).
Yield: 9.8%: .sup.1H NMR (D.sub.2O, 400 MHz) .delta. 8.12 (s, 1H),
7.60 (d, J=10 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.93
(d, J=9 Hz, 1H), 6.73 (dd, J=8, 2 Hz, 1H), 3.91 (d, J=13 Hz, 2H),
3.60 (d, J=11 Hz, 2H), 3.24 (app. t, J=11 Hz, 2H), 3.02 (app. t,
J=12 Hz, 2H), 2.89 (s, 3H); MS (TSP) m/z 398 (M.sup.++1).
Example 57
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-s-
ulfonamide Hydrochloride
[0264] The reaction was performed as described in Example 55 using
6-chloro-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide.
Purification on a silica gel column using chloroform/methanol/conc.
NH.sub.3(aq), (80:19:1), as the eluent gave the title compound as
the base.
[0265] Yields: 9.8%. 15 mg of the base was dissolved in methylene
chloride/tetrahydrofuran/methanol (3 is mL total volume) and
treated with 5 M HCl in diethyl ether. The hydrochloride salt was
dried at 40.degree. C. in vacuo to afford 11 mg of the title
compound as an orange powder: .sup.1H NMR (D.sub.2O, 400 MHz)
.delta. 7.96 (s, 1H), 7.47 (d, J=9 Hz, 1H), 6.87 (s, 1H), 6.74 (d,
J=8 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 3.61 (m,
2H), 3.25 (m, 4H), 3.02 (m, 2H), 1.97 (m, 4H); MS (TSP) m/z 412
(M.sup.++1).
Example 58
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitril-
e
[0266] To a suspension of sodium hydride (105 mg, 2.62 mmol, 60% in
oil) in N,N-dimethylformamide (2 mL) was added 5-cyanooxindole (310
mg, 1.96 mmol). The mixture was stirred at room temperature for 10
min. To the obtained yellowish solution was added
2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (299 mg, 1.31
mmol) and the mixture was heated under nitrogen at 130.degree. C.
for 30 min. The dark reaction mixture was allowed to cool and the
solvent was removed in vacuo. The residue was partitioned between a
2 M aqueous solution of HCl and ethyl acetate. The aqueous layer
was carefully saturated with NaHCO.sub.3 (s) and extracted twice
with ethyl acetate. The two last organic layers were combined,
dried (Na.sub.2SO.sub.4) and the solvent was removed in vacuo. The
residue was dissolved in ethyl acetate (50 mL) and a concentrated
solution of phosphorus trichloride (0.5 mL, 5.7 mmol) in ethyl
acetate (3 mL) was added. A yellowish precipitate was formed. The
mixture was stirred at room temperature overnight and then heated
at 60.degree. C. for 30 min and finally at reflux for 10 min. The
mixture was allowed to cool and was then diluted with ethyl acetate
and washed with a saturated aqueous NaHCO.sub.3 solution. The
aqueous layer was extracted repeatedly with ethyl acetate. The
combined organic layers were dried (Na.sub.2SO.sub.4) and the
solvent was removed in vacuo. The residue was purified on a silica
gel column using chloroform/ethyl acetate, (9:1), as the eluent
affording 195 mg (45% yield) of the title compound as a yellow
solid: mp 228-230.degree. C.; .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 14.79 (br s, 1H), 10.87 (s, 1H), 8.10 (s, 1H), 7.91 (s,
1H), 7.84 (d, J=9 Hz, 1H), 7.79 (dd, J=9, 1 Hz, 1H), 7.28 (d, J=8
Hz, 1H), 7.00 (d, J=8 Hz, 1H), 3.58 (t, J=4 Hz, 4H), 3.39 (s, 2H),
2.38 (br s, 4H); .sup.13C NMR (DMSO-d6, 100 MHz) .delta. 168.6,
148.4, 142.0, 136.9, 135.9, 125.2, 124.0, 122.3, 121.0, 118.7,
118.3, 108.7, 101.2, 84.4, 66.1, 58.3, 52.8; MS (ESP) m/z 335
(M.sup.++1).
Example 59
2-Hydroxy-3-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitri-
le hydrochloride
[0267] To a suspension of sodium hydride (60% in mineral oil, 72
mg, 1.80 mmol) in N,N-dimethylformamide (1 mL) was added
5-cyanooxindole (213 mg, 1.35 mmol), and the mixture was stirred at
ambient temperature for 15 min. To the obtained brownish solution
was added a solution of 2-chloro-5-(pyrrolidin-1-ylmethyl)pyridine
1-oxide (191 mg, 0.90 mmol) in N,N-dimethylformamide (1.5 mL). The
obtained red solution was heated at 125.degree. C. for 20 min, and
was then allowed to cool. The mixture was dissolved in 2 M HCl(aq)
and washed with ethyl acetate. The organic layer was extracted with
2 M HCl(aq). The combined aqueous layers were alkalized to
saturation with NaHCO.sub.3 (s), and extracted two times with ethyl
acetate. The extracts were combined, dried (Na.sub.2SO.sub.4) and
the solvent was removed in vacuo to give 270 mg of a crude product.
The material was dissolved in ethyl acetate (15 mL), and a solution
of phosphorus trichloride (0.25 mL, 2.87 mmol) in ethyl acetate (3
mL) was added. An orange precipitate was immediately formed. The
mixture was heated at reflux for 30 min, and was then allowed to
cool. The mixture was partitioned between ethyl acetate and a
saturated aqueous NaHCO.sub.3 solution. The aqueous layer was
extracted with another two portions of ethyl acetate. The combined
organic layers were dried (Na.sub.2SO.sub.4) and the solvent was
evaporated to give a crude product which was purified on a silica
gel column using chloroform/methanol/conc. NH.sub.3(aq),
(90:10:0.5), as the eluent affording 85 mg (37% yield) of the title
compound as the free base as an orange solid: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 14.9 (br s, 1H), 9.02 (s, 1H), 7.78
(dd, J=9, 2 Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.46 (d, J=9 Hz,
1H), 7.25-7.22 (m, 1H), 7.05 (d, J=8 Hz, 1H), 3.56 (s, 2H),
2.55-2.51 (m, 4H), 1.83-1.79 (m, 4H); MS (ES) m/z 319 (M.sup.++1).
The base (65 mg) was dissolved in a mixture of ethyl acetate (20
mL), methylene chloride (10 mL), and methanol (2 mL), and was then
cooled on an ice-bath. A solution of HCl in diethyl ether (1 M) was
added until acidic pH. About 60% of the solvent volume was
evaporated and to the residual suspension was added ethyl acetate.
The obtained orange hydrochloride was filtered, washed with ethyl
acetate, and dried in vacuo at 40.degree. C. affording 65 mg (95%
yield from the base) of the title compound as a brownish solid:
.sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.70 (br s, 1H), 11.00 (br
s, 1H), 10.97 (s, 1H), 8.31 (s, 1H), 8.07 (dd, J=9, 1 Hz, 1H), 8.02
(s, 1H), 7.91 (d, J=8 Hz, 1H), 7.32 (d, J=7 Hz, 1H), 7.02 (d, J=7
Hz, 1H), 4.29 (d, J=6 Hz, 2H), 3.45-3.39 (m, 2H), 3.09-3.02 (m,
2H), 2.04-1.98 (m, 2H), 1.92-1.87 (m, 2H).
Example 60
2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indole-
-5-carbonitrile Hydrochloride
[0268] To a suspension of sodium hydride (60% in mineral oil, 263
mg, 6.58 mmol) in N,N-dimethylformamide (3 mL) was added
5-cyanooxindole (0.78 g, 4.94 mmol) in portions. The mixture was
stirred at ambient temperature for 10 min. To the obtained brownish
solution was added a solution of
1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-methyl-1,4-diazepane
(842 mg, 3.29 mmol) in N,N-dimethylformamide (3 mL). The reaction
mixture was heated at 130.degree. C. under a nitrogen atmosphere
for 30 min. The dark mixture was allowed to cool and the solvent
was removed in vacuo. To the residual oil was added 2 M HCl(aq) and
the obtained suspension was washed twice with ethyl acetate. The
aqueous layer was neutralized with 45% NaOH and alkalized to
saturation with NaHCO.sub.3 (s), and extracted two times with ethyl
acetate, and once with tetrahydrofuran. The extracts were combined,
dried (Na.sub.2SO.sub.4) and the solvent was removed in vacuo
affording 1.0 g of the crude N-oxide: MS (ES) m/z 278 (M.sup.++1).
Part of the material (841 mg, 2.23 mmol) was dissolved in
acetonitrile (70 mL) during heating. To the warm solution was added
phosphorus trichloride (1 mL, 11.1 mmol), dropwise initially and
then at a faster rate. The obtained orange suspension was heated at
reflux for 1 h, and was then allowed to cool. The precipitate was
filtered, washed with acetonitrile, and dried in vacuo affording
780 mg of an orange residue. Part of the material (240 mg) was
dissolved in H.sub.2O, NaHCO.sub.3 (s) was added until saturation,
and the mixture was extracted three times with ethyl acetate and
once with tetrahydrofuran. The combined organic layers were dried
(Na.sub.2SO.sub.4 and MgSO.sub.4), and the solvent was evaporated
to give 165 mg of an oil which was purified on a silica gel column
using chloroform/methanol/conc. NH.sub.3(aq), (80:20:1), as the
eluent to give 84 mg of the title compound as the free base as a
brownish solid: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.70 (br s,
1H), 10.79 (br s, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.87 (d, J=9 Hz,
1H), 7.79 (d, J=8 Hz, 1H), 7.25 (d, J=7 Hz, 1H), 6.98 (d, J=7 Hz,
1H), 3.53 (s, 2H), 2.69-2.57 (m, 8H), 2.30 (s, 3H), 1.78-1.70 (m,
2H). The base (66 mg) was converted to the hydrochloride using the
method described for Example 59. Yield: 99% (calculated from the
base) of the title compound as an orange solid: .sup.1H NMR
(D.sub.2O, 400 MHz) .delta. 7.91 (s, 1H), 7.65 (dd, J=9, 2 Hz, 1H),
7.01-6.95 (m, 3H), 6.74 (d, J=7 Hz, 1H), 4.32 (s, 2H), 3.80-3.54
(m, 8H), 2.97 (s, 3H), 2.31 (br s, 2H).
[0269] The following Examples, 61-62, were prepared as described
for Example 60:
Example 61
2-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-i-
ndole-5-carbonitrile Hydrochloride
[0270] Starting material:
2-chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridine
1-oxide. The product was purified on a silica gel column using
chloroform/methanol/conc. NH.sub.3(aq), (90:10:0.5), as the eluent.
Yield: 15% of the title compound as the base as an orange solid:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.75 (br s, 1H), 7.76
(dd, J=9, 2 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.49 (d, J=9 Hz,
1H), 7.29-7.25 (m, 1H), 7.05 (d, J=8 Hz, 1H), 3.41 (s, 2H), 2.88
(d, J=11 Hz, 2H), 2.58 (br s, 4H), 2.11-1.99 (m, 3H), 1.90 (d, J=12
Hz, 2H), 1.80 (br s, 4H), 1.65-1.53 (m, 2H); MS (ES) m/z 402
(M.sup.++1). The base (72 mg) was dissolved in a mixture of ethyl
acetate (5 mL), methylene chloride (10 mL), and was then cooled on
an ice-bath. A solution of HCl in diethyl ether was (1 M) added
until acidic pH. The obtained orange hydrochloride was filtered,
washed with ethyl acetate, and dried in vacuo at room temperature
affording 68 mg (80% yield, calculated from the base) of the title
compound as an orange solid: .sup.1H NMR (D.sub.2O, 400 MHz)
.delta. 7.90 (s, 1H), 7.71 (d, J=9 Hz, 1H), 7.25 (s, 1H), 7.15 (d,
J=9 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 4.00 (br
s, 2H), 3.55-3.41 (m, 5H), 2.92-2.82 (m, 2H), 2.43 (d, J=13 Hz,
2H), 2.09 (br s, 4H), 1.98-1.87 (m, 2H).
Example 62
3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H--
indole-5-carbonitrile
[0271] Starting material:
1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N,N-dimethylpyrrolidin-3-amine.
The crude product was purified on a silica gel column using
chloroform/methanol/conc. NH.sub.3(aq), (85:15:1), as the eluent.
The obtained material was purified further by preparative HPLC
(column: Xterra, C.sub.8, 7 .mu.m, 19.times.300 mm; eluent: 0.1 M
NH.sub.4OAc buffer/acetonitrile, 8:2 to 4:6) affording the title
compound as an orange solid. Yield: 6%: .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 9.12 (br s, 1H), 7.77 (d, J=9 Hz, 1H), 7.71 (s,
1H), 7.63 (s, 1H), 7.49 (d, J=9 Hz, 1H), 7.28-7.24 (m, 1H), 7.06
(d, J=8 Hz, 1H), 3.60-3.48 (m, 2H), 2.95-2.89 (m, 1H), 2.82-2.76
(m, 1H), 2.72-2.68 (m, 1H), 2.64-2.58 (m, 1H), 2.53-2.48 (m, 1H),
2.27 (s, 6H), 2.09-2.00 (m, 1H), 1.87-1.79 (m, 1H); MS (ES) m/z 362
(M.sup.++1).
Example 63
2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-c-
arbonitrile
[0272] To a suspension of sodium hydride (60% in mineral oil, 54
mg, 1.35 mmol) in N,N-dimethylformamide (1 mL) was added
5-cyanooxindole (161 mg, 1.02 mmol), and the mixture was stirred at
ambient temperature for 10 min. To the obtained brownish solution
was added a solution of
2-chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide (163
mg, 0.677 mmol) in N,N-dimethylformamide (1.5 mL). The reaction
mixture was heated at 130.degree. C. for 25 min, and was then
allowed to cool. The solvent was removed in vacuo, and to the
residue was added 2 M HCl(aq). The obtained precipitate was
partitioned between a saturated aqueous NaHCO.sub.3 solution and
ethyl acetate. The aqueous layer was extracted with another two
portions of ethyl acetate. The combined organic layers were dried
(Na.sub.2SO.sub.4), and the solvent was removed in vacuo affording
a crude product. The material was dissolved in ethyl acetate (25
mL), and phosphorus trichloride (0.24 mL, 2.71 mmol) was added. An
orange precipitate was immediately formed. The mixture was heated
at reflux for 30 min, and was then allowed to cool. The mixture was
partitioned between ethyl acetate and a saturated aqueous
NaHCO.sub.3 solution. The aqueous layer was extracted with another
portion of ethyl acetate. The combined organic layers were dried
(Na.sub.2SO.sub.4), and the solvent was evaporated. The crude
product was purified on a silica gel column using
chloroform/methanol, (95:5), as the eluent followed by preparative
HPLC (column: Xterra, C.sub.8, 7 .mu.m, 19.times.300 mm; eluent:
0.1 M NH.sub.4OAc buffer/acetonitrile, 8:2 to 4:6) affording 4 mg
(2% yield) of the title compound as an orange solid: .sup.1H NMR
(acetone-d6, 400 MHz) .delta. 9.88 (br s, 1H), 8.11 (d, J=1 Hz,
1H), 7.90 (dd, J=9, 2 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.82 (d, J=1
Hz, 1H), 7.26 (dd, J=8, 2 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 3.44 (s,
2H), 2.91-2.86 (m, 2H), 2.10-1.98 (m, 2H), 1.65-1.59 (m, 2H),
1.40-1.35 (m, 1H), 1.28-1.16 (m, 2H), 0.92 (d, J=7 Hz, 3H); MS (ES)
m/z 347 (M.sup.++1).
Example 64
2-Hydroxy-3-{5-[(4-phenylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-c-
arbonitrile
[0273] To a suspension of sodium hydride (60% dispersion in mineral
oil, 45 mg, 1.12 mmol) in N,N-dimethylformamide (1 mL) was added
5-cyanooxindole (133 mg, 0.84 mmol). The mixture was stirred for 15
min, and a suspension of
1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-phenylpiperazine (0.56
mmol) in N,N-dimethylformamide (2.3 mL) was added. The reaction
mixture was heated at 130.degree. C. for 10 min and was then
allowed to cool to room temperature. The dark reaction mixture was
acid/base-extracted using an Allex robot. The following steps were
included: addition of HCl (aq), washing with ethyl acetate (to
remove excess of 5-cyanooxindole), alkalization with (sat)
NaHCO.sub.3, and finally repeated extractions with ethyl acetate.
The combined organic extracts were dried (Na.sub.2SO.sub.4), and
the solvent was removed in vacuo. The residue was dissolved in
ethyl acetate (10 mL), and phosphorus trichloride (0.2 mL, 2.24
mmol) was added. The resulting suspension was stirred at ambient
temperature for 1.5 h, and then heated at reflux for 30 min. The
reaction mixture was allowed to cool to room temperature. The
mixture was washed with a saturated aqueous NaHCO.sub.3 solution
using an Allex robot. The aqueous layer was repeatedly extracted
with ethyl acetate. The combined organic layers were dried
(Na.sub.2SO.sub.4), and the solvent was evaporated to give 20 mg of
an orange product which was purified on silica using
chloroform/ethanol, (95:5), as the eluent. The obtained material
(10 mg) was purified further by preparative HPLC (column: Xterra,
C.sub.8, 7 .mu.m, 19.times.300 mm; eluent: 0.1 M NH.sub.4OAc
buffer/acetonitrile, 8:2 to 4:6) affording 5 mg (1.1% yield) of the
title compound: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.78 (br s,
1H), 10.86 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.86-7.82 (m, 2H),
7.27 (d, J=8 Hz, 1H), 7.23-7.16 (m, 2H), 7.00 (d, J=8 Hz, 1H), 6.93
(d, J=8 Hz, 2H), 6.77 (t, J=7 Hz, 1H), 3.46 (s, 2H), 3.16-3.12 (m,
4H), 2.57-2.53 (m, 4H); MS (ES) m/z 410 (M.sup.++1).
[0274] The following Examples, 65-70, were prepared as described
for Example 64:
Example 65
3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitrile
[0275] Starting material: 5-(azetidin-1-ylmethyl)-2-chloropyridine
1-oxide. The title compound was purified on a silica gel column
using chloroform/methanol/conc. NH.sub.3(aq), (90:10:0.5). Yield:
1%: .sup.1H NMR (acetone-d6, 400 MHz) .delta. 9.86 (br s, 1H), 8.10
(s, 1H), 7.86-7.83 (m, 2H), 7.81 (d, J=2 Hz, 1H), 7.26 (dd, J=8, 2
Hz, 1H), 7.11 (d, J=8 Hz, 1H), 3.51 (d, J=1 Hz, 2H), 3.22 (t, J=7
Hz, 4H); MS (ES) m/z 305 (M.sup.++1).
Example 66
2-Hydroxy-3-[5-({4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}methy-
l)pyridin-2-yl]-1H-indole-5-carbonitrile
[0276] Starting material:
1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)ph-
enyl]piperazine. Yield: 1%: .sup.1H NMR (DMSO-d6, 400 MHz) .delta.
14.79 (br s, 1H), 10.85 (s, 1H), 8.15-8.12 (m, 2H), 7.90 (s, 1H),
7.87-7.80 (m, 3H), 7.43 (d, J=9 Hz, 1H), 7.27 (d, J=8 Hz, 1H), 7.00
(d, J=8 Hz, 1H), 3.47 (s, 2H), 3.17-3.14 (m, 4H), 2.55-2.52 (m,
4H); MS (ES) m/z 523 (M.sup.++1).
Example 67
3-(5-{[(2-Cyanoethyl)(ethyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-
-5-carbonitrile
[0277] Starting material:
3-[[(6-chloro-1-oxidopyridin-3-yl)methyl](ethyl)amino]propanenitrile.
Yield: 1%: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.80 (br s, 1H),
10.84 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.86 (d, J=9 Hz, 1H),
7.83 (d, J=9 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 6.99 (d, J=8 Hz, 1H),
3.52 (s, 2H), 2.73-2.70 (m, 2H), 2.69-2.65 (m, 2H), 2.53 (q, J=7
Hz, 2H), 1.00 (t, J=7 Hz, 3H); MS (ES) m/z 346 (M.sup.++1).
Example 68
3-(5-{[(4-Chlorobenzyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-ind-
ole-5-carbonitrile
[0278] Starting material:
N-(4-chlorobenzyl)-N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methylamine-
. Yield: 1%: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.79 (br s,
1H), 10.85 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.85-7.82 (m, 2H),
7.41-7.36 (m, 4H), 7.27 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 3.52
(s, 2H), 3.44 (s, 2H), 2.11 (s, 3H); MS (ES) m/z 401
(M.sup.++1).
Example 69
3-(5-{[(2-Furylmethyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indo-
le-5-carbonitrile
[0279] Starting material:
N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-(2-furylmethyl)-N-methylamine.
Yield: 4%: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.80 (br s, 1H),
10.86 (s, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=9 Hz, 1H),
7.79 (d, J=9 Hz, 1H), 7.61 (d, J=1 Hz, 1H), 7.27 (d, J=8 Hz, 1H),
7.00 (d, J=8 Hz, 1H), 6.43 (dd, J=3, 2 Hz, 1H), 6.34 (d, 3 Hz, 1H),
3.59 (s, 2H), 3.42 (s, 2H), 2.15 (s, 3H); MS (ES) m/z 359
(M.sup.++1).
Example 70
2-Hydroxy-3-(5-{[methyl(phenyl)amino]methyl}pyridin-2-yl)-1H-indole-5-carb-
onitrile
[0280] Starting material:
N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methyl-N-phenylamine.
The product was purified on a silica gel column using
chloroform/methanol/conc. NH.sub.3(aq), (90:10:0.5), as the eluent.
Yield 2%: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.82 (br s, 1H),
8.06 (s, 1H), 7.91-7.68 (m, 3H), 7.26-7.23 (m, 1H), 7.22-7.16 (m,
2H), 7.00-6.96 (m, 1H), 6.80 (d, J=8 Hz, 2H), 6.66 (t, J=7 Hz, 1H),
4.49 (s, 2H), 2.98 (s, 3H); MS (ES) m/z 353 (M.sup.+-1).
Example 71
2-Hydroxy-3-{5-[(3-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-c-
arbonitrile
[0281] To a suspension of sodium hydride (60% in mineral oil, 45
mg, 1.12 mmol) in N,N-dimethylformamide (1 mL) was added
5-cyanooxindole (133 mg, 0.84 mmol), and the mixture was stirred at
ambient temperature for 10 min. To the obtained brownish solution
was added a solution of
2-chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide (0.56
mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture was
heated at 130.degree. C. for 30 min, and was then allowed to cool.
To the residue was added 2 M HCl(aq) and the obtained suspension
was washed with ethyl acetate. The aqueous layer was neutralized
with 45% NaOH(aq) and alkalized to saturation with NaHCO.sub.3 (s),
and extracted two times with ethyl acetate. The extracts were
combined, dried (MgSO.sub.4) and the solvent was removed in vacuo
affording 84 mg of the crude product. The material was dissolved in
ethyl acetate (10 mL), and to the solution was added phosphorus
trichloride (0.2 mL, 2.24 mmol). The obtained orange suspension was
heated at reflux for 1 h and was then allowed to cool. The
precipitate was filtered, washed with ethyl acetate, and dried in
vacuo affording 70 mg of an orange residue. The material was
purified by preparative HPLC (column: Xterra, C.sub.8, 7 .mu.m,
19.times.300 mm; eluent: 0.1 M NH.sub.4OAc buffer/acetonitrile, 8:2
to 4:6) affording 15 mg (8% yield) of the title compound as an
orange solid: .sup.1H NMR (acetone-d6, 400 MHz) .delta. 9.86 (br s,
1H), 8.11 (s, 1H), 7.91 (dd, J=9, 2 Hz, 1H), 7.84 (d, J=9 Hz, 1H),
7.82 (d, J=1 Hz, 1H), 7.26 (dd, J=8, 2 Hz, 1H), 7.11 (d, J=8 Hz,
1H), 3.44 (s, 2H), 2.00-1.50 (m, 6H), 0.95-0.81 (m, 4H); MS (ES)
m/z 347 (M.sup.++1).
[0282] The following Examples, 72-73, were prepared as described
for Example 71:
Example 72
3-(5-{[Cyclohexyl(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5--
carbonitrile
[0283] Starting material:
N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-cyclohexyl-N-methylamine.
Yield: 3%: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.64 (br s,
1H), 7.79 (dd, J=9, 2 Hz, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.53 (d,
J=9 Hz, 1H), 7.30 (dd, J=8, 1 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 3.52
(s, 2H), 2.23 (s, 3H), 1.88-1.80 (m, 5H), 1.36-1.02 (m, 6H); MS
(ES) m/z 361 (M.sup.++1).
Example 73
2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitril-
e
[0284] Starting material: 2-chloro-5-(piperidin-1-ylmethyl)pyridine
1-oxide. Yield: 4%: .sup.1H NMR (acetone-d.sub.6, 400 MHz) .delta.
9.85 (br s, 1H), 8.11 (s, 1H), 7.91 (dd, J=9, 2 Hz, 1H), 7.85 (d,
J=9 Hz, 1H), 7.82 (d, J=1 Hz, 1H), 7.26 (dd, J=8, 2 Hz, 1H), 7.12
(d, J=8 Hz, 1H), 3.43 (s, 2H), 2.47-2.41 (m, 4H), 1.61-1.54 (m,
4H), 1.49-1.41 (m, 2H); MS (ES) m/z 333 (M.sup.++1).
Example 74
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol
Hydrochloride
[0285] Sodium hydride (46 mg, 60% dispersion in paraffin) was
washed with hexane and dried in vacuo. N,N-Dimethylformamide (3
mL), oxindole (72 mg, 0.54 mmol) and
1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (100 mg, 0.36
mmol; described in: Thunus L., Annales Pharmaceutiques Francaises
1977, 35, 197-203) were added to the sodium hydride and the
reaction mixture was stirred at room temperature for 5 min. The
reaction mixture was then heated for 10 min at 130.degree. C. After
cooling to room temperature, a saturated aqueous sodium hydrogen
carbonate solution was added. The mixture was extracted twice with
methylene chloride and the combined organic layers were dried
(Na.sub.2SO.sub.4), filtrated and the solvent was removed in vacuo.
The residue was purified on a silica gel column using a gradient
ethyl acetate/methanol, (40:1 to 1:1), as the eluent. The product
was dissolved in a mixture of methylene chloride (5 mL) and
methanol (5 mL). Hydrogen chloride (3 mL, 1 M in diethyl ether) was
added and stirring was continued for 10 min. The precipitate was
washed with diethyl ether and dried in vacuo to give 50 mg (37%
yield) of the title compound: .sup.1H NMR (D.sub.2O, 400 MHz)
.delta. 7.95 (m, 1H), 7.45 (d, J=2 Hz, 1H), 7.43 (dd, J=9, 2 Hz,
1H), 7.23 (m, 1H), 7.14 (d, J=9 Hz, 1H), 7.00 (m, 2H), 3.88 (d,
J=14 Hz, 2H), 3.60 (d, J=12 Hz, 2H), 3.23 (m, 2H), 2.94 (m, 2H),
2.90 (s, 3H); MS (ES) m/z 373 (M.sup.++1).
Example 75
6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-o-
l Hydrochloride
[0286] The title compound was prepared as described for Example 74
using 6-chlorooxindole. The base was purified on a silica gel
column using a gradient chloroform/methanol, (100:0 to 4:1), as the
eluent. The product was dissolved in a mixture of chloroform (10
mL) and methanol (10 mL). Hydrogen chloride (3 mL, 1 M in diethyl
ether) was added and stirring was continued for 10 min. The
precipitate was washed with diethyl ether and dried in vacuo to
give 50 mg (29% yield) of the title compound: .sup.1H NMR (DMSO-d6,
400 MHz) .delta. 10.95 (m, 1H), 10.79 (s, 1H), 8.49 (s, 1H), 7.68
(m, 1H), 7.64 (m, 1H), 7.55 (d, J=8 Hz, 1H), 6.98 (m, 1H), 6.93 (m,
1H), 3.74 (m, 2H), 3.45 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 2.75
(m, 3H); MS (ES) m/z 407 (M.sup.++1).
Example 76
3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol
[0287] Ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (0.327
g, 1.0 mmol) was suspended in benzene (13 mL) followed by the
addition of morpholine (0.218 g, 2.5 mmol). The mixture was stirred
(N2 atmosphere) for 5 min at 0.degree. C. To this mixture,
trimethyl aluminum (2 M solution in hexane, 2 mL, 4 mmol) was added
via a syringe. After 10 min the temperature was raised to
70.degree. C. and the reaction mixture was stirred for 20 h then
poured onto an ice-cold aqueous saturated NaHCO.sub.3 solution and
extracted with chloroform. The combined organic layer was
concentrated and the light brown residue was purified on a silica
gel column using chloroform/methanol/triethylamine, (50:10:1), as
eluent to give 0.22 g (60% yield) of the title compound: .sup.1H
NMR (acetone-d6, 400 MHz) .delta. 8.47 (s, 1H), 8.41 (s, H), 8.05
(d, J=8 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.19
(d, J=8 Hz, 1H), 3.79 (br s, 2H), 3.73 (br s, 4H), 2.68 (br s, 4H);
MS (EI) m/z 369 (M+1.sup.+).
Example 77
6-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
Hydrochloride
[0288] To a N,N-dimethylformamide (1.5 mL) suspension of sodium
hydride (60% dispersion in oil, 40 mg, 1.0 mmol, pre-washed with
hexane) was added 6-bromoxindole (0.159 g, 0.75 mmol). The formed
mixture was stirred for 5 min at room temperature followed by the
addition of 2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide
(0.114 g, 0.5 mmol). The resulting reaction mixture was stirred
(N.sub.2 atmosphere) for 30 min at 120.degree. C. The solvent was
evaporated in vacuo and the residual oil was purified on a silica
gel column using chloroform/methanol, (10:1), as eluent affording
the N-oxide product. The N-oxide was dissolved in chloroform (3 mL)
and phosphorus trichloride (0.412 g, 3.0 mmol) was added. The
reaction mixture was stirred for 30 min at 60.degree. C. and then
cooled to room temperature. The mixture was quenched with methanol
and concentrated. The residue was purified on a silica column using
a chloroform/methanol gradient, (10:1 to 1:2), as the eluent to
give 52 mg (4% yield) of the title compound as the base as brownish
solid. The base (30 mg, 0.077 mmol) was dissolved in methylene
chloride/methanol, (1:1), and treated with 1 M HCl in diethyl ether
at 0.degree. C. The resulting yellowish orange crystals were
collected by filtration and washed with diethyl ether to give 5 mg
(15% yield) of the title compound: .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 10.61 (s, 1H), 8.59 (br s, 1H), 8.23 (s, 1H), 7.96 (s, 1H),
7.70 (s, 1H), 7.54 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 7.05 (s,
1H), 4.17 (br s, 2H), 3.85 (br s, 4H), 3.10 (br s, 4H); MS (EI) m/z
388 (M), 390 (M.sup.++2).
Example 78
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitril-
e Hydrochloride
[0289] The title compound was prepared as described for Example 77
using 6-cyanooxindole. The base was obtained as a yellow solid
after purification by preparative HPLC (column: Xterra, C.sub.8, 7
.mu.m, 19.times.300 mm; eluent: 0.1 M NH.sub.4OAc
buffer/acetonitrile, 8:2 to 4:6). Yield: 13%. The base was
transformed to the yellow hydrochloride salt in 33% yield: .sup.1H
NMR (D.sub.2O, 400 MHz) .delta. 8.21 (s, 1H), 8.04 (d, J=8 Hz, 1H),
7.82 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.29 (s, 1H), 7.28 (d,
J=8 Hz, 1H), 3.97 (s, 2H), 3.69 (br s, 4H), 2.65 (br s, 4H); MS
(EI) m/z 335 (M.sup.++1).
Example 79
5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
Hydrochloride
[0290] To a N,N-dimethylformamide (3.0 mL) suspension of sodium
hydride (60% dispersion in oil, is 0.480 g, 12.0 mmol, pre-washed
with hexane) was added 5-bromooxindole (1.9 g, 9.0 mmol). The
mixture was stirred for 10 min at 0.degree. C. and for 5 min at
room temperature. 2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide
(1.37 g, 6.0 mmol) was added and the resulting reaction mixture was
stirred (N.sub.2 atmosphere) for 50 min at 120.degree. C., then
cooled to room temperature. The N,N-dimethylformamide solution was
diluted with an aqueous saturated NaHCO.sub.3 solution and NaCl (s,
2 g) was added followed by extraction with chloroform and ethyl
acetate. The combined organic phases were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo. The remaining N,N-dimethylformamide was
removed by co-evaporation with toluene two times. The residual oil
was dissolved in chloroform (10 mL) and phosphorus trichloride (3.0
g, 21.8 mmol) was added. The reaction mixture was stirred for 30
min at 60.degree. C. and then cooled to room temperature. The
mixture was poured into an aqueous saturated NaHCO.sub.3
solution.
[0291] A brown precipitate was formed, which was filtered off, and
the filtrate (containing some product) was treated separately (see
bellow).
[0292] The brown solid was dissolved in methanol (150 mL) and
insoluble materials were removed by filtration. This solution was
concentrated to a brownish yellow solid, which was suspended in
ethyl acetate (15 mL) and stirred overnight at room temperature.
The yellow solid was collected by filtration and dried to afford
1.28 g of the product.
[0293] To the NaHCO.sub.3 solution (filtrate, see above), NaCl(s)
(2.0 g) was added followed by extractions with chloroform and ethyl
acetate. The combined organic phases were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo. The residue was purified on a silica gel
column using chloroform/methanol, (5:1) as eluent. The residue was
suspended in ethyl acetate (15 mL) and stirred overnight at room
temperature. The solid was filtered, dried to give 90 mg of the
title compound as a yellow solid as the base. The obtained total
amount of the base was 1.37 g (59% yield). A small amount of the
free base (12 mg, 0.03 mmol) was dissolved in methylene
chloride/methanol, (1:1) and treated with 1 M HCl in diethyl ether
at 0.degree. C. The resulting yellow crystals were collected by
filtration and washed with diethyl ether to obtain 13 mg (100%
yield) of the title compound: .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 10.52 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.70 (d,
J=8 Hz, 1H), 7.61 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz,
1H), 3.62 (br s, 4H), 3.40 (s, 2H), 2.42 (br s, 4H); MS (EI) m/z
388 (M.sup.+), 390 (M.sup.++2).
Example 80
5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
Hydrochloride
[0294] The title compound was prepared as described for Example 79
using 5,6-dibrom-1,3-dihydro-indol-2-one. The base (27% yield) was
transformed to the hydrochloride salt. The salt was purified by
re-crystallization from chloroform/methanol/diethyl ether and the
crystals were washed with dimethylsulfoxide (1 mL) to give the
title compound. Yield: 4%: .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.29 (s, 1H), 7.75 (d, J=10 Hz, 1H), 7.68 (s, 1H), 7.62 (s,
1H), 7.47 (d, J=10 Hz, 1H), 7.21 (s, 1H), 3.72 (br s, 4H), 3.40 (s,
2H), 2.48 (br s, 4H).
Example 81
3-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carbonit-
rile Hydrochloride
[0295]
2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carb-
onitrile (0.10 g, 0.3 mmol) was dissolved in
tetrahydrofuran/dioxane, (1:1, 16 mL), under N.sub.2 atmosphere and
stirred at -20.degree. C. for 5 min. To this mixture, sodium
bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 0.30 mL,
0.3 mmol) was added via syringe and the reaction was allowed to
stir for 20 min at ambient temperature.
1-Fluoro-2,4,6-trimethylpyridinium triflate (0.112 g, 0.33 mmol)
was added and the reaction was allowed to warm to room temperature
and stirred for 16 h. The solvent was removed in vacuo and the
residue was taken up in ethyl acetate and washed with an aqueous
saturated NaHCO.sub.3 solution. The organic phase was dried
(Na.sub.2SO.sub.4) and evaporated in vacuo. The crude product was
purified by preparative HPLC (column: Xterra, C.sub.8, 10 .mu.m,
19.times.300 mm; eluent: 0.05 M NH.sub.4OAc buffer/acetonitrile,
8:2-2:8) affording 50 mg (47% yield) of a yellowish brown solid.
The solid (40 mg, 0.11 mmol) was dissolved in methylene
chloride/methanol, (1:1), and treated with 1 M HCl in diethyl ether
at 0.degree. C. The resulting yellow crystals were collected by
filtration and washed with diethyl ether to give 18 mg (42% yield)
of the title compound: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 8.42
(s, 1H), 7.96 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.50 (d, J=8
Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.44 (s, 1H), 3.60 (br s, 4H), 3.54
(s, 2H), 2.38 (br s, 4H): MS (EI) m/z 353 (M.sup.++1).
Example 82
3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-
-carbonitrile Hydrochloride
[0296] To a suspension of sodium hydride (0.09 g, 2.2 mmol, 60%
dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide
(3 mL), cooled on an ice-bath, was added a solution of
5-cyanooxindole (0.32 g, 2.0 mmol) in N,N-dimethylformamide (3 mL).
The mixture was stirred for 20 min under a nitrogen atmosphere and
the ice-bath was removed.
1-Benzyl-4-[(6-chloropyridine-3-yl)sulfonyl]piperazine (0.35 g, 1.0
mmol), dissolved in N,N-dimethylformamide (4 mL), was added
dropwise and the mixture was heated at 130.degree. C. for 40 min.
The solvent was evaporated in vacuo and the residue was partitioned
between methylene chloride and aqueous NaHCO.sub.3 (pH>7). The
mixture was extracted with methylene chloride. The organic layers
were combined, dried (Na.sub.2SO.sub.4) and the solvent was removed
in vacuo. The crude product was purified on a silica gel column
using chloroform/ethanol, (20:1), as the eluent. The base (120 mg)
was dissolved in chloroform/methanol and a solution of HCl in
diethyl ether (1 M) was added until acidic pH. The formed
precipitation was filtered and washed with diethyl ether affording
71 mg (14% yield) of the title compound as a yellow solid: .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 11.15 (br s, 1H), 10.54 (br s, 1H),
8.54 (br s, 1H), 8.01 (br s, 1H), 7.88-7.81 (m, 1H), 7.70 (dd, J=9,
2 Hz, 1H), 7.56-7.47 (m, 2H), 7.47-7.38 (m, 4H), 7.06 (d, J=8 Hz,
1H), 4.40-4.28 (m, 2H), 3.83-3.66 (m, 2H), 3.23-3.04 (m, 4H),
3.04-2.88 (m, 2H); MS (ES) m/z 474 (M.sup.++1).
Example 83
2-Hydroxy-3-(5-{[4-(3-methylbutyl)piperazin-1-yl]sulfonyl}pyridin-2-yl)-1H-
-indole-5-carbonitrile Hydrochloride
[0297] The title compound was prepared as described for Example 82
using 5-cyanooxindole and
1-[(6-chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine.
Yield: 5% of the title compound as a yellow solid: .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 1.15 (br s, 1H), 10.63 (br s, 1H), 8.57
(s, 1H), 8.02 (s, 1H), 7.94-7.81 (m, 1H), 7.73 (d, J=9 Hz, 1H),
7.41 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 3.82-3.67 (m, 2H),
3.62-3.34 (m, 2H), 3.20-2.92 (m, 6H), 1.64-1.46 (m, 3H), 0.86 (d,
J=6 Hz, 6H); MS (ES) m/z 454 (M.sup.++1).
Example 84
2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-
e-5-carbonitrile Hydrochloride
[0298] The title compound was prepared as described for Example 82
using 5-cyanooxindole and
1-[(6-chloropyridin-3-yl)sulfonyl]-4-isopropylpiperazine. Yield:
30% of the title compound as a yellow solid; .sup.1H NMR (DMSO-d6,
400 MHz) .delta. 11.56 (br s, 1H), 10.68 (br s, 1H), 8.57 (br s,
1H), 8.02 (s, 1H), 7.93-7.81 (m, 1H), 7.74 (dd, J=9, 2 Hz, 1H),
7.42 (dd, J=8, 1 Hz, 1H), 7.06 (d, J=8 Hz, 1H) 3.82-3.71 (m, 2H),
3.58-3.31 (m, 3H), 3.24-1.82 (m, 4H), 1.24 (d, J=7 Hz, 6H); MS (ES)
m/z 304 (M.sup.++1).
Example 85
3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5--
carbonitrile Hydrochloride
[0299] The title compound was prepared as described for Example 82
using 5-cyanooxindole and
1-[(6-chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine. Yield: 4% of
the title compound as a yellow solid: .sup.1H NMR (DMSO-d6, 400
MHz) .delta. 11.15 (br s, 1H), 10.75 (br s, 1H), 8.56 (br s, 1H),
8.04 (s, 1H), 7.93-7.82 (m, 1H), 7.73 (dd, J=9, 2 Hz, 1H), 7.41
(dd, J=8, 1 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 3.83-3.69 (m, 2H),
3.69-3.42 (m, 2H), 3.18-2.92 (m, 6H), 1.20 (t, J=7.2 Hz, 3H); MS
(ES) m/z 412 (M.sup.++1).
Example 86
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol
[0300] To a solution of
3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol--
2-ol (200 mg, 0.6 mmol) in ethyl acetate (60 mL) was added
phosphorus trichloride (0.4 mL). A yellow precipitate was formed
and the mixture was refluxed for 3 h, and then diluted with ethyl
acetate and washed with an aqueous saturated NaHCO.sub.3 solution.
The aqueous layer was extracted with two portions of ethyl acetate
and one portion of chloroform. The organic layers were combined,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude
product was purified by preparative HPLC (column: Xterra,
19.times.300 mm, eluent: water/acetonitrile, (0:100 to 100:0),
gradient) affording 6 mg (3% yield) of the title compound as a
yellow solid: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.50 (br s,
1H), 8.92 (d, J=2 Hz, 1H), 8.49 (dd, J=4, 1 Hz, 1H), 8.12-8.06 (m,
1H), 8.02 (s, 1H), 7.90-7.71 (m, 1H), 7.71-7.67 (m, 2H), 7.43 (dd,
J=8, 5 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H),
3.63-3.53 (m, 4H), 3.40-3.24 (m, 2H), 2.42-2.34 (m, 4H); MS (ES)
m/z 388 (M.sup.++1).
Example 87
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol
Hydrochloride
[0301] The title compound was prepared as described for Example 86
using
3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2--
ol and phosphorus trichloride. The base was dissolved in
chloroform/methanol, (3:1), and a solution of HCl in diethyl ether
(1 M) was added until acidic pH. The formed precipitation was
filtered, washed with diethyl ether and dried. Yield: 9% of the
title compound as an yellow solid: .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 11.10 (br s, 1H), 10.55 (s, 1H), 8.21 (s, 1H), 8.02-7.90
(m, 1H), 7.85-7.62 (m, 2H), 7.54-7.46 (m, 1H), 7.46-7.37 (m, 1H),
7.18 (d, J=8 Hz, 1H), 7.15-7.06 (m, 1H), 6.92 (d, J=8 Hz, 1H), 4.24
(s, 2H), 4.03-3.89 (m, 2H), 3.84-3.51 (m, 2H), 3.39-3.28 (m, 2H)
3.16-3.05 (m, 2H); MS (ES) m/s 392 (M.sup.++1).
Example 88
5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol
Hydrochloride
[0302] The title compound was prepared as described for Example 86
using
5-(2-furyl)-3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-1H-indol-2-o-
l. Yield: 6% of the title compound as an yellow solid: .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.26 (br s, 1H), 10.56 (s, 1H), 8.22
(s, 1H), 8.03-7.94 (m, 1H), 7.83-7.71 (m, 2H), 7.66 (s, 1H), 7.30
(d, J=8 Hz, 1H), 6.98-6.86 (m, 2H), 6.59-6.53 (m, 1H), 4.31-4.10
(m, 2H), 4.16-3.85 (m, 2H), 3.85-3.70 (m, 2H), 3.39-3.26 (m, 2H),
3.17-3.01 (m, 2H); MS (ES) m/z 376 (M.sup.++1).
Example 89
3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-in-
dol-2-ol Hydrochloride
[0303] The title compound was prepared as described for Example 55
using 5-nitrooxindole and
1-1-[(5-bromo-6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine.
Purification on a silica gel column using chloroform/methanol,
(8:2), as the eluent gave the title compound as the base: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.78 (br s, 1H), 8.47 (br s, 1H),
8.24 (dd, J=9, 2 Hz, 1H), 7.96 (m, 1H), 7.10 (d, J=9 Hz, 1H), 3.12
(m, 4H), 2.50 (t, J=5 Hz, 4H), 2.26 (s, 3H).
[0304] The base was dissolved in chloroform and treated with 5 M
HCl in diethyl ether. The hydrochloride was dried in vacuo and
recrystallized from methanol to afford of the title compound.
Yield: 9.5%.
Example 90
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-ol
Hydrochloride
[0305] The title compound was prepared as described for Example 55
using 5-trifluoromethyloxindole. Yield: 8%: .sup.1H NMR (D.sub.2O,
400 MHz) 7.87 (s, 1H), 7.64 (d, J=9 Hz, 1H), 7.55 (s, 1H), 7.44 (d,
J=9 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 4.15 (s,
2H), 4.06-3.85 (m, 4H), 3.41-3.26 (m, 4H).
Example 91
2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-
-carbonitrile Hydrochloride
[0306] The title compound was prepared as described for Example 55
using 6-cyanooxindole (1.5 equ) and
1-(6-chloropyridine-3-sulfonyl)-4-methylpiperazine (1 equ;
described in: Thunus L., Annales Pharmaceutiques Francaises 1977,
35, 197-203). Purification on a silica gel column using
chloroform/methanol/conc. NH.sub.3(aq), (76:23:1), as the eluent
gave the title compound as the base. The base was dissolved in
acetone/chloroform/methanol and treated with 5 M HCl in diethyl
ether. The hydrochloride was dried to afford 24 mg (5.1% yield) of
title compound: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 14.87 (s,
1H), 11.00 (s, 1H), 10.21 (s, 1H), 8.62 (s, 1H), 7.83 (s, 2H), 7.73
(d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.23 (s, 1H), 3.81-3.67 (m,
2H), 3.57-3.38 (m, 2H), 3.22-3.05 (m, 2H), 2.97-2.85 (m, 2H), 2.77
(s, 3H).
Example 92
N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nico-
tinamide Hydrochloride
[0307] To a suspension of ethyl
6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (100 mg, 0.30 mmol)
in toluene (5 mL) was added 2-(aminomethyl)-1-ethylpyrrolidine (78
mg, 0.61 mmol) and the mixture was cooled to 0.degree. C. under a
nitrogen atmosphere. Trimethyl aluminium (0.6 mL, 2 M in hexane,
1.2 mmol) was added dropwise during 5 min and the reaction was
heated to 70.degree. C. over night. The reaction was quenched with
water and an aqueous saturated NaHCO.sub.3 solution and is
extracted with chloroform. The combined extracts were dried
(Na.sub.2SO.sub.4) and the solvent was evaporated in vacuo. The
residue was purified on a silica gel column using
chloroform/methanol/conc. NH.sub.3(aq), (80:19:1), as the eluent.
Fractions containing product were collected and evaporated in vacuo
and dried at 25.degree. C. in a vacuum-cabinet over night. The
residue was dissolved in methanol/chloroform and treated with 5 M
HCl in diethyl ether. The hydrochloride was dried in vacuo to
afford 30 mg (20% yield) of title compound as an orange solid:
.sup.1H NMR (D.sub.2O, 400 MHz) .delta. 7.65 (s, 1H), 7.42 (d, J=8
Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.16 (s, 1H), 6.63 (d, J=9 Hz, 1H),
6.53 (d, J=8 Hz, 1H), 3.66-3.52 (m, 4H), 3.49-3.41 (m, 1H),
3.13-3.02 (m, 2H), 2.23-2.16 (m, 1H), 2.05-1.88 (m, 2H), 1.87-1.76
(m, 1H), 1.26 (t, J=7 Hz, 3H).
[0308] The following Examples, 93-97, was prepared as described for
Example 92:
Example 93
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide
Hydrochloride
[0309] Starting material: 4-(2-aminoethyl)morpholine. The formed
hydrochloride was recrystallized from methanol. Yield: 4.1%:
.sup.1H NMR (D.sub.2O, 400 MHz) .delta. 7.70 (s, 1H), 7.52 (d, J=9
Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.29 (s, 1H), 6.78 (d, J=9 Hz, 1H),
6.64 (d, J=8 Hz, 1H), 4.05-3.75 (m, 4H), 3.65-3.62 (m, 2H),
3.50-3.20 (m, 6H).
Example 94
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nic-
otinamide Hydrochloride
[0310] Starting material: 1-methyl-4-(methylamino)piperidine. The
formed hydrochloride was recrystallized from methanol. Yield: 3.3%:
MS (ES) m/z 410 (M.sup.++1).
Example 95
5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H-i-
ndol-2-ol Hydrochloride
[0311] Starting material: 4-(1-pyrrolidinyl)piperidine. The formed
hydrochloride was recrystallized from methanol. Yield: 5.2%: MS
(EI, 70 eV) m/z (relative intensity) 435 (M.sup.+, 1), 298 (6), 282
(7), 207 (5), 174 (14), 154 (17), 124 (17), 110 (100), 98 (75), 84
(26), 70 (61), 52 (23).
Example 96
3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H--
indol-2-ol Hydrochloride
[0312] Starting material: 3-(dimethylamino)pyrrolidine. The formed
hydrochloride was recrystallized from methanol. Yield: 1.5%:
.sup.1H NMR (DMSO-d6, 400 MHz) .delta. 11.22 (s, 1H), 8.50 (s, 1H),
8.29 (s, 1H), 8.04 (dd, J=9, 2 Hz, 1H), 7.91 (dd, J=9, 2 Hz, 1H),
7.73 (d, J=9 Hz, 1H), 7.05 (d, J=9 Hz, 1H), 4.05-3.83 (m, 2H),
3.82-3.70 (m, 2H), 3.66-3.54 (m, 1H), 2.80 (br s, 6H), 2.40-2.29
(m, 1H), 2.23-2.10 (m, 1H).
Example 97
N-[2-(Dimethylamino)-1-methylethyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nic-
otinamide Hydrochloride
[0313] Starting material: 3-(dimethylamino)pyrrolidine. Yield:
3.2%: .sup.1H NMR (D.sub.2O, 400 MHz) .delta. 7.85 (s, 1H), 7.60
(d, J=9 Hz, 1H), 7.47 (d, J=9 Hz, 1H), 7.36 (s, 1H), 6.84 (d, J=9
Hz, 1H), 6.64 (d, J=9 Hz, 1H), 4.51-4.40 (m, 1H), 3.27-3.12 (m,
2H), 2.88-2.77 (m, 6H), 1.25 (d, J=6 Hz, 3H).
Example 98
6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-pyrollindin-1-ylethyl)nicotinamid-
e Fumarate
[0314] A solution of ethyl
6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (200 mg, 0.61 mmol)
in 2-pyrrolidin-1-yl-ethylamine (1.5 mL) was heated at 120.degree.
C. in a closed vessel for 24 h. The mixture was cooled to room
temperature and diluted with water and an aqueous solution of
NaHCO.sub.3 followed by extraction with chloroform. The phases were
separated and evaporated in vacuo. Purification on a silica gel
column using chloroform/methanol/conc NH.sub.3(aq), (100:15:1.5),
as the eluent gave 90 mg (37% yield) of the title compound as the
base. The base was converted to the fumarate salt according to the
procedure described for Example 103: MS (ES) m/z 396
(M.sup.++1).
Example 99
3-{5-[(4-Methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol
Fumarate
[0315] The title compound was prepared as described for Example 92
using ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (1 eqv),
trimethyl aluminium (4 eqv), N-methylpipearzine (2 eqv) and benzene
as the solvent. The crude product was purified on a silica gel
column using chloroform/methanol/conc NH.sub.3(aq), (100:12:1.2),
as the eluent. Yield: 69% of the title compound as the base. The
base was converted to the fumarate salt according to the procedure
described for Example 103: MS (ES) m/z 382 (M.sup.++1).
Example 100
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)nicotinamide
Fumarate
[0316] The title compound was prepared as described for Example 98
using ethyl 6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate and
2-pyrrolidin-1-yl-ethylamine. Yield: 13% of the title compound:
.sup.1H NMR (on the base, CDCl.sub.3, 300 MHz) .delta. 10.8 (br s,
1H), 8.80-8.52 (m, 2H), 8.18-7.86 (m, 3H), 7.35-7.18 (m, 1H), 6.98
(d, J=7 Hz, 1H), 6.55 (s, 1H), 3.60-3.35 (m, 2H), 2.83 (m, 6H),
1.80 (br s, 4H).
Example 101
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyr-
idine-3-sulfonamide Hydrochloride
[0317] To an ice-cooled solution of 5-cyanooxindole (200 mg, 1.26
mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60
mg, 1.5 mmol). The reaction mixture was stirred for 25 min
whereafter
6-chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide
(303 mg, 1 mmol) was added. The reaction mixture was heated at
130.degree. C. for 1 h and then allowed to cool to room
temperature. An aqueous saturated solution of NaHCO.sub.3 (50 mL)
was added and the water phase was extracted with ethyl acetate. The
organic phase was dried (Na.sub.2SO.sub.4) and purified on a silica
gel column using chloroform/methanol/conc NH.sub.3(aq), (500:35:3.5
to 500:50:5), as the eluent. The solvents were evaporated in vacuo
and the residue was stirred over night in ethyl acetate, filtered
and dried to give 160 mg (38% yield) of the title compound as the
base. The base, dissolved in chloroform/methanol, was treated with
HCl in diethyl ether to give the title compound: MS (ES) m/z 426
(M.sup.++1).
Example 102
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]pyridine-3-s-
ulfonamide Fumarate
[0318] The title compound was prepared as described for Example 101
using 6-chloro-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide and
5-cyanooxindole. The crude product was purified on a silica gel
column using chloroform/methanol/conc NH.sub.3(aq), (100:10:1), as
the eluent followed by another purification on a silica gel column
using chloroform/methanol/conc NH.sub.3(aq), (100:7:0.7), as the
eluent. The base was converted to the fumarate salt according to
the procedure described for Example 103: Yield: 20%: MS (ES) m/z
386 (M.sup.++1).
Example 103
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpyri-
dine-3-sulfonamide Fumarate
[0319] The title compound was prepared as described for Example 101
using
6-chloro-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide
and 5-cyanooxindole. The crude product was purified on a silica gel
column using chloroform/methanol/conc NH.sub.3(aq), (100:10:1), as
the eluent: MS (ES) m/z 414 (M.sup.++1). The base was dissolved in
chloroform (15 mL) and methanol (2 mL) and fumaric acid dissolved
in methanol (2 mL) was added. Diethyl ether (20 mL) was added and
the formed precipitate was filtered and dried to give the title
compound. Yield: 10%: MS (ES) m/z 414 (M.sup.++1).
Example 104
6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyri-
dine-3-sulfonamide Fumarate
[0320] The title compound was prepared as described for Example 101
using
6-chloro-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide
and 5-cyanooxindole. The crude product was purified on a silica gel
column using chloroform/methanol/conc NH.sub.3(aq), (100:18:1.8),
as the eluent. Yield: 50%: MS (ES) m/z 426 (M.sup.++1). The base
was converted to the fumarate salt according to the procedure
described for Example 103.
Example 105
2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]pyridin-2-yl}-1H-indo-
le-5-carbonitrile Fumarate
[0321] The title compound was prepared as described for Example 101
using 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methyl-1,4-diazepane and
5-cyanooxindole. The crude product was purified on a silica gel
column using chloroform/methanol/conc NH.sub.3(aq), (100:15:1.5),
as the eluent. Yield: 50%: MS (ES) m/z 412 (M.sup.++1). The base
was converted to the fumarate salt according to the procedure
described for Example 103.
Example 106
2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonitr-
ile
[0322] The title compound was prepared as described for Example 101
using 4-[(6-chloropyridin-3-yl)sulfonyl]morpholine and
5-cyanooxindole. The reaction mixture was quenched with water and
the solvents were evaporated in vacuo. Water was added and the
mixture was filtered. The solid material was washed with water,
methanol, ethyl acetate and diethyl ether to give the title
compound. Yield: 44%: MS (ES) m/z 385 (M.sup.++1).
Example 107
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thiaz-
ol-4-yl)-1H-indol-2-ol Hydrochloride
[0323] The title compound was prepared as described for Example 101
using 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine
(described in: Thunus L., Annales Pharmaceutiques Francaises 1977,
35, 197-203) and
5-(2-methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one. The crude
product was purified on a silica gel column using
chloroform/methanol/conc NH.sub.3(aq), (50:3:0.3), as the eluent.
The base was dissolved in chloroform/methanol and converted to the
hydrochloride salt using HCl in diethyl ether (1 M). Yield: 35% of
the title compound: MS (ES) m/z 470 (M.sup.++1).
Example 108
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-thiazol-4-yl)--
1H-indol-2-ol Fumarate
[0324] The title compound was prepared as described for Example 101
using 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine
(described in: Thunus L., Annales Pharmaceutiques Francaises 1977,
35, 197-203) and 5-(1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one.
The crude product was purified on a silica gel column using
chloroform/methanol/conc NH.sub.3(aq), (100:7:0.7), as the eluent.
The base was converted to the fumarate salt according to the
procedure described for Example 103: Yield: 8% of the title
compound: MS (ES) m/z 456 (M.sup.++1)
Example 109
3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-oxazol-5-yl)-1-
H-indol-2-ol
[0325] The title compound was prepared as described for Example 101
using 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine
(described in: Thunus L., Annales Pharmaceutiques Francaises 1977,
35, 197-203) and 5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one.
The crude product was purified on a silica gel column using
chloroform/methanol/conc NH.sub.3(aq), (100:10:1), as the eluent
followed by trituration in ethyl acetate. Yield: 1% of the title
compound: MS (ES) m/z 441 (M.sup.++1).
Example 110
3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol
Hydrochloride
[0326] To a suspension of sodium hydride (60% dispersion in oil,
0.048 g, 1.19 mmol, pre-washed with hexane) in
N,N-dimethylformamide (2.0 mL) was added 5-nitrooxindole (0.185 g,
1.04 mmol). The formed mixture was stirred for 5 min at room
temperature and 2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide
(0.16 g, 0.7 mmol) was added. The resulting reaction mixture was
stirred for 30 minutes at 130.degree. C. (N.sub.2 atmosphere). The
solvent was removed in vacuo and the residual oil was purified on a
silica gel column using chloroform/methanol, (10:1) as the eluent
affording the N-oxide product. The N-oxide was dissolved in
chloroform (2 mL) and phosphorous trichloride (0.385 g, 2.80 mmol)
was added. The reaction mixture was stirred for 30 min at
60.degree. C. followed by extraction with an aqueous saturated
NaHCO.sub.3 solution. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated to a yellowish red oil which
was purified on a silica gel column using chloroform/methanol,
(10:1) as the eluent to give 10 mg (4% yield) of the title compound
as the free base as an yellow solid. The base (10 mg, 0.028 mmol)
was dissolved in methylene chloride/methanol, (1:1) and treated
with 1 M HCl in diethyl ether at 0.degree. C. The resulting
yellowish orange crystals were collected by filtration and washed
with diethyl ether to obtain 2 mg (16% yield) of the title
compound: .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 11.23 (s, 1H),
10.83 (br s, 1H), 8.36 (s, 2H), 8.10 (dd, J=10, 2 Hz, 1H), 7.94
(dd, J=9, 2 Hz, 1H), 7.87 (d, J=10 Hz, 1H), 7.09 (d, J=9 Hz, 1H),
4.34 (s, 2H), 4.02 (d, J=13 Hz, 2H), 3.77 (t, J=12 Hz, 2H), 3.38
(d, J=11 Hz, 2H), 3.14 (d, J=0 Hz, 2H).
Pharmacology
Determination of ATP Competition in Scintillation Proximity
GSK3.beta. Assay
GSK3b Scintillation Proximity Assay.
[0327] The competition experiments were carried out in duplicate
with 10 different concentrations of the inhibitors in clear-bottom
microtiter plates (Wallac, Finland). A biotinylated peptide
substrate,
Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO.sub.3H.sub.2)-Pro-G-
ln-Leu (AstraZeneca, Lund), was added at a final concentration of 1
.mu.M in an assay buffer containing 1 mU recombinant human
GSK3.beta. (Dundee University, UK), 12 mM morpholinepropanesulfonic
acid (MOPS), pH 7.0, 0.3 mM EDTA, 0.01% .beta.-mercaptorethanol,
0.004% Brij 35 (a natural detergent), 0.5% glycerol and 0.5 .mu.g
BSA/25 .mu.l. The reaction was initiated by the addition of 0.04
.mu.Ci [.gamma.-.sup.33P]ATP (Amersham, UK) and unlabelled ATP at a
final concentration of 1 .mu.M and assay volume of 25 .mu.l. After
incubation for 20 minutes at room temperature, each reaction was
terminated by the addition of 25 .mu.l stop solution containing 5
mM EDTA, 50 .mu.M ATP, 0.1% Triton X-100 and 0.25 mg streptavidin
coated Scintillation Proximity Assay (SPA) beads (Amersham, UK).
After 6 hours the radioactivity was determined in a liquid
scintillation counter (1450 MicroBeta Trilux, Wallac). The
inhibition curves were analysed by non-linear regression using
GraphPad Prism, USA. The K.sub.m value of ATP for GSK3.beta., used
to calculate the inhibition constants (K.sub.i) of the various
compounds, was 20 .mu.M.
The following abbreviations have been used: MOPS
Morpholinepropanesulfonic acid EDTA Ethylenediaminetetraacetic
acid
BSA Bovin Serum Albumin
ATP Adenosine Triphosphate
SPA Scintillation Proximity Assay
[0328] GSK3 Glycogen synthase kinase 3 MP-Carbonate Macroporous
triethylamonium methylpolystyrene carbonate
PS-Diisopropylethylamine
N,N-(Diisopropyl)aminomethylpolystyrene
PS-Thiophenol 3-(3-Mercaptophenyl)propanamidomethylpolystyrene
[0329] PS-Isocyanate Polystyrene methylisocyanate
RESULTS
[0330] Typical K.sub.i values for the compounds of the present
invention are in the range of about 0.001 to about 10,000 nM. Other
values for K.sub.i are in the range of about 0.001 to about 1000
nM. Further values for K.sub.i are in the range of about 0.010 nM
to about 300 nM.
* * * * *