U.S. patent application number 12/832343 was filed with the patent office on 2010-11-04 for novel 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels.
Invention is credited to Palle Christophersen, Tina Holm Johansen, Karin Sandager Nielsen, Dan Peters, Ulrik Svane Sorensen, Dorte Strob.ae butted.k, Lene Teuber.
Application Number | 20100280087 12/832343 |
Document ID | / |
Family ID | 36010294 |
Filed Date | 2010-11-04 |
United States Patent
Application |
20100280087 |
Kind Code |
A1 |
Sorensen; Ulrik Svane ; et
al. |
November 4, 2010 |
NOVEL 2-AMINO BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS MODULATORS
OF SMALL-CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNELS
Abstract
This invention relates to novel 2-amino benzimidazole
derivatives useful as modulators of small-conductance
calcium-activated potassium channels (SK channels). In other
aspects the invention relates to the use of these compounds in a
method for therapy and to pharmaceutical compositions comprising
the compounds of the invention.
Inventors: |
Sorensen; Ulrik Svane;
(Soborg, DK) ; Teuber; Lene; (Vaerlose, DK)
; Peters; Dan; (Malmo, DK) ; Strob.ae butted.k;
Dorte; (Farum, DK) ; Johansen; Tina Holm;
(Amorum, DK) ; Nielsen; Karin Sandager;
(Fredensborg, DK) ; Christophersen; Palle;
(Ballerup, DK) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
36010294 |
Appl. No.: |
12/832343 |
Filed: |
July 8, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11795018 |
Sep 28, 2007 |
|
|
|
PCT/EP06/50108 |
Jan 10, 2006 |
|
|
|
12832343 |
|
|
|
|
60642538 |
Jan 11, 2005 |
|
|
|
60653513 |
Feb 17, 2005 |
|
|
|
Current U.S.
Class: |
514/388 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 9/10 20180101; A61P 1/02 20180101; A61P 25/14 20180101; A61P
27/16 20180101; A61P 9/04 20180101; A61P 21/00 20180101; A61P 25/16
20180101; A61P 27/02 20180101; A61P 35/00 20180101; A61P 13/12
20180101; A61P 25/00 20180101; A61P 13/10 20180101; A61P 15/00
20180101; A61P 29/00 20180101; A61P 43/00 20180101; A61P 9/00
20180101; A61P 1/04 20180101; A61P 1/00 20180101; A61P 25/06
20180101; A61P 37/04 20180101; A61P 3/00 20180101; A61P 1/12
20180101; A61P 25/24 20180101; A61P 3/10 20180101; A61P 11/06
20180101; A61P 25/28 20180101; A61P 21/04 20180101; A61P 9/06
20180101; C07D 235/30 20130101; A61P 17/14 20180101; A61P 9/12
20180101; A61P 1/10 20180101; A61P 15/06 20180101; A61P 25/22
20180101; A61P 25/08 20180101; A61P 25/18 20180101 |
Class at
Publication: |
514/388 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61P 11/06 20060101 A61P011/06; A61P 25/22 20060101
A61P025/22; A61P 25/28 20060101 A61P025/28; A61P 9/12 20060101
A61P009/12; A61P 13/10 20060101 A61P013/10; A61P 17/14 20060101
A61P017/14; A61P 9/00 20060101 A61P009/00; A61P 35/00 20060101
A61P035/00; A61P 25/08 20060101 A61P025/08; A61P 29/00 20060101
A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 11, 2005 |
DK |
PA 2005 00049 |
Feb 16, 2005 |
DK |
PA 2005 00240 |
Claims
1. A method for treatment, prevention or alleviation of a disease
or a disorder or a condition of a living animal body, including a
human, which disorder, disease or condition is responsive to
modulation of SK channels, which method comprises the step of
administering to such a living animal body in need thereof a
therapeutically effective amount of a 2-amino benzimidazole
derivative of Formula Ib: ##STR00010## or any of its isomers or any
mixture of its isomers, or a pharmaceutically acceptable salt
thereof, wherein m is 1; n is 1; R' is hydrogen; R.sup.1 represents
4-fluorophenyl, 3,4-difluorophenyl, or 3,5-difluorophenyl, and
R.sup.2 represents 4-fluorophenyl, 3,4-difluorophenyl, or
3,5-difluorophenyl; and R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are
hydrogen.
2. The method according to claim 1, wherein the disease, disorder
or condition responsive to modulation of SK channels is: absence
seizures, age-related memory loss, Alzheimer's disease, angina
pectoris, arrhythmia, asthma, anxiety, ataxia, attention deficits,
baldness, bipolar disorder, bladder hyperexcitability, bladder
outflow obstruction, bladder spasms, brain tumors, cerebral
ischaemia, chronic obstructive pulmonary disease, cancer,
cardiovascular disorders, cognitive dysfunction, colitis,
constipation, convulsions, coronary artery spasms, coronary hearth
disease, cystic fibrosis, dementia, depression, diabetes type II,
dysmenorrhoea, epilepsy, gastrointestinal dysfunction,
gastroesophageal reflux disorder, gastrointestinal hypomotility
disorders gastrointestinal motility insufficiency, hearing loss,
hyperinsulinemia, hypertension, immune suppression, inflammatory
bowel disease, inflammatory pain, intermittent claudication,
irritable bowel syndrome, ischaemia, ischaemic hearth disease,
learning deficiencies, male erectile dysfunction, manic depression,
memory deficits, migraine, mood disorders, motor neuron diseases,
myokymia, myotonic dystrophy, myotonic muscle dystrophia,
narcolepsy, neuropathic pain, pain, Parkinson's disease, polycystic
kidney disease, postoperative ileus, premature labour, psychosis,
psychotic disorders, renal disorders, Reynaud's disease,
rhinorrhoea, secretory diarrhoea, seizures, Sjorgren's syndrome,
sleep apnea, spasticity, sleeping disorders, stroke, traumatic
brain injury, trigeminal neuralgia, urinary incontinence,
urinogenital disorders, vascular spasms, vision loss, or
xerostomia.
3. The method of claim 1, wherein said 2-amino benzimidazole
derivative is
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine,
or any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof.
4. A method for treatment, prevention or alleviation of a disease
or a disorder or a condition of a living animal body, including a
human, which disorder, disease or condition is responsive to
modulation of SK channels, which method comprises the step of
administering to such a living animal body in need thereof a
pharmaceutical composition comprising a therapeutically effective
amount of a 2-amino benzimidazole derivative of Formula Ib:
##STR00011## or any of its isomers or any mixture of its isomers,
or a pharmaceutically acceptable salt thereof, wherein m is 1; n is
1; R' is hydrogen; R.sup.1 represents 4-fluorophenyl,
3,4-difluorophenyl, or 3,5-difluorophenyl, and R.sup.2 represents
4-fluorophenyl, 3,4-difluorophenyl, or 3,5-difluorophenyl; and
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are hydrogen.
5. The method according to claim 4, wherein the disease, disorder
or condition responsive to modulation of SK channels is: absence
seizures, age-related memory loss, Alzheimer's disease, angina
pectoris, arrhythmia, asthma, anxiety, ataxia, attention deficits,
baldness, bipolar disorder, bladder hyperexcitability, bladder
outflow obstruction, bladder spasms, brain tumors, cerebral
ischaemia, chronic obstructive pulmonary disease, cancer,
cardiovascular disorders, cognitive dysfunction, colitis,
constipation, convulsions, coronary artery spasms, coronary hearth
disease, cystic fibrosis, dementia, depression, diabetes type II,
dysmenorrhoea, epilepsy, gastrointestinal dysfunction,
gastroesophageal reflux disorder, gastrointestinal hypomotility
disorders gastrointestinal motility insufficiency, hearing loss,
hyperinsulinemia, hypertension, immune suppression, inflammatory
bowel disease, inflammatory pain, intermittent claudication,
irritable bowel syndrome, ischaemia, ischaemic hearth disease,
learning deficiencies, male erectile dysfunction, manic depression,
memory deficits, migraine, mood disorders, motor neuron diseases,
myokymia, myotonic dystrophy, myotonic muscle dystrophia,
narcolepsy, neuropathic pain, pain, Parkinson's disease, polycystic
kidney disease, postoperative ileus, premature labour, psychosis,
psychotic disorders, renal disorders, Reynaud's disease,
rhinorrhoea, secretory diarrhoea, seizures, Sjorgren's syndrome,
sleep apnea, spasticity, sleeping disorders, stroke, traumatic
brain injury, trigeminal neuralgia, urinary incontinence,
urinogenital disorders, vascular spasms, vision loss, or
xerostomia.
6. The method of claim 4, wherein said 2-amino benzimidazole
derivative is
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine,
or any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a 37 CFR .sctn.1.53(b)
continuation of U.S. application Ser. No. 11/795,018 filed Sep. 28,
2007, which claims priority on U.S. Provisional Application Nos.
60/642,538 filed Jan. 11, 2005, and 60/653,513 filed Feb. 17, 2005.
The present application also claims priority on Danish Patent
Application Nos. PA 2005 00049 filed Jan. 11, 2005, and PA 2005
00240 filed Feb. 16, 2005. The entire contents of each of these
applications is hereby incorporated by reference.
TECHNICAL FIELD
[0002] This invention relates to novel 2-amino benzimidazole
derivatives useful as modulators of small-conductance
calcium-activated potassium channels (SK channels).
[0003] In other aspects the invention relates to the use of these
compounds in a method for therapy and to pharmaceutical
compositions comprising the compounds of the invention.
BACKGROUND ART
[0004] Three subtypes of small-conductance calcium-activated
potassium channels (SK channels) have been cloned: SK1, SK2 and SK3
(corresponding to KCNN1-3 using the genomic nomenclature). The
activity of these channels is determined by the concentration of
free intracellular calcium ([Ca.sup.2+].sub.i) via calmodulin that
is constitutively bound to the channels. SK channels are tightly
regulated by [Ca.sup.2+].sub.i in the physiological range being
closed at [Ca.sup.2+].sub.i up to around 0.1 .mu.M but fully
activated at a [Ca.sup.2+].sub.i of 1 .mu.M. Being selective for
potassium, open or active SK channels have a hyperpolarizing
influence on the membrane potential of the cell. SK channels are
widely expressed in the central nervous system. The distribution of
SK1 and SK2 show a high degree of overlap and display the highest
levels of expression in neocortical, limbic and hippocampal areas
in the mouse brain. In contrast, the SK3 channels show high levels
of expression in the basal ganglia, thalamus and the brain stem
monoaminergic neurons e.g. dorsal raphe, locus coeruleus and the
ventral tegmental area (Sailer et al. "Comparative
immunohistochemical distribution of three small-conductance
Ca.sup.2+-activated potassium channel subunits, SK1, SK2, and SK3
in mouse brain, Mol. Cell. Neurosci. 2004, 26, 458-469). The SK
channels are also present in several peripheral cells including
skeletal muscle, gland cells, liver cells and T-lymphocytes.
[0005] The hyperpolarizing action of active SK channels plays an
important role in the control of firing pattern and excitability of
excitable cells. SK channel inhibitors such as apamin and
bicuculline-methobromide have been demonstrated to increase
excitability whereas the opener 1-EBIO is able to reduce electrical
activity. In non-excitable cells where the amount of Ca.sup.2+
influx via voltage-independent pathways is highly sensitive to the
membrane potential an activation of SK channels will increase the
driving force whereas a blocker of SK channels will have a
depolarising effect and thus diminish the driving force for
calcium.
[0006] Based on the important role of SK channels in linking
[Ca.sup.2+].sub.i and membrane potential, SK channels are an
interesting target for developing novel therapeutic agents.
[0007] WO 03/094861 (Icagen Inc) describes bis-benzimidazoles and
related compounds as potassium channel modulators.
[0008] A review of SK channels and SK channel modulators may be
found in Liegeois, J.-F. et al.: "Modulation of small conductance
calcium-activated potassium (SK) channels: a new challenge in
medicinal chemistry", Current Medicinal Chemistry, 2003, 10,
625-647.
[0009] Known modulators of SK channels suffer from being large
molecules or peptides (apamin, scyllatoxin, tubocurarine,
dequalinium chloride, UCL1684) or having low potency (1-EBIO,
riluzole). Thus, there is a continued need for compounds with an
optimized pharmacological profile. In particular, there is a great
need for selective ligands, such as SK3 channel modulators.
[0010] WO 00/01676 (NeuroSearch A/S) describes novel potassium
channel blocking agents.
SUMMARY OF THE INVENTION
[0011] In its first aspect, the invention provides a 2-amino
benzimidazole derivative of Formula Ia or Ib:
##STR00001##
or any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R', m and n are as defined
below.
[0012] In its second aspect, the invention provides a
pharmaceutical composition, comprising a therapeutically effective
amount of a compound of the invention, or any of its isomers or any
mixture of its isomers, or a pharmaceutically acceptable salt
thereof, together with at least one pharmaceutically acceptable
carrier, excipient or diluent.
[0013] In a further aspect, the invention provides the use of a
compound of the invention, or any of its isomers or any mixture of
its isomers, or a pharmaceutically acceptable salt thereof, for the
manufacture of a pharmaceutical composition for the treatment,
prevention or alleviation of a disease or a disorder or a condition
of a mammal, including a human, which disease, disorder or
condition is responsive to modulation of SK channels.
[0014] In a still further aspect, the invention relates to a method
for treatment, prevention or alleviation of a disease or a disorder
or a condition of a living animal body, including a human, which
disorder, disease or condition is responsive to modulation of SK
channels, which method comprises the step of administering to such
a living animal body in need thereof a therapeutically effective
amount of a compound of the invention, or any of its isomers or any
mixture of its isomers, or a pharmaceutically acceptable salt
thereof.
[0015] Other objects of the invention will be apparent to the
person skilled in the art from the following detailed description
and examples.
DETAILED DISCLOSURE OF THE INVENTION
2-amino benzimidazole Derivatives
[0016] In its first aspect the present invention provides 2-amino
benzimidazole derivatives of formula Ia or Ib:
##STR00002##
or any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof, wherein [0017] m is 0, 1
or 2; [0018] n is 0, 1 or 2; [0019] R' is hydrogen or alkyl; [0020]
R.sup.1 and R.sup.2 independent of each other represent a phenyl
group, which phenyl group is optionally substituted with one or
more substituents independently selected from the group consisting
of: [0021] halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl,
R.sup.aR.sup.bN- and R.sup.aR.sup.bN-alkyl; [0022] wherein R.sup.a
and R.sup.b independent of each other are hydrogen or alkyl; and
[0023] R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independent of each
other are selected from the group consisting of: [0024] hydrogen,
halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl and
alkoxy.
[0025] In one embodiment, R' is hydrogen.
[0026] In a second embodiment, R' is alkyl, such as methyl.
[0027] In a third embodiment, m is 1. In a fourth embodiment, m is
0. In a further embodiment, n is 1. In a still further embodiment,
n is 0. In a special embodiment, m is 0 and n is 0. In a further
embodiment, m is 1 and n is 0. In a still further embodiment, m is
0 and n is 1. In a further embodiment, m is 1 and n is 1.
[0028] In a further embodiment, R.sup.1 and R.sup.2 independent of
each other represent a phenyl group, which phenyl group is
optionally substituted with one or more substituents independently
selected from the group consisting of: halo, trifluoromethyl and
trifluoromethoxy.
[0029] In a further embodiment, R.sup.1 represents a substituted
phenyl group. In a still further embodiment, R.sup.2 represents a
substituted phenyl group. In a further embodiment, R.sup.1
represents a substituted phenyl group and R.sup.2 represents a
substituted phenyl group.
[0030] In a still further embodiment, R.sup.1 represents
4-substituted phenyl, such as 4-halophenyl. In a special
embodiment, R.sup.1 represents 4-chlorophenyl or 4-fluorophenyl. In
a further embodiment, R.sup.1 represents 3-substituted phenyl, such
as 3-trifluoromethylphenyl. In a further embodiment, R.sup.1
represents 3,4-disubstituted phenyl, such as 3,4-dihalophenyl. In a
special embodiment, R.sup.1 represents 3,4-dichlorophenyl or
3,4-difluorophenyl. In a still further embodiment, R.sup.1
represents 3,5-disubstituted phenyl, such as 3,5-dihalophenyl. In a
special embodiment, R.sup.1 represents 3,5-difluorophenyl. In a
further embodiment, R.sup.1 represents
4-halo-3-trifluoromethylphenyl, such as
4-chloro-3-trifluoromethylphenyl.
[0031] In a still further embodiment, R.sup.2 represents
4-substituted phenyl, such as 4-halophenyl or
4-trifluoromethylphenyl. In a special embodiment, R.sup.2
represents 4-chlorophenyl, 4-fluorophenyl or
4-trifluoromethylphenyl. In a further embodiment, R.sup.2
represents 3-substituted phenyl, such as 3-trifluoromethylphenyl.
In a further embodiment, R.sup.2 represents 3,4-disubstituted
phenyl, such as 3,4-dihalophenyl. In a special embodiment, R.sup.2
represents 3,4-dichlorophenyl or 3,4-difluorophenyl. In a still
further embodiment, R.sup.2 represents 3,5-disubstituted phenyl,
such as 3,5-dihalophenyl. In a special embodiment, R.sup.2
represents 3,5-difluorophenyl. In a further embodiment, R.sup.2
represents 4-halo-3-trifluoromethylphenyl, such as
4-chloro-3-trifluoromethylphenyl.
[0032] In a still further embodiment, R.sup.1 and R.sup.2
independent of each other represent 4-halophenyl. In a special
embodiment, R.sup.1 represents 4-chlorophenyl, and R.sup.2
represents 4-chlorophenyl. In a further special embodiment, R.sup.1
represents 4-fluorophenyl and R.sup.2 represents
4-fluorophenyl.
[0033] In a still further embodiment, R.sup.1 and R.sup.2
independent of each other represent 3-substituted phenyl. In a
special embodiment, R.sup.1 represents 3-trifluoromethylphenyl, and
R.sup.2 represents 3-trifluoromethylphenyl.
[0034] In a further embodiment, R.sup.1 represents
3,4-dihalophenyl, such as 3,4-dichlorophenyl or 3,4-difluorophenyl,
and R.sup.2 represents 3,4-dihalophenyl, such as 3,4-dichlorophenyl
or 3,4-difluorophenyl. In a still further embodiment, R.sup.1
represents 4-halophenyl, such as 4-chlorophenyl, and R.sup.2
represents 3,4-dihalophenyl, such as 3,4-dichlorophenyl. In a
further embodiment, R.sup.1 represents 3,4-dihalophenyl, such as
3,4-dichlorophenyl, and R.sup.2 represents 4-halophenyl, such as
4-chlorophenyl. In a still further embodiment, R.sup.1 represents
3,4-dihalophenyl, such as 3,4-fluorophenyl, and R.sup.2 represents
4-trifluoromethylphenyl.
[0035] In a still further embodiment, R.sup.1 represents
3,5-dihalophenyl, such as 3,5-difluorophenyl, and R.sup.2
represents 3,5-dihalophenyl, such as 3,5-difluorophenyl.
[0036] In a further embodiment, R.sup.1 represents
4-halo-3-trifluoromethylphenyl, such as
4-chloro-3-trifluoromethylphenyl, and R.sup.2 represents
4-halo-3-trifluoromethylphenyl, such as
4-chloro-3-trifluoromethylphenyl. In a still further embodiment,
R.sup.1 represents 4-halo-3-trifluoromethylphenyl, such as
4-chloro-3-trifluoromethylphenyl, and R.sup.2 represents
3,4-dihalophenyl, such as 3,4-difluorophenyl.
[0037] In a further embodiment, R.sup.1 represents phenyl, and
R.sup.2 represents phenyl.
[0038] In a still further embodiment, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 represent hydrogen.
[0039] In a further embodiment, one of R.sup.4, R.sup.5, R.sup.6
and R.sup.7 represents halo, trifluoromethyl, trifluoromethoxy,
cyano, alkyl or alkoxy, and the remaining three of R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 represent hydrogen. In a special
embodiment, R.sup.5 represents halo, trifluoromethyl,
trifluoromethoxy, cyano, alkyl or alkoxy; and R.sup.4, R.sup.6 and
R.sup.7 represent hydrogen. In a special embodiment, R.sup.5
represents halo, such as chloro, fluoro or bromo.
[0040] In a further embodiment, the compound of the invention is a
derivative of Formula Ia. In a still further embodiment, the
compound of the invention is a derivative of Formula Ib.
[0041] In a special embodiment the chemical compound of the
invention is [0042]
1,3-Bis(4-chlorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine;
[0043]
1,3-Bis(3,4-dichlorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamin-
e; [0044]
1,3-Bis(4-fluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine;
[0045]
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamin-
e; [0046]
N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-3,4-difluoroaniline;
[0047]
N-[1-(4-Chlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine;
[0048]
N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-4-trifluoromethylanili-
ne; [0049]
N-[1-(4-Chloro-3-trifluoromethylbenzyl)benzimidazol-2-yl]-4-chl-
oro-3-trifluoromethyl-aniline; [0050]
N-[1-(4-Chloro-3-trifluoromethylbenzyl)benzimidazol-2-yl]-3,4-difluoroben-
zylamine; [0051]
N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-3,4-difluorobenzylamine;
[0052] N-[1-(4-Chlorobenzyl)benzimidazol-2-yl]-4-chlorobenzylamine;
[0053]
N-[1-(3,4-Dichlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamin-
e; [0054]
N-[1-(4-Fluorobenzyl)benzimidazol-2-yl]-4-fluorobenzylamine; [0055]
1,3-Bis(3,5-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamin-
e; [0056]
1-(3,4-Difluorobenzyl)-3-(3,4-difluorophenyl)-1,3-dihydrobenzoim-
idazol-2-ylideneamine; [0057]
1,3-Dibenzyl-1,3-dihydrobenzoimidazol-2-ylideneamine; [0058]
1,3-Bis(3,4-difluorobenzyl)-5-fluoro-1,3-dihydrobenzoimidazol-2-ylideneam-
ine; [0059]
1,3-Bis[3-(trifluoromethyl)benzyl]-1,3-dihydrobenzoimidazol-2-ylideneamin-
e; [0060]
1,3-Bis(3,4-difluorobenzyl)-5-bromo-1,3-dihydrobenzoimidazol-2-y-
lideneamine; [0061]
[1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylidene]methylami-
ne; [0062]
(3,4-Difluorobenzyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-
-yl]amine; [0063]
(3,4-Difluorophenyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-yl]amine;
or a pharmaceutically acceptable salt thereof.
[0064] Any combination of two or more of the embodiments as
described above is considered within the scope of the present
invention.
Definition of Substituents
[0065] In the context of this invention halo represents fluoro,
chloro, bromo or iodo.
[0066] In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contains of from one to six carbon
atoms (C.sub.1-6-alkyl), including pentyl, isopentyl, neopentyl,
tertiary pentyl, hexyl and isohexyl. In a preferred embodiment
alkyl represents a C.sub.1-4-alkyl group, including butyl,
isobutyl, secondary butyl, and tertiary butyl. In another preferred
embodiment of this invention alkyl represents a C.sub.1-3-alkyl
group, which may in particular be methyl, ethyl, propyl or
isopropyl.
[0067] Alkoxy is O-alkyl, wherein alkyl is as defined above.
Pharmaceutically Acceptable Salts
[0068] The chemical compound of the invention may be provided in
any form suitable for the intended administration. Suitable forms
include pharmaceutically (i.e. physiologically) acceptable salts,
and pre- or prodrug forms of the chemical compound of the
invention.
[0069] Examples of pharmaceutically acceptable addition salts
include, without limitation, the non-toxic inorganic and organic
acid addition salts such as the hydrochloride, the hydrobromide,
the nitrate, the perchlorate, the phosphate, the sulphate, the
formate, the acetate, the aconate, the ascorbate, the
benzenesulphonate, the benzoate, the cinnamate, the citrate, the
embonate, the enantate, the fumarate, the glutamate, the glycolate,
the lactate, the maleate, the malonate, the mandelate, the
methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the
salicylate, the sorbate, the stearate, the succinate, the tartrate,
the toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
[0070] Other acids such as oxalic acid, which may not be considered
pharmaceutically acceptable, may be useful in the preparation of
salts useful as intermediates in obtaining a chemical compound of
the invention and its pharmaceutically acceptable acid addition
salt.
[0071] Examples of pharmaceutically acceptable cationic salts of a
chemical compound of the invention include, without limitation, the
sodium, the potassium, the calcium, the magnesium, the zinc, the
aluminium, the lithium, the choline, the lysinium, and the ammonium
salt, and the like, of a chemical compound of the invention
containing an anionic group. Such cationic salts may be formed by
procedures well known and described in the art.
[0072] In the context of this invention the "onium salts" of
N-containing compounds are also contemplated as pharmaceutically
acceptable salts. Preferred "onium salts" include the alkyl-onium
salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium
salts.
[0073] Examples of pre- or prodrug forms of the chemical compound
of the invention include examples of suitable prodrugs of the
substances according to the invention include compounds modified at
one or more reactive or derivatizable groups of the parent
compound. Of particular interest are compounds modified at a
carboxyl group, a hydroxyl group, or an amino group. Examples of
suitable derivatives are esters or amides.
[0074] The chemical compound of the invention may be provided in
dissoluble or indissoluble forms together with a pharmaceutically
acceptable solvent such as water, ethanol, and the like. Dissoluble
forms may also include hydrated forms such as the monohydrate, the
dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and
the like. In general, the dissoluble forms are considered
equivalent to indissoluble forms for the purposes of this
invention.
Steric Isomers
[0075] It will be appreciated by those skilled in the art that the
compounds of the present invention may contain one or more chiral
centers, and that such compounds exist in the form of isomers.
[0076] Moreover, the chemical compounds of the present invention
may exist as enantiomers in (+) and (-) forms as well as in racemic
forms (.+-.). The racemates of these isomers and the individual
isomers themselves are within the scope of the present
invention.
[0077] The invention includes all such isomers and any mixtures
thereof including racemic mixtures.
[0078] Racemic forms can be resolved into the optical antipodes by
known methods and techniques. One way of separating the isomeric
salts is by use of an optically active acid, and liberating the
optically active amine compound by treatment with a base. Another
method for resolving racemates into the optical antipodes is based
upon chromatography on an optical active matrix. Racemic compounds
of the present invention can thus be resolved into their optical
antipodes, e.g., by fractional crystallisation of d- or l-
(tartrates, mandelates, or camphorsulphonate) salts for
example.
[0079] The chemical compounds of the present invention may also be
resolved by the formation of diastereomeric amides by reaction of
the chemical compounds of the present invention with an optically
active activated carboxylic acid such as that derived from (+) or
(-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic
acid or by the formation of diastereomeric carbamates by reaction
of the chemical compound of the present invention with an optically
active chloroformate or the like.
[0080] Additional methods for the resolving the optical isomers are
known in the art. Such methods include those described by Jaques J,
Collet A, & Wilen S in "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, New York (1981).
[0081] Optical active compounds can also be prepared from optical
active starting materials.
Labelled Compounds
[0082] The compounds of the invention may be used in their labelled
or unlabelled form. In the context of this invention the labelled
compound has one or more atoms replaced by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature. The labelling will allow easy quantitative
detection of said compound.
[0083] The labelled compounds of the invention may be useful as
diagnostic tools, radio tracers, or monitoring agents in various
diagnostic methods, and for in vivo receptor imaging.
[0084] The labelled isomer of the invention preferably contains at
least one radionuclide as a label. Positron emitting radionuclides
are all candidates for usage. In the context of this invention the
radionuclide is preferably selected from .sup.2H (deuterium),
.sup.3H (tritium), .sup.13C, .sup.14C, .sup.131I, .sup.125I,
.sup.123I, and .sup.18F.
[0085] The physical method for detecting the labelled isomer of the
present invention may be selected from Position Emission Tomography
(PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic
Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and
Computed Axial X-ray Tomography (CAT), or combinations thereof.
Methods of Preparation
[0086] The chemical compounds of the invention may be prepared by
conventional methods for chemical synthesis, e.g. those described
in the working examples. The starting materials for the processes
described in the present application are known or may readily be
prepared by conventional methods from commercially available
chemicals.
[0087] Also one compound of the invention can be converted to
another compound of the invention using conventional methods.
[0088] The end products of the reactions described herein may be
isolated by conventional techniques, e.g. by extraction,
crystallisation, distillation, chromatography, etc.
Biological Activity
[0089] Compounds of the invention may be tested for their ability
to modulate SK channels in vitro. Functional modulation can be
determined by measuring the compound-induced change in SK current
by the patch clamp technique as described in Strob.ae butted.k et
al.: "Pharmacological characterization of small-conductance
Ca.sup.2+-activated K channels expressed in HEK293 cells", British
Journal of Pharmacology (2000) 129, 991-999. From this type of
measurements the potency of a given compound can be determined as
e.g. K.sub.i or IC.sub.50 values for blockers/inhibitors and
EC.sub.50 values for openers/activators. Similar data can be
obtained from other patch clamp configurations and from channels
expressed endogenously in various cell lines.
[0090] In one embodiment, the compounds of the invention show
selectivity for SK3 over SK1 and SK2. In a further embodiment, the
compounds of the invention are positive SK channel modulators, such
as positive SK3 channel modulators. In a still further embodiment,
the compounds of the invention are negative modulators, such as
negative SK3 channel modulators. In a special embodiment, the
compounds of the invention are SK channel blockers, such as SK3
channel blockers.
[0091] Based on the activity observed in the patch clamp
experiments, the compound of the invention is considered useful for
the treatment, prevention or alleviation of a disease or a disorder
or a condition of a mammal, including a human, which disease,
disorder or condition is responsive to modulation of SK
channels.
[0092] In a special embodiment, the compounds of the invention are
considered useful for the treatment, prevention or alleviation of:
absence seizures, age related memory loss, Alzheimer's disease,
angina pectoris, arrhythmia, asthma, anxiety, ataxia, attention
deficits, baldness, bipolar disorder, bladder hyperexcitability,
bladder outflow obstruction, bladder spasms, brain tumors, cerebral
ischaemia, chronic obstructive pulmonary disease, cancer,
cardiovascular disorders, cognitive dysfunction, colitis,
constipation, convulsions, coronary artery spasms, coronary hearth
disease, cystic fibrosis, dementia, depression, diabetes type II,
dysmenorrhoea, epilepsy, gastrointestinal dysfunction,
gastroesophageal reflux disorder, gastrointestinal hypomotility
disorders gastrointestinal motility insufficiency, hearing loss,
hyperinsulinemia, hypertension, immune suppression, inflammatory
bowel disease, inflammatory pain, intermittent claudication,
irritable bowel syndrome, ischaemia, ischaemic hearth disease,
learning deficiencies, male erectile dysfunction, manic depression,
memory deficits, migraine, mood disorders, motor neuron diseases,
myokymia, myotonic dystrophy, myotonic muscle dystrophia,
narcolepsy, neuropathic pain, pain, Parkinson's disease, polycystic
kidney disease, postoperative ileus, premature labour, psychosis,
psychotic disorders, renal disorders, Reynaud's disease,
rhinorrhoea, secretory diarrhoea, seizures, Sjorgren's syndrome,
sleep apnea, spasticity, sleeping disorders, stroke, traumatic
brain injury, trigeminal neuralgia, urinary incontinence,
urinogenital disorders, vascular spasms, vision loss, and
xerostomia.
[0093] It is at present contemplated that a suitable dosage of the
active pharmaceutical ingredient (API) is within the range of from
about 0.1 to about 1000 mg API per day, more preferred of from
about 10 to about 500 mg API per day, most preferred of from about
30 to about 100 mg API per day, dependent, however, upon the exact
mode of administration, the form in which it is administered, the
indication considered, the subject and in particular the body
weight of the subject involved, and further the preference and
experience of the physician or veterinarian in charge.
[0094] Preferred compounds of the invention show a biological
activity in the sub-micromolar and micromolar range, i.e. of from
below 1 to about 100 .mu.M.
Pharmaceutical Compositions
[0095] In another aspect the invention provides novel
pharmaceutical compositions comprising a therapeutically effective
amount of the chemical compound of the invention.
[0096] While a chemical compound of the invention for use in
therapy may be administered in the form of the raw chemical
compound, it is preferred to introduce the active ingredient,
optionally in the form of a physiologically acceptable salt, in a
pharmaceutical composition together with one or more adjuvants,
excipients, carriers, buffers, diluents, and/or other customary
pharmaceutical auxiliaries.
[0097] In a preferred embodiment, the invention provides
pharmaceutical compositions comprising the chemical compound of the
invention, or a pharmaceutically acceptable salt or derivative
thereof, together with one or more pharmaceutically acceptable
carriers, and, optionally, other therapeutic and/or prophylactic
ingredients, known and used in the art. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not harmful to the recipient
thereof.
[0098] Pharmaceutical compositions of the invention may be those
suitable for oral, rectal, bronchial, nasal, pulmonal, topical
(including buccal and sub-lingual), transdermal, vaginal or
parenteral (including cutaneous, subcutaneous, intramuscular,
intraperitoneal, intravenous, intraarterial, intracerebral,
intraocular injection or infusion) administration, or those in a
form suitable for administration by inhalation or insufflation,
including powders and liquid aerosol administration, or by
sustained release systems. Suitable examples of sustained release
systems include semipermeable matrices of solid hydrophobic
polymers containing the compound of the invention, which matrices
may be in form of shaped articles, e.g. films or microcapsules.
[0099] The chemical compound of the invention, together with a
conventional adjuvant, carrier, or diluent, may thus be placed into
the form of pharmaceutical compositions and unit dosages thereof.
Such forms include solids, and in particular tablets, filled
capsules, powder and pellet forms, and liquids, in particular
aqueous or non-aqueous solutions, suspensions, emulsions, elixirs,
and capsules filled with the same, all for oral use, suppositories
for rectal administration, and sterile injectable solutions for
parenteral use. Such pharmaceutical compositions and unit dosage
forms thereof may comprise conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and such unit dosage forms may contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed.
[0100] The chemical compound of the present invention can be
administered in a wide variety of oral and parenteral dosage forms.
It will be obvious to those skilled in the art that the following
dosage forms may comprise, as the active component, either a
chemical compound of the invention or a pharmaceutically acceptable
salt of a chemical compound of the invention.
[0101] For preparing pharmaceutical compositions from a chemical
compound of the present invention, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, pills, capsules, cachets, suppositories,
and dispersible granules. A solid carrier can be one or more
substances which may also act as diluents, flavouring agents,
solubilizers, lubricants, suspending agents, binders,
preservatives, tablet disintegrating agents, or an encapsulating
material.
[0102] In powders, the carrier is a finely divided solid, which is
in a mixture with the finely divided active component.
[0103] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted in the shape and size desired.
[0104] The powders and tablets preferably contain from five or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid forms suitable for oral administration.
[0105] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glyceride or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized moulds, allowed to cool, and thereby to
solidify.
[0106] Compositions suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0107] Liquid preparations include solutions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol
solution.
[0108] The chemical compound according to the present invention may
thus be formulated for parenteral administration (e.g. by
injection, for example bolus injection or continuous infusion) and
may be presented in unit dose form in ampoules, pre-filled
syringes, small volume infusion or in multi-dose containers with an
added preservative. The compositions may take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and may contain formulation agents such as suspending, stabilising
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form, obtained by aseptic isolation of sterile solid
or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.
[0109] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavours, stabilising and thickening agents, as
desired.
[0110] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well known
suspending agents.
[0111] Also included are solid form preparations, intended for
conversion shortly before use to liquid form preparations for oral
administration. Such liquid forms include solutions, suspensions,
and emulsions. In addition to the active component such
preparations may comprise colorants, flavours, stabilisers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0112] For topical administration to the epidermis the chemical
compound of the invention may be formulated as ointments, creams or
lotions, or as a transdermal patch. Ointments and creams may, for
example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilising agents,
dispersing agents, suspending agents, thickening agents, or
colouring agents.
[0113] Compositions suitable for topical administration in the
mouth include lozenges comprising the active agent in a flavoured
base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin
and glycerine or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0114] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The compositions may be provided in single or multi-dose
form.
[0115] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurised pack with a suitable propellant such
as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon
dioxide, or other suitable gas. The aerosol may conveniently also
contain a surfactant such as lecithin. The dose of drug may be
controlled by provision of a metered valve.
[0116] Alternatively the active ingredients may be provided in the
form of a dry powder, for example a powder mix of the compound in a
suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0117] In compositions intended for administration to the
respiratory tract, including intranasal compositions, the compound
will generally have a small particle size for example of the order
of 5 microns or less. Such a particle size may be obtained by means
known in the art, for example by micronization.
[0118] When desired, compositions adapted to give sustained release
of the active ingredient may be employed.
[0119] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packaged
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0120] Tablets or capsules for oral administration and liquids for
intravenous administration and continuous infusion are preferred
compositions.
[0121] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0122] A therapeutically effective dose refers to that amount of
active ingredient, which ameliorates the symptoms or condition.
Therapeutic efficacy and toxicity, e.g. ED.sub.50 and LD.sub.50,
may be determined by standard pharmacological procedures in cell
cultures or experimental animals. The dose ratio between
therapeutic and toxic effects is the therapeutic index and may be
expressed by the ratio LD.sub.50/ED.sub.50. Pharmaceutical
compositions exhibiting large therapeutic indexes are
preferred.
[0123] The dose administered must of course be carefully adjusted
to the age, weight and condition of the individual being treated,
as well as the route of administration, dosage form and regimen,
and the result desired, and the exact dosage should of course be
determined by the practitioner.
[0124] The actual dosage depends on the nature and severity of the
disease being treated, and is within the discretion of the
physician, and may be varied by titration of the dosage to the
particular circumstances of this invention to produce the desired
therapeutic effect. However, it is presently contemplated that
pharmaceutical compositions containing of from about 0.1 to about
500 mg of active ingredient per individual dose, preferably of from
about 1 to about 100 mg, most preferred of from about 1 to about 10
mg, are suitable for therapeutic treatments.
[0125] The active ingredient may be administered in one or several
doses per day. A satisfactory result can, in certain instances, be
obtained at a dosage as low as 0.1 .mu.g/kg i.v. and 1 .mu.g/kg
p.o. The upper limit of the dosage range is presently considered to
be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from
about 0.1 .mu.g/kg to about 10 mg/kg/day i.v., and from about 1
.mu.g/kg to about 100 mg/kg/day p.o.
Methods of Therapy
[0126] In another aspect the invention provides a method for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disease, disorder or condition is responsive to modulation of SK
channels, and which method comprises administering to such a living
animal body, including a human, in need thereof an effective amount
of a chemical compound of the invention.
[0127] It is at present contemplated that suitable dosage ranges
are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and
especially 30-100 milligrams daily, dependent as usual upon the
exact mode of administration, form in which administered, the
indication toward which the administration is directed, the subject
involved and the body weight of the subject involved, and further
the preference and experience of the physician or veterinarian in
charge.
EXAMPLES
[0128] The invention is further illustrated with reference to the
following examples, which are not intended to be in any way
limiting to the scope of the invention as claimed.
General: The procedures represent generic procedures used to
prepare compounds of the invention. Abbreviations used are as
follows: [0129] Ac: acetyl [0130] DMSO: dimethylsulfoxide [0131]
DMF: dimethylformamide [0132] EDCI:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide [0133] Et: ethyl
[0134] eq: equivalents [0135] LCMS: Liquid chromatography mass
spectrometry [0136] Me: methyl [0137] mp: melting point [0138] MW:
microwave [0139] NMP: 1-methyl-2-pyrrolidone [0140] rt: room
temperature [0141] TEA: triethylamine [0142] THF:
tetrahydrofurane
Procedure A
[0143] 2-Aminobenzimidazole and K2CO.sub.3 (4 eq) dissolved in dry
acetonitrile was (under N.sub.2) added the required benzyl halide
(2 eq) and stirred at 50.degree. C. overnight. Water was added and
the mixture extracted with EtOAc. The combined organic phases were
dried (MgSO.sub.4), filtered and concentrated in vacuo to give the
crude product which was purified by preparative LCMS or,
alternatively, by column chromatography and/or
recrystallization.
[0144] An example of Procedure A, the preparation of
1,3-bis(4-chlorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine, is
shown in Scheme 1.
##STR00003##
Procedure B
[0145] A stirred solution of 2-chlorobenzimidazole in dry DMF was
(under N.sub.2) cooled to 0.degree. C. and added NaH (1.3 eq).
After stirring 30 min at rt, the required benzyl halide was added
dropwise and the reaction mixture stirred at rt overnight.
Saturated aqueous NaHCO.sub.3 was added and the mixture extracted
with EtOAc. The combined organic phases were dried (MgSO.sub.4),
filtered and concentrated in vacuo to give the desired
2-chloro-1-benzylbenzimidazole. This intermediate was subsequently
dissolved in acetonitrile, added the required amine derivative (1-2
eq) and heated by means of MW irradiation at 190-200.degree. C. for
15-40 min. The reaction mixture was evaporated to dryness,
redissolved in DMSO and purified by preparative LCMS to give the
desired 1-benzyl-2-(arylamino)benzimidazole as the free base.
[0146] Alternatively, precipitated product was filtered off the
reaction mixture and recrystallized to give the desired product as
a hydrochloride salt.
[0147] An example of Procedure B, the preparation of
N-[1-(3,4-difluorobenzyl)benzimidazol-2-yl]-3,4-difluoroaniline, is
shown in Scheme 2.
##STR00004##
Procedure C
[0148] 2-Aminobenzimidazole and K.sub.2CO.sub.3 (2 eq) dissolved in
dry acetonitrile was (under N.sub.2) added the required benzyl
halide (1 eq) and stirred at 50.degree. C. overnight. Water was
added and the mixture extracted with EtOAc. The combined organic
phases were dried (MgSO.sub.4), filtered and concentrated in vacuo
to give the crude 1-benzylated 2-aminobenzimidazole which was
purified by preparative LCMS or, alternatively, by column
chromatography. The isolated 2-aminobenzimidazole was subsequently
in acetonitrile added the required substituted benzaldehyde, a
catalytic amount of AcOH and sodium triacetoxyborohydride (2 eq).
The reaction mixture was heated by means of MW irradiation at
100.degree. C. for 30 min and isolated using preparative LCMS to
give the desired 1-benzyl-2-(benzylamino)benzimidazole as the free
base.
[0149] An example of Procedure C, the preparation of
N-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine, is
shown in Scheme 3.
##STR00005##
Procedure D
[0150] A stirred solution of 2-chlorobenzimidazole is dissolved in
acetonitrile, added the required amine derivative (1-2 eq) and
heated by means of MW irradiation at 190-200.degree. C. for 15-40
min. The reaction mixture was evaporated to dryness, and the
desired 2-(arylamino)benzimidazole isolated by filtration, LCMS or
column chromatography. Subsequently, this intermediate was
redissolved in acetonitrile and added K.sub.2CO.sub.3 (2 eq) and
the required alkyl halide (1 eq) and stirred at 50.degree. C.
overnight. Water was added and the mixture extracted with EtOAc.
The combined organic phases were dried (MgSO.sub.4), filtered and
concentrated in vacuo to give the crude 1,2-disubstituted
2-aminobenzimidazole which was purified by preparative LCMS or,
alternatively, by column chromatography.
[0151] An example of Procedure D, the preparation of
N-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine, is
shown in Scheme 4.
##STR00006##
Procedure E
[0152] 1-Fluoro-2-nitrobenzene, TEA (1 eq) and the required amine
(1 eq) were dissolved in NMP and heated in a sealed vial by means
of MW irradiation at 240.degree. C. for 60 min (Step A, Scheme 5).
Water was added and the mixture extracted with EtOAc. The combined
organic phases were dried (MgSO.sub.4), filtered and concentrated
in vacuo to give the crude (2-nitrophenyl)arylamine which was
purified by column chromatography.
[0153] In a second step (B), the (2-nitrophenyl)arylamine was
dissolved in EtOH, added a catalytic amount of 10% Pd/C and stirred
in a H.sub.2 atmosphere for 5 hours at rt. The reaction mixture was
filtered through celite, evaporated to dryness and the crude
material purified by column chromatography to give the desired
N-arylbenzene-1,2-diamine.
[0154] In Step C, the N-arylbenzene-1,2-diamine was dissolved in
dry acetonitrile, added BrCN (1.5 eq) and the mixture stirred under
N2 overnight at rt.
[0155] 1 M aqueous NaOH was added and the mixture extracted with
EtOAc. The combined organic phases were dried (MgSO.sub.4),
filtered and concentrated in vacuo to give the
1-aryl-1H-benzoimidazol-2-ylamine
[0156] In the last step (Step D, Scheme 5), the
1-aryl-1H-benzoimidazol-2-ylamine was dissolved in dry
acetonitrile, added the required benzyl halide (1.2 eq) and heated
in a sealed vial by means of MW irradiation at 170.degree. C. for
15-40 min. The reaction mixture was cooled to rt and the
precipitate filtered off and washed with acetonitrile to give the
desired product as a hydrobromide salt. Alternatively, the reaction
mixture was added water and extracted with EtOAc. The combined
organic phases were dried (MgSO.sub.4), filtered and concentrated
in vacuo to give the crude product which was purified by
preparative LCMS or by column chromatography and/or
recrystallization.
[0157] An example of Procedure E, the preparation of
1-(3,4-difluorobenzyl)-3-(3,4-difluorophenyl)-1,3-dihydrobenzoimidazol-2--
ylideneamine, is shown in Scheme 5.
##STR00007##
Procedure F
[0158] 1,4-Difluoro-2-nitrobenzene, K.sub.2CO.sub.3 (1.5 eq) and
the required amine (1 eq) were dissolved in THF and stirred at
reflux overnight (Step A, Scheme 6). Aqueous HCl was added and the
formed precipitate filtered off and washed with water and isopropyl
ether to give the (4-fluoro-2-nitrophenyl)arylamine as the HCl
salt.
[0159] In a second step (B), the (4-fluoro-2-nitrophenyl)arylamine
was dissolved in THF, added a catalytic amount of Raney Nickel and
stirred under hydrogen overnight at rt. The reaction mixture was
filtered through celite, evaporated to dryness and the crude
material purified by column chromatography to give the desired
N.sup.1-aryl-4-fluorobenzene-1,2-diamine.
[0160] In Step C, the N.sup.1-aryl-4-fluorobenzene-1,2-diamine was
dissolved in EtOH, added BrCN (3 eq) and the mixture stirred under
nitrogen overnight at rt.
[0161] 1 M aqueous NaOH was added and the mixture extracted with
EtOAc. The combined organic phases were dried (MgSO.sub.4),
filtered and concentrated in vacuo to give the
1-aryl-5-fluoro-1H-benzoimidazol-2-ylamine.
[0162] In the last step (Step D, Scheme 6), the
1-aryl-5-fluoro-1H-benzoimidazol-2-ylamine and K.sub.2CO.sub.3 (1.1
eq) dissolved in dry THF were added the required benzyl halide (1
eq) and heated to reflux overnight. The reaction mixture was cooled
to rt, added water and extracted with EtOAc. The combined organic
phases were dried (MgSO.sub.4), filtered and concentrated in vacuo
to give the crude product which was purified by preparative LCMS or
by column chromatography and/or recrystallization.
[0163] An example of Procedure F, the preparation of
1,3-bis(3,4-difluorobenzyl)-5-fluoro-1,3-dihydrobenzoimidazol-2-ylideneam-
ine, is shown in Scheme 6.
##STR00008##
Procedure G
[0164] An N-arylbenzene-1,2-diamine dissolved in acetonitrile was
added the required phenyl isothiocyanate and stirred under nitrogen
overnight at rt. After conversion into the corresponding thiourea
intermediate, the mixture was added a coupling reagent such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and the reaction
mixture stirred overnight at 65.degree. C. The mixture was cooled
to rt, evaporated to dryness and the remaining crude product
purified by preparative LCMS or by column chromatography and/or
recrystallization.
[0165] An example of Procedure G, the preparation of
(3,4-difluorophenyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-yl]amine,
is shown in Scheme 7.
##STR00009##
Example 1
1,3-Bis(4-chlorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine
[0166] The title compound was prepared from 2-aminobenzimidazole
and 4-chlorobenzyl chloride by Procedure A. The product was
isolated by preparative LCMS to give the title compound as the free
base (white solid, mp 185-187.degree. C.). MS(ES.sup.+) m/z 382
(M.sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 5.08 (br s, 4H), 5.76
(s, 1H), 6.80-6.90 (m, 4H), 7.25-7.42 (m, 8H).
Example 2
1,3-Bis(3,4-dichlorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine
[0167] The title compound was prepared from 2-aminobenzimidazole
and 3,4-dichlorobenzyl bromide by Procedure A. The product was
isolated by filtration, treatment with aqueous NaOH and
recrystallized (EtOH/H.sub.2O) to give the title compound as the
free base (white solid, mp 145-146.degree. C.). MS(ES.sup.+) m/z
450 M.sup.+, 100) .sup.1NMR (DMSO-d6) .delta. 5.10 (br s, 4H), 5.90
(s, 1H), 6.85-6.99 (m, 4H), 7.15-7.36 (m, 2H), 7.50-7.65 (m,
4H).
Example 3
1,3-Bis(4-fluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine
[0168] The title compound was prepared from 2-aminobenzimidazole
and 4-fluorobenzyl bromide by Procedure A. The product was isolated
by preparative LCMS to give the title compound as the free base
(white solid, mp 148-150.degree. C.). MS(ES.sup.+) m/z 351
([M+1].sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 5.07 (s, 4H), 5.75
(br s, 1H), 6.78-6.91 (m, 4H), 7.12-7.18 (m, 4H), 7.30-7.42 (m,
4H).
Example 4
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine
[0169] The title compound was prepared from 2-aminobenzimidazole
and 3,4-difluorobenzyl bromide by Procedure A. The product was
isolated by preparative LCMS to give the title compound as the free
base (white solid, mp 114-117.degree. C.). MS(ES.sup.+) m/z 387
([M+1].sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 5.08 (br s, 4H),
5.86 (br s, 1H), 6.72-6.96 (m, 4H), 7.05-7.22 (m, 2H), 7.35-7.45
(m, 4H).
Example 5
N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-3,4-difluoroaniline
[0170] The title compound was prepared by Procedure B in two steps
from 2-chloro-benzimidazole, 3,4-difluorobenzyl bromide and
3,4-difluoroaniline. The product was isolated by filtration and
recrystallization (MeOH/Et.sub.2O) to give the title compound as
its hydrochloride salt (white solid, mp 236-238.degree. C.).
MS(ES.sup.+) m/z 372 ([M+1].sup.+, 100). .sup.1NMR (DMSO-d6)
.delta. 5.61 (s, 2H), 7.19-7.30 (m, 3H), 7.36-7.61 (m, 6H),
7.83-7.91 (m, 1H), 11.0 (br s, 1H).
Example 6
N-[1-(4-Chlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine
[0171] The title compound was prepared by Procedure C in two steps
from 2-amino-benzimidazole, 4-chlorobenzyl chloride and,
subsequently, 3,4-dichlorobenzaldehyde. The product was isolated by
preparative LCMS to give the title compound as the free base
(yellowish oil). Alternatively, the title compound can be prepared
in two steps from 2-chlorobenzimidazole, 4-chlorobenzyl chloride
and 3,4-dichlorobenzylamine by use of either Procedure B or by
Procedure D. MS(ES.sup.+) m/z 416 (M.sup.+, 100). .sup.1NMR (CDCl3)
.delta. 4.70 (s, 2H), 5.23 (s, 2H), 7.08-7.33 (m, 11H), 7.46-7.50
(m, 1H).
Example 7
N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-4-trifluoromethylaniline
[0172] The title compound was prepared by Procedure B in two steps
from 2-chloro-benzimidazole, 3,4-difluorobenzyl bromide and
4-trifluoromethylaniline. The product was isolated by preparative
LCMS and recrystallization (EtOAc/Et.sub.2O) to give the title
compound as the free base (off-white solid, mp 167-170.degree. C.).
MS(ES.sup.+) m/z 404 ([M+1].sup.+, 100). .sup.1NMR (DMSO-d6)
.delta. 5.55 (s, 2H), 6.90-6.97 (m, 1H), 7.02-7.13 (m, 2H),
7.25-7.50 (m, 4H), 7.65-7.71 (m, 2H), 8.04-8.12 (m, 2H), 9.55 (s,
1H).
Example 8
N-[1-(4-Chloro-3-trifluoromethylbenzyl)benzimidazol-2-yl]-4-chloro-3-trifl-
uoromethylaniline
[0173] The title compound was prepared by Procedure B in two steps
from 2-chloro-benzimidazole, 4-chloro-3-trifluoromethylbenzyl
bromide and 4-chloro-3-trifluoromethyl-aniline. The product was
isolated by preparative LCMS to give the title compound as the free
base (off-white solid, mp 88-92.degree. C.). MS(ES.sup.+) m/z 504
(M.sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 5.60 (s, 2H), 7.02-7.15
(m, 2H), 7.25-7.32 (m, 2H), 7.45-7.52 (m, 1H), 7.63-7.70 (m, 2H),
7.81 (s, 1H), 8.23-8.40 (m, 2H), 9.62 (br s, 1H).
Example 9
N-[1-(4-Chloro-3-trifluoromethylbenzyl)benzimidazol-2-yl]-3,4-difluorobenz-
ylamine
[0174] The title compound was prepared by Procedure B in two steps
from 2-chloro-benzimidazole, 4-chloro-3-trifluoromethylbenzyl
bromide and 3,4-difluorobenzylamine. The product was isolated by
preparative LCMS to give the title compound as the free base
(off-white solid, mp 158-161.degree. C.). MS(ES.sup.+) m/z 452
([M+1].sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 4.55 (s, 2H), 5.36
(s, 2H), 6.87-6.98 (m, 2H), 7.13-7.37 (m, 6H), 7.50-7.55 (m, 1H),
7.68-7.71 (m, 2H).
Example 10
N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-3,4-difluorobenzylamine
[0175] The title compound was prepared by Procedure B in two steps
from 2-chloro-benzimidazole, 3,4-difluorobenzyl bromide and
3,4-difluorobenzylamine. The product was isolated by column
chromatography to give the title compound as the free base (oil).
MS(ES.sup.+) m/z 386 ([M+1].sup.+, 100). .sup.1NMR (DMSO-d6)
.delta. 4.59 (d, 2H), 5.30 (s, 2H), 6.87-6.97 (m, 3H), 7.16-7.49
(m, 8H).
Example 11
N-[1-(4-Chlorobenzyl)benzimidazol-2-yl]-4-chlorobenzylamine,
N-[1-(3,4-Dichloro-benzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine
and
N-[1-(4-Fluorobenzyl)-benzimidazol-2-yl]-4-fluorobenzylamine
[0176] The three title compounds are prepared analogously to the
compound of Example 10.
Example 12
1,3-Bis(3,5-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine
[0177] The title compound was prepared from 2-aminobenzimidazole
and 3,5-difluorobenzyl bromide by Procedure A. The title product
was isolated by filtration and washed with acetonitrile and water
to give the title compound as the free base (white solid, mp
144-145.degree. C.). MS(ES.sup.+) m/z 386 ([M+1].sup.+, 100).
Example 13
1-(3,4-Difluorobenzyl)-3-(3,4-difluorophenyl)-1,3-dihydrobenzoimidazol-2-y-
lideneamine
[0178] The title compound was prepared by Procedure E in four steps
from 1-fluoro-2-nitrobenzene, 3,4-difluoroaniline and, in the last
step, 3,4-difluorobenzyl bromide. After the last step, the product
was isolated from the reaction mixture by filtration and washed
with acetonitrile to give the title compound as the hydrobromide
salt (off-white solid, mp 259-260.degree. C.). MS(ES.sup.+) m/z 372
([M+1].sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 5.52 (s, 2H),
7.05-7.16 (m, 1H), 7.24-7.72 (m, 7H), 7.80-7.92 (m, 1H), 8.00-8.09
(m, 1H), 8.93 (br s, 2H).
Example 14
1,3-Dibenzyl-1,3-dihydrobenzoimidazol-2-ylideneamine
[0179] The title compound was prepared from 2-aminobenzimidazole
and benzyl bromide by Procedure A. The title product was isolated
by filtration and washed with acetonitrile and water to give the
title compound as the hydrobromide salt (solid, mp>300.degree.
C.). MS(ES.sup.+) m/z 314 ([M+1].sup.+, 100).
Example 15
1,3-Bis(3,4-difluorobenzyl)-5-fluoro-1,3-dihydrobenzoimidazol-2-ylideneami-
ne
[0180] The title compound was prepared by Procedure F in four steps
from 1,4-difluoro-2-nitrobenzene, 3,4-difluorobenzylamine and, in
the last step, 3,4-difluorobenzyl bromide. After the last step, the
product was isolated by aqueous workup and recrystallized from
heptane/Et.sub.2O/EtOAc to give the title compound as the free base
(off-white solid, mp>166.degree. C. (decomp.)). MS(E) m/z 404
([M+1].sup.+, 100). .sup.1NMR (DMSO-d6) .delta. 5.44 (s, 2H), 5.45
(s, 2H), 7.10-7.27 (m, 3H), 7.40-7.58 (m, 6H), 9.16 (br s, 1H).
Example 16
1,3-Bis[3-(trifluoromethyl)benzyl]-1,3-dihydrobenzoimidazol-2-ylideneamine
[0181] The title compound was prepared from 2-aminobenzimidazole
and 3-trifluorobenzyl bromide by Procedure A. The product was
isolated by filtration and purified by column chromatography to
give the title compound as the free base (solid, mp 175-177.degree.
C.). MS(ES.sup.+) m/z 450 ([M+1].sup.+, 100).
Example 17
1,3-Bis(3,4-difluorobenzyl)-5-bromo-1,3-dihydrobenzoimidazol-2-ylideneamin-
e
[0182]
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine-
, prepared by Procedure A, was dissolved in dichloromethane, added
bromine (2 eq) and stirred overnight at rt. Saturated aqueous
NaHCO.sub.3 was added and the mixture extracted with EtOAc. The
combined organic phases were dried (MgSO.sub.4), filtered,
concentrated in vacuo and purified by preparative LCMS to give the
title compound as the free base (solid, mp 88-89.5.degree. C.).
MS(ES.sup.+) m/z 465 ([M+1].sup.+, 100). .sup.1NMR (DMSO-d6)
.delta. 5.05 (s, 4H), 6.08 (br s, 1H), 6.85-6.93 (m, 1H), 6.98-7.23
(m, 4H), 7.35-7.45 (m, 4H).
Example 18
[1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylidene]methylamin-
e
[0183]
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine-
, prepared by Procedure A, was dissolved in THF, added
K.sub.2CO.sub.3 (2 eq) and iodomethane (3 eq) and the mixture
stirred under N2 for 3 days at rt. Water was added and the mixture
extracted with EtOAc. The combined organic phases were dried
(MgSO.sub.4), filtered, concentrated in vacuo and purified by
preparative LCMS to give the title compound as the free base
(yellowish oil). MS(ES.sup.+) m/z 400 ([M+1].sup.+, 100). .sup.1NMR
(CDCl.sub.3) .delta. 3.25 (s, 3H), 5.15 (s, 4H), 6.70 (m, 2H),
6.92-7.25 (m, 8H).
Example 19
(3,4-Difluorobenzyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-yl]amine
[0184] 1-(3,4-Difluorophenyl)-1H-benzoimidazol-2-ylamine, prepared
as described in Procedure E (Scheme 5, Steps A-C), was dissolved in
acetonitrile, added 3,4-difluorobenzaldehyde (1 eq), sodium
triacetoxyborohydride (2 eq) and a catalytic amount of AcOH. The
reaction mixture was heated in a sealed vial by means of MW
irradiation at 100.degree. C. for 25 min Saturated aqueous
NaHCO.sub.3 was added and the mixture extracted with EtOAc. The
combined organic phases were dried (MgSO.sub.4), filtered,
concentrated in vacuo and purified by preparative LCMS to give the
title compound as the free base (solid, mp 158.5-159.5.degree. C.).
MS(ES.sup.+) m/z 372 ([M+1].sup.+, 100). .sup.1NMR (DMSO-d6)
.delta. 4.50 (d, 2H), 6.85-6.92 (m, 2H), 6.99-7.15 (m, 2H),
7.20-7.46 (m, 5H), 7.68-7.74 (m, 1H), 7.78-7.83 (m, 1H).
Example 20
(3,4-Difluorophenyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-yl]amine
[0185] The title compound was prepared by Procedure G from
N-(3,4-difluorophenyl)-benzene-1,2-diamine (Scheme 5),
3,4-difluorophenyl isothiocyanate and, in the last step,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction mixture
was evaporated to dryness and the remaining crude product purified
by preparative LCMS to give the title compound as the free base
(solid, mp 115-117.degree. C.). MS(ES.sup.+) m/z 358 ([M+1].sup.+,
100).
* * * * *