Note: Descriptions are shown in the official language in which they were submitted.
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1
Substituted indoline and indole derivatives
Field of the invention
The present invention relates to novel substituted indole and indoline
derivatives
being openers of the KCNQ family potassium ion channels. The compounds are
useful for the prevention, treatment and inhibition of disorders and diseases
being
responsive to opening of the KCNQ family potassium ion channels, one such
disease
is epilepsy.
Background of the invention
Ion channels are cellular proteins that regulate the flow of ions, including
potassium,
calcium, chloride and sodium into and out of cells. Such channels are present
in all
animal and human cells and affect a variety of processes including neuronal
transmission, muscle contraction, and cellular secretion.
Humans have over 70 genes encoding potassium channel subtypes (Jentsch Nature
Reviews Neuroscience 2000, 1, 21-30) with a great diversity with regard to
both
stucture and function. Neuronal potassium channels, which are found in the
brain, are
primarily responsible for maintaining a negative resting membrane potential,
as well
2o as controlling membrane repolarisation following an action potential.
One subset of potassium channel genes is the KCNQ family. Mutations in four
out of
five KCNQ genes have been shown to underlie diseases including cardiac
arrhythmias, deafiiess and epilepsy (Jentsch Nature Reviews Neuroscience 2000,
1,
21-30).
The KCNQ4 gene is thought to encode the molecular correlate of a potassium
channel
found in outer hair cells of the cochlea and in Type I hair cells of the
vestibular
apparatus, in which, mutations can lead to a form of inherited deafiiess.
KCNQ1 (KvLQTl) is co-assembled with the product of the KCNE1 (miumal K(+)_
channel protein) gene in the heart to form a cardiac-delayed rectifier-lilce
K(+)
current. Mutations in this channel can cause one form of inherited long QT
syndrome
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2
type 1 (LQT1), as well as being associated with a form of deafness (Bobbins
Phaf°macol TZaeY 2001, 90, 1-19).
The genes KCNQ2 and KCNQ3 were discovered in 1988 and appear to be mutated in
an inherited form of epilepsy l~nown as benign familial neonatal convulsions
(Rogawslci Trends in Neu~osciences 2000, 23, 393-398). The proteins encoded by
the
KCNQ2 and KCNQ3 genes are localised in the pyramidal neurons of the human
cortex and hippocampus, regions of the brain associated with seizure
generation and
propagation (Cooper et al. Proceedings National Academy of Science U S A 2000,
97,
4914-4919).
KCNQ2 and KCNQ3 are two potassium channel subunits that form "M-currents"
when expressed in vitro. The M-current is a non-inactivating potassium current
found
in many neuronal cell types. In each cell type, it is dominant in controlling
membrane
excitability by being the only sustained current in the range of action
potential
initiation (Marrion Ayanual Review Physiology 1997, 59, 483-504). Modulation
of the
M-curl ent has dramatic effects on neuronal excitability, for example
activation of the
current will reduce neuronal excitability. Openers of these KCNQ channels, or
activators of the M-current, will reduce excessive neuronal activity and may
thus be
2o of use in the treatment, prevention or inhibition of seizures and other
diseases and
disorders characterised by excessive neuronal activity, such as neuronal
hyperexcitability including convulsive disorders, epilepsy and neuropathic
pain.
Retigabine (D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid
ethyl ester) and analogues thereof are disclosed in EP554543. Retigabine is an
anti-
convulsive compound with a broad spectrum and potent anticonvulsant
properties,
both in vitro and in vivo. It is active after oral and intraperitoneal
administration in
rats and mice in a range of anticonvulsant tests including: electrically
induced
seizures, seizures induced chemically by pentylenetetrazole, picrotoxin and N-
methyl-
3o D-aspartate (NMDA) and in a genetic animal model, the DBA/2 mouse (Rostocl~
et al.
Epilepsy Research 1996, 23, 211-223). In addition, retigabine is active in the
amygdala lcindling model of complex partial seizures, further indicating that
this
compound has potential for anti-convulsive therapy. In clinical trials,
retigabine has
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recently shown effectiveness in reducing the incidence of seizures in
epileptic patients
(Bialer et al. Epilepsy Research 2002, 51, 31-71).
Retigabine has been shown to activate a K(+) current in neuronal cells and the
pharmacology of this induced current displays concordance with the published
pharmacology of the M-channel, which recently was correlated to the KCNQ2/3
K(+)
chamlel heteromultimer. This suggests that activation of KCNQ2/3 channels may
be
responsible for some of the anticonvulsant activity of this agent (Wiclcenden
et al.
Molecular Pharmacology 2000, 58, 591-600) - and that other agents working by
the
to same mechanism may have similar uses.
KCNQ 2 and 3 channels have also been reported to be upregulated in models of
neuropathic pain (Wickenden et al. Society for Neuroscience Abstracts 2002,
454.7),
and potassium channel modulators have been hypothesised to be active in both
neuropathic pain and epilepsy (Schroder et al. Neuropharmacology 2001, 40, 888-
898).
Retigabine has also been shown to be beneficial in animal models of
neuropathic pain
(Blaclcburn-Munro and Jensen European Journal of Pharmacology 2003, 460, 109-
116), and it is thus suggested that openers of KCNQ channels will be of use in
treating
pain disorders including neuropathic pain.
The localisation of KCNQ channel mRNA is reported in brain arid other central
nervous system areas associated with pain (Goldstein et al. Society for
Neuroscieh.ce
Abstracts 2003, 53.8).
In addition to a role in neuropathic pain, the expression of mRNA for KCNQ 2-5
in
the trigeminal and dorsal root ganglia and in the trigeminal nucleus caudalis
implies
that openers of these channels may also affect the sensory processing of
migraine pain
(Goldstein et al. Society for Neuroscience Abstracts 2003, 53.8).
Recent reports demonstrate that mRNA for KCNQ 3 and 5, in addition to that for
KCNQ2, are expressed in astrocytes and glial cells. Thus KCNQ 2, 3 and 5
channels
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may help modulate synaptic activity in the CNS and contribute to the
neuroprotective
effects of KCNQ channel openers (Noda et al., Society fog Neuy-osciefZCe
Abstracts
2003, 53.9).
Retigabine and other KCNQ modulators may thus exhibit protection against the
neurodegenerative aspects of epilepsy, as retigabine has been shown to prevent
limbic
neurodegeneration and the expression of markers of apoptosis following kainic
acid-
induced status epilepticus in the rat (Ebert et al. Epilepsia 2002, 43 Suppl
5, 86-95).
This may have relevance for preventing the progression of epilepsy in
patients, i.e. be
1o anti-epileptogenic. Retigabine has also been shown to delay the progression
of
hippocampal leindling in the rat, a further model of epilepsy development
(Tober et al.
European Journal OfPharmacology 1996, 303, 163-169).
It is thus suggested that these properties of retigabine and other KCNQ
modulators
may prevent neuronal damage induced by excessive neuronal activation, and may
be
of use in the treatment of neurodegenerative diseases, and be disease
modifying (or
antiepileptogenic) in patients with epilepsy.
Given that anticonvulsant compounds such as benzodiazepines and
chlormetluazole
2o are used clincially in the treatment of the ethanol withdrawal syndrome and
that other
anticonvulsant compounds e.g. gabapentin, are very effective in animal models
of this
syndrome (Watson et al. Neuropha~macology 1997, 36, 1369-1375), other
anticonvulsant compounds such as KCNQ openers are thus expected to be
effective in
this condition.
mRNA for KCNQ 2 and 3 subunits are found in brain regions associated with
anxiety
and emotional behaviours such as bipolar disorder e.g. hippocampus and
amygdala
(Saganich et al. .Iour~nal of Neuroscience 2001, 21, 4609-4624), and
retigabine is
reportedly active in some animal models of anxiety-like behaviour (Hartz et
al.
.Tour-raal ofPsycl2oplaarmacology 2003, 17 suppl 3, A28,B16), and other
clinically
used anticonvulsant compounds are used in the treatment of bipolar disorder.
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WO 2004/096767 PCT/DK2004/000283
WO 200196540 discloses the use of modulators of the M-current formed by
expression of KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526
discloses that modulators of KCNQS can be utilized for the treatment of sleep
disorders.
W001/022953 describes the use of retigabine for prophylaxis and treatment of
neuropathic pain such as allodynia, hyperalgesic pain, phantom pain,
neuropathic pain
related to diabetic neuropathy and neuropathic pain related to migraine.
to W002/049628 describes the use of retigabine for the prevention, treatment,
inhibition
and amelioration of anxiety disorders such as anxiety, generalized anxiety
disorder,
panic a~zxiety, obsessive compulsive disorder, social phobia, performance
anxiety,
post-traumatic stress disorder, acute stress reaction, adjustment disorders,
hypochondriacal disorders, separation anxiety disorder, agoraphobia and
specific
15 phobias.
W097/15300 describes the use of retigabine for the treatment of
neurodegenerative
disorders such as Alzheimer's disease; Huntington's chorea; sclerosis such as
multiple
sclerosisand amyotrophic lateral sclerosis; Creutzfeld-Jakob disease;
Parkinson's
2o disease; encephalopathies induced by AIDS or infection by rubella viruses,
herpes
viruses, borrelia and unknown pathogens; trauma-induced neurodegenerations;
neuronal hyperexcitation states such as in medicament withdrawal or
intoxication; and
neurodegenerative diseases of the peripheral nervous system such as
polyneuropathies
and polyneuritides.
Hence, there is a great desire for novel compounds, which are potent openers
of the
KCNQ family potassium channels.
Also desired are novel compounds with improved properties relative to known
compounds, which are openers of the KCNQ family potassium channels, such as
retigabine. Improvement of one or more of the following parameters is desired:
half life, clearance, selectivity, interactions with other medications,
bioavailability,
potency, formulability, chemical stability, metabolic stability, membrane
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permeability, solubility and therapeutic index. The improvement of such
parameters
may lead to improvements such as:
~ an improved dosing regime by reducing the number of required doses a day,
~ ease of administration to patients on multiple medications,
~ reduced side effects,
~ enlarged therapeutic index,
~ improved tolerability or
~ improved compliance.
to
Summary of the invention
One object of the present invention is to provide novel compounds, which are
potent
openers of the KCNQ family potassium channels.
The compounds of the invention are substituted indoline and indole derivatives
of the
general formula I or salts thereof
R2
~s
~ N~ X ~ ~Z)q~ 3
- ~\ R
Ri N
Y
Rl,
(I)
wherein the dotted line, q, s, U, Y, X, Z, R1, Rl~, R2 and R3 are as defined
below.
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The invention further relates to a pharmaceutical composition comprising a
compound
of formula I, and the use thereof.
Description of the invention
Accordingly, the present invention relates to substituted indole and indoline
derivatives of the general formula I
R2
~ 3
\ R
,,
Rl N ~ s
R1.
(I)
wherein
the dotted line represents an optional bond;
Rl and Rl~ are independently selected from the group consisting of hydrogen,
C1_~-
alk(en/yn)yl, C3_8-cycloallc(en)yl, C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl,
hydroxy-C1_s-
all~(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3_$-cycloalk(en)yl-C1_~-
allc(en/yn)yl, halo-C1_~-allc(en/yn)yl, halo-C3_$-cycloallc(en)yl, halo-C3_8-
cycloalle(en)yl-Cl_~-allc(en/yn)yl, cyano-C1_~-alk(en/yn)yl, cyano-C3_8-
cycloallc(en)yl
and cyano-C3_8-cycloalk(en)yl-C1_~-allc(en/yn)yl; or
Rl and Rl~ together with the carbon atom to which they are attached form a 3-~
membered saturated or unsaturated ring which optionally contains 1 or 2
heteroatoms;
sis0orl;
U is O, NRII, S, 502, S02NR11, CO-O or CO-NRII; wherein Rll is selected from
the
group consisting of hydrogen, Cl_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, C3_$-
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cycloalk(en)yl-C1_G-alk(en/yn)yl; or R2 and Rll together with the nitrogen
atom to
which they are attached form a 4-8 membered saturated or unsaturated ring
which
optionally contains 1, 2 or 3 further heteroatoms;
RZ is selected from the group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_$-
cycloalk(en)yl, C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, Ar, Ar-C1_~-
alk(en/yn)yl, Ar-C3_
8-cycloallc(en)yl, Ar-C3_$-cycloalk(en)yl-C1_~-all~(en/yn)yl, acyl, hydroxy-
C1_~-
allc(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-C1_~-
alk(en/yn)yl, halogen, halo-C1_6-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-
C3_8-
to cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano, cyano-C1_~-alk(en/yn)yl, cyano-
C3_g-
c cloalk en 1 c ano-C3_$-cycloallc en 1-C1_~-alk en/ 1 -N02, NRloRlo~-Ci_6-
Y ( )Y ~ Y ( )Y ( Yn)Y
alk(en/yn)yl, NRl°Rlo~-C3_8-cycloalk(en)yl and NRl°Rlo~-C3_$-
cycloalk(en)yl-C1_~-
alk(en/yn)yl; wherein
Rl° and Rl°~ are independently selected from the group
consisting of hydrogen, Cl_s-
alk(en/yn)yl, C3_g-cycloallc(en)yl, C3_8-cycloalk(en)yl-Cl_6-alk(en/yn)yl,
hydroxy-C1_s-
alk(en/yn)yl, hydroxy-C3_~-cycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-Cl_~-
allc(en/yn)yl, halo-Cl_~-alk(en/yn)yl, halo-C3_g-cycloalk(en)yl, halo-C3_$-
cycloalk(en)yl-C1_~-alk(euyn)yl, cyano-C1_6-alk(en/yn)yl, cyano-C3_8-
cycloalk(en)yl
and cyano-C3_8-cycloalk(en)yl-Cl_~-alk(en/yn)yl, or
2o Rl° and Rl°~ together with the nitrogen atom to which they
are attached form a 4-8
membered saturated or unsaturated ring which optionally contains 1, 2 or 3
further
heteroatoms;
with the proviso that when RZ is N02, halogen or cyano then s is 0; and
with the proviso that when R2 is a hydrogen atom or acyl and s is 1 then U is
NRII, O
or S;
wherein the group -(U)S R2 is linked to position 4 or 6 of the indole or
indoline;
qis0orl;
Z is O or S;
X is CO or 502; with the proviso that q is 0 when X is 502;
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R3 is selected from the group consisting of C1_6-alk(en/yn)yl, C3_8-
cycloalk(en)yl,
heterocycloallc(en)yl, C3_g-cycloallc(en)yl-Cl_~-allc(en/yn)yl, C1_~-
alk(euyn)yl-C3_8-
cycloalk(en)yl, C1_~-ally(en/yn)yl-heterocycloalk(en)yl, Ar, Ar-Cl_~-
alk(en/yn)yl, Ar-
C3_8-cycloallc(en)yl, Ar-heterocycloalk(en)yl, Ar-C3_$-cycloalk(en)yl-C1_~-
alk(en/yn)yl, Ar-C1_~-alk(en/yn)yl-C3_8-cycloalk(en)yl, Ar-Cl_G-allc(en/yn)yl-
heterocycloallc(en)yl, C1_~-allc(en/yn)yloxy-C1_~-alk(enlyn)yl, C3_8-
cycloall~(en)yloxy-
C1_~-allc(en/yn)yl, C1_G-allc(en/yn)yloxy-C3_$-cycloallc(en)yl, C1_G-
alk(en/yn)yloxy-
heterocycloalk(en)yl, Ar-oxy-C1_6-alk(en/yn)yl, Ar-C1_~-alk(en/yn)yloxy-C1_~-
allc(en/yn)yl, C1_~-alk(enlyn)yloxy-carbonyl-C1_~-alk(en/yn)yl, C3_8-
cycloalk(en)yloxy-
to carbonyl-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yloxy-
carbonyl-C1_~-
alk(en/yn)yl, hydroxy-C1_~-alk(en/yn)yl, hydroxy-C3_$-cycloalk(en)yl, hydroxy-
heterocycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, hydroxy-
C1_~-
alk(en/yn)yl-C3_8-cycloalk(en)yl, hydroxy-C1_G-ally(en/yn)yl-
heterocycloallc(en)yl,
halo-C1_~-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-heterocycloalk(en)yl,
halo-C3_$-
cycloalk(en)yl-C1_~-alk(en/yn)yl, halo-Cl_6-alk(en/yn)yl-C3_g-cycloalk(en)yl,
halo-C1_
~-alk(en/yn)yl-heterocycloalk(en)yl, halo-C1_6-alk(en/yn)yl-Ar, halo-C3_$-
. cycloalk(en)yl-Ar, halo-C3_8-cycloalk(en)yl-Cl_~-alk(en/yn)yl-Ar, halo-C1_~-
alk(en/yn)yl-C3_8-cycloalk(en)yl-Ar, cyano-Cl_~-alk(en/yn)yl, cyano-C3_8-
cycloallc(en)yl, cyano-heterocycloalk(en)yl, cyano-C3_8-cycloalk(en)yl-Cl_6-
2o alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl-C3_$-cycloalk(en)yl, cyano-C1_~-
alk(en/yn)yl-
heterocycloallc(en)yl, acyl-C1_G-alk(en/yn)yl, acyl-C3_8-cycloalk(en)yl, acyl-
heterocycloalk(en)yl, acyl-C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, acyl-C1_~-
alk(en/yn)yl-C3_$-cycloalk(en)yl, acyl-C1_~-alk(en/yn)yl-heterocycloalk(en)yl
and -
~12R12'~ optionally substituted NR12R12~-C1_~-alk(en/yn)yl, optionally
substituted
NR12R12~-C3_8-cycloallc(en)yl, optionally substituted NRiZRiz~-C3_8-
cycloalk(en)yl-Ci_
~-allc(en/yn)yl; wherein
R12 and R12~ are independently selected from the group consisting of hydrogen,
Ci-~-
allc(en/yn)yl, C3_8-cycloall~(en)yl, C3_$-cycloalk(en)yl-Cl_G-alk(en/yn)yl,
Ar, Ar-Ci-~-
alk(en/yn)yl, Ar-C3_8-cycloall~(en)yl, Ar-C3_$-cycloalk(en)yl-C1_~-
alk(en/yn)yl,
3o hydroxy-C1_~-alk(en/yn)yl, hydroxy-C3_$-cycloallc(en)yl, hydroxy-C3_$-
cycloall~(en)yl-
C1_~-allc(en/yn)yl, halo-C1_~-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-
C3_$-
cycloallc(en)yl-C1_~-allc(en/yn)yl, cyano-C1_~-allc(enlyn)yl, cyano-C3_8-
cycloalk(en)yl
and cyano-C3_$-cycloall~(en)yl-C1_~-allc(en/yn)yl, or
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R12 and R12~ together with the nitrogen atom to which they are attached form a
4-8
membered saturated or unsaturated ring which optionally contains 1, 2 or 3
further
heteroatoms;
with the proviso that when R3 is NR12R12' then q is 0;
5
and
Y represents a group of formula II, III, IV, V, , VI, XXX and XXXI:
(RS)a (RS)b i
w w
II III (R )°
(Rs)a
w~ ~~p /
~5)e
IV V
(Rs)g \ (R )~
N~
T
(RS)n
VI XXX
(Rs) L \
~N
or
10 _X_XXT
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11
wherein
the line represents a bond attaching the group represented by Y to the carbon
atom;
WisOorS;
TisN,NHorO;
L is N, C or CH;
to
ais0, l,2or3;
b is 0, 1, 2, 3 or 4;
cis0orl;
d is 0, 1, 2 or 3;
a is 0, 1 or 2;
f is 0, l, 2, 3, 4 or 5;
g is 0, 1, 2, 3 or 4;
h is 0, 1, 2 or 3;
j is 0, 1, 2 or 3; with the proviso that when T is a nitrogen atom then j is
0, l, 2 or 3;
and when T is NH or an oxygen atom then j is 0, 1 or 2;
3o k is 0, 1, 2, 3 or 4; and
each RS is independently selected from the group consisting of a C1_~-
allc(en/yn)yl, C3_
8-cycloallc(en)yl, C3_$-cycloallc(en)yl-C1_~-alk(en/yn)yl, Ar, Ar-C1_~-
allc(enlyn)yl, Ar
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12
thio, Ar-oxy, acyl, Cl_G-allc(en/yn)yloxy, C3_8-cycloalk(en)yloxy, C3_$-
cycloalk(en)yl-
C1_G-alle(en/yn)yloxy, halogen, halo-C1_~-alk(enlyn)yl, halo-C3_8-
cycloalk(en)yl, halo-
C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, -CO-NR6R6', cyano, cyano-C1_~-
allc(en/yn)yl,
cyano-C3_$-cycloall~(en)yl, cyano-C3_$-cycloalk(en)yl-C1_~-alk(en/yn)yl, -
NR~R~', -S-
R8 and -S02R8, or
two adjacent RS together with the aromatic group to which they are attached
form a 4-
8 membered ring which optionally contains one or two heteroatoms;
R6 and R~' are independently selected from the group consisting of hydrogen,
Cl_~-
1o alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_$-cycloalk(en)yl-C1_~-allc(en/yn)yl
and Ar;
R' and R'' are independently selected from the group consisting of hydrogen,
C1_~-
alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-Cl_~-alk(en/yn)yl, Ar
and acyl;
15 and
R8 is selected from the group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_8-
cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_6-alk(en/yn)yl, Ar and NR9R9'; wherein
R9 and R~' are independently selected from the group consisting of hydrogen,
C1_6-
20 alk(en/yn)yl, C3_8-cycloalk(en)yl and C3_8-cycloalk(en)yl-C1_~-
alk(en/yn)yl;
provided that when R8 is NR9R9' then R5 is not -S-R8;
or salts thereof.
A particular embodiment of the invention relates to substituted indole and
indoline
derivatives of the general formula I
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13
R2
~s
\ N\ / (Z)q\
\ X Rs
6
Ri N
Y
R1,
(I)
wherein
the dotted line represents an optional bond;
Rl and Rl~ are independently selected from the group consisting of hydrogen,
C1_~-
alk(en/yn)yl, C3_8-cycloallc(en)yl, C3_8-cycloalk(en)yl-Cl_~-alk(en/yn)yl,
hydroxy-Cl_~-
alk(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3_$-cycloalk(en)yl-C1_~-
alle(en/yn)yl, halo-C1_G-alk(en/yn)yl, halo-C3_$-cycloalk(en)yl, halo-C3_$-
to cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl, cyano-C3_g-
cycloallc(en)yl
and cyano-C3_$-cycloalk(en)yl-C1_~-alk(enlyn)yl; or
Rl and Rl~ form a 3-8 membered saturated or unsaturated ring which optionally
contains 1 or 2 further heteroatoms;
sis0orl;
U is O, NRII, S, 502, S02NRl, CO-O or CO-NRII; wherein Rll is selected from
the
group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_$-cycloalk(en)yl, C3_$-
cycloalk(en)yl-C1_~-allc(en/yn)yl; or
RZ and Rll together with the nitrogen atom to which they are attached form a 4-
8
membered saturated or unsaturated ring which optionally contains 1, 2 or 3
further
heteroatoms;
RZ is selected from the group consisting of hydrogen, C1_~-allc(en/yn)yl, C3_8-
cycloallc(en)yl, C3_$-cycloallc(en)yl-Cl_~-allc(en/yn)yl, Ar, Ar-Cl_~-
allc(en/yn)yl, Ar-C3_
$-cycloalk(en)yl, Ar-C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl, acyl, hydroxy-
Cl_~-
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14
all~(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3_g-cycloalk(en)yl-C1_~-
all~(en/yn)yl, halogen, halo-Cl_~-alk(enlyn)yl, halo-C3_$-cycloalk(en)yl, halo-
C3_8-
cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano, cyano-Cl_~-alk(en/yn)yl, cyano-C3_8-
c cloalk en 1 c ano-C3_$ c cloalk en 1-C1_~-alk en/ 1 -N02,
NRl°Rl°'-C1_~-
Y ( )Y ~ Y - Y ( )Y ( Yn)Y
allc(en/yn)yl, NRl°Rio~-C3_8-cycloalk(en)yl and NRl°Rlo~-C3_8-
cycloalk(en)yl-Ci_~-
alk(en/yn)yl; wherein
Rl° and R1°~ are independently selected from the group
consisting of hydrogen, Cl_~-
alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_$-cycloallc(en)yl-Cl_~-alk(en/yn)yl,
hydroxy-C1_~-
all~(en/yn)yl, hydroxy-C3_$-cycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-C1_~-
l0 all~(en/yn)yl, halo-Cl_~-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-C3_8-
cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano-C1_~-alk(en/yn)yl, cyano-C3_$-
cycloalk(en)yl
and cyano-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, or
Ri° and Rl°~ together with the nitrogen atom to which they are
attached form a 4-8
membered saturated or unsaturated ring which optionally contains l, 2 or 3
further
15 heteroatoms;
with the proviso that when R2 is N02, halogen or cyano then s is 0; and
with the proviso that when R2 is a hydrogen atom or aryl and s is 1 then U is
NRII, O
or S;
2o wherein the group -(U)S R2 is linked to position 4 or 6 of the indole or
indoline;
qis0orl;
Z is O or S;
X is CO or 502; with the proviso that q is 0 when X is 502;
R3 is selected from the group consisting of Cl_6-alk(en/yn)yl, C3_$-
cycloallc(en)yl,
heterocycloalk(en)yl, C3_8-cycloallc(en)yl-C1_6-alk(enlyn)yl, C1_~-
alk(en/yn)yl-C3_$-
3o cycloallc(en)yl, Cl_~-ally(en/yn)yl-heterocycloalk(en)yl, Ar, Ar-Cl_~-
alk(en/yn)yl, Ar-
C3_$-cycloallc(en)yl, Ar-heterocycloallc(en)yl, Ar-C3_8-cycloalk(en)yl-C1_~-
allc(en/yn)yl, Ar-Cl_~-allc(en/yn)yl-C3_8-cycloallc(en)yl, Ar-Cl_~-
alk(en/yn)yl-
heterocycloallc(en)yl, C1_~-alk(en/yn)yloxy-Cl_~-allc(en/yn)yl, C3_$-
cycloallc(en)yloxy-
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C1_~-alle(en/yn)yl, Cl_G-allc(en/yn)yloxy-C3_8-cycloalk(en)yl, C1_~-
alk(en/yn)yloxy-
heterocycloalk(en)yl, Ar-oxy-C1_~-alk(enlyn)yl, Ar-C1_~-alk(en/yn)yloxy-C1_~-
all~(en/yn)yl, Cl_~-alk(en/yn)yloxy-carbonyl-C1_~-allc(en/yn)yl, C3_8-
cycloalk(en)yloxy-
carbonyl-C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl-C1_~-allc(en/yn)yloxy-carbonyl-
C1_~-
5 allc(en/yn)yl, hydroxy-C1_~-alk(en/yn)yl, hydroxy-C3_$-cycloallc(en)yl,
hydroxy-
heterocycloalle(en)yl, hydroxy-C3_8-cycloalk(en)yl-C1_~-allc(enlyn)yl, hydroxy-
C1_~-
alk(en/yn)yl-C3_8-cycloalk(en)yl, hydroxy-C1_~-alk(en/yn)yl-
heterocycloalk(en)yl,
halo-C1_~-allc(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-heterocycloalk(en)yl,
halo-C3_8-
cycloallc(en)yl-C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl-C3_8-cycloalk(en)yl,
halo-C1_
l0 ~-allc(en/yn)yl-heterocycloalk(en)yl, halo-C1_~-alk(en/yn)yl-Ar, halo-C3_8-
cycloalk(en)yl-Ar, halo-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl-Ar, halo-C1_~-
alk(eWyn)yl-C3_g-cycloalk(en)yl-Ar, cyano-Ci_~-alk(en/yn)yl, cyano-C3_8-
cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3_8-cycloalk(en)yl-C1_~-
allc(en/yn)yl, cyano-C1_6-alk(en/yn)yl-C3_8-cycloalk(en)yl, cyano-C1_~-
alk(en/yn)yl-
15 heterocycloalk(en)yl, acyl-C1_~-alk(en/yn)yl, acyl-C3_8-cycloalk(en)yl,
acyl-
heterocycloalk(en)yl, acyl-C3_$-cycloalk(en)yl-C1_~-alk(en/yn)yl, acyl-C1_~-
alk(en/yn)yl-C3_$-cycloalk(en)yl, acyl-C1_~-alk(enlyn)yl-heterocycloalk(en)yl
and -
~12R12'; wherein
R12 and R12' are independently selected from the group consisting of hydrogen,
C1_s-
2o alk(en/yn)yl, C3_$-cycloalk(en)yl, C3_$-cycloalk(en)yl-C1_~-alk(en/yn)yl,
Ar, Ar-C1_s-
alk(en/yn)yl, Ar-C3_$-cycloalk(en)yl, Ar-C3_8-cycloalk(en)yl-C1_~-
alk(en/yn)yl,
hydroxy-C1_~-allc(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3_8-
cycloalk(en)yl-
C1_~-alk(en/yn)yl, halo-Cl_~-alk(en/yn)yl, halo-C3_$-cycloallc(en)yl, halo-
C3_g-
cycloalk(en)yl-C1_~-allc(en/yn)yl, cyano-Cl_~-alk(en/yn)yl, cyano-C3_8-
cycloalk(en)yl
and cyano-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, or
R12 and R12' together with the nitrogen atom to which they are attached form a
4-8
membered saturated or unsaturated ring which optionally contains 1, 2 or 3
further
heteroatoms;
with the proviso that when R3 is NRiZRI2' then q is 0;
and
Y represents a group of formula II, III, IV, V and VI:
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16
~R5)a (R5)b
W W
II I~ ~s)~
(Rs)a
~Rs)f \
W ERs) /
IV V
~Rs)g \
~s)n
VI
wherein
the line represents a bond attaching the group represented by Y to the carbon
atom;
WisOorS;
to ais0,1,2or3;
bis0,1,2,3or4;
cis0orl;
is
dis0, l,2or3;
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a is 0, 1 or 2;
fis0, 1,2,3,4or5;
g is 0, 1, 2, 3 or 4;
his0, l,2or3;and
each RS is independently selected from the group consisting of a C1_~-
alk(en/yz)yl, C3_
l0 8-cycloalk(en)yl, C3_8-cycloalk(en)yl-Ci_~-alk(en/yn)yl, Ar, Ar-Cl_~-
alk(en/yn)yl, acyl,
C1_~-allc(en/yn)yloxy, C3_8-cycloalk(en)yloxy, C3_$-cycloalk(en)yl-Cl_~-
alk(en/yn)yloxy, halogen, halo-C1_6-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl,
halo-C3_8-
cycloalk(en)yl-C1_~-alk(en/yn)yl, -CO-NR6R6~, cyano, cyano-C1_~-alk(en/yn)yl,
cyano-
C3_8-cycloalk(en)yl, cyano-C3_8-cycloalk(en)yl-C1_~-alk(enyn)yl, -NR~R~~, -S-
Rg and -
SOZRB, or
two adjacent RS together with the aromatic group to which they are attached
form a 4-
8 membered ring which optionally contains one or two heteroatoms;
R6 and R6~ are independently selected from the group consisting of hydrogen,
C1_~-
2o alk(en/yn)yl, C3_$-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl
and Ar;
R' and R~~ are independently selected from the group consisting of hydrogen,
C1_~-
alk(en/yn)yl, C3_g-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-allc(enlyn)yl, Ar
and acyl;
and
R8 is selected from the group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_8-
cycloalk(en)yl, C3_8-cycloall~(en)yl-Cl_~-allc(en/yn)yl, Ar and NR~R~';
wherein
R9 and R~~ axe independently selected from the group consisting of hydrogen,
C1_~-
3o allc(en/yn)yl, C3_~-cycloalk(en)yl and C3_8-cycloalk(en)yl-C1_~-
alk(en/yn)yl;
provided that when R8 is NR9R9~ then RS is not -S-R8;
or salts thereof.
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18
One embodiment of the invention relates to compounds of formula I, wherein the
dotted line represents a bond.
Another embodiment of the invention relates to compounds of formula I, wherein
the
dotted line does not represent a bond.
One further embodiment of the invention relates to compounds of formula I,
wherein
Rl and Rl~ are independently selected from the group consisting of hydroxy-
C1_~-
to allc(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-
C1_~-
alk(en/yn)yl, halo-Cl_~-alk(en/yn)yl, halo-C3_$-cycloalk( en)yl, halo-C3_8-
cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano-Cl_~-alk(en/yn)yl, cyano-C3_8-
cycloalk(en)yl
amd cyano-C3_$-cycloalk(en)yl-C1_~-alk(en/yn)yl.
15 Another embodiment of the invention relates to compounds of formula I,
wherein Rl
and Rl~ are independently selected from the group consisting of hydrogen, C1_~
alk(en/yn)yl, C3_8-cycloalk(en)yl and C3_8-cycloalk(en)yl-C1_~-alk(euyn)yl.
A further embodiment of the invention relates to compounds of formula I,
wherein Rl
2o and Rl~ form a 3-~ membered saturated or unsaturated ring which optionally
contains
1 or 2 heteroatoms. In a further embodiment the 3-~ membered saturated or
unsaturated ring is a saturated carbocyclic ring, typically cyclopropyl,
cyclobutyl,
cyclopentyl, or cyclohexyl.
25 Yet another embodiment of the invention relates to compounds of formula I,
wherein
Rl and Rl~ are independently selected from the group consisting of hydrogen
and C1_G-
allc(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
3o at least one of Rl and Rl~ is Cl_~-alk(en/yn)yl, typically Cl_3-
alk(en/yn)yl.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Rl or Rl~ is a hydrogen atom.
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In a preferred embodiment, the invention relates to compounds of formula I,
wherein
at least one of Rl and Rl~ is a hydrogen atom.
In a more preferred embodiment, the invention relates to compounds of formula
I,
wherein both Rl and Rl~ are hydrogen atoms.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
sis0.
to In another preferred embodiment, the invention relates to compounds of
formula I,
wherein s is 1.
In one embodiment, the invention relates to compounds of formula I, wherein s
is 1
andUisO.
In another embodiment, the invention relates to compounds of formula I,
wherein s is
1 and U is S.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 1 and U is 502.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 1 and U is S02NR11.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 1 and U is CO-O.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 1 and U is CO-NRI.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
sis 1 andUisNRI.
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In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 1 and U is SOZNRiI, CO-NRII or NRII and Rll is a hydrogen atom.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
s is 1 and U is NRII and Rll is a hydrogen atom.
One embodiment of the invention relates to compounds of formula I, wherein R2
is
selected from the group consisting of acyl, hydroxy-C1_~-allc(en/yn)yl,
hydroxy-C3_$-
cycloalk(en)yl, hydroxy-C3_g-cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano-C1_~-
1o alk(euyn)yl, cyano-C3_8-cycloalk(en)yl, cyano-C3_~-cycloalk(en)yl-C1_6-
alk(en/yn)yl,
NRioRlo~-C1_~-allc(en/yn)yl, NRioRlo~-C3_8-cycloalk(en)yl and
NRl°Rio~ C3_$_
cycloalk(en)yl-C1_~-alk(en/yn)yl;
with the proviso that when RZ is acyl and s is 1 then U is NRiI, O or S.
15 Another embodiment of the invention relates to compounds of formula I,
wherein R2
is selected from the group consisting of C1_6-alk(en/yn)yl, C3_$-
cycloalk(en)yl and C3_
$-cycloalk(en)yl-C1_~-alk(en/yn)yl.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
2o R2 is selected from the group consisting of Ar, Ar-C1_G-alk(en/yn)yl, Ar-
C3_8-
cycloalk(en)yl and Ar-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
RZ is selected from the group consisting of halogen, halo-C1_6-alk(en/yn)yl,
halo-C3_8-
cycloalk(en)yl, halo-C3_$-cycloalk(en)yl-C1_~-alk(enlyn)yl and cyano;
with the proviso that when RZ is halogen or cyano then s is 0;.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
RZ is NOZ or a hydrogen atom;
3o with the proviso that when R2 is N02 then s is 0; and
with the proviso that when R2 is a hydrogen atom and s is 1 then U is NRII, O
or S.
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21
In one embodiment, the invention relates to compounds of formula I, wherein R2
is
N02 or a hydrogen atom or a halogen atom;
with the proviso that when R2 is N02 or a halogen atom then s is 0; and
with the proviso that when R2 is a hydrogen atom and s is 1 then U is NRII, O
or S.
In another embodiment, the invention relates to compounds of formula I,
wherein s is
0 and RZ is N02 or a halogen atom.
In one embodiment, the invention relates to compounds of formula I, wherein RZ
is a
to hydrogen atom.
In one embodiment, the invention relates to compounds of formula I, wherein s
is 0
and R2 is selected from the group consisting of N02, halogen and cyano.
In another embodiment, the invention relates to compounds of formula I,
wherein s is
0 and R2 is a hydrogen atom.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R2 is C1_~-allc(en/yn)yl, typically C1_3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
RZ is C3_8-cycloalk(en)yl, typically C3_~-cycloalk(en)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R2 is Ar:
In yet another embodiment, the invention relates to compounds of formula I,
wherein
RZ is Ar-C1_~-alk(en/yn)yl, typically Ar-C1_3-allc(enlyn)yl.
3o In yet another embodiment, the invention relates to compounds of formula I,
wherein
RZ is halo-C1_~-alk(en/yn)yl, typically halo-Cl_3-alk(en/yn)yl.
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22
In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 0 and R2 is a halogen atom.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
s is 0 and R2 is cyano.
In another preferred embodiment, the invention relates to compounds of formula
I,
wherein s is 0 and RZ is N02.
to In a preferred embodiment, the invention relates to compounds of formula I,
wherein
R2 is a hydrogen atom; with the proviso that when s is 1 then U is NRII, O or
S.
In one embodiment, the invention relates to compounds of formula I, wherein R2
is a
hydrogen atom; with the proviso that when s is 1 then U is NRII.
In another embodiment, the invention relates to compounds of formula I,
wherein R2
is a hydrogen atom, s is 1, U is NRII and Rll is a hydrogen atom.
In one embodiment, the invention relates to compounds of formula I, wherein
the
group -(U)S R2 is linked to position 6 of the indole or indoline.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
the group -(U)S R2 is linked to position 4 of the indole or indoline.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
X is CO.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
X is 502.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
q is 0.
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23
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
q is 1.
In one embodiment, the invention relates to compounds of formula I, wherein q
is 1
and Z is a sulphur atom.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
q is 1 and Z is an oxygen atom.
to
In one embodiment, the invention relates to compounds of formula I, wherein X
is
S02 and q is 0.
In one embodiment, the invention relates to compounds of formula I, wherein X
is
15 COandqis0.
In one embodiment, the invention relates to compounds of formula I, wherein X
is
CO, q is 1 and Z is an oxygen atom.
2o In one embodiment, the invention relates to compounds of formula I, wherein
R3 is
selected from the group consisting of C1_~-alk(en/yn)yl-heterocycloalk(en)yl,
Ar-
heterocycloalk(en)yl, Ar-Cl_~-alk(en/yn)yl-heterocycloalk(en)yl, C1_~-
alk(en/yn)yloxy-heterocycloalk(en)yl, C1_~-alk(en/yn)yloxy-carbonyl-Cl_~-
alk(en/yn)yl, C3_$-cycloalk(en)yloxy-carbonyl-Cl_6-alk(en/yn)yl, C3_8-
cycloalk(en)yl-
2s C1_~-alk(en/yn)yloxy-carbonyl-C1_~-alk(en/yn)yl, hydroxy-C1_6-alk(enlyn)yl,
hydroxy-
C3_8-cycloallc(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3_8-
cycloallc(en)yl-C1_~-
alk(en/yn)yl, hydroxy-C1_~-alk(en/yn)yl-C3_8-cycloallc(en)yl, hydroxy-Cl_~-
alk(en/yn)yl-heterocycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C1_~-
allc(euyn)yl-
heterocycloalk(en)yl, cyano-C1_~-alk(en/yn)yl, cyano-C3_$-cycloalk(en)yl,
cyano-
3o heterocycloalk(en)yl, cyano-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, cyano-
C1_~-
allc(en/yn)yl-C3_8-cycloalk(en)yl, cyano-C1_~-alk(en/yn)yl-
heterocycloalk(en)yl, acyl-
C1_~-allc(en/yn)yl, acyl-C3_$-cycloalk(en)yl, acyl-heterocycloall~(en)yl, acyl-
C3_8-
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24
cycloallc(en)yl-C1_~-alk(en/yn)yl, acyl-C1_~-alk(enlyn)yl-C3_8-cycloalk(en)yl
and acyl-
C 1 _G-alk(en/yn)yl-heterocyclo alk(en)yl.
In another embodiment, the invention relates to compounds of formula I,
wherein R3
is selected from the group consisting of C1_~-allc(euyn)yl, C3_8-
cycloalk(en)yl,
heterocycloalk(en)yl, C3_$-cycloalk(en)yl-Cl_6-alk(en/yn)yl, C1_~-alk(en/yn)yl-
C3_g-
cycloalk(en)yl, Ar, Ar-C1_~-alk(en/yn)yl, Ar-C3_8-cycloalk(en)yl, Ar-C3_8-
cycloalk(en)yl-C1_~-all~(en/yn)yl, Ar-C1_~-alk(enlyn)yl-C3_$-cycloalk(en)yl,
C1_~-
alk(en/yn)yloxy-C1_G-alk(en/yn)yl, C3_8-cycloalk(en)yloxy-Cl_~-alk(en/yn)yl,
C1_~-
to alk(enlyn)yloxy-C3_8-cycloalk(en)yl, Ar-oxy-C1_~-alk(enlyn)yl, Ar-C1_~-
allc(enlyn)yloxy-C1_~-allc(en/yn)yl, halo-C1_6-alk(en/yn)yl, halo-C3_$-
cycloalk(en)yl,
halo-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl-C3_8-
cycloalk(en)yl,
halo-Cl_~-alk(en/yn)yl-Ar, halo-C3_$-cycloalk(en)yl-Ar, halo-C3_$-
cycloalk(en)yl-C1_~-
allc(en/yn)yl-Ar, halo-C1_~-alk(en/yn)yl-C3_8-cycloalk(en)yl-Ar and -NR12R12'~
15 with the proviso that when R3 is NRl2Ria° then q is 0.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is selected from the group consisting of C1_6-alk(en/yn)yl, C3_8-
cycloalk(en)yl,
heterocycloalk(en)yl, C3_8-cycloalk(en)yl-Cl_~-alk(en/yn)yl, C1_~-alk(en/yn)yl-
C3_8-
20 cycloallc(en)yl, Ar, Ar-C1_~-alk(en/yn)yl, Ar-C3_8-cycloalk(en)yl, Ar-C3_$-
cycloallc(en)yl-C1_~-alk(en/yn)yl, Ar-C1_6-alk(enlyn)yl-C3_8-cycloalk(en)yl,
Ar-oxy-C1_
~-all~(euyn)yl, Ar-C1_G-alk(en/yn)yloxy-Cl_~-alk(en/yn)yl, halo-Cl_G-
alk(en/yn)yl,
halo-C3_$-cycloalk(en)yl, halo-C3_8-cycloalk(en)yl-C1_~-allc(en/yn)yl, halo-
Cl_~-
alk(en/yn)yl-C3_8-cycloalk(en)yl and -NR12Ri2';
25 with the proviso that when R3 is NRl2Ria° then q is 0.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is selected from the group consisting of C1_~-allc(en/yn)yl, C3_8-
cycloalk(en)yl, C3_
8-cycloallc(en)yl-C1_~-alk(en/yn)yl, C1_~-alk(en/yn)yl-C3_8-cycloall~(en)yl,
Ar, Ar-C1_~-
3o allc(en/yn)yl, Ar-C3_$-cycloallc(en)yl, Ar-C3_8-cycloalk(en)yl-C1_~-
alk(enlyn)yl, Ar-C1_
~-allc(en/yn)yl-C3_$-cycloallc(en)yl, Ar-oxy-Cl_~-alk(en/yn)yl, Ar-C1_6-
alk(en/yn)yloxy-
C1_~-allc(en/yn)Yl and -NR12R12';
with the proviso that when R3 is NR12R12' then q is 0.
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In a preferred embodiment, the invention relates to compounds of formula I,
wherein
R3 is selected from the group consisting of C1_~-alk(euyn)yl, C3_g-
cycloalk(en)yl,
heterocycloalk(en)yl, Ar, Ar-Cl_~-alk(en/yn)yl, Ar-oxy-Cl_~-alk(en/yn)yl, Ar-
C1_~-
allc(en/yn)yloxy-C1_~-alk(enlyn)yl, halo-Cl_G-alk(en/yn)yl and -NR12R12~;
with the proviso that when R3 is NR1zR12~ then q is 0.
In another preferred embodiment, the invention relates to compounds of formula
I,
wherein R3 is selected from the group consisting of Cl_~-alk(en/yn)yl, C3_8-
cycloallc(en)yl, Ar, Ar-C1_~-alk(en/yn)yl, Ar-oxy-C1_~-alk(en/yn)yl, Ar-C1_~-
to alk(enlyn)yloxy-C1_~-alk(en/yn)yl and -NRl2Rlz~;
with the proviso that when R3 is NR12R12' then q is 0.
In another preferred embodiment, the invention relates to compounds of formula
I,
wherein R3 is C1_6-all~(en/yn)yl, typically Cl_3-alk(en/yn)yl.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is C3_8-cycloalk(en)yl.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is C3_$-cycloalk(en)yl-C1_~-alk(eWyn)yl.
In yetanother preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is heterocycloalk(en)yl.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is Ar.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is Ar-Cl_~-allc(en/yn)yl.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is Cl_~-allc(en/yn)yl-oxy-C1_~-alk(en/yn)yl.
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26
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is Ar-oxy-C1_~-alk(en/yn)yl.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is Ar-C1_~-allc(en/yn)yloxy-C1_~-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is C1_~-alk(euyn)yloxy-carbonyl-C1_6-alk(en/yn)yl.
l0 In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is halo-C1_~-allc(enlyn)yl, such as halo-C1_3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is halo-C1_~-alk(enlyn)yl-Ar, such as halo-C1_3-alk(en/yn)yl-Ar.
In yet another preferred embodiment, the invention relates to compounds of
formula I,
wherein R3 is -NR12R12', and q is 0.
In one embodiment, the invention relates to compounds of formula I, wherein X
is
2o CO, q is 1, Z is an oxygen atom and R3 is selected from the group
consisting of Cl_~-
alk(enlyn)yl, C3_$-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl, C1_~-
allc(en/yn)yl-C3_$-cycloalk(en)yl, Ar-C1_~-alk(en/yn)yl, Ar-C3_g-
cycloalk(en)yl, Ar-C3_
$-cycloallc(en)yl-C1_~-alk(en/yn)yl, Ar-Cl_6-alk(en/yn)yl-C3_8-cycloalk(en)yl,
Ar-oxy-
C1_~-alk(enlyn)yl, Ar-C1_~-alk(en/yn)yloxy-C1_~-alk(en/yn)yl, halo-C1_~-
alk(en/yn)yl,
halo-C3_8-cycloalle(en)yl, halo-C3_$-cycloalk(en)yl-C1_~-alk(en/yn)yl and halo-
C1_~-
alk(enlyn)yl-C3_8-cycloallc(en)yl.
In another embodiment, the invention relates to compounds of formula I,
wherein X is
CO, q is 1, Z is an oxygen atom and R3 is selected from the group consisting
of C1_G-
3o allc(en/yn)yl, Ar-C1_~-alk(en/yn)yloxy-C1_6-alk(en/yn)yl and halo-Cl_~-
alk(en/yn)yl.
In one further embodiment, the invention relates to compounds of formula I,
wherein
X is CO, q is 0 and R3 is selected from the group consisting of C1_~-
alk(en/yn)yl, C3_8-
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cycloall~(en)yl, C3_g-cycloalk(en)yl-C1_6-alk(en/yn)yl, C1_6-alk(en/yn)yl-C3_8-
cycloalk(en)yl, heterocycloalk(en)yl, Ar, Ar-C1_~-allc(en/yn)yl, Ar-C3_8-
cycloalk(en)yl,
Ar-C3_$-cycloalk(en)yl-C1_~-alk(en/yn)yl, Ar-C1_~-alle(en/yn)yl-C3_$-
cycloalk(en)yl,
Ar-oxy-C1_~-alk(en/yn)yl, Ar-C1_~-ally(en/yn)yloxy-C1_~-allc(en/yn)yl and -
NRizRl2'.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
X is CO, q is 0 and R3 is selected from the group consisting of C1_~-
alk(enlyn)yl, C3_8-
cycloalk(en)yl, heterocycloalk(en)yl, Ar, Ar-C1_~-alk(en/yn)yl, Ar-oxy-Cl_~-
alk(en/yn)yl and -NRlzRiz~.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
X is SO2, q is 0 and R3 is selected from the group consisting of C1_~-
alk(en/yn)yl, C3_
8-cycloalk(en)yl, C3_g-cycloalk(en)yl-Cl_~-alk(en/yn)yl, Cl_~-alk(enlyn)yl-
C3_8-
cycloalk(en)yl, Ar-C1_~-alle(en/yn)yl, Ar-C3_8-cycloalk(en)yl, Ar-C3_$-
cycloalk(en)yl-
C1_~-alk(enlyn)yl and Ar-C1_~-alk(en/yn)yl-C3_8-cycloalk(en)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
X is SO2, q is 0 and R3 is C1_~-alk(en/yn)yl or Ar-C1_~-alk(en/yn)yl.
In one embodiment, the invention relates to compounds of formula I, wherein R3
is
NRizRlz~ and q is 0 and wherein Rlz and Rlz~ are independently selected from
the
group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-
cycloallc(en)yl-C1_~-alk(enlyn)yl, Ar, Ar-C1_~-alk(en/yn)yl, Ar-C3_$-
cycloalk(en)yl and
Ar-C3 _$-cyclo alk(en)yl-C 1 _~-alk(en/yn)yl.
In another embodiment, the invention relates to compounds of formula I,
wherein R3
is NRlzRiz~ and q is 0 and wherein Rlz and Rlz~ are independently selected
from the
group consisting of hydrogen, Cl_~-allt(en/yn)yl, Ar and Ar-C1_~-alk(en/yn)yl
or
wherein Rlz and Rlz~ together with the nitrogen atom to which they are
attached form
a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or
3
further heteroatoms.
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In a preferred embodiment, the invention relates to compounds of formula I,
wherein
R3 is NR1zR12' and q is 0 and wherein Rlz and Rlz~ are independently selected
from
the group consisting of hydrogen, C1_~-alk(en/yn)yl, Ar and Ar-C1_~-
alk(en/yn)yl.
In another preferred embodiment, the invention relates to compounds of formula
I,
wherein R3 is NRlzRiz~ and q is 0 and wherein Rlz and Rlz~ together with the
nitrogen
atom to which they are attached form a 4-8 membered saturated or unsaturated
ring
which optionally contains 1, 2 or 3 further heteroatoms.
In one embodiment, the invention relates to compounds of formula I, wherein R3
is
NRizRlz~ and q is 0 and wherein at least one of Rlz and Rlz~ is a hydrogen
atom.
In another embodiment, the invention relates to compounds of formula I,
wherein R3
is NRlzRiz~ and q is 0 and at least one of Rlz and Rlz~ is C1_6-alk(enlyn)yl,
typically
C1_3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is I~R12R12' and q is 0 and one of Rlz and Rlz~ is Ar.
2o In yet another embodiment, the invention relates to compounds of formula I,
wherein
R3 is NR1zR12' and q is 0 and one of Riz and Rlz~ is Ar-C1_~-alk(en/yn)yl,
typically
Ar-C 1 _3-all~(en/yn)Yl.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula II, III, V, ~;XX or XXXI.
In one embodiment, the invention relates to compounds of formula I, wherein Y
is of
formula III or IV.
3o In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula II or V.
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In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula V or ~;XXI.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula II or III and W is a sulphur atom.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula II or III and W is an oxygen atom.
l0 In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula V.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula ~;XX and T is NH.
1s
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula ~!:XX and T is a nitrogen atom or an oxygen atom.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
20 Y is of formula ~S;~XI and L is a nitrogen atom.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
Y is of formula XXXI and L is C or CH.
2s In one embodiment, the invention relates to compounds of formula I, wherein
each RS
is independently selected from the group consisting of Ar-Cl_~-alk(en/yn)yl,
acyl, -
CO-NR~R6~, cyano, cyano-C1_~-alk(en/yn)yl, cyano-C3_8-cycloalk(en)yl and cyano-
C3_
8-cycloallc(en)yl-C1_~-allc(en/yn)yl.
3o In another embodiment, the invention relates to compounds of formula I,
wherein
each RS is independently selected from the group consisting of Cl_~-
allc(enlyn)yl, C3_$-
cycloallc(en)yl, C3_$-cycloallc(en)yl-Cl_~-allc(enlyn)yl, Ar, Cl_~-
alk(en/yn)yloxy, C3_8-
cycloallc(en)yloxy, C3_$-cycloalk(en)yl-C1_G-allc(enlyn)yloxy, halogen, halo-
C1_~-
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all~(en/yn)yl, halo-C3_8-cycloalle(en)yl, halo-C3_8-cycloallc(en)yl-C1_~-
alk(en/yn)yl, -
NR~R~~, -S-R8 and -S02Rg; or
two adj acent RS together with the aromatic group to which they are attached
form a 4-
8 membered ring which optionally contains one or two heteroatoms.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
each RS is independently selected from the group consisting of C1_~-
alk(en/yn)yl, C3_$-
cycloalk(en)yl, C3_8-cycloalk(en)yl-Cl_6-alk(en/yn)yl, Ar, C1_~-
alk(en/yn)yloxy, C3_$-
cycloallc(en)yloxy, C3_8-cycloalk(en)yl-C1_6-alk(en/yn)yloxy, -NR~R~~, -S-Rg
and -
to S02R8; or
two adjacent RS together with the aromatic group to which they are attached
form a 4-
8 membered ring which optionally contains one or two heteroatoms.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
15 each RS is independently selected from the group consisting of halogen,
halo-C1_~-
all~(en/yn)yl, halo-C3_8-cycloalk(en)yl and halo-C3_$-cycloalk(en)yl-C1_6-
alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
each RS is independently selected from the group consisting of C1_6-
allc(en/yn)yl, C3_$-
2o cycloallc(en)yl, C3_8-cycloalk(en)yl-C1_6-alk(en/yn)yl, Ar, Ar-thio, Ar-
oxy, halogen,
halo-C1_~-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-C3_8-cycloalk(en)yl-
C1_~-
alk(en/yn)yl, or
two adjacent RS together with the aromatic group to which they are attached
form a 4-
8 membered ring which optionally contains one or two heteroatoms.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
each RS is independently selected from the group consisting of C1_~-
alk(en/yn)yl, Ar,
Ar-thio, Ar-oxy, halogen, halo-C1_~-alk(en/yn)yl, or
two adjacent RS together with the aromatic group to which they are attached
form a 4-
8 membered ring which optionally contains one or two heteroatoms.
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In another preferred embodiment, the invention relates to compounds of formula
I,
wherein each RS is independently selected from the group consisting of halogen
and
halo-C 1 _~-alk(en/yn)yl.
In an embodiment, the invention relates to compounds of formula I, wherein at
least
one substituent R5 is a halogen atom.
In another embodiment, the invention relates to compounds of formula I,
wherein at
least one substituent RS is halo-C1_6-alk(en/yn)yl, typically halo-C1_3-
alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is C1_~-alk(enlyn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is Ar.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is Ar-thio.
2o In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is Ar-oxy.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is C1_~-alk(en/yn)yloxy.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -NR~R~~.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -S-R8.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -S02R8.
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In yet another embodiment, the invention relates to compounds of formula I,
wherein
two adjacent RS together with the aromatic group form a 4-8 membered ring,
which
optionally contains one or two heteroatoms.
In a preferred embodiment, the invention relates to compounds of formula I,
wherein
two adjacent RS together form
-(CHz)"~-CHz-, -CH=CH-(CHz)m~-, -CHz-CH=CH-(CHz)p~-,-CH=CH-CH=CH-,
-(CHz)"~-O-, -O-(CHz)m~-O-, -CHz-O-(CHz)p°-O-, -CHz-O-CHz-O-CHz-,
-(CHz)"~-S-, -S_(CHz)m~-S-, -CHz-S-(CHz)p°-S-~ -CH2-S-CHz-S-CHz-~
-(CHz)"~ NH- , NH-(CHz)m~ NH-, -CHz-NH-(CHz)r'-NH-, - CH=CH-NH-,
-O-(CHz)m~-NH-, -CHz-O-(CHz)p,_~_ or _O_(CHz)p'-WCHz-~ -S-(CHz)m~-~-
-N=CH-NH-, -N=CH-O- or -N=CH-S-, wherein m' is 1, 2 or 3, n' is 2, 3 or 4 and
p'
islor2.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
two adjacent RS together form -CHz-O-CHz-.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
two adj acent RS together form -CH=CH-CH=CH-.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
two adj acent RS together form -O-CHz-O-.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
two adjacent RS together form-O-CHz-O-CHz-.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -NR~R~~; and wherein R' and R~~ are
independently
selected from the group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_8-
cycloalk(en)yl
3o and C3_8-cycloallc(en)yl-C1_~-alk(en/yn)yl.
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In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -NR~R~~; and wherein R' and R~~ are
independently
selected from the group consisting of hydrogen and Cl_~-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -NR~R~~; and wherein both R' and R~~ are C1_~-
allc(en/yn)yl, typically Cl_3-alk(en/yn)yl.
to In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -S-R8 or -S02Rg; and wherein Rg is selected
from the
group consisting of hydrogen, C1_~-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-
cycloalk(en)yl-C1_~-alk(en/yn)yl and Ar .
In yet another embodiment, the invention relates to compounds of formula I,
wherein
at least one substituent RS is -S-R8 or -S02R8; and wherein R8 is selected
from the
group consisting of Ci_~-alk(en/yn)yl and Ar .
2o One embodiment of the invention relates to compounds of formula I, wherein
s is 0
andqis0.
Another embodiment of the invention relates to compounds of formula I, wherein
R2
is a hydrogen atom and X is CO.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
sisOandXisCO.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
3o R2 is a hydrogen atom and q is 0.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
q is 0 and X is CO.
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One embodiment of the invention relates to compounds of formula I, wherein the
total
number of Ar-groups in the substituents R2, R3 and RS equals to 0, 1, 2, or 3,
typically
0 or 1.
Another embodiment of the invention relates to compounds of formula I wherein
neigther R2, R3 or RS comprises an Ar-group.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
the total number of Ar-groups in the substituents R2, R3 and RS equals to 1.
to
Yet another embodiment of the invention relates to compounds of formula I,
wherein
the total number of Ar-groups in the substituents R2, R3 and R5 equals to 2.
One embodiment of the invention relates to compounds of formula I, wherein R3
is
15 not CH3 when X is S02 and q is 0.
Another embodiment of the invention relates to compounds of formula I, wherein
X-
(Z)q R3 is not SOZ-CH3 when Y is of formula V.
2o Yet another embodiment of the invention relates to compounds of formula I,
wherein
R3 is NRl2Rlz~ and both R12 and Rl2~is different from Ar.
Yet another embodiment of the invention relates to compounds of formula I,
wherein
R3 is NR12R12' and one of R12 and Rl2~is Ar, with the proviso that Ar is
different from
25 quinoline or phenyl.
Another embodiment of the invention relates to compounds of formula I, wherein
Y is
not of formula V when X is CO and q is 0 and R3 is NR12R12' and one of R12 and
Rl2~is Ar, typically quinoline or phenyl.
In another embodiment, the compound of formula I is not:
N-[1-(phenylmethyl)-1H-indol-5-yl]-Methanesulfonamide;
N-[ 1-[(4-fluorophenyl)methyl]-1 H-indol-5-yl]-Methanesulfonamide;
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N-[2, 3-dihydro-1-(phenylmethyl)-1 H-indol-5-yl]-Methanesulfonamide;
N-[1-(phenylmethyl)-1H-indol-5-yl]-N'-4-quinolinyl-Urea;
N-[1-(phenylmethyl)-1H-indol-5-yl]-N'-4-quinolinyl-Urea; or
1-( 1-b enzyl-5-indolinyl)-3-phenyl-Urea.
5
One aspect of the invention, relates to compounds of general formula VII and
salts
thereof:
3
~ X ~ (z)9\ R
~5)f
(VII)
1 o wherein the dotted line, f, q, s, U, X, Z, Rl, Rl', Rz, R3 and RS are as
defined under
formula I. Any of the embodiments related to formula I are also embodiments of
formula VII.
In one embodiment, the invention relates to compounds of the general formula
VII,
1 s wherein f is 0.
In another embodiment, the invention relates to compounds of the general
formula
VII being substituted by one substituent R5, such as in the orto-, meta- or
para-
position.
In a preferred embodiment, the invention relates to compounds of the general
formula
VII, which are substituted by one substituent RS in the para-position.
Rz
!r
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36
In one embodiment, the invention relates to compounds of the general formula
VII
being substituted by two independently selected RS substituents, such as in
the ortho-
and para-position, in the meta- and para-position and in the orto- and meta-
position.
In another embodiment, the invention relates to compounds of the general
formula
VII being substituted by three independently selected RS substituents.
Another aspect of the invention relates to compounds of the general formula
VIII or
l0 salts thereof:
R2
~s
\ N\ ~ (Z)a\
~ X R3
Ri N
(R5)g / ~ \
\ Ri,
(RS)h (VIII)
wherein the dotted line h
g, , q, s, U, X, Z, Rl, Rl , R2, R3 and RS are as defined under
formula I. Any of the embodiments related to formula I are also embodiments of
formula VIII.
In one embodiment, the invention relates to compounds of the general formula
VIII,
wherein the nitrogen atom is attached to position 1 of the naphtyl group via
the
methylene group.
In another embodiment, the invention relates to compounds of the general
formula
VIII, wherein the nitrogen atom is attached to position 2 of the naphtyl group
via the
methylene group.
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37
In yet another embodiment, the invention relates to compounds of the general
formula
VIII, wherein g is 0, 1, 2 or 3, typically 0, 1 or 2.
In yet another embodiment, the invention relates to compounds of the general
formula
VIII, wherein h is 0, 1 or 2, typically 0 or 1.
In yet another embodiment, the invention relates to compounds of the general
formula
VIII, wherein g + h equals to 0, 1, 2 or 3.
to In yet another embodiment, the invention relates to compounds of the
general formula
VIII, wherein both g and h are 0.
In yet another embodiment, the invention relates to compounds of the general
formula
VIII being substituted by one substituent R5.
In yet another embodiment, the invention relates to compounds of the general
formula
VIII being substituted by two independently selected RS substituents.
In yet another embodiment, the invention relates to compounds of the general
formula
VIII being substituted by three independently selected RS substituents.
Yet another aspect of the invention relates to compounds of the general
formula IX or
salts thereof:
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38
Rz
3
~ x ~ (z)q\ R
~5)
(IX)
wherein the dotted line, a, q, s, U, X, Z, Rl, Rl ~, R2, R3 and RS are as
defined under
formula I. Any of the embodiments related to formula I are also embodiments of
formula IX.
In an embodiment, the invention relates to compounds of the general formula
IX,
wherein the nitrogen atom is attached to position 2 of the heteroaromatic
group via the
methylene group.
In another embodiment, the invention relates to compounds of the general
formula IX,
wherein the nitrogen atom is attached to position 3 of the heteroaromatic
group via the
methylene group.
In yet another embodiment, the invention relates to compounds of the general
formula
IX, wherein W is an oxygen atom.
In a preferred embodiment, the invention relates to compounds of the general
formula
IX, wherein W is a sulphur atom.
In another embodiment, the invention relates to compounds of the general
formula IX,
wherein a is 0, 1 or 2.
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(U)s
39
In yet another embodiment, the invention relates to compounds of the general
formula
IX, wherein a is 0.
In yet another embodiment, the invention relates to compounds of the general
formula
IX being substituted by one substituent R5, such as in position 5.
In yet another embodiment, the invention relates to compounds of the general
formula
IX being substituted by two independently selected RS substituents.
to In an embodiment, the invention relates to compounds of the general formula
IX,
wherein the nitrogen atom is attached to position 2 via the methylene group
and
wherein a substituent RS is attached to position 5 of the heteroaromatic
group.
Yet another aspect of the invention relates to compounds of the general
formula X or
salts thereof:
R2
~RS)v
,
~ N~ X ~ ~z)9~ R3
,
Ri N
~Ri,
W
(RS)~ (X)
wherein the dotted line, b, c, q, s, U, X, Z, Rl, Rl ~, R2, R3 and RS are as
defined under
2o formula I. Any of the embodiments related to formula I are also embodiments
of
formula X.
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In an embodiment, the invention relates to compounds of the general formula X,
wherein the nitrogen atom is attached to position 2 of the heteroaromatic
group via the
methylene group.
5 In another embodiment, the invention relates to compounds of the general
formula X,
wherein the nitrogen atom is attached to position 3 of the heteroaromatic
group via the
methylene group.
In yet another embodiment, the invention relates to compounds of the general
formula
10 X, wherein W is an oxygen atom.
In yet another embodiment, the invention relates to compounds of the general
formula
X, wherein W is a sulphur atom.
15 In yet another embodiment, the invention relates to compounds of the
general formula
X, wherein b is 0, 1, 2 or 3, typically 0, 1 or 2.
In yet another embodiment, the invention relates to compounds of the general
formula
X, wherein c is 0 or 1, typically 0.
In yet another embodiment, the invention relates to compounds of the general
formula
X, wherein b + c equals to 0, 1, 2, 3 or 4.
In yet another embodiment, the invention relates to compounds of the general
formula
X, wherein both b and c are 0.
In yet another embodiment, the invention relates to compounds of the general
formula
X, wherein b + c equals to 1. In one aspect thereof b is 1 and c is 0. In
another aspect
thereof b is 0 and c is 1.
In yet another embodiment, the invention relates to compounds of the general
formula
X being substituted by one substituent R5.
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In yet another embodiment, the invention relates to compounds of the general
formula
X being substituted by two independently selected RS substituents.
In yet another embodiment, the invention relates to compounds of the general
formula
X being substituted by three independently selected RS substituents.
Yet another aspect of the invention relates to compounds of the general
formula XI or
salts thereof:
3
~ X ~ (z)q\ R
~s
~Rs)a
R2
~s)e
wherein the dotted line, d, e, q, s, U, X, Z, Rl, Rl~, R2, R3 and RS are as
defined under
formula I. Any of the embodiments related to formula I are also embodiments of
formula XI.
In an embodiment, the invention relates to compounds of the general formula
XI,
wherein the nitrogen atom is attached to position 4 of the heteroaromatic
group via the
methylene group.
2o In another embodiment, the invention relates to compounds of the general
formula XI,
wherein the nitrogen atom is attached to position 5 of the heteroaromatic
group via the
methylene group.
R2,
\ ~~)s,
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In an embodiment, the invention relates to compounds of the general formula
XI,
wherein the nitrogen atom is attached to position 6 of the heteroaromatic
group via the
methylene group.
In another embodiment, the invention relates to compounds of the general
formula XI,
wherein the nitrogen atom is attached to position 7 of the heteroaromatic
group via the
methylene group.
In yet another embodiment, the invention relates to compounds of the general
formula
l0 XI, wherein W is an oxygen atom.
In yet another embodiment, the invention relates to compounds of the general
formula
XI, wherein W is a sulphur atom.
In yet another embodiment, the invention relates to compounds of the general
formula
XI, wherein d is 0, 1 or 2, typically 0 or 1.
In yet another embodiment, the invention relates to compounds of the general
formula
XI, wherein a is 0, 1 or 2.
In yet another embodiment, the invention relates to compounds of the general
formula
XI, wherein d + a is 0, 1, 2, 3 or 4.
In yet another embodiment, the invention relates to compounds of the general
formula
XI, wherein both d and a are 0.
In yet another embodiment, the invention relates to compounds of the general
formula
XI being substituted by one substituent R5.
3o In yet another embodiment, the invention relates to compounds of the
general formula
XI being substituted by two independently selected RS substituents.
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In yet another embodiment, the invention relates to compounds of the general
formula
XI being substituted by three independently selected RS substituents.
Yet another aspect of the invention relates to compounds of the general
formula
XXXII or salts thereof
R2
~s
TT
(RS)~
X / (Z)q \ R
3
(XXXII)
wherein the dotted line, j, q, s, T, U, X, Z, Rl, Rl~, R2, R3 and R5 are as
defined under
formula I. Any of the embodiments related to formula I are also embodiments of
to formula XXXII.
In an embodiment, the invention relates to compounds of the general formula
~!:XXII,
wherein the nitrogen atom is attached to the position indicated with 1 of the
heteroaromatic group via the methylene group.
In another embodiment, the invention relates to compounds of the general
formula
XXXII, wherein the nitrogen atom is attached to the position indicated with 2
of the
heteroaromatic group via the methylene group.
2o In another embodiment, the invention relates to compounds of the general
formula
~:XXII, wherein the nitrogen atom is attached to the position indicated with 3
of the
heteroaromatic group via the methylene group.
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44
In yet another embodiment, the invention relates to compounds of the general
formula
XXXII, wherein T is an oxygen atom.
In yet another embodiment, the invention relates to compounds of the general
formula
XXXTI, wherein T is a nitrogen atom.
In yet another embodiment, the invention relates to compounds of the general
formula
~:XXII, wherein T represents NH.
to In another embodiment, the invention relates to compounds of the general
formula
~;XXII, wherein j is 0, 1, 2 or 3.
In yet another embodiment, the invention relates to compounds of the general
formula
XXXII, wherein j is 0.
In yet another embodiment, the invention relates to compounds of the general
formula
XXXII being substituted by at least one substituent R5. In one aspect thereof,
the
compound of the general formula ~:XXII is substituted in the position
indicated with
1. In smother aspect thereof, the compound of the general formula XXXII is
2o substituted in the position indicated with 2. In yet another aspect
thereof, the
compound of the general formula ~:XXII is substituted in the position
indicated with
3. In yet another aspect thereof, T represents a nitrogen atom at which the
compound
of the general formula ~;XYII is substituted.
In yet another embodiment, the invention relates to compounds of the general
formula
XXXII being substituted by two independently selected R5 substituents.
In yet another embodiment, the invention relates to compounds of the general
formula
_X_X_XTI being substituted by two or three independently selected R5
substituents.
In yet another embodiment, the invention relates to compounds of the general
formula
XXXII being substituted by three independently selected RS substituents.
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One aspect of the invention, relates to compounds of general formula ~;XXIII
and
salts thereof
Ra
~S
3
~ x ~ (z)q \ R
(RSO<
(XXXIII)
5 wherein the dotted line, k, q, s, L, U, X, Z, Rl, Rl~, RZ, R3 and RS are as
defined
iulder formula I. Any of the embodiments related to formula I are also
embodiments
of formula XXXIII.
In one embodiment, the invention relates to compounds of the general formula
10 _X_X_XTII, wherein k is 0.
In another embodiment, the invention relates to compounds of the general
formula
XXXIII being substituted by one substituent R5, such as in the position being
onto,
meta or para to the nitrogen atom.
In a preferred embodiment, the invention relates to compounds of the general
formula
XXXIII, which are substituted by one substituent RS in the position being para
to the
nitrogen atom.
2o In one embodiment, the invention relates to compounds of the general
formula
~;XXIII being substituted by two independently selected RS substituents, such
as in
the in the positions being ortho and para to the nitrogen atom, or in the
positions being
meta and para to the nitrogen atom, or in the positions being orto and meta to
the
nitrogen atom.
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In another embodiment, the invention relates to compounds of the general
formula
~S;XXIII being substituted by three independently selected RS substituents.
In one embodiment of the invention, the compounds of the following list and
salts
thereof are preferred:
N ~4-Chlo~~o-1-(4-t~ifluoromethylbenzyl)-2, 3-dihydno-1 H indol-5 ylJ-3, 3-
dimethylbuty~~amide,
1 o N ~4-Chlono-1-(5-chlorothiophen-2 ylmethyl)-2, 3-dihydno-1 H indol-S ylJ-
3, 3-
dimetlzylbuty~an2ide,
~l -(4-Fluonobenzyl)-2, 3-dihydno-1 H indol-S ylJ-ca~~bamic acid p~~opyl
estef;
N ~1-(4-Fluo~obenzyl)-2,3-dihyd~o-IH indol-5 ylJ-C phenyl-methanesulfonamide,
4-Fluo~o-N ~l -(4 fZuorobenzyl)-2, 3-dihydno-1 H indol-5 ylJ-benzamide,
15 N ~1-(4-Fluof°oberazyl)-2, 3-dihydno-1 H indol-5 ylJ-3, 3-
dimethylbutyramide,
N ~1-(4-Fluorobenzyl)-2, 3-dihydf°o-1 H indol-5 ylJ-2-thioplaen-2
ylacetamide,
N ~1-(4-Fluo~obenzyl)-2, 3-dilaydno-1 H indol-5 ylJ-2-(4 fluo~ophenyl)-
acetarnide,
3-~l-(5-Chlo~othiopheyz.-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-l,l-
diisop~opylunea,
Mo~pholine-4-carboxylic acid ~1-(5-chlorothiophen-2 ylmetlayl)-2,3-dihydro-IH
20 indol-5 ylJ-amide,
Pyrnolidine-1-carboxylic acid ~1-(5-chlo~othiophen-2 ylnZethyl)-2,3-
dihyd~°o-1H
indol-5 ylJ-amide,
~1-(5-ChlonothioplZen-2 ylmetlzyl)-2,3-dihydro-1H indol-5-ylJ-canbamic acid 2-
berazyloxyetlayl ester,
25 3-~1-(5-Cl2lorothiophen-2 ylrnethyl)-2, 3-dihydr~o-I H indol-S ylJ-1-
naetlzyl-1-
propylurea,
~1-(5-Chlor~otlziophen-2 ylmethyl)-2,3-dihyd~o-1H indol-5 ylJ-carbamic acid
tert-
butyl ester-,
N ~1-(5-Chlor~othiophen-2 ylmetlZyl)-~,3-dihydro-IH indol-5 ylJ-C phenyl-
30 methanesulfonamide,
Butafze-1-sulfonic acid ~1-(S-chlonothiophen-~ ylmethyl)-2,3-dihydr~o-IH
iradol-5 ylJ-
amide,
N ~1-(S-Clalo~othiophen-~ ylrnethyl)-2,3-dihydno-IH iradol-5 ylJ-4
fluof~obenzamide,
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47
N ~l-(5-Chloz~othioplzen-2 ylznethyl)-2,3-dihydz~o-IH indol-5 ylJ-2,2-
dimethylpt~opionamide,
N ~1-(5-Chlo>~othiophezz-2-ylmethyl)-2,3-dihydf~o-1H izzdol-5 ylJ-2-
phenoxyacetamide,
N ~l-(5-Chlot~otlziophen-2 ylmetlzyl)-2,3-dihydro-IH indol-5 ylJ-3,3-
ditnethylbutyramide,
N ~1-(S-Clzlorothiophen-2 ylmethyl)-2, 3-dihydYO-IH irzdol-5 ylJ-butyt~amide,
Cyclopentanecaz~boxylic acid ~1-(5-chloz~othiophezt-2 ylznethyl)-2,3-dihyd~o-
IH indol-
S ylJ-amide,
to N ~l-(5-Chlot°othiophen-2 yltnethyl)-2,3-dihydro-IH indol-5 ylJ-2-
thiophezt-2-
ylacetantide,
N ~l-(5-Clzlo~othiophezz-2 ylmethyl)-2,3-dihydz~o-IH indol-S-ylJ-
isonicotittamide,
N ~l-(S-Chlorothiophen-2-~lmethyl)-2,3-dihydzro-IH indol-S ylJ-4-
dimethylaminobenzamide,
N ~l-(5-Chlorotlziophen-2 ylznethyl)-2,3-dihydYO-IH indol-S ylJ-2-(4
fluorophenyl)-
acetanzide,
N ~1-(5-Chlorothiophen-2 ylmetlzyl)-2,3-dihyd>"o-IH indol-5 ylJ-6-
trifluo~omethyl>zicotinafzzide,
1-test-Butyl-3-~l-(5-clalo~othioplzen-2 ylmethyl)-2,3-dihydz~o-IH indol-5 ylJ-
u>~ea,
1-~1-(5-Chlorot7ziophen-2 ylznethyl)-2, 3-dihyd>"o-1 H indol-5 ylJ-3-
ethylurea,
1-Benzyl-3-~1-(5-chlorothiophen-2 ylmethyl)-2,3-dihydro-IH iztdol-5 ylJ-uz~ea,
1-~1-(5-Chlo>~othiophert-2 ylmethyl)-2,3-dihydz~o-IH indol-5 ylJ-3
phenethylurea,
1-~l -(S-Chlorothiophezz-2 ylntethyl)-2, 3-dilzydro-IH indol-S ylJ-3-thiophetz-
2 ylu>~ea,
1-~1-(S-Clalot°othiophen-2 ylmetltyl)-2,3-dihydro-1H indol-5 ylJ-3-
thioplzen-3 ylunea,
2,2-Diznethyl-N ~6-nit~o-1-(4-tz~ifluo~ozzaethylberazyl)-2,3-dihydro-IH indol-
5 ylJ-
p~opionanaide,
N ~1-(5-Chlorothiophen-2 ylmethyl)-6-nit>~o-2,3-dihydz~o-IH indol-5 ylJ-2,2-
dimethylpropiortamide,
2-(4-Fluo~oplzenyl)-N ~6-yzitt~o-1-(4-tt~ifluoromethylbenzyl)-2,3-dihydro-IH
indol-S-
3o ylJ-acetamide,
N ~6-Atnino-1-(5-chloYOthiophezt-2 ylmethyl)-2, 3-diltydYO-1 H indol-S ylJ-3,
3-
dimethylbutyramide,
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N ~6 Amino-I-(4-tnifluo~omethylbenzyl)-2,3-dihydz°o-IH indol-5 ylJ-
2,2-
dimethylpropionamide,
N ~6 Amino-1-(5-chlorothiophen-2 yhnetltyl)-2,3-dihydro-IH ittdol-5 ylJ-2,2-
dimethylpropiortantide,
N ~6-Amino-1-(4-t~ifluo>~omethylbenzyl)-2, 3-dihydt~o-1 H indol-5 ylJ-2-(4-
fluorophenyl)-acetamide, or
N ~1-(S-Chlorotlziophen-2 ylmethyl)-IH iyzdol-5 ylJ-3,3-dimethylbutyramide.
In another embodiment of the invention, the compounds of the following list
and salts
to thereof are preferred:
N ~4-Chloro-1-(4-tz~ifluof°omethylbenzyl)-2, 3-dihydro-1 H indol-5
ylJ-3, 3-
dimetlzylbutyramide;
N ~4-Chloro-1-(5-chlorothiophezz-2 ylmethyl)-2, 3-dihydro-1 H indol-5 ylJ-3, 3-
dimethylbutyramide;
15 ~l -(4-Fluorobenzyl)-2, 3-dihydro-1 H indol-5 ylJ-carbamic acid propyl
ester;
N ~1-(4-Fluorobenzyl)-2, 3-dihydro-1 H indol-S ylJ-C phenyl-
methartesulfonamide;
4-Fluoro-N ~1-(4 fluorobezzzyl)-2, 3-dihydro-1 H indol-5 ylJ-benzaznide;
N ~l -(4-Fluorobenzyl)-2, 3-dihydro-1 H indol-5 ylJ-3, 3-dimethylbutyranzide;
N ~1-(4-Fluorobenzyl)-2, 3-dihydf°o-1 H indol-S ylJ-2-thiophen-2
ylacetamide;
20 N ~1-(4-Fluorobenzyl)-2, 3-dihydro-1 H indol-5 ylJ-2-(4 fluoropheztyl)-
acetamide;
3-~l-(5-Chlorotlziophen-2 ylznetlzyl)-2,3-dihydro-1H izadol-S ylJ-l,l-
diisopropylurea;
Morpholizze-4-carboxylic acid ~l-(5-chlorothiop7zen-2 ylntethyl)-2,3-dihydro-
1H
izzdol-5 ylJ-amide;
Pyrrolidine-1-carboxylic acid (1-(5-chlorothiophezt-2 yltnethyl)-2,3-dihydro-
1H
25 indol-5 ylJ-amide;
~1-(S-Chlorothioplzen-2 ylznethyl)-2,3-dihydro-IH indol-S ylJ-carbaznic acid 2-
benzyloxyethyl ester;
3-~1-(5-Clzlorotlzioplzen-2 ylmetltyl)-2, 3-dihydro-1 H indol-5 ylJ-1-methyl-1-
propylurea;
30 ~l-(5-Chlorothiophen-2 ylmethyl)-2,3-dihydro-1H indol-5 ylJ-carbamic acid
tert-
butyl ester;
N (1-(5-Clzlorothiophen-2 ylmethyl)-2,3-dihydro-1H indol-S ylJ-C phenyl-
metlzanesulfozzamide;
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Butane-1-sulfonic acid ~l-(5-chlorothiophen-2 ylmethyl)-2,3-dihydro-IH indol-5
ylJ-
atttide;
N ~1-(5-Chlot°ot7z.iophen-2 yltnethyl)-2,3-dihydt°o-1H indol-S
ylJ-4 fluorobenzarnide;
N ~1-(5-Chlorothiophen-2 ylntet72yl)-2,3-dihydro-IH indol-S ylJ-2,2-
ditnethylpropionamide;
N ~1-(5-Chlorothiophen-2 ylmethyl)-2, 3-dihydro-1 H indol-5 ylJ-2-
pltenoxyacetamide;
N ~1-(5-Chlorothioplten-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-3,3-
dintethylbutyramide;
to N ~1-(5-Chlorothiophen-2 ylmethyl)-2,3-dihydro-1H indol-5 ylJ-butyrantide;
Cyclopentanecarboxylic acid (1-(5-chlorothiophen-2 yhnetlZyl)-2,3-dihydro-IH
indol-
S ylJ-amide;
N ~1-(5-ChlorothioplZen-2 yln2ethyl)-2,3-dihydro-IH indol-5 ylJ-2-thiophen-2-
ylacetantide;
N ~l-(5-Chlot°othiophen-2 ylmethyl)-2,3-dihydno-1H indol-5 ylJ-
isonicotinamide;
N~1-(5-Clzlorothiophen-2 ylmethyl)-2,3-dihydro-IH itZdol-5 ylJ-4-
dimethylantinobenzatnide;
N ~1-(5-Chlot°othiophen-2 ylmethyl)-2, 3-dihydro-1 H indol-5 ylJ-2-(4
fluot°ophenyl)-
acetamide;
2o N ~l-(5-Clalorothiophen-2 ylntethyl)-2,3-dihydro-IH indol-S ylJ-6-
trifluoromethylnicotinamide;
1-tent-Butyl-3-~1-(5-chlorothiophen-2 yhnethyl)-2,3-dihydro-IH indol-5 ylJ-
urea;
1-~l -(5-Chlorothiophen-2 yhnethyl)-2, 3-diltydro-1 H indol-S ylJ-3-ethylurea;
1-Bertzyl-3-~l -(S-chlorothiophen-2 ylmethyl)-2, 3-dihydro-1 H indol-5 ylJ-
us°ea;
1-~1-(5-Chlorothiophen-2 yhttetlZyl)-2,3-dilaydro-IH indol-S ylJ-3
phenethylurea;
1-~1-(5-Chlorothiophen-2 yhnethyl)-2,3-dihydro-IH indol-5 ylJ-3-thiophen-2
ylurea;
1-~l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-IH indol-S-ylJ-3-thiophen-3
ylurea;
~1-(5-Chlorothiophen-2 ylrnethyl)-2,3-dihydro-IH indol-S ylJ-carbamic acid
propyl
ester;
2,2-Dintethyl-N ~6-vitro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-IH iradol-S
ylJ-
propionantide;
N ~1-(5-Chlorothiophett-2 ylmethyl)-6-vitro-2,3-dihydro-IH iradol-S ylJ-2,2-
dimethylpropionamide;
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2-(4-Fluo~ophenyl)-N ~6-vitro-I-(4-trifluoYOmetlaylbenzyl)-2,3-dilaydro-1H
iyadol-5-
ylJ-acetamide;
N ~l-(5-Chlorothiophen-2 ylmethyl)-6-vitro-2,3-dihydro-1H indol-5 ylJ-2-(4-
fluorophenyl)-acetamide;
s N ~1-(5-ChlorothiophetZ-2 ylmetlzyl)-6-raitro-2,3-dihydro-IH indol-5 ylJ-3,3-
dimetlaylbutyramide;
N ~6-Amino-1-(5-chlorothiopheya-2 ylrnethyl)-~, 3-dihydro-1 H indol-5 ylJ-3, 3-
dimethylbutyramide;
N ~6-An2ino-1-(4-trifluorornetlaylbenzyl)-2, 3-dihydro-1 H indol-5 ylJ-2, 2-
10 dimetlaylpropionamide;
N ~6 Amino-1-(5-chlorothiophen-2 ylmethyl)-2,3-dihydro-IH indol-S ylJ-2,2-
dimethylpropionanaide;
N ~6-Amino-1-(4-trifluoromethylbenzyl)-2, 3-dihydro-1 H indol-S ylJ-2-(4-
fluorophenyl)-acetamide;
15 N ~6 Amino-1-(4-trifluorometlzylbenzyl)-2,3-dihydro-IH indol-S ylJ-3,3-
dimetliylbutyramide;
N ~6-Arnino-1-(4 fluorobenzyl)-2,3-dihydro-IH indol-5 ylJ-3,3-
dimetlzylbutyramide;
N ~6 Amino-1-(3 fluoro-4-trifluof°omethylbenzyl)-2, 3-di7zydro-1 H
indol-5 ylJ-3, 3-
dimetlaylbutyramide;
20 N ~1-(S-ChlorothioplZen-2 ylmethyl)-1H indol-5 ylJ-3,3-dimethylbutyramide;
N ~6-Bromo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-IH indol-S ylJ-3,3-
dinaethylbutyramide;
N ~6-Brorno-1-(5-chlorothiophen-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-3,3-
dinaetlaylbutyramide;
25 N ~l -(4-ClZlorobenzyl)-2, 3-dihydro-1 H indol-5 ylJ-3, 3-
ditnethylbutyramide;
3, 3-Din2etlayl-N ~1-(4-trifluoromethylbenzyl)-2, 3-dihydro-1 H indol-S ylJ-
butyrarnide;
N ~l -(4 Isopropylbenzyl)-2, 3-dihydro-1 H indol-5 ylJ-3, 3-
dimethylbutyramide;
N ~l -(3-Fluoro-4-trifluoronaetlaylbetazyl)-2, 3-dihydro-1 H indol-S ylJ-3, 3-
dimetlaylbutyrarnide;
3o N ~l-(6-Ch.lorobenzo(l,3Jdioxol-5 ylmethyl)-2,3-dihydro-1H indol-S ylJ-3,3-
dimetlaylbutyramide;
N ~l -(3, 5-Dirnethyl-1 phenyl-IH pyrazol-4 ylnaethyl)-2, 3-dihyds-o-1 H indol-
5 ylJ-3, 3-
dimethylbutyramide;
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N j1 -(2-Chlo~o-S-trifluo~omethylbenzyl)-2, 3-dilaydro-I H indol-5 ylJ-3, 3-
dimethylbuty~anaide;
N ~1-j5-(4-Chlorophenoxy)-1,3-dimethyl-IHpyr~azol-4 ylrnethylJ-2,3-dilayd~o-IH
iradol-5 ylJ-3, 3-dimetlaylbutyf°amide;
3, 3-Dinaetlayl-N j1 -(6 p-tolyloxy py~idin-3 ylmetlayl)-2, 3-di7zydt°o-
1 H indol-S ylJ-
buty~~amide;
N j1 - j6-(4-Clalo~ophenylsulfanyl) py~idin-3 ylmethylJ-2, 3-dihyd~o-1 H indol-
5 ylJ-
3, 3-dimethylbutyramide;
N jl-jd-(4-Cyanophenoxy) py~idin-3 ylmethylJ-2,3-dihyd~o-IH indol-5-ylJ-3,3-
l0 dimethylbuty~arraide;
3, 3-Dimethyl-N j1 -(6-trifluorometlzylpyridin-3 ylrnethyl)-2, 3-dihydno-1 H
indol-5 ylJ-
butyramide;
3, 3-Dimethyl-N j1 -(3-methyl-benzo jbJthioplaen-2 ylmetlayl)-2, 3-dihyd~o-1 H
indol-5-
ylJ-butyl°amide;
N j1 -(6-Fluo~o-4H benzo j1 , 3Jdioxin-~ ylmethyl)-2, 3-dihydno-1 H indol-S
ylJ-3, 3-
dimetlzylbutyramide;
3, 3-Dimetlayl-N j1 -(6 phetaoxypyridin-3 ylmethyl)-2, 3-dihydro-1 H indol-S
ylJ-
buty~amide;
3,3-Dimethyl-N jl-(3-methyl-5 phenyl-isoxazol-4 ylynethyl)-2,3-dihyd~o-1H
iradol-S-
ylJ-buty~~amide;
N (1-BenzojbJtlZioplZen-2 ylmethyl-2,3-dihydno-IH indol-S yl)-3,3-
dimethylbuty~amide;
N ~1- j1 -(4-Fluo~ophenyl)-S-methyl-1 H pyrazol-4 ylmethylJ-2, 3-dihydro-1 H
indol-S-
ylJ-3, 3-dimethylbutyr~amide;
3,3-Dimethyl-N jl-(5-methylthiophen-2 ylmethyl)-2,3-dihydYO-IH indol-S ylJ-
butyranZide;
3, 3-Dimethyl-N j1 -(4 pyrrol-1 yl-berazyl)-2, 3-dihydro-1 H iradol-5 ylJ-
butyt~amide;
N jl-(4-Chlorobenzyl)-2,3-dilayd~o-1H indol-S ylJ-2-(4 fluorophenyl)-
acetamide;
2-(4-Fluof°ophenyl)-N jl-(4-trifluoromethylbenzyl)-2,3-dihydro-IH indol-
S ylJ-
acetamide;
2-(4-Fluof~ophenyl)-N j1 -(4-isopropylbetzzyl)-2, 3-dihydro-1 H indol-5 ylJ-
acetanaide;
~-(4-Fluor~ophenyl)-N j1-(3 fluoro-4-trifluoronaethylberzzyl)-2,3-dihydro-1H
indol-5-
ylJ-acetamide;
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52
N ~l-(6-Chlo~obenzo~l,3Jdioxol-5 ylmethyl)-2,3-dihyd~o-IH indol-5 ylJ-2-(4-
fluor~opherzyl)-acetanzide;
N ~1-(3, 5-Dimethyl-I phenyl-1 H pyz~azol-4-ylmetlzyl)-2, 3-dilzydro-1 H
irzdol-5 ylJ-2-
(4 fluo>"oplzerzyl)-acetarnide;
N ~1-(2-Chloro-5-tt°ifluoromethylbenzyl)-2, 3-dihydro-I H indol-S
ylJ-2-(4-
fluoz"opherzyl)-aceta~rzide;
N ~l-~5-(4-Chlo~oplzenoxy)-1,3-dimethyl-IHpyr~azol-4 ylmetlzylJ-2,3-dihydf-o-
IH
indol-5 ylJ-2-(4 fluof~ophenyl)-acetamide;
N ~l-~6-(4-Cyanophenoxy) pyridin-3 ylznethylJ-2,3-dihydro-IH irzdol-S yl)-2-(4-
fluof°opherzyl)-acetamide;
2-(4-Fluoi~ophenyl)-N ~l-(3-methyl-benzo(bJthiopherz-2-ylmethyl)-2,3-dihyd~o-
IH
irzdol-5 ylJ-acetamide;
N ~1-(6-Fluoro-4H benzo~l,3Jdioxin-8 ylznethyl)-2,3-dihydf~o-1H indol-5 ylJ-2-
(4-
fluof°oplzenyl)-acetamide;
2-(4-Fluorophenyl)-N ~1-(6 pherzoxypyridin-3 ylnzethyl)-2,3-dilzyd~o-IH indol-
S-ylJ-
acetamide;
N (1-Berzzo~bJthiophen-2-ylmethyl-2,3-dihyd~~o-IH indol-5 yl)-2-(4
fluof°ophenyl)-
acetamide;
2-(4-Fluorophenyl)-N ~l -~l -(4 fluot°ophenyl)-5-methyl-1 H py~azol-4
ylmethylJ-2, 3-
2o dihydro-IH indol-5 yl~-acetamide;
2-(4-Fluoi°ophetzyl)-N ~l-(S-metlzylthiophen-2 ylmethyl)-2,3-dilzydz"o-
IH indol-5 ylJ-
acetamide; and
2-(4-Fluo~ophenyl)-N ~l -(4 pyrrol-1 yl-benzyl)-2, 3-dihyd~o-1 H indol-5 ylJ-
acetamide.
According to one embodiment, the invention relates to a pharmaceutical
composition
comprising one or more pharmaceutically acceptable Garners or diluents and a
compound of formula I wherein the dotted line, s, q, U, X, Z, Y, Rl, Rl~, R2
and
3o R3are as defined above, accordingly any of the dotted line, a, b, c, d, e,
f, g, h, j, k, s,
L~ T~ U~ X~ Z~ Y~ w~ Ri Ru Ra R3 Rs R6 Rs~ R~ R~~ Rs R9 R9' Rio Rio
> > > > > > > > > > > > > >
Rm, R12 and R12~ are as defined under formula I, or salts thereof.
Pharmaceutical
compositions of the invention may thus comprise one or more compounds of
formula
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53
I or salts thereof, such as one compound of formula I or a salt thereof; or
two
compounds of formula I or salts thereof; or three compounds of formula I or
salts
thereof.
The invention thus provides a pharmaceutical composition for oral or
parenteral
administration, said pharmaceutical composition comprising at least one
compound of
formula I or a salt thereof in a therapeutically effective amount together
with one or
more pharmaceutically acceptable carriers or diluents.
to In one aspect, the compounds of the invention may be administered as the
only
therapeutically effective compound.
In another aspect the compounds of the invention may be administered as a part
of a
combination therapy, i.e. the compounds of the invention may be administered
in
combination with other therapeutically effective compounds having e.g. anti-
convulsive properties. The effects of such other compounds having anti-
convulsive
properties may include but not be limited to activities on:
~ ion channels such as sodium, potassium, or calcium channels
~ the excitatory amino acid systems e.g. blockade or modulation of NMDA
receptors
~ the inhibitory neurotransmitter systems e.g. enhancement of GABA release, or
blockade of GABA-uptake or
~ membrane stabilisation effects.
Current anti-convulsive medications include, but are not limited to,
tiagabine,
carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin,
ethosuximide,
levetiracetam, phenytoin, topiramate, zonisamide as well as members of the
benzodiazepine and barbiturate class.
In one aspect, the compounds of the invention have been found to have effect
on
3o potassiwn channels of the KCNQ family, in particular the KCNQ2 subunit.
In one embodiment, the invention relates to the use of one or more compounds
according to the invention in a method of treatment. The disorder or condition
to be
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54
prevented, treated or inhibited is responsive to an increased ion flow in a
potassium
channel such as the KCNQ family potassium ion channels. Such disorder or
condition
is preferably a disorder or condition of the central nervous system.
The compounds of the invention are considered useful for increasing ion flow
in a
voltage-dependent potassium channel in a mammal such as a human.
The compounds of the invention are considered useful for the prevention,
treatment or
inhibition of a disorder or condition being responsive to an increased ion
flow in a
to potassium channel such as the KCNQ family potassium ion channels. Such
disorder
or condition is preferably a disorder or condition of the central nervous
system.
The compounds of the invention are thus considered useful for preventing,
treating or
inhibiting disorders or diseases such as seizure disorders, neuropathic and
migraine
15 pain disorders, anxiety disorders and neurodegenerative disorders.
Accordingly, the compounds of the invention are considered useful for the
prevention,
treatment or inhibition of disorders or conditions such as convulsions,
epilepsy,
anxiety disorders, neuropathic pain and neurodegenerative disorders.
According to one particular embodiment, the compounds of the invention are
thus
considered to be useful for preventing, treating or inhibiting seizure
disorders such as
convulsions, epilepsy and status epilepticus.
In one embodiment, the compounds of the invention are considered useful in the
prevention, treatment and inhibition of convulsions.
In another embodiment, the compounds of the invention are considered useful in
the
prevention, treatment and inhibition of epilepsy, epileptic syndromes and
epileptic
seizures.
In yet another embodiment, the compounds of the invention are considered
useful in
the prevention, treatment and inhibition of anxiety disorders such as anxiety
and
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conditions and diseases related to panic attaclc, agoraphobia, panic disorder
with
agoraphobia, panic disorder without agoraphobia, agoraphobia without history
of
panic disorder, specific phobia, social phobia and other specific phobias,
obsessive-
compulsive disorder, posttraumatic stress disorder, acute stress disorders,
generalized
5 anxiety disorder, anxiety disorder due to general medical condition,
substance-
induced anxiety disorder, separation anxiety disorder, adjustment disorders,
performance anxiety, hypochondriacal disorders, anxiety disorder due to
general
medical condition and substance-induced anxiety disorder and anxiety disorder
not
otherwise specified.
to In yet another embodiment, the compounds of the invention are considered
useful in
the prevention, treatment and inhibition of anxiety disorders such as anxiety,
generalized anxiety disorder, pasuc anxiety, obsessive compulsive disorder,
social
phobia, performance anxiety, post-traumatic stress disorder, acute stress
reaction,
adjustment disorders, hypochondriacal disorders, separation anxiety disorder,
15 agoraphobia, specific phobias, anxiety disorder due to general medical
condition and
substance-induced anxiety disorder.
In yet another embodiment, the compounds of the invention are also considered
useful
in the prevention, treatment and inhibition of neuropathic pain and migraine
pain
2o disorders such as allodynia, hyperalgesic pain, phantom pain, neuropathic
pain related
to diabetic neuropathy and neupathic pain related to migraine.
In yet another embodiment" the compounds of the invention are considered
useful in
the prevention, treatment and inhibition of neurodegenerative disorders such
as
25 Alzheimer's disease; Huntington's chorea; multiple sclerosis; amyotrophic
lateral
sclerosis; Creutzfeld-Jalcob disease; Parlcinson's disease; encephalopathies
induced by
AIDS or infection by rubella viruses, herpes viruses, borrelia and unknown
pathogens;
trauma-induced neurodegenerations; neuronal hyperexcitation states such as in
medicament withdrawal or intoxication; and neurodegenerative diseases of the
3o peripheral nervous system such as polyneuropathies and polyneuritides.
In yet another embodiment, the compounds of the invention are considered
useful in
the prevention, treatment and inhibition of neurodegenerative disorders such
as
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Alzheimer's disease; Huntington's chorea; multiple sclerosis; amyotrophic
lateral
sclerosis; Creutzfeld-Jakob disease; Parkinson's disease; encephalopathies
induced by
AIDS or infection by rubella viruses, herpes viruses, borrelia and unknown
pathogens;
and trauma-induced neurodegenerations.
In yet another embodiment, the compounds of the invention are considered
useful in
the prevention, treatment and inhibition of neuronal hyperexcitation states
such as in
medicament withdrawal or intoxication.
to The invention provides compounds showing effect in one or more of the
following
tests:
~ "Relative efflux through the KCNQ2 channel"
Which is a measure of the potency of the compound at the target chaimel
~ "Maximum electroshock"
Which is a measure of seizures induced by non-specific CNS stimulation by
electrical means
~ "Pilocarpine induced seizures"
Seizures induced by pilocarpine are often difficult to treat with many
existing
antiseizure medications and so reflect a model of "drug resistant seizures"
~ "Electrical seizure-threshold tests" and "Chemical seizure-threshold tests"
These models measure the threshold at which seizures are initiated, thus being
models that detect whether compounds could delay seizure initiation.
~ "Amygdala kindling"
Which is used as a measure of disease progression, as in normal animals the
seizures in this model get more severe as the animal receives further
stimulations.
According to one particular aspect of the invention, the compounds axe KCNQ2
active
with an ECSO of less than 15000nM such as less than 10000nM as measured by the
3o test "Relative efflux through the KCNQ2 channel" which is described below.
According to another particular aspect of the invention, the compounds are
KCNQ2
active with an ECSO of less than 2000nM such as less than 1500nM as measured
by
the test "Relative efflux through the KCNQ2 channel" which is described below.
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According to yet another particular aspect of the invention, the compounds are
KCNQ2 active with an ECso of less than 200nM such as less than 150nM as
measured
by the test "Relative efflux through the KCNQ2 channel" which is described
below.
According to one particular aspect of the invention, the compounds have an
EDso of
less than 15 mg/lcg in the test "Maximum electroshock" which is described
below.
According to another particular aspect of the invention, the compounds have an
EDso
of less than 5 mg/lcg in the test "Maximum electroshock" which is described
below.
to According to one particular aspect of the invention, the compounds have an
EDso of
less than 5 mg/kg in the "Electrical seizure -threshold test" and "Chemical
seizure -
threshold test" which is described below.
Some compounds have few or clinically insignificant side effects. Some of the
compounds are thus tested in models of the unwanted sedative, hypothermic and
ataxic actions of the compounds.
Some of the compounds have a large therapeutic index between anticonvulsant
efficacy and side-effects such as impairment of locomotor activity or ataxic
effects as
2o measured by performance on a rotating rod. This means that the compounds
will
expectedly be well tolerated in patients permitting high doses to be used
before side
effects are seen. Thereby compliance with the therapy will expectedly be good
and
administration of high doses may be permitted making the treatment more
efficacious
in patients who would otherwise have side effects with other medications.
Definitions
The term heteroatom refers to a nitrogen, oxygen or sulphur atom.
Halogen means fluoro, chloro, bromo or iodo.
The expressions C1_~-allc(en/yn)yl and C1_~-alk(an/en/yn)yl mean a C1_~-
allcyl, Ca_~-
all~enyl or a Ca_~-allcynyl group. The term C1_~-all~yl refers to a branched
or un-
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branched allcyl group having from one to six carbon atoms inclusive, including
but not
limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-
propyl and
2-methyl-1-propyl. Similarly, C2_~-alkenyl and CZ_6-alkynyl, respectively,
designate
such groups having from two to six carbon atoms, including one double bond and
one
triple bond respectively, including but not limited to ethenyl, propenyl,
butenyl,
ethynyl, propynyl and butynyl.
The expression C1_3-alk(en/yn)yl means a C1_3-alkyl, C2_3-alkenyl or a C2_3-
alkynyl
group. The term C1_3-alkyl refers to a branched or un-branched allcyl group
having
to from one to three carbon atoms inclusive, including but not limited to
methyl, ethyl,
1-propyl and 2-propyl. Similarly, C2_3-alkenyl and CZ_3-alkynyl, respectively,
designate such groups having from two to three carbon atoms, including one
double
bond and one triple bond respectively, including but not limited to ethenyl, 1-
propenyl, 2-propenyl, 3-propenyl, ethynyl, 1-propynyl and 3-propynyl.
The expressions C3_$-cycloalk(en)yl and C3_8-cycloalk(an/en)yl mean a C3_8-
cycloalkyl- or cycloall~enyl group. The term C3_8-cycloalkyl designates a
monocyclic
or bicyclic carbocycle having three to eight C-atoms, including but not
limited to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term C3_8-
cycloalkenyl
2o designates a monocyclic or bicyclic carbocycle having three to eight C-
atoms and
including one double bond.
The expressions C3_~-cycloallc(en)yl and C3_~-cycloallc(an/en)yl mean a C3_6-
cycloallcyl- or cycloallcenyl group. The term C3_~-cycloalkyl designates a
monocyclic
or bicyclic carbocycle having three to six C-atoms, including but not limited
to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
The term heterocycloalk(en)yl designates a monocyclic or bicyclic ring system
3o wherein the ring is formed by 4 to 8 atoms selected from 2-7 carbonatoms
and 1 or 2
heteroatoms selected from N, S, or O.
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When two substituents together with a carbon atom to which they are attached
form a
3-8 membered saturated or unsaturated ring which optionally contains 1 or 2
heteroatoms, then a monocyclic ring system is formed by 3 to 8 atoms selected
from
1-8 carbonatoms and 0-2 heteroatoms selected from N, S, or O. Examples of such
ring
systems are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term halo-C1_~-allc(en/yn)yl designates Cl_~-alk(en/yn)yl being
substituted with
one or more halogen atoms, including but not limited to trifluoromethyl.
Similarly,
halo-C3_8-cycloalk(en)yl designates C3_8-cycloalk(en)yl being substituted with
one or
l0 more halogen atoms and halo-heterocycloalk(en)yl designates
heterocycloalk(en)yl
being substituted with one or more halogen atoms.
The teen NRlzRlz'-C1_~-alk(en/yn)yl designates C1_~-alk(euyn)yl being
substituted
with NRlzRi2y The term NRlzRlz~-C3_$-cycloallc(en)yl designates C3_8-
cycloalk(en)yl
15 being substituted with NRlzRlz~. The term NRlzRlz~-C3_8-cycloalk(en)yl-Cl_~-
alk(en/yn)yl designates C3_$-cycloalk(en)yl-Cl_~-alk(en/yn)yl being
substituted with
~12R12'. den any of NRlzRlz~-Cl_~-alk(en/yn)yl, NRlzRlz~ C3_$-cycloalk(en)yl
and
NRlzRiz~-C3_$-cycloalk(en)yl-C1_G-alk(en/yn)yl is optionally substituted, then
any of
C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-Cl_~-alk(en/yn)yl
is
20 optionally substituted with one or more substituents independently being
C1_~-
allc(enlyn)yl, C3_$-cycloalk(en)yl, C3_8-cycloalk(en)yl-C1_~-allc(en/yn)yl or
Ar.
As used herein, the term acyl refers to formyl, C1_6-alk(en/yn)ylcarbonyl,
C3_8-
cycloalk(en)ylcarbonyl, Ar-carbonyl, Ar-C1_~-alk(en/yn)ylcarbonyl or a C3_8-
25 cycloalle(en)yl-C1_~-allc(en/yn)yl-caxbonyl group, wherein C1_~-
alk(en/yn)yl, C3_$-
cycloallc(en)yl and Ar are as defined above.
When two substituents together with a nitrogen atom to which they are attached
form
a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or
3
3o further heteroatoms, then a monocyclic ring system is formed by 4 to 8
atoms selected
from the nitrogen atom, 1-7 carbonatoms and 0-3 further heteroatoms selected
from
N, S, or O. Examples of such ring systems are azetidine, beta-lactame,
pyrrolidine,
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piperidine, piperazine, morpholine, pyrrole, oxazolidine, thiazolidine,
imida.zolidine,
azetidine, beta-lactame, tetrazole and pyrazole.
When two adj acent substituents together with the aromatic group to which they
are
5 attached form a 4-8 membered ring, which optionally contains one or two
heteroatoms, then a ring system is formed by 4-8 atoms selected from 3-8
carbonatoms and 0-2 heteroatoms selected from N, S, or O. Such two adjacent
substituents may together form:
-(CHZ)"~~-CH2-, -CH=CH-(CHZ)",»-, -CHZ-CH=CH-(CHZ)p»-, -CH=CH-CH=CH-,
10 -(CH2)"~<-O-, -O-(CH2)m,~_O_~ -CHZ_O_(CH2)p°~-O-~ -CH2-O_CHZ_O_CHZ_~
-(CHZ)""-S-, -S_(CH2)m»_S_~ -CH2-S-(CH2)p°~-S-~ -CH2-S-CH2_S_CH2_~
-(CH2)"»NH- , NH-(CH2),,,>s ~_~ -CH2_~_(CH2)p,._j~j~_~ - CH=CH-NH-
-O-(CHZ)n.,»NH-, -CH2_O_(CHz)p~._~_ or _O_(CHZ)p~,_~_CH2_~ -S_(CH2)m»_~_~ _
N=CH-NH-, -N=CH-O- or -N=CH-S-, wherein m' ' is 1, 2 or 3, n' ' is 2, 3 or 4
and p' '
15 islor2.
The term Ar refers to optionally substituted aromatic systems of 5-10 carbon
atoms,
wherein 0, l, 2, 3 or 4 carbon atoms may be replaced by heteroatoms
independently
selected from N, S, or O. Examples of such Ar groups are optionally
substituted
2o phenyl, optionally substituted naphtyl, optionally substituted pyridine,
optionally
substituted pyrrole, optionally substituted pyrimidine, optionally substituted
quinoline, optionally substituted indole, optionally substituted thiophene,
optionally
substituted furan, optionally substituted thiazole and optionally substituted
oxazole.
Ar may be substituted with one or more substituents independently being
hydroxy,
25 halogen, C1_~-allc(enlyn)yl, C3_8-cycloalk(en)yl, C3_8-cycloallc(en)yl-Cl_~-
alk(enJyn)yl,
halo-Cl_~-allc(e1~/yn)yl, Cl_~-alk(en/yn)yloxy, C3_8-alk(en/yn)yloxy, acyl,
nitro or
cyano, -CO-NH-C1_~-allc(enlyn)yl, -CO-N(Cl_~-alk(enlyn)yl)a, -NH2, -NH-C1_~_
alk(en/yn)yl, -N(C1_~-allc(en/yn)yl)2, -S- C1_~-alk(en/yn)yl, -SOz-Cl_~-
alk(en/yn)yl,
S02N(C1_~-allc(en/yn)yl)2 and -SOaNH-C1_~-alk(en/yn)yl; or two adjacent
substituents
30 may together with the axomatic group to which they are attached form a 4-8
membered ring, which optionally contains one or two heteroatoms and which may
be
saturated or unsaturated.
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The terms C3_8-cycloalk(en)yl-C1_~-alk(enlyn)yl, Cl_~-alk(en/yn)yl-C3_8-
cycloalk(en)yl,
Cl_~-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar-Ci_~-alk(en/yn)yl, Ar-C3_$-
cycloall~(en)yl, Ar-heterocycloalk(en)yl, Ar-C3_8-cycloalk(en)yl-C1_~-
alk(en/yn)yl, Ar-
C1_~-allc(en/yn)yl-C3_8-cycloalk(en)yl, Ar-C1_~-alk(en/yn)yl-
heterocycloalk(en)yl, C1_
~-allc(en/yn)yloxy, CZ_~-alkenyloxy, C2_G-alkynyloxy, C3_8-cycloalk(en)yloxy,
C1_~-
allc(en/yn)yloxy-C1_~-alk(en/yn)yl, C3_$-cycloall~(en)yloxy-Cl_~-alk(enlyn)yl,
Cl_~-
alk(en/yn)yloxy-C3_8-cycloallc(en)yl, C1_~-alk(en/yn)yloxy-
heterocycloalk(en)yl, Ar-
oxy-C1_~-allc(en/yn)Yl, Ar-Cl_~-alk(en/yn)Yloxy-C1_~-alk(en/yn)Yl, Ci-~-
alk(en/yn)ylcarbonyl, C3_$-alk(en/yn)ylcarbonyl, Ar-carbonyl, Ar-C1_~-
lo all~(en/yn)ylcarbonyl, C3_$-cycloalk(en)yl-Cl_6-alk(en/yn)ylcarbonyl, -CO-
C1_~-
alk(en/yn)yl, -S-C1_~-alk(en/yn)yl, -SOZ-C1_~-alk(en/yn)yl and -SOaO-C1_s-
alk(en/yn)yl, C1_~-allc(en/yn)yloxy-carbonyl-C1_~-alk(en/yn)yl, C3_8-
cycloalk(en)Yloxy-
carbonyl-C1_~-allc(en/yn)yl, C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yloxy-carbonyl-
C1_~-
alk(eWyn)y1, acyl, acyl-C1_~-alk(en/yn)yl, acyl-C3_$-cycloalk(en)yl, acyl-
heterocycloalk(en)yl, acyl-C3_8-cycloalk(en)yl-Cl_6-alk(en/yn)yl, acyl-C1_~-
allc(en/yn)yl-C3_8-cycloallc(en)yl, acyl-C1_~-allc(en/yn)yl-
heterocycloalk(en)yl,
hydroxy-Cl_~-alk(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-
heterocycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-C1_~-alk(euyn)yl, hydroxy-
Cl_s-
alk(en/yn)yl-C3_8-cycloalk(en)yl, hydroxy-Ci_~-alk(en/yn)yl-
heterocycloalk(en)yl,
2o halo-C1_~-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-
heterocycloalk(en)yl, halo-C3_8-
cycloalk(en)yl-C1_~-alk(en/yn)yl, halo-C1_~-alk(en/yn)yl-C3_g-cycloalk(en)yl,
halo-C1_
~-allc(en/yn)yl-heterocycloalk(en)yl, halo-C1_6-alk(en/yn)yl-Ar, halo-C3_8-
cycloalk(en)yl-Ar, halo-C3_8-cycloalk(en)yl-C1_~-alk(en/yn)yl-Ar, halo-Cl_~-
alk(en/yn)yl-C3_$-cycloalk(en)yl-Ar, halo-heterocycloalk(en)yl-Ar, cyano-C1_~-
alk(en/yn)yl, cyano-C3_8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-
C3_8
cycloallc(en)yl-C1_~-alk(en/yn)yl, cyano-C1_6-alk(en/yn)yl-C3_8-
cycloallc(en)yl, cyano
C1_~-allc(en/yn)yl-heterocycloallc(en)yl etc. designate such groups in which
the C1_~
allc(en/yn)yl, C2_G-allcenyl, Ca_~-allcynyl, C3_8-cycloall~(en)yl,
heterocycloalk(en)yl, Ar,
cyano, halo-C1_~-alk(en/yn)yl, halo-C3_g-cycloalk(en)yl, halo-
heterocycloallc(en)yl and
3o acyl are as defined above.
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The salts of the invention are preferably pharmaceutically acceptable salts.
Such salts
include pharmaceutical acceptable acid addition salts, pharmaceutically
acceptable
metal salts, ammonium and all~ylated ammonium salts.
The pharmaceutically acceptable salts of the invention are preferably acid
addition
salts. The acid addition salts of the invention are preferably
pharmaceutically
acceptable salts of the compounds of the invention formed with non-toxic
acids.Acid
addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric,
to hydrobromic, hydroiodic, sulfuxic, sulfamic, phosphoric and nitric acids
and the like.
Representative examples of suitable organic acids include formic, acetic,
trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric,
fumaric, glycolic,
lactic, malefic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic,
succinic,
ethanesulfonic, tartaric, ascorbic, pamoic, gluconic, citraconic, aspartic,
stearic,
palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, bis-methylenesalicylic,
methanesulfonic, ethanedisulfonic, itaconic, benzenesulfonic, p-
toluenesulfonic acids,
theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-
bromotheophylline and the like. Further examples of pharmaceutical acceptable
inorganic or organic acid addition salts include the pharmaceutically
acceptable salts
listed in J. Phamn. Sci. 1977,66,2, which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts
and the
like.
Examples of ammonium and alkylated ammonium salts include anunonium, methyl-,
dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-,
tent-butyl-,
tetramethylamrnonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the
hydrates,
3o which the present compounds are able to form.
The compounds of the present invention may have one or more asymmetric centres
and it is intended that any optical isomers, as separated, pure or partially
purified
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63
optical isomers or racemic mixtures thereof are included within the scope of
the
invention.
Furthermore, when a double bond or a fully or partially saturated ring system
is
present in the molecule geometric isomers may be formed. It is intended that
any
geometric isomers, as separated, pure or partially purified geometric isomers
or
mixtures thereof are included within the scope of the invention. Likewise,
molecules
having a bond with restricted rotation may form geometric isomers. These are
also
intended to be included within the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in
different
tautomeric forms and it is intended that any tautomeric forms that the
compounds are
able to form are included within the scope of the present invention.
The compounds of this invention may exist in unsolvated as well as in solvated
forms
with solvents such as water, ethanol and the like. In general, the solvated
forms are
considered equivalent to the unsolvated forms for the purposes of this
invention.
Racemic forms can be resolved into the optical antipodes by known methods, for
example, by separation of diastereomeric salts thereof with an optically
active acid,
2o 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 optically active matrix. Racemic compounds of the present
invention can also be resolved into their optical antipodes, e.g. by
fractional
crystallization of d- or 1- (tartrates, mandelates or camphorsulphonate)
salts. The
compounds of the present invention may also be resolved by the formation of
diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those
skilled in the
art, may be used. Such methods include those discussed by J. Jaques, A. Collet
and S.
3o Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons,
New
York (1981).
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64
Optically active compounds can also be prepared from optically active starting
materials.
The invention also encompasses prodrugs of the present compounds, which on
administration undergo chemical conversion by metabolic processes before
becoming
pharmacologically active substances. In general, such prodrugs will be
functional
derivatives of the compounds of the general formula I, VII, VIII, IX, X, XI,
~i:XXII
or _X_XXTII which are readily convertible in vivo into the required compound
of the
formula I, VII, VIII, IX, X, XI, ~;XXII or XXXIII. Conventional procedures for
the
to selection and preparation of suitable prodrug derivatives are described,
for example,
in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
Whenever mentioned in relation to the compounds of the formulas I, VII, VIII,
IX,
X, XI, ~:XXII or ~;XXIII, the terms epilepsy and epilepsies embrace any of the
epilepsies, epileptic syndromes and epileptic seizures referred to in
International
League Against Epilepsy: Proposal for revised clinical and
electroencephalographic
classification of epileptic seizures. Commission on Classification and
Terminology of
2o the International League Against Epilepsy. Epilepsia 1981 22: 489-501 and
in
International League Against Epilepsy: Proposal for revised classification of
epilepsies and epileptic syndromes. Commission on Classification and
Terminology
of the International League Against Epilepsy. Epilepsia 1989 30(4): 389-399.
Whenever mentioned in relation to the compounds of the formulas I, VII, VIII,
IX,
X; XI, _X_X_X_II or XXXIII, the term anxiety disorders embraces conditions and
diseases related to panic attack, agoraphobia, panic disorder with
agoraphobia, panic
disorder without agoraphobia, agoraphobia without history of panic disorder,
specific
phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress
disorder,
3o acute stress disorders, generalized anxiety disorder, anxiety disorder due
to general
medical condition, substance-induced anxiety disorder, separation anxiety
disorder,
adjustment disorders and anxiety disorder not otherwise specified as defined
by
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American Psychiatric Association Diagnostic and statistical ynanual of mental
disorders, 4ed 1994: 110-113, 393-444 and 623-627.
Pharmaceutical compositions
The compounds of this invention are generally utilized as the free base or as
a
pharmaceutically acceptable salt thereof. Representative examples are
mentioned
above.
If desired, the pharmaceutical composition of the invention may comprise the
1o compound of formula I in combination with further pharmacologically active
substances such as those described in the foregoing.
The compounds of the invention may be administered alone or in combination
with
pharmaceutically acceptable earners or excipients, in either single or
multiple doses.
15 The pharmaceutical compositions according to the invention may be
formulated with
pharmaceutically acceptable carriers or diluents as well as any other known
adjuvants
and excipients in accordance with conventional techniques such as those
disclosed in
Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed.,
Mack
Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for
administration
by any suitable route such as the oral, rectal, nasal, pulmonary, topical
(including
buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal
and
parenteral (including subcutaneous, intramuscular, intrathecal, intravenous
and
intradermal) route, the oral route being preferred. It will be appreciated
that the
preferred route will depend on the general condition and age of the subject to
be
treated, the nature of the condition to be treated and the active ingredient
chosen.
Pharmaceutical compositions for oral administration include solid dosage forms
such
3o as capsules, tablets, dragees, pills, lozenges, powders and granules. Where
appropriate, they can be prepared with coatings such as enteric coatings or
they can be
formulated so as to provide controlled release of the active ingredient such
as
sustained or prolonged release according to methods well lrnown in the art.
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Liquid dosage forms for oral administration include solutions, emulsions,
suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile
aqueous and
nonaqueous injectable solutions, dispersions, suspensions or emulsions as well
as
sterile powders to be reconstituted in sterile injectable solutions or
dispersions prior to
use. Depot injectable formulations are also contemplated as being within the
scope of
the present invention.
Other suitable administration forms include suppositories, sprays, ointments,
cremes,
gels, inhalants, dermal patches, implants etc.
The pharmaceutical compositions of this invention or those which are
manufactured
in accordance with this invention may be administered by any suitable route,
for
example orally in the form of tablets, capsules, powders, syrups, etc., or
parenterally
in the form of solutions for injection. For preparing such compositions,
methods well
known in the art may be used, and any pharmaceutically acceptable carriers,
diluents,
excipients or other additives normally used in the art may be used.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg
body
weight per day, preferably from about 0.01 to about 50 mg/kg body weight per
day,
and more preferred from about 0.05 to about 10 mg/kg body weight per day
administered in one or more dosages such as 1 to 3 dosages. The exact dosage
will
depend upon the frequency and mode of administration, the sex, age, weight and
general condition of the subject treated, the nature and severity of the
condition
treated and any concomitant diseases to be treated and other factors evident
to those
spilled in the art.
3o The formulations may conveniently be presented in unit dosage form by
methods
lcnown to those slcilled in the art. A typical unit dosage form for oral
administration
one or more times per day such as 1 to 3 times per day may contain from 0.05
to
about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred
from
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67
about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramusculax and
similar
administration, typically doses are in the order of about half the dose
employed for
oral administration.
The compounds of this invention are generally utilized as the free substance
or as a
pharmaceutically acceptable salt thereof. One example is a base addition salt
of a
compound having the utility of a free acid. When a compound of the invention
to contains a free acid such salts may be prepared in a conventional manner by
treating a
solution or suspension of a free acid of the compound of the invention with a
chemical
equivalent of a pharmaceutically acceptable base. Representative examples are
mentioned above.
15 For parenteral administration, solutions of the novel compounds of the
invention in
sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or
sesame or
peanut oil may be employed. Such aqueous solutions should be suitably buffered
if
necessary and the liquid diluent first rendered isotonic with sufficient
saline or
glucose. The aqueous solutions are particularly suitable for intravenous,
2o intramuscular, subcutaneous and in traperitoneal administration. The
sterile aqueous
media employed are all readily available by standard techniques known to those
slcilled in the art.
Solutions for injections may be prepared by dissolving the active ingredient
and
25 possible additives in a part of the solvent for injection, preferably
sterile water,
adjusting the solution to a desired volume, sterilising the solution and
filling it in
suitable ampules or vials. Any suitable additive conventionally used in the
art may be
added, such as tonicity agents, preservatives, antioxidants, etc.
3o Suitable pharmaceutical carriers include inert solid diluents or fillers,
sterile aqueous
solution and various organic solvents.
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68
Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin,
talc, agar,
pectin, acacia, stearic acid and lower alkyl ethers of cellulose corn starch,
potato
starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like.
Any other adjuvants or additives usually used for such purposes such as
colourings,
flavourings, preservatives etc. may be used provided that they are compatible
with the
active ingredients.
Examples of liquid Garners are syrup, peanut oil, olive oil, phospho lipids,
fatty acids,
to fatty acid amines, polyoxyethylene and water. Similarly, the carrier or
diluent may
include any sustained release material known in the art, such as glyceryl
monostearate
or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical compositions formed by combining the novel compounds of the
15 invention and the pharmaceutical acceptable carriers are then readily
administered in a
variety of dosage forms suitable for the disclosed routes of administration.
The
formulations may conveniently be presented in unit dosage form by methods
known
in the art of pharmacy.
2o Formulations of the present invention suitable for oral administration may
be
presented as discrete units such as capsules or tablets, each containing a
predetermined amount of the active ingredient, and which may include one or
more
suitable excipients. Furthermore, the orally available formulations may be in
the form
of a powder or granules, a solution or suspension in an aqueous or non-aqueous
25 liquid, or an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be
tablette,
placed in a hard gelatine capsule in powder or pellet form or it can be in the
form of a
troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25
mg to
about 1 g.
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If a liquid carrier is used, the preparation may be in the form of a syrup,
emulsion, soft
gelatine capsule or sterile injectable liquid such as an aqueous or non-
aqueous liquid
suspension or solution.
If desired, the pharmaceutical composition of the invention may comprise the
compound of the formula I, VII, VIII, IX, X or XI in combination with further
pharmacologically active substances such as those described in the foregoing.
Typical examples of recipes for the formulation of the invention are as
follows:
to
1) Tablets containing 5.0 mg of
a compound of the invention calculated
as the
free base:
Compound of formula I, VII, VIII,
IX, X or XI 5.0 mg
Lactose 60 mg
Maize starch 30 mg
Hydroxypropylcellulose 2.4 mg
Microcrystalline cellulose 19.2 mg
Croscarmellose Sodium Type A 2.4 mg
Magnesium stearate 0.84 mg
2) Tablets containing 0.5 mg of
a compound of the invention calculated
as
the free base:
Compound of formula I, I, VII, VIII,
IX, X or XI 0.5 mg
Lactose 46.9 mg
Maize starch 23.5 mg
Povidone 1.8 mg
Microcrystalline cellulose 14.4 mg
Croscarmellose Sodium Type A 1.8 mg
Magnesium stearate 0.63 mg
3) Syrup containing per millilitre:
Compound of formula I, VII, VIII, IX, X or XI 25 mg
Sorbitol 500 mg
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Hydroxypropylcellulose 15 mg
Glycerol 50 mg
Methyl-paraben 1 mg
Propyl-paraben 0.1 mg
5 Ethanol 0.005 mL
Flavour 0.05 mg
Saccharin sodium 0.5 mg
Water ad 1 mL
10 4) Solution for injection containing per millilitre:
Compound of formula I, VII, VIII, IX, X or XI 0.5 mg
Sorbitol 5.1 mg
Acetic Acid 0.05 mg
Saccharin sodium 0.5 mg
15 Water
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71
Preparation of the compounds of the invention
Scheme 1
4 4
\ \ \
N / (U)s N / s (U)s N I / s (U)s
1
PG XIV ~ 2 XI I I R~ XII
/(Z)4\
R3 X/(z)q\
\ NOZ ~ \ NH2 \ NH \ NH R
N I N ~~ ~ ~ N'~~ ~
/ N)s ~ N)s / N)S N~\~C
PG1 XV I PG1 XVI I PG1 XVII I XVIII
Rz Rz Rz
Rz
H
\ NOa \ N02 \ NHa \ NIX
~: '
N (U)s R1 N (U)s R1 N (U)s R1 ,N (U)s (Z)q
XIX I Y~ XX I Z Y~ XXI I ~ Y~ I \Rs
R2 R1, R R1, R R1, I R2
Scheme 2 Ra
H
\ N02 \ N02 \ NH2 \ NwX/(Z)q
N I / ~ N I / ~ N I / ~ N ( /
XXII G1 XXIII ~ XXIV
PG1 PG1
R3 ~ Rs
R~
H I
\ NwX/(Z)q N~ /(Z) \ Nw
,-' I \ X ~ %i~ X
R1 ,N / (U)s N' \% \(U) ~ / N)S
Y~ I I XXVI I S PG1
R1' R2 Rz XXV R2
s=0, R2=CI, Br, I, N02
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72
The compounds of the invention of the general formula I, wherein the the
dotted line,
q, s, U, Y, X, Z, Rl, Rl~, R2 and R3 are as defined above, accordingly any of
dotted
line, a, b, c, d, e, f, g, h, s, q, U, X, Z, Y, W, Rl, Rl~, R2, R3, R5, R6,
R~~, R', R'', R8,
R9, R9', Rlo, Rio, Ry Riz and R12~ are defined under formula I are prepared by
the
methods as described below and as represented in the Schemes 1 and 2.
Indoles and indolines of the general formula XII and XIII substituted at
position 4 or
6 with RZ-(U)S are commercially available, described in the literature or
prepared
according to methods known to chemists skilled in the art [R. J. Sundberg
"Pyrroles
1o and their Benzo Derivatives: (iii) Synthesis and Applications" in
Comprehensive
Heterocyclic Chemistry, A. R. I~atritzky, C.W. Rees (Editors), vol. IV, pp 313-
376,
Pergamon Press, 1984]. Indoles of the general formula XII can be converted
into
indolines of the general formula XIII by methods known to chemists skilled in
the art
such as catalytic hydrogenation or reduction with NaBH3CN in appropriate
solvents
such as acetic acid [S. M. Bromidge, S. Dabbs, D. T. Davies, D. M. Duckworth,
I. T.
Forties et al. J. Med. Chem. 41, 1998, 1598-1612]. Compounds of the general
formula
XII or XIII with s being 0 and R2 being in particular but not limited to
substituted
aryl or substituted heteroaryl as defined above can be prepared from
corresponding
compounds with R2 being I or Br by means of C-C coupling reactions known to
2o chemists skilled in the art, such as Suzuki coupling, Stille coupling, or
other traalsition
metal catalysed cross-coupling reactions [D.W. Knight "Coupling Reactions
Between
sp2 Carbon Centers" in Compreherasive Organic Synthesis, v. 3, pp. 481-520,
Pergamon Press 1991].
Compounds of the general formula XIV are prepaxed by protection of the
indoline
nitrogen of the compounds of the general formula XIII with an appropriate
protecting
group (PGl) [Protective Groups in Organic Synthesis, 3rd Edition T. W. Greene,
P. G.
M. Wuts, Wiley Interscience 1999], such as a trifluoroacetyl group known to
chemists
skilled in the art as TFA group, by reaction with the reagent forming the
protective
3o group such as trifluoroacetic acid anhydride in a suitable solvent, such as
1,2-
dichloroethane at appropriate temperatures.
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73
The obtained compounds of the general formula XIV are converted into compounds
of the general formula XV by regioselective nitration at position 5 of the
indoline
moiety by methods known to chemists skilled in the art [R. Behnisch "
Aromatische
Nitro-Verbindungen" in Methoden den O~ganisch.e Chemiel(Houben-Weyl) p. 255,
v.
El6d, Tlueme: 1992] such as reaction with concentrated nitric acid in
appropriate
solvent such as acetic anhydride, acetic acid, concentrated sulphuric acid or
mixtures
thereof at appropriate temperatures. The nitro compounds of the general
formula XV
where R2 is halogen, in particular fluorine, and s is 0 can be converted into
compounds of the general formula XV, where U is O, NRII or S and RZ is as
defined
to above, by nucleophilic aromatic substitution reactions known to chemists
skilled in
the art such as reaction with the appropriate nucleophiles forming the -(LT)S
RZ group
such as thiophenols, alkylsulfides, alcohols, phenols, amines, and anilines in
their
neutral or deprotonated form. The compounds of the general formula XV where U
is
SOZ can be obtained from the compounds of the general formula XV, where U is
S,
by oxidation according to methods known to the chemist skilled in the art, for
example by oxidation with NaI04 in the presence of RuCl3 as a catalyst or with
3-
chloroperoxybenzoic acid.
The nitro group in compounds of the general formula XV can be reduced with
2o suitable reducing agents such as zinc or iron powder in the presence of
acid such as
acetic acid or aqueous hydrochloric acid, or hydrogen gas or ammonium formiate
in
the presence of a suitable hydrogenation catalyst such as palladium on
activated
carbon in suitable solvents such as methanol, ethanol, or tetrahydrofuran, at
suitable
temperatures or under ultrasonic irradiation, to obtain anilines of the
general formula
XVI. Alternatively, tin (II) chloride or sodium dithionite can be used as
reducing
agents under conditions well known to the chemist spilled in the art.
Compounds of the general formula XVII are prepared from compounds of the
general
formula XVI by the reaction with suitable electrophilic reagents forming an R3-
(Z)9
3o X group, such as allcyl, aryl or heteroaryl chloroformiates or carbamyl
chlorides, acid
chlorides, acid bromides, acid iodides, sulfonyl chlorides, isocyanates,
carbonic acid
anhydrides, activated carbonic acids with activating reagents such as
carbodiimides or
others as known to chemists skilled in the art in suitable solvents, such as
acetonitrile,
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74
tetrahydrofuran, 1,2-dichloroethane, or methylene chloride, at suitable
temperature,
such as room temperature or reflux, with or without addition of bases, such as
magnesium oxide, potassium carbonate, sodium hydride, trialkylamines, sodium-
or
potassium alcoholates, or pyridine, reactions well laiown to the chemist
skilled in the
art. Then the protective group PGl is removed according to methods known to
chemists slcilled in the art [Protective Groups ih Organic Synthesis, 3rd
Edition T. W.
Greene, P. G. M. Wuts, Wiley Interscience 1999], furnishing compounds of the
general formula XVIII. For example, when PGl is TFA, it can be removed by
hydrolysis with aqueous potassium carbonate in an appropriate solvent, such as
methanol, at a suitable temperature.
Finally, the obtained anilines of the general formula XVIII are subjected to
reductive
alkylation reactions, known to chemists skilled in the art, with aldehydes of
the
general formula YCHO where Y is defined as above in the presence of suitable
reducing agent such as NaBH3CN in suitable solvents such as methanol, ethanol,
tetrahydrofuran, acetonitrile or mixtures thereof, with or without addition of
catalytic
amounts of acid, such as acetic acid, at suitable temperatures forming
compounds of
the invention of the general formula I, where Rl and Rl~ are hydrogens.
Alternatively,
a (Y)(Rl)(Rl~)C- group can be introduced by nucleophilic substitution
reactions with
the appropriate electrophiles of the general formula ('~(Rl)(Rl')C-LG, where
LG is a
suitable leaving group such as iodide, bromide, or sulphonate, under
conditions
known to the chemist skilled in the art, furnishing the compounds of the
invention of
the general formula I.
Alternatively, compounds of the general formula XIX are commercially
available,
described in the literature or can be prepared from compounds of the general
formula
XV by deprotection as described above. Then they are subjected to reductive
allcylation with aldehydes of the general formula YCHO or to nucleophilic
substitution reactions with electrophiles of the general formula (Y)(Rl)(Rl')C-
LG as
3o described above, furnishing compounds of the general formula XX. Then the
vitro
group is reduced as described above forming compounds of the general formula
XXI.
Finally, the compounds of the invention of the general formula I with indoline
moiety
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are obtained by the method described above for the conversion of compounds of
the
general formula XVI into compounds of the general formula XVII.
Optionally, compounds of the invention of the general formula I with indole
moiety
5 can be obtained from indolines of the general formula I by means of
dehydrogenation
known to chemists skilled in the art such as oxidation with appropriate
reagents such
as 2,3,5,6-tetrachloro-[1,4]benzoquinone, Mn02, or catalytic dehydrogenation
in the
presence of a catalyst such as Pd on charcoal or RuCl2(PPh3)3 in appropriate
solvents
such as toluene or xylene at appropriate temperatures.
l0
Alternatively, compounds of the general formula I where -(ins RZ is attached
to the
position 6 of the indoline moiety, can be prepared by a route shown in Scheme
2 as
follows:
15 5-Nitroindoline is protected with an appropriate protecting group, such as
TFA group,
as described above for compounds of the general formula XIV, furnishing
compounds
of the general formula XXII. Then the nitro group is reduced as described
above for
preparation of compounds of the general formula XVI, furnishing compounds of
the
general formula XXIII. They are converted into compounds of the general
formula
2o XXIV with appropriate electrophiles forming R3-(Z)q-X as described above
for
compounds of the general formula XVII. Compounds of the general formula XXV
where s is 0 and R2 is NOZ or halogen such as Cl, Br or I, are obtained by
means of
regioselective electrophilic aromatic substitution, well known to chemists
skilled in
the art, with appropriate electrophiles such as N-chlorosuccinimide, bromine,
iodine,
25 iodochloride in the appropriate solvent such as acetic acid or by nitration
under
conditions as described for compounds of the general formula XV.
Compounds of the general formula XXV where s is 0 and R2 is substituted aryl
or
substituted heteroaryl as defined above can be prepared from corresponding
3o compounds of the same general formula where R2 is I or Br by means of C-C
coupling reactions known to chemists skilled in the art as described above.
Then the
protective group is removed as described above, furnishing the compounds of
the
general formula XXVI.
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Finally, the compounds of the invention of the general formula I with indoline
moiety
are prepared from the compounds of the general formula XXVI by reductive
all~ylation or by nucleophilic substitution reactions as described above.
Also, the
compounds of the invention of the general formula I with indole moiety can be
obtained from indolines of the general formula I by means of dehydrogenation
as
described above.
Examples
Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument
equipped
with an APPI (atmospheric pressure photo ionisation) ion source and Shimadzu
LC-
8A/SLC-l0A LC system. Column: 30 X 4.6 mm Waters Symmetry C18 column with
3.5 ~m paxticle size; Solventsystem: A = water/trifluoroacetic acid (100:0.05)
and B =
water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient
elution
with 90% A to 100% B in 4 minutes and with a flow rate of 2 mL/minute. Purity
was
determined by integration of the UV (254 nm) and ELSD trace. The retention
times
(RT) are expressed in minutes.
Preparative LC-MS-purification was performed on the same instrument. Column:
50
X 20 mm YMC ODS-A with 5 ~,m particle size; Method: Linear gradient elution
with
80% A to 100% B in 7 minutes and with a flow rate of 22.7 mL/minute. Fraction
collection was performed by split-flow MS detection.
1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500
instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.8%D) were
used as solvents. TMS was used as internal reference standard. Chemical shift
values
are expressed in ppm-values. The following abbreviations are used for
multiplicity of
NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui =
quintet, h = heptet,
dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of
triplets, m
= multiplet and br. = broad.
Preparation of intermediates
Preparation of intermediates of the general formula XXII and XIV
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77
1-Tz~ifZuo~oacetyl-S-zzitroifzdoline.
To a suspension of 5-nitroindoline (5.51 g, 33.56 mrnol) in 1,2-dichloroethane
(15 ml)
trifluoroacetic anhydride (20 ml) was added. After 60 min the obtained
solution was
quenched with heptane (200 ml) acid the title compound was separated by
filtration in
two crops. Yield 7.12 g, 81.5%. 1H NMR (DMSO-d~): 3.34 (t, 2H), 4.38 (t, 2H),
8.19
(m, 3H).
1-Trifluo>~oacetyl-4-clzlo>~oindolihe was prepared analogously from 4-
chloroindoline
to [S. M. Bromidge, S. Dabbs, D. T. Davies, D. M. Duckworth, I. T. Forbes et
al. J.
Med. Clzezzz. 41, 1998, 1598-1612]. 1H NMR (DMSO-d~): 3.26 (t, 2H), 4.34 (t,
2H),
7.27 (d, 1H), 7.34 (t, 1H), 8.01 (d, 1H).
Preparation of intermediates of the general formula XV
1-Ti~ifluo~oacetyl-4-clzloz~o-5-nitroindoliyze.
To a solution of 1-trifluoroacetyl-4-chloroindoline (197 mg, 0.838 mmol) in
acetic
anhydride (3 ml) and acetic acid (0.3 ml) a solution of fuming HN03 (0.4 ml)
was
added by small portions during 5 hours. The resulting reaction mixture was
poured
2o into ice, neutralised with saturated aqueous NaHC03, and extracted with
ethyl acetate.
The organic solution was filtered via plug of SiOa (10 g), evaporated in vacuo
and
purified by flash chromatography on SiOa with gradient heptane - 1:4 ethyl
acetate/heptane to give 70 mg of the title compound as yellow solid, yield 31
%. 1H
NMR (DMSO-d~): 3.33 (t, 2H), 4.42 (t, 2H), 8.10 (s, 2H).
Preparation of intermediates of the general formula XX
1-(5-Clzlo>rothioplzezz-2 ylzyzethyl)-S->zitroizzdolifze.
3o To a solution of 5-nitroindoline (3.23 g, 19.67 mmol) and 5-chlorothiophene-
2-
carboxaldehyde (4.2 g, 28.6 mmol) in methanol (45 ml) and acetic acid (8 ml) a
solution of NaBH3CN (0.9 g) in methanol (8 ml) was added dropwise during 10
min.
The obtained reaction mixture was stirred overnight. The title compound was
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78
separated by filtration, washed with methanol and water and dried in vacuo to
furnish
4.6 g of red crystalline solid. Yield 79.3%. LC/MS (m/z) 293.9 ([M]+); RT =
3.59,
(UV, ELSD) 98%, 99.8%. 1H NMR (DMSO-d~): 3.04 (t, 2H), 3.62 (t, 2H), 4.68 (s,
2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.01 (d, 1H), 7.85 (unresolved m, 1H), 8.00
(dd, 1H).
The following compound was prepared analogously using appropriate aldehydes:
1-(4-Fluoroberzzyl)-5-hitroitzdolitze.
Yellow needles, yield 3.66 g, 72.2%. LC/MS (m/z) 272.0 ([M]+); RT = 3.35, (UV,
ELSD) 99%, 100%. 1H NMR (DMSO-d6): 3.06 (t, 2H), 3.61 (t, 2H), 4.52 (s, 2H),
6.63 (d, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.83 (unresolved m, 1H), 7.97 (dd,
1H).
Preparation of intermediates of the general formula XXI, XXII, and XVI
1-(5-Chloz~otlziophen-2 ylmethyl)-5-ami>zoifzdolizze.
To a cold (ice/water bath) vigorously stirred solution of 1-(5-Chlorothiophen-
2-
ylmethyl)-5-nitroindoline (4.013 g, 13.62 mmol) in THF (100 ml) and acetic
acid (15
ml) zinc powder (25 g) was added by small portions maintaining the temperature
below 40°C. The cold bath removed and the stirring continued at room
temperate until
2o reaction completion (1 hour). The obtained suspension was filtered via a
plug of Si02
(25 g) with ethyl acetate as an eluent and obtained solution was evaporated in
vacuo.
The obtained residue was treated with saturated aqueous NaHC03, extracted with
ethyl acetate, dried over Na2S04 and evaporated in vacuo to give the title
compound
as a darl~ green oil. Yield 3.30 g, 91.5%. LC/MS (m/z) 265.9 ([M+1]+); RT =
1.85,
(UV, ELSD) 93%, 100%. 1H NMR (DMSO-d6): 2.73 (t, 2H), 3.08 (t, 2H), 4.25 (s,
2H), 4.40 (br. s, 2H, NHz), 6.30 (dd, 1H), 6.41 (d, 1H), 6.43 (unresolved m,
1H), 6.89
(d, 1H), 6.95 (d, 1H).
The following compounds were prepared analogously:
1-(4-Fluorobehzyl)-5-aminoindoline.
The obtained crude product after filtation via SiOz was dissolved in a small
amount of
methanol, quenched with saturated aqueous NaHC03, and the title compound was
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79
separated by filtration, washed with water, and dried in vacuo. Yield 2.40 g,
93.2%,
darlc violet solid. LC/MS (m/z) 265.9 ([M+1]+); RT = 1.74, (UV, ELSD) 87%,
98%.
1H NMR (DMSO-d~): 2.72 (t, 2H), 3.01 (t, 2H), 4.04 (s, 2H), 4.36 (br. s, 2H,
NHa),
6.28 (d, 1H), 6.34 (d, 1H), 6.44 (s, 1H), 7.14 (t, 2H), 7.38 (t, 2H).
1-Ti~ifluos°oacetyl-5-aminoindolihe.
The title compound was prepared from 1-trifluoroacetyl-5-nitroindoline (6.67
g, 25.65
mmol). The crude product after filtration via Si02 was used in the next step
without
purification. Yield 6.11 g, 100%. LC/MS (m/z) 230.1 ([M]+); RT = 1.29, (UV,
ELSD)
l0 97%, 98%. 1H NMR (DMSO-dG): 3.10 (t, 2H), 4.18 (t, 2H), 5.18 (br. s, 2H,
NH2),
6.43 (dd, 1H), 6.53 (s, 1H), 7.75 (d, 1H).
1-Ti~ifluoYOacetyl-4-chlo~o-5-aminoindolirae.
1H NMR (CDCl3): 3.23 (t, 2H), 4.28 (t, 2H), 6.67 (d, 1H), 7.93 (d, 1H).
Preparation of intermediates of the general formula _X_XTV and XVII
3,3-Dimethyl-N ~1-(2,2,2-tf~ifluor~oacetyl)-2,3-dil2ydf°o-IH indol-S
ylJ-buty~amide.
To a cold (ice/water bath) solution of 1-trifluoroacetyl-5-aminoindoline (2.69
g, 11.7
2o mmol) in CH2Cl2 test-butylacetyl chloride (1.88 g, 14 rmnol) was added
followed by
addition of Et3N (4 ml). After 5 min the reaction mixture was quenched with
saturated
aqueous NaHCO3 and stirred for 30 min. The organic layer was filtered via plug
of
SiOz (20 g) with ethyl acetate as an eluent and evaporated to a small volume.
It was
quenched with heptane and the title compound was separated by filtration.
Yield 3.10
g, 81%, white solid. LC/MS (m/z) 329.2 ([M+1]+); RT = 3.04, (UV, ELSD) 97%,
100%. 1H NMR (DMSO-d~): 1.02 (s, 9H), 2.18 (s, 2H), 3.22 (t, 2H), 4.26 (t,
2H), 7.38
(dd, 1H), 7.72 (s, 1H), 7.96 (d, 1H), 9.86 (s, 1H, NHCO).
The following compounds were prepared analogously from 1-trifluoroacetyl-5-
aminoindoline and appropriate acid chloride or chloroformiate:
N ~4-Chloro-1-(2, 2, 2-trifluoroacetyl)-2, 3-dihydro-I H indol-S-ylJ-3, 3-
dimethylbutyranaide was prepared from 1-trifluoroacetyl-4-chloro-5-
aminoindoline.
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The reaction mixture was evaporated and used in the next step without
characterisation.
2, 2-Dimethyl-N ~1-(2, 2, 2-t~ifluo~oacetyl)-2, 3-dihyd~o-1 H ihdol-5-ylJ
pr~opionamide.
5 1H NMR (DMSO-d~): 1.22 (s, 9H), 3.23 (t, 2H), 4.28 (t, 2H), 7.47 (dd, 1H),
7.71 (s,
1H), 7.96 (d, 1H), 9.26 (s, 1H, NHCO).
2-(4-Fluo~ophefzyl)-N ~1-(2,2,2-t~~ifluoroacetyl)-2,3-dilaydy~o-IH ih.dol-5
ylJ-
acetanaide.
1o LC/MS (m/z) 367.0 ([M+1]+); RT = 3.00, (UV, ELSD) 92%, 99%. 1H NMR (DMSO-
d~): 3.22 (t, 2H), 3.63 (s, 2H), 4.27 (t, 2H), 7.15 (t, 2H), 7.36 (dd, 2H),
7.39 (dd, 1H),
7.69 (s, 1H), 7.97 (d, 1H), 10.24 (s, 1H, NHCO).
~1-(2,~,2-Ti~ifluof°oacetyl)-2,3-dilaydro-IH indol-S ylJ-ca~bamic acid
ethyl ester'.
15 The title compound was prepared using 1,2-dichloroethane as a solvent and
pyridine
as a base. LC/MS (m/z) 302.1 ([M]+); RT = 2.85 (UV, ELSD) 79%, 100%. 1H NMR
(DMSO-d~): 1.24 (t, 3H), 3.22 (t, 2H), 4.12 (q, 2H), 4.26 (t, 2H), 7.31 (br. d
(unresolved dd), 1H), 7.49 (s, 1H), 7.94 (d, 1H), 9.70 (s, 1H, NHCO).
20 ~l-(2,2,2-T~ifluoroacetyl)-2,3-dihydt~o-IH indol-5 ylJ-ca~bamic acid p~opyl
ester.
The title compound was prepared using 1,2-dichloroethane as a solvent and
pyridine
as a base. LC/MS (m/z) 315.9 ([M]+); RT = 3.11 (UV, ELSD) 89%, 99%. 1H NMR
(DMSO-d~): 0.93 (t, 3H), 1.64 (m, 2H), 3.22 (t, 2H), 4.03 (t, 2H), 4.26 (t,
2H), 7.32
(br. d (unresolved dd), 1H), 7.50 (s, 1H), 7.94 (d, 1H), 9.71 (s, 1H, NHCO).
Preparation of intermediates of the general formula XXV and XXVI
3, 3-DiTnethyl-N (6-vitro-2, 3-dilaydro-1 H iradol-S yl)-butyramide.
To a cold (ice/water bath) stirred solution of 3,3-dimethyl-N-[1-(2,2,2
3o trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-butyramide (1.96 g, 5.98 mmol)
in acetic
anhydride (30 ml) and acetic acid (5 ml) a solution of fuming HN03 (650 mg,
10.3
mtnol) in acetic acid (5 ml) was added dropwise during 5 min. After 5 min the
reaction mixture was poured into ice and neutralised with solid NaHC03 which
was
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added by small portions with stirring until gas formation ceased. The yellow
solid of
3,3-dimethyl-N-[6-nitro-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-
butyramide was filtered, washed with water and dried in vacuo. LC/MS (m/z)
374.0
([M+1]+); RT = 3.45 (UV, ELSD) 94%, 99%. 1H NMR (DMSO-d~): 1.03 (s, 9H),
2.23 (s, 2H), 3.35 (t, 2H), 4.36 (t, 2H), 7.66 (s, 1H), 7.51 (s, 1H), 10.17
(s, 1H,
NHCO).
The solid was redissolved in methanol (30 ml) followed by addition of I~aC03
(2.0 g) in water (7 ml). The colour changed immediately from yellow to dark
red.
After stirring for 15 min the reaction mixture was poured into ice/water and
the title
l0 compound was isolated by filtration to give 1.52 g of purple solid, yield
91.8%.
LC/MS (mlz) 277.0 ([M]+); RT = 2.30 (UV, ELSD) 91%, 99%. 1H NMR (CDC13):
1.10 (s, 9H), 2.29 (s, 2H), 3.10 (t, 2H), 3.63 (t, 2H), 4.80 (very br. s, NH),
7.30 (s,
1H), 8.46 (s, 1H), 10.14 (s, 1H, NHCO).
The following compounds were prepared analogously:
2,2-Dimetlayl-N (6-hit~o-2,3-dihydro-IH indol-S yl) p~opiofaamide.
LC/MS (m/z) 264.1 ([M+1]+); RT = 2.19 (UV, ELSD) 96%, 95%. 1H NMR (DMSO-
d~): 1.19 (s, 9H), 3.00 (t, 2H), 3.51 (dt, 2H), 5.98 (br. s, NH), 6.97 (s,
1H), 7.44 (s,
2o 1H), 9.57 (s, 1H, NHCO).
2-(4-Fluorophenyl)-N (6-nit~o-2,3-dihyd~~o-IH indol-5 yl)-acetamide.
LC/MS (m/z) 315.0 ([M]+); RT = 2.33 (UV, ELSD) 87%, 99%. 1H NMR (DMSO-d~):
2.99 (t, 2H), 3.49 (dt, 2H), 3.62 (s, 2H), 6.00 (br. s, NH), 6.91 (s, 1H),
7.15 (t, 2H),
7.28 (s, 1H), 7.33 (dd, 2H), 9.95 (s, 1H, NHCO).
(6-Nit~o-2,3-dilzydro-1H indol-5 ylJ-carbarnic acid ethyl ester.
LC/MS (m/z) 250.9 ([M]+); RT = 1.92 (UV, ELSD) 93%, 98%. 1H NMR (DMSO-d~):
1.19 (t, 3H), 2.99 (t, 2H), 3.50 (dt, 2H), 4.06 (q, 2H), 5.96 (br. s, NH),
6.92 (s, 1H),
7.24 (s, 1H), 9.22 (s, 1H, NHCO).
~6-Nit~o-2, 3-dilayd~o-1 H indol-5 ylJ-carbatraic acid p~opyl ester.
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LC/MS (m/z) 264.9 ([M]+); RT = 2.36 (UV, ELSD) 93%, 99%. 1H NMR (DMSO-d6):
0.89 (t, 3H), 1.59 (m, 2H), 2.99 (t, 2H), 3.50 (t, 2H), 3.97 (t, 2H), 5.96
(br. s, NH),
6.92 (s, 1H), 7.24 (s, 1H), 9.22 (s, 1H, NHCO).
3,3-Di~raetlayl-N (6-bf~omo-2,3-dihyd~o-IH iradol-S yl)-butyramide.
To a stirred solution of 3,3-dimethyl-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-
1H-
indol-5-yl]-butyramide (0.624 g, 1.90 mmol) in acetic acid (20 ml) bromine
(0.195
ml, 1 eq.) was added. After 45 min more bromine (0.195 ml) was added. The
reaction
mixture was poured into soution of NaZS03 (5 g) in water (100 ml). The product
N-[6-
io bromo-1-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-indol-5-yl]-3,3-
dimethylbutyramide
was separated by filtration, washed with saturated aqueous NaHC03 and water to
furnish 0.555 g of colorless solid. Yield 71%. LC/MS (m/z) 409.0 ([M+1]+); RT
=
3.38 (UV, ELSD) 97.5%, 85.5%. 1H NMR (DMSO-d6): 1.05 (s, 9H), 2.25 (s, 2H),
3.22 (t, 2H), 4.30 (t, 2H), 7.55 (s, 1H), 8.25 (s, 1H), 9.37 (s, 1H, NHCO).
The solid (100 mg) was redissolved in methanol (10 ml) followed by addition of
K2CO3 (0.52 g) in water (5 ml). After stirring at 50°C for 5 min, the
reaction mixture
was poured into ice/water mixture and the title compound was isolated by
filtration to
give 0.057 g of colorless solid. Yield 75%. LC/MS (m/z) 313.0 ([M+1]+); RT =
1.71,
(UV, ELSD) 97.5%, 98.9%.
Preparation of intermediates of the general formula XVIII
N (4-Claloro-2, 3-dihydf°o-1 H indol-5 yl)-3, 3-
ditnethylbutyramide.
To a solution of crude N-[4-Chloro-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-
indol-5-
yl]-3,3-dimethylbutyramide (ca. 100 mg) in MeOH (10 ml) a solution of K2C03
(0.5
g) in water (2 ml) was added. The obtained mixture was heated at 50°C
for 5 min and
quenched with ethyl acetate and water. The organic solution was filtered via
Si02 (5
g) and evaporated in vacuo to furnish 20 mg of the title compound. The crude
product
was used in the next step without purification. LC/MS (m/z) 267.1 ([M+1]+); RT
=
1.61 (UV, ELSD) 45%, 78%.
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N (2,3-Dilzydro-IH indol-5 yl)-2-(4 fluoro phenyl)-acetamide.
To a solution of 2-(4-Fluorophenyl)-N-[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-
1H-
indol-5-yl]-acetamide (1.3 g, 3.55 mmol) in methanol (50 ml) K2C03 (7.6 g) in
water
(20 ml) was added. The reaction mixture was lcept at 50°C for 5 min,
poured into
water and the title compound was separated by filtration. Yield 0.742 g,
77.4%.
LC/MS (m/z) 271.0 ([M+1]+); RT = 1.42, (UV, ELSD) 94.5%, 98.7%. 1H NMR
(DMSO-d~): 2.85 (t, 2H), 3.36 (t, 2H), 3.55 (s, 2H); 5.28 (br, 1H, NH); 6.41
(d, 1H);
7.06 (dd, 1H); 7.12 (t, 2H); 7.28 (d, 1H); 7.35 (dd, 2H); 9.75 (s, 1H, NHCO).
to The following compound was prepared analogously from 3,3-dimethyl-N-[1-
(2,2,2-
trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]-butyramide:
N (2,3-Dihydr~o-IH indol-5 yl)-3,3-dirnethyl-buty~amide.
LC/MS (m/z) 232.9 ([M+1]+); RT = 1.43, (UV, ELSD) 94.4%, 88.1%. 1H NMR
(DMSO-d~): 1.00 (s, 9H); 2.09 (s, 2H); 2.84 (t, 2H); 3.37 (t, 2H); 5.25 (br,
1H, NH);
6.41 (d, 1H); 7.02 (dd, 1H); 7.29 (d, 1H); 9.34 (s, 1H, NHCO).
Compounds of the invention
Example 1
1 a N ~4-Chloro-1-(4-trifluoromethylbenzyl)-2, 3-dihydro-1 H indol-5 ylJ-3, 3-
dimethylbuty~an2ide.
To a solution of N-(4-chloro-2,3-dihydro-1H-indol-5-yl)-3,3-dimethylbutyramide
(10
mg), 4-trifluomethylbenzaldehyde (0.06 ml) and acetic acid (0.03 ml) in
methanol
(0.3 ml) NaBH3CN (100 mg) was added. After 60 min the reaction mixture was
partitioned between ethyl acetate and saturated aqueous NaHC03 solution. The
organic layer was filtered via plug of SiOz (2 g), evaporated and purified by
3o preparative LC/MS to give 11 mg of the title compound as colourless solid.
LC/MS
(m/z) 425.2 ([M+1]+); RT = 4.01, (CTV, ELSD) 95%, 99%. 1H NMR (DMSO-d~): 1.03
(s, 9H), 2.16 (s, 2H), 2.97 (t, 2H), 3.40 (t, 2H), 4.41 (s, 2H), 6.48 (d, 1H),
7.03 (d,
1H), 7.56 (d, 2H), 7.72 (d, 2H), 9.12 (s, 1H, NHCO).
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The following compound was prepared analogously using 5-chloro-2-
thiophenecarboxaldehyde:
1b N ~4-Chloro-1-(S-chlorothiophen-2 ylnaethyl)-2,3-dilaydf-o-IH indol-SyIJ-
3,3-
dimethylbutyrarnide.
LC/MS (m/z) 397.0 ([M+1]+); RT = 3.91, (UV, ELSD) 97%, 99%. 1H NMR (DMSO-
d~): 1.03 (s, 9H), 2.17 (s, 2H), 2.92 (t, 2H), 3.37 (t, 2H), 4.46 (s, 2H),
6.60 (d, 1H),
6.95 (d, 1H), 6.99 (d, 1H), 7.07 (d, 1H), 9.12 (s, 1H, NHCO).
to Example 2
2a ~1-(4-Fluo~obenzyl)-2,3-dihydno-1H indol-5 ylJ-car~bamic acid propyl ester
To a cold (ice/water bath) solution of 1-(4-fluorobenzyl)-5-aminoindoline in
acetonitrile (0.2 M, 0.15 ml) propyl chloroformiate (0.02 ml or ca. 20 mg) was
added
i5 followed by pyridine (0.03 ml). The reaction mixture was allowed to stand
at room
temperature for 60 min and evaporated in vacuo. The title compound was
separated
by preparative LC/MS, yield 5.8 mg, 59%. LC/MS (m/z) 329.1 ([M+1]+); RT =
2.68,
(LTV, ELSD) 94%, 99%.
2o The following compounds were obtained analogously from corresponding 5-
aminoindolines and commercially available appropriate chloroformiates,
carbamyl
chlorides, sulphonyl chlorides, acid chlorides, di-tert-butyl dicarbonate
(Boc20) or
isocyanates, which are listed in the Table 1 below. Pyridine was used as a
base in case
of chloroformiates, carbamyl chlorides, and sulphonyl chlorides. Triethylamine
was
25 used as a base in case of acid chlorides. No base was used in case of
isocyanates and
Boc20:
2b N ~l-(4-Fluoroberazyl)-~,3-dilaydro-IH indol-S ylJ-C phenyl-
methanesulforzamide.
LC/MS (m/z) 395.3 ([M-1]+); RT = 3.17, (UV, ELSD) 80%, 100%.
2c 4-Fluo~o-N ~l-(4 fluorobenzyl)-2,3-dihydro-IH indol-5 ylJ-benzarnide.
LC/MS (mlz) 365.4 ([M+1]+); RT = 2.90, (UV, ELSD) 96%, 100%.
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2dN ~l-(4-Fluoroberzzyl)-~,3-dihyd>"o-IH indol-5 ylJ-3,3-dimethylbutyramide.
LC/MS (m/z) 341.1 ([M+1]+); RT = 2.79, (W, ELSD) 94%, 100%.
2e N ~1-(4-Fluorobenzyl)-2,3-dihydz~o-IH indol-S ylJ-2-thioplzen-~
ylacetanzide.
LC/MS (rn/z) 367.1 ([M+1]+); RT = 2.72, (UV, ELSD) 93%, 100%.
2f N ~1-(4-Fluor~obenzyl)-2,3-dihydro-1H indol-5 ylJ-2-(4 fluoropherzyl)-
acetamide.
LC/MS (m/z) 379.3 ([M+1]+); RT = 2.82, (UV, ELSD) 95%, 100%.
l0 2g 3-~1-(5-Chlorothioplaen-2-ylmethyl)-2,3-dihyd>"o-IH indol-5 ylJ-1,1-
diisopnopylurea.
LC/MS (m/z) 392.3 ([M+1]~); RT = 3.14, (UV, ELSD) 75%, 89%.
2h Mo3pholine-4-carboxylic acid ~l-(5-chlol"otlziophen-2 ylmethyl)-2,3-dihydro-
IH
15 indol-5-ylJ-amide.
LC/MS (m/z) 378.2 ([M+1]+); RT = 2.33, (UV, ELSD) 97%, 100%.
2i Pyrnolidine-1-caz"boxylic acid ~l-(S-chloz"othiophen-2 ylznetlzyl)-2,3-
dihyd~o-IH
indol-5 ylJ-amide.
2o LC/MS (m/z) 362.0 ([M+1]+); RT = 2.48, (UV, ELSD) 83%, 99%.
2j ~1-(S-Clzlorothioplzen-2 ylnzethyl)-2,3-dihydro-IH indol-S ylJ-carbamic
acid 2-
benzyloxyethyl este>=
LC/MS (m/z) 442.1 ([M]+); RT = 3.52, (UV, ELSD) 62%, 86%.
2k 3-~1-(5-Chloy~othiophen-2 ylmethyl)-2,3-dilayd~o-IH indol-S ylJ-1-methyl-1-
propyluz~ea.
LC/MS (m/z) 364.3 ([M+1]+); RT = 2.73, (UV, ELSD) 94%, 100%.
21 ~1-(5-Chlo~otlaiophen-2 ylmethyl)-2,3-dilzydro-IH indol-5 ylJ-ca~bamic acid
tert-
butyl ester:
LC/MS (m/z) 364.3 ([M]+); RT = 3.50, (UV, ELSD) 97%, 100%.
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86
Zm N ~I-(5-Chlor~otlziophen-2 ylmethyl)-2,3-dihydz°o-IH indol-5 ylJ-C
plaenyl-
methazzesulfonamide.
LC/MS (mlz) 418.2 ([M]+); RT = 3.44, (UV, ELSD) 98%, 100%.
2n Butane-1-sulfonic acid ~l-(5-chlo~othioplzen-2 ylmet7zyl)-2,3-dihydro-IH
indol-5-
ylJ-amide.
LC/MS (m/z) 384.1 ([M]+); RT = 3.43, (UV, ELSD) 98%, 100%.
2o N ~l-(5-Clzlo~otlziopl2en-2 ylmethyl)-2,3-dilzydro-IH irzdol-5 ylJ-4-
l0 fluorobenzamide.
LC/MS (m/z) 386.0 ([M]+); RT = 3.35, (UV, ELSD) 91%, 100%.
2p N ~1-(5-Chlo~othiophen-2 ylmethyl)-2,3-dihydz°o-IH izzdol-S ylJ-2,2-
dimethylpropionamide.
15 LC/MS (mlz) 349.0 ([M+1]+); RT = 3.21, (UV, ELSD) 94%, 100%.
2q N ~1-(5-CJzlorothiophen-2 ylmethyl)-2,3-dihyd>"o-IH indol-5 ylJ-2-
phenoxyacetamide.
LC/MS (m/z) 398.0 ([M]+); RT = 3.46, (ITV, ELSD) 80%, 100%.
2r N ~1-(5-Chloz°ot7zioplzezZ-2 ylmethyl)-2, 3-dihydf°o-1 H
indol-5 ylJ-3, 3-
diznethylbuty>"amide.
LC/MS (rn/z) 362.1 ([M]+); RT = 3.34, (LTV, ELSD) 84%, 99%.
2s N ~l-(5-Chlof°othiophen-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-
butyramide.
LC/MS (m/z) 335.0 ([M+1]+); RT = 2.95, (UV, ELSD) 78%, 99%.
2t Cyclopentanecaz~boxylic acid ~1-(S-chlonothiophen-2-ylznethyl)-2,3-dihydro-
IH
indol-5 ylJ-amide.
LC/MS (m/z) 361.1 ([M+1]+); RT = 3.22, (UV, ELSD) 84%, 99%.
2u N ~l-(5-Chlorotlziophen-2 ylznetlzyl)-2,3-dihydro-1H izzdol-S ylJ-2-
thiophen-2-
ylacetamide.
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LC/MS (m/z) 388.1 ([M]+); RT = 3.22, (UV, ELSD) 76%, 98%.
2v N ~1-(5-Chlorothioplaen-2 ylmethyl)-2,3-dihydro-IH indol-S ylJ-
isonicotinamide.
LC/MS (m/z) 370.0 ([M+1]+); RT = 2.22, (UV, ELSD) 96%, 100%.
2w N ~1-(5-Clalorothiophen-2 ylmethyl)-~, 3-dihydro-1 H itadol-5 ylJ-4-
dimethylanairaobenzamide.
LC/MS (m/z) 412.0 ([M+1]+); RT = 3.09, (IJV, ELSD) 87%, 100%.
2x N ~l-(S-Chlorothiopheya-2 ylmethyl)-2,3-dihydro-1H indol-5 ylJ-2-(4-
fluorophenyl)-acetamide.
LC/MS (m/z) 401.0 ([M+1]+); RT = 3.31, (UV, ELSD) 84%, 100%.
2y N ~1-(S-Clalorothiophen-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-6-
trifluorometlaylnicotinamide.
LC/MS (m/z) 437.1 ([M]+); RT = 3.46, (UV, ELSD) 90%, 99%.
2z 1-tent-Butyl-3-~l-(5-chlorothiopl2en-2 ylmetlayl)-2,3-dihydro-1H indol-5
ylJ-urea.
LCIMS (m/z) 364.3 ([M+1]+); RT = 2.80, (UV, ELSD) 97%, 100%.
2aa 1-~1-(5-Chlorothiophen-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-3-ethylurea.
LC/MS (m/z) 335.1 ([M]+); RT = 2.34, (UV, ELSD) 96%, 100%.
tab 1-Benzyl-3-~1-(S-chlorothiophera-2 ylmethyl)-2,3-dihydro-IH indol-5 ylJ-
urea.
LC/MS (m/z) 398.2 ([M+1]+); RT = 2.85, (UV, ELSD) 84%, 100%.
2ac 1-~1-(S-Chlorotlaiophen-2 ylmethyl)-2,3-dilaydro-IH indol-5 ylJ-3
phenethylurea.
LC/MS (rn/z) 411.9 ([M+1]+); RT = 3.00, (UV, ELSD) 87%, 97%.
tad 1-~l-(5-Chlorothiopheta-2 ylmethyl)-2,3-dilaydro-1H indol-S ylJ-3-thiophen-
2-
ylurea.
LC/MS (m/z) 390.0 ([M+1]+); RT = 3.01, (CTV, ELSD) 94%, 92%.
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tae 1-~1-(5-ChlorotlZiophen-2 ylrnethyl)-2,3-dihydro-IH indol-S ylJ-3-thiophen-
3-
ylurea.
LC/MS (m/z) 390.2 ([M+1]+); RT = 2.98, (UV, ELSD) 96%, 100%.
2af ~1-(5-Chlorothiophen-2 ylntethyl)-2,3-dihydro-IH indol-5-ylJ-ca>~bamic
acid
propyl ester.
LC/MS (m/z) 351.2 ([M]+); RT = 3.48, (TJV, ELSD) 94.0%, 98.0%. 1H NMR
(DMSO-d~): 0.92 (t, 3H); 1.62 (sextet, 2H); 2.84 (t, 2H); 3.22 (t, 2H), 3.89
(t, 2H),
4.38 (s, 2H), 6.59 (d, 1H); 6.92 (d, 1H); 6.98 (d, 1H); 7.07 (br. d (dd), 1H);
7.18 (br. s,
l0 1H); 9.20 (br s, 1H, NH).
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Table 1. Chloroformiates, sulphonyl chlorides, carbamyl chlorides, acid
chlorides,
and isocyanates used in the preparation of compounds of the invention 2a - 2af
Compound
Catalog
of the Reagent MW Supplier
n~ber
invention
2a n-PROPYL CHLOROFORMATE 122.55 Aldrich 24,946-7
2b ALPHA-TOLUENESULFONYL 190.649
CHLORIDE Aldrich 15,971-9
2c 4-FLUOROBENZOYL CHLORIDE 158.559Aldrich 11,994-6
2d TERT-BUTYLACETYL CHLORIDE 134.605Aldrich B8,880-2
2e THIOPHENE-2-ACETYL CHLORIDE 160.624Aldrich 19,599-5
2f 4-FLUOROPHENYLACETYL CHLORIDE Aldrich 46,695-6
172.585
2g DIISOPROPYLCARBAMYL CHLORIDE 163.647Aldrich 531,027-1
2h MORPHOLINE-4-CARBONYL 149.576
CHLORIDE Aldrich 34,829-5
2i 1-PYRROLIDINECARBONYL CHLORIDE133.577 Aldrich 20,635-0
2j 2-BENZYLOXYETHYL 214.647
CHLOROFORMATE Aldrich 52,514-6
2k N-ISOPROPYL-N-METHYL-CARBAMYL LundbeclcC0005221
135.59
CHLORIDE
21 DI-TERT-BUTYL DICARBONATE 218.247 Fluka 34660
2m ALPHA-TOLUENESULFONYL 190.649
CHLORIDE Aldrich 15,971-9
2n 1-BUTANESULFONYL CHLORIDE 156.632 Aldrich 26,360-5
20 4-FLUOROBENZOYL CHLORIDE 158.559 Aldrich 11,994-6
2p PIVALOYL CHLORIDE 120.578 Aldrich T7,260-5
2q PHENOXYACETYL CHLORIDE 170.594 Aldrich 15,862-3
2r TERT-BUTYLACETYL CHLORIDE 134.605 Aldrich B8,880-2
2s BUTYRYL CHLORIDE 106.551 Aldrich 10,961-4
2t CYCLOPENTANECARBONYL 132.589
CHLORIDE Aldrich 32,831-6
2u THIOPHENE-2-ACETYL CHLORIDE 160.624 Aldrich 19,599-5
2v ISONICOTINOYL CHLORIDE 178.018 Aldrich 22,875-3
HYDROCHLORIDE
2w 4-DIMETHYLAM1NOBENZOYL 183.637
CHLORIDE Aldrich 52,611-8
2x 4-FLUOROPHENYLACETYL CHLORIDE Aldrich 46,695-6
172.585
2y 6-(TRIFLUOROMETHYL)NICOTINOYL 209.554 Fluoroche9368
CHLORIDE m
2z TERT-BUTYL ISOCYANATE 99.132 Aldrich 14,445-2
2aa ETHYL ISOCYANATE 71.08 Aldrich E3,330-0
tab BENZYL ISOCYANATE 133.149 Aldrich 22,726-9
2ac PHENETHYL ISOCYANATE 147.176 Aldrich 45,617-9
tad 2-THIENYL ISOCYANATE 125.151 MaybridgeCC 13006
tae 3-THIENYL ISOCYANATE 125.151 MaybridgeCC 13106
2af n-PROPYL CHLOROFORMATE 122.55 Aldrich 24,946-7
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Example 3
3a 2,2-Dimetlayl-N ~6-raitf°o-1-(4-t~ifluo~omethylbehzyl)-2,3-dihydro-
IH indol-5 ylJ-
propiofaamide.
5 To a stirred solution of 2,2-Dimethyl-N-(6-vitro-2,3-dihydro-1H-indol-5-yl)-
propionamide (0.379 g, 1.44 ~ mmol) in methaaiol (25 ml) 4-
trifluoromethylbenzaldehyde (0.8 ml), acetic acid (0.8 ml) and a solution of
NaBH3CN (0.8 g) in methanol (10 ml) were added in 4 portions during 3 hours
until
reaction completion. The obtained reaction mixture was concentrated in vacuo
to a
to small volume, quenched with saturated aqueous NaHCO3 solution, and
sonicated for
several minutes. The title compound was separated by filtration to give 0.574g
of red
solid, yield 95%. LC/MS (m/z) 422.1 ([M+1]+); RT = 4.11, (UV, ELSD) 96%, 99%.
1H NMR (DMSO-dG): 1.20 (s, 9H), 3.04 (t, 2H), 3.42 (t, 2H), 4.49 (s, 2H), 7.09
(s,
1H), 7.48 (s, 1H), 7.57 (d, 2H), 7.73 (d, 2H), 9.62 (s, 1H, NHCO).
The following compounds were prepared analogously:
3b N ~1-(5-Clalorothiophen-2 ylmethyl)-6-fzitro-2,3-dilayd~o-IH indol-5 ylJ-
2,2-
dimethylpropiof2anzide.
2o LC/MS (m/z) 394.0 ([M+1]+); RT = 4.07, (UV, ELSD) 97%, 98%. 1H NMR (DMSO-
d~): 1.20 (s, 9H), 3.00 (t, 2H), 3.41 (t, 2H), 4.55 (s, 2H), 6.97 (d, 1H),
7.01 (d, 1H),
7.22 (s, 1H), 7.47 (s, 1H), 9.62 (s, 1H, NHCO).
3c 2-(4-Fluo~oplaenyl)-N ~6-vitro-1-(4-trifluor~omethylbeyazyl)-2,3-
dihydt°o-IH indol-
5 ylJ-acetamide.
LC/MS (m/z) 474.2 ([M+1]+); RT = 3.89, (UV, ELSD) 80%, 97%.
3d N ~l-(S-Chlorothiophera-2 ylrnethyl)-6-vitro-2,3-dihydro-IH ihdol-S ylJ-2-
(4-
fluoroplaenyl)-acetanaide.
3o LC/MS (m/z) 445.1 ([M]+); RT = 3.88, (LTV, ELSD) 79.8%, 98.9%. 1H NMR
(DMSO-d~): 2.98 (t, 2H); 3.41 (t, 2H), 3.63 (s, 2H), 4.54 (s, 2H), 6.96 (d,
1H); 7.0 (d,
1H); 7.16 (t, 2H); 7.17 (s, 1H); 7.31 (s, 1H); 7.34 (dd, 2H); 10.03 (s, 1H,
NH).
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3e N~1-(S-Chlo~otlaiophen-2 ylynethyl)-6-rait~o-2,3-dihydno-IH iradol-5 ylJ-
3,3-
dinaethylbuty~arnide.
LC/MS (m/z) 407.1 ([M]+); RT = 4.07, (UV, ELSD) 72.4%, 98.7%. 1H NMR
(DMSO-d~): 1.01 (s, 9H); 2.16 (s, 2H); 2.99 (t, 2H); 3.41 (t, 2H), 4.54 (s,
2H), 6.98 (d,
1H); 7.01 (d, 1H); 7.14 (s, 1H); 7.23 (s, 1H); 9.76 (s, 1H, NH).
Example 4
4aN~6-Amino-1-(S-chlorot7ziophen-2 ylmethyl)-2,3-dihydro-IH indol-S ylJ-3,3-
l0 dimethylbuty~amide.
To a solution of 3,3-dimethyl-N-(6-vitro-2,3-dihydro-1H-indol-5-yl)-butyramide
(15
mg), 5-chloro-2-thiophenecarboxaldehyde (50 mg), and acetic acid (0.1 ml) in
methanol (5 ml) NaBH3CN (200 mg) was added. After 30 min the reaction mixture
was concentrated in vacuo to a small volume and partitioned between ethyl
acetate
and water. The organic solution was washed with aqueous HCl (1 M) and
saturated
aqueous NaHCO3 and evaporated in vacuo.
The obtained residue was dissolved in tetrahydrofuran (10 ml) and acetic acid
(2 ml) followed by addition of Zn powder (1 g). The obtained suspension was
sonicated for 5 min, more Zn powder was added (0.5 g) and sonication continued
for
2 min. The obtained suspension was filtered via a plug of Si02 (2 g),
evaporated, and
the title compound was separated by preparative LC/MS to give 6.5 mg of
colourless
solid, yield 32%. LC/MS (m/z) 378.0 ([M+1]+); RT = 2.36, (UV, ELSD) 93%, 98%.
%. 1H NMR (DMSO-d~): 1.03 (s, 9H), 2.17 (s, 2H), 2.82 (t, 2H), 3.30 (t, 2H),
3.55
(very br. s, NHZ and HZO), 4.38 (s, 2H), 6.27 (s, 1H), 6.81 (s, 1H), 6.93 (d,
1H), 7.00
(d, 1H), 9.27 (br. s, 1H, NHCO).
4b N ~6 ~lmirao-1-(4-tr~ifluoromethylbenzyl)-2,3-dihydro-IH iradol-5 ylJ-2,2-
dimetlaylpropionamide.
The title compound was prepared from the above 2,2-dimethyl-N-[6-vitro-1-(4-
3o trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-propionamide (see example
3) by
reduction with Zn powder as described above for 1-(5-Chlorothiophen-2-
ylmethyl)-5-
aminoindoline (see preparation of intermediates of the general formula XXI).
The
crude solid residue after filtration via Si02 was treated with ethyl acetate
and heptane
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and the title compound was separated by filtration. Yield 0.375 g, 71%,
colourless
solid. LC/MS (m/z) 392.3 ([M+1]+); RT = 2.38, (UV, ELSD) 97%, 99%. 1H NMR
(DMSO-d~): 1.20 (s, 9H), 2.77 (t, 2H), 3.25 (t, 2H), 4.28 (s, 2H), 4.34 (s,
2H, NH2)a
5.96 (s, 1H), 6.64 (s, 1H), 7.56 (d, 2H), 7.71 (d, 2H), 8.47 (s, 1H, NHCO).
The following compounds were prepared analogously from corresponding 6-
utroindolines of the general formula XXV in two steps via reductive alkylation
with
appropriate aldehyde as described in the example 3 followed by reduction with
Zn
powder as described above.
1o
4c N ~6-An2ino-1-(S-chlorothioplzen-2 ylmethyl)-2,3-dihydno-IH indol-S ylJ-2,2-
dimetl2ylpz°opionamide.
LCIMS (m/z) 364.2 ([M+1]+); RT = 2.19, (LTV, ELSD) 98%, 99%. 1H NMR (DMSO
d~): 1.20 (s, 9H), 2.72 (t, 2H), 3.21 (t, 2H), 4.33 (s, 2H), 4.39 (br. s, 2H,
NHZ), 6.07 (s,
1H), 6.64 (s, 1H), 6.91 (d, 1H), 6.98 (d, 1H), 8.48 (s, 1H, NHCO).
4d N ~6 Amino-1-(4-trifluonomethylbenzyl)-2,3-dihyd~o-1H indol-5 ylJ-2-(4-
fluoz°opheszyl)-acetaznide.
LC/MS (m/z) 444.0 ([M+1]+); RT = 2.65, (UV, ELSD) 95%, 99%. 1H NMR (DMSO
2o d~): 2.76 (t, 2H), 3.24 (t, 2H), 3.57 (s, 2H), 4.26 (s, 2H), 4.51 (br. s,
2H, NH2), 5.92 (s,
1H), 6.73 (s, 1H), 7.14 (t, 2H), 7.36 (dd, 2H), 7.55 (d, 2H), 7.71 (dd, 2H),
9.08 (s, 1H,
NHCO).
4e N ~6 Amino-1-(4-tf°ifluo~oTnethylberzzyl)-2,3-dihydro-IH indol-S ylJ-
3,3-
dimethylbuty~amide.
LC/MS (m/z) 406.0 ([M+1]+); RT = 2.58, (UV, ELSD) 97.4%, 99.0%. 1H NMR
(DMSO-dG): 1.02 (s, 9H); 2.12 (s, 2H); 2.78 (t, 2H); 3.24 (t, 2H); 4.28 (s,
2H), 4.48 (s,
2H, NH2); 5.93 (s, 1H); 6.74 (s, 1H); 7.56 (d, 2H); 7.71 (d, 2H); 8.81 (s, 1H,
NH).
4f N ~6 Anzino-1-(4 fluorobenzyl)-2,3-dilzydno-IH indol-S ylJ-3,3-
dimetlzylbutyramide.
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LC/MS (m/z) 356.0 ([M+1]+); RT = 2.26, (UV, ELSD) 96.7%, 98.9%. 1H NMR
(DMSO-d~): 1.02 (s, 9H); 2.13 (s, 2H); 2.73 (t, 2H); 3.18 (t, 2H); 4.16 (s,
2H), 4.48 (s,
2H, NH2); 5.98 (s, 1H); 6.71 (s, 1H); 7.17 (t, 2H); 7.36 (dd, 2H); 8.80 (s,
1H, NH).
4g N ~6-Amino-1-(3 fluoy°o-4-tnifluof~ornethylbenzyl)-2, 3-dihydro-I H
indol-5 ylJ-3, 3-
dimethylbuty~amide.
LCIMS (m/z) 424.0 ([M+1]+); RT = 2.58, (UV, ELSD) 92.0%, 98.8%. 1H NMR
(DMSO-d~): 1.01 (s, 9H); 2.12 (s, 2H); 2.79 (t, 2H); 3.28 (t, 2H); 4.27 (s,
2H), 4.48 (s,
2H, NHZ); 5.90 (s, 1H); 6.75 (s, 1H); 7.39 (d, 1H); 7.45 (d, 1H); 7.78 (t,
1H); 8.80 (s,
l0 1H, NH).
Example 5
5a N ~l-(5-ChloYOthiophen-2 ylmethyl)-IH indol-5 ylJ-3,3-dimetlaylbutyramide.
To a solution of N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-
3,3-
dimethylbutyramide (20 mg) in dimethylsulfoxide-d6 (0.6 ml) 2,3,5,6-
tetrachloro-
[1,4]benzoquinone (65 mg) was added. The obtained mixture was heated at
70°C for
5 min, allowed to cool and poured into aqueous NaHSO3 solution (1 g in 5 ml)
followed by addition of 25% aqueous NH3 (5 ml) and 10% aqueous NaOH (5 ml).
2o The mixture was extracted with CHZC12 (3 x 10 ml), the combined organic
solution
was washed with water and 1M HCI, filtered via plug of Si02 (10 g) and eluted
with
ethyl acetate/heptane (1:1). The crude product after evaporation was purified
by
preparative LC/MS to give 5 mg of the title compound as colourless solid.
LC/MS
(rn/z) 361.1 ([M+1]+); RT = 3.43, (UV, ELSD) 96%, 99%. 1H NMR (DMSO-d~): 1.03
2s (s, 9H), 2.16 (s, 2H), 5.51 (s, 2H), 6.41 (d, 1H), 6.95 (d, 1H), 6.98 (d,
1H), 7.21 (dd,
1H), 7.41 (d, 1H), 7.44 (d, 1H), 7.87 (d, 1H), 9.60 (s, 1H, NHCO).
Example 6
3o 6a N ~6-Bromo-1-(4-trifluoromethylbenzyl)-2,3-dilaydr-o-IH indol-5 ylJ-3,3-
dimethylbutyf°amide.
The title compound was prepared from 3,3-dimethyl-N-(6-bromo-2,3-dihydro-1H-
indol-5-yl)-butyramide (25 mg) and 4-trifluoromethylbenzaldehyde (64 mg) as
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described in example 1. Yield 16.7 mg. LC/MS (m/z) 469.1 ([M+1]+); RT = 3.99,
(UV, ELSD) 97.4%, 95.1 %.
The following compound was prepared analogously using appropriate aldehyde:
6b N ~6-Bf°onao-1-(S-chlo~othiopheya-2 ylmethyl)-2,3-dihydro-IH iyadol-
S ylJ-3,3-
dimethylbuty~amide.
Yield 16.8 mg. LC/MS (m/z) 443.1 ([M+1]+); RT = 3.92, (UV, ELSD) 96.3%, 94.9%.
Example 7
General procedure: To a mixture of aldehyde (25 mg or 0.025 ml) and
appropriate
indoline (7 mg) in methanol (0.5 ml) NaBH3CN (20 mg) in methanol (0.2 ml) was
added followed by acetic acid (0.05 ml). The obtained solution or suspension
was
sonicated for 5 min and then kept at 50°C for 60 min followed by
evaporation in
vacuo. The residue was dissolved in DMSO (2.5 ml) and water (100 ml). The
product
was isolated by preparative LC/MS.
The following compounds were prepared accordingly from either N-(2,3-Dihydro-
1H-
indol-5-yl)-3,3-dimethyl-butyramide (compounds 7a-7z) or from N-(2,3-Dihydro-
1H-
2o indol-5-yl)-2-(4-fluoro-phenyl)-acetamide (compounds 7aa-law) and the
appropriate
aldehyde (see Table 2 below):
7a N ~l-(4-Chlorobenzyl)-2,3-dilayd~o-IH indol-5 ylJ-3,3-dimethylbuty~amide.
LC/MS (m/z) 357.2 ([M+1]+); RT = 3.17, (UV, ELSD) 77.1%, 97.2%.
7b 3, 3-Dimet7zyl-N ~l -(4-trifluorometlaylbenzyl)-2, 3-dilayd~o-1 H indol-S
ylJ-
butyramide.
LC/MS (m/z) 391.4 ([M+1]+); RT = 3.44, (UV, ELSD) 91.8%, 99.6%.
7c N ~l -(4-Isop~opylbenzyl)-2, 3-dihyd~o-I H indol-S ylJ-3, 3-
dimethylbutyt~amide.
LC/MS (m/z) 365.4 ([M+1]+); RT = 3.13, (UV, ELSD) 89.4%, 99.2%.
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7d N ~l-(3-Fluoro-4-t~ifluo~omethylbenzyl)-2,3-dihydr~o-IH indol-5 ylJ-3,3-
dimethylbutyf°amide.
LC/MS (rn/z) 409.2 ([M+1]+); RT = 3.60, (UV, ELSD) 69.6%, 98.2%.
7e N ~1-(6-Chlorobenzo~l, 3Jdioxol-5 ylmethyl)-~, 3-dihydro-I H iradol-5 ylJ-
3, 3-
dirfaethylbuty~~atnide.
LC/MS (m/z) 401.0 ([M+1]+); RT = 3.22, (ITV, ELSD) 94.6%, 99.5%.
7f N ~l -(3, 5-Dimethyl-1 phenyl-1 H pynazol-4 ylmetlayl)-2, 3-
dilzydy°o-1 H indol-5 ylJ-
l0 3, 3-dimethylbutyramide.
LC/MS (m/z) 417.2 ([M+1]+); RT = 2.23, (LTV, ELSD) 93.3%, 98.9%.
7g N ~1-(2-Chlor~o-5-t~ifluoromethylbenzyl)-2, 3-dilaydno-1 H indol-5 ylJ-3, 3-
dimetlzylbutyramide.
15 LC/MS (m/z) 425.2 ([M+1]+); RT = 3.79, (UV, ELSD) 75.4%, 98.4%.
7h N ~1-~5-(4-Chlo~~ophenoxy)-1,3-dinaethyl-IH pyrazol-4 ylmethylJ-2,3-dihydro-
1H
indol-5 yl)-3, 3-dimethylbutyj°amide.
LC/MS (m/z) 467.3 ([M+1]+); RT = 2.71, (UV, ELSD) 95.2%, 99.8%.
7j 3,3-Dimetlayl-N ~l-(6 p-tolyloxy pys°idin-3 ylmethyl)-2,3-dihydro-IH
indol-5 ylJ-
buty~amide.
LC/MS (m/z) 430.2 ([M+1]+); RT = 3.15, (UV, ELSD) 76.6%, 97.9%.
7kN ~1-~6-(4-Clalorophenylsulfanyl) pyridin-3 ylmethylJ-2,3-dihydro-IH indol-S-
yl)-3, 3-dimetlaylbuty~amide.
LC/MS (m/z) 466.0 ([M+1]+); RT = 3.45, (TJV, ELSD) 69.3%, 97.1%.
71 N ~l -~6-(4-Cyanoplzenoxy) pyridin-3 ylmethylJ-2, 3-dihydno-1 H indol-S yl~-
3, 3-
3o dimetl2ylbutyranaide.
LC/MS (m/z) 441.4 ([M+1]+); RT = 2.98, (LJV, ELSD) 79.8%, 98.9%.
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7m 3, 3-Dirnethyl-N ~l -(6-trifluor~omethylpyridin-3 ylmethyl)-2, 3-dihydro-1
H indol-5-
ylJ-butyr~arnide.
LC/MS (m/z) 392.4 ([M+1]+); RT = 3.10, (W, ELSD) 82..5%, 99.5%.
7p 3,3-Dimethyl-N ~l-(3-methyl-berazo~bJthiophen-2 ylmethyl)-2,3-
dihydr°o-IH indol-
ylJ-butyr~amide.
LC/MS (m/z) 393.3 ([M+1]+); RT = 3.56, (UV, ELSD) 72.8%, 97.9%.
7q N ~l -(6-Fluor~o-4H benzo~l, 3Jdioxin-8 ylmethyl)-2, 3-dihydr~o-1 H indol-S
ylJ-3, 3-
dimethylbutyr~amide.
LC/MS (m/z) 399.2 ([M+1]+); RT = 2.75, (UV, ELSD) 84.9%, 99.3%.
7s 3, 3-Dirnethyl-N ~l -(6 phenoxypyr~idin-3 ylnaethyl)-2, 3-dihydr~o-1 H
indol-5 ylJ-
buty~arnide.
1s LC/MS (m/z) 416.2 ([M+1]+); RT = 2.98, (UV, ELSD) 67.5%, 96.5%.
7u 3,3-Dirnethyl-N ~I-(3-methyl-5 phenyl-isoxazol-4 ylmethyl)-2,3-dihydr~o-IH
indol-
5 ylJ-butyr°arnide.
LC/MS (m/z) 404.4 ([M+1]+); RT = 3.24, (UV, ELSD) 97.6%, 99.9%.
7v N (1-Benzo~bJthiophen-2 ylmethyl-2, 3-dihydro-1 H indol-S y1)-3, 3-
dimethylbuty~amide.
LC/MS (m/z) 379.3 ([M+1]+); RT = 3.44, (UV, ELSD) 71.8%, 97.6%.
2s 7w N ~1-~1-(4-Fluorophertyl)-5-methyl-1 H pyrazol-4 ylmethylJ-2, 3-dihydro-
1 H
indol-5 yl)-3,3-dinaethylbutyr°amide.
LC/MS (m/z) 421.4 ([M+1]+); RT = 2.24, (UV, ELSD) 79.5%, 98.9%.
7y 3,3-Dirnethyl-N ~l-(S-rraethylthiophen-2 ylmetlayl)-2,3-dihydro-IH indol-S
ylJ-
butyramide.
LC/MS (m/z) 343.1 ([M+1]+); RT = 2.84, (UV, ELSD) 59.9%, 89.1%.
7z 3, 3-Dirnethyl-N ~1-(4 pyr~r~ol-1 yl-berazyl)-~, 3-dilaydro-I H irrdol-S
ylJ-butyramide.
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LC/MS (m/z) 388.3 ([M+1]+); RT = 3.03, (UV, ELSD) 81.1%, 99.5%.
7aa N ~1-(4-Chlo~obenzyl)-2,3-dilzydy~o-IH iyadol-5 ylJ-2-(4 fluorophenyl)-
acetarnide.
LC/MS (m/z) 395.1 ([M+1]+); RT = 2.99, (UV, ELSD) 93.4%, 93.1%.
lab 2-(4-Fluorophenyl)-N ~l-(4-t~ifluorometlaylbenzyl)-2,3-dihydro-1H indol-S
ylJ-
acetamide.
LC/MS (m/z) 429.1 ([M+1]+); RT = 3.24, (UV, ELSD) 76.6%, 87.4%.
l0 7ac 2-(4-Fluoroplaenyl)-N ~1-(4-isopropylbenzyl)-2,3-dilaydro-IH indol-5
ylJ-
acetamide.
LC/MS (m/z) 403.1 ([M+1]~); RT = 2.96, (LTV, ELSD) 91.5%, 83.7%.
lad 2-(4-Fluof°ophenyl)-N ~1-(3 fluo~o-4-trifluoromethylbenzyl)-2,3-
dihydro-IH
15 indol-S ylJ-acetamide.
LC/MS (m/z) 447.2 ([M+1]+); RT = 3.36, (UV, ELSD) 79.3%, 90.4%.
7ae N ~l -(6-Chlo~obenzo~l, 3Jdioxol-S ylmethyl)-2, 3-dihyd~o-1 H indol-5 ylJ-
2-(4-
fluo~oplaenyl)-acetamide.
2o LC/MS (m/z) 439.0 ([M+1]+); RT = 3.02, (UV, ELSD) 94.0%, 92.2%.
7af N ~1-(3,5-Dimethyl-1 phenyl-IH py~azol-4 ylmethyl)-2,3-dihydro-IH indol-S
ylJ-
2-(4 fluo~~ophenyl)-acetanaide.
LC/MS (mlz) 455.0 ([M+1]+); RT = 2.14, (CTV, ELSD) 97.1%, 91.4%.
lag N ~1-(2-Chloro-5-t~ifluo~ometlaylbenzyl)-2, 3-dihydro-1 H indol-S ylJ-2-(4-
fluorophenyl)-acetanzide.
LC/MS (~n/z) 463.1 ([M+1]+); RT = 3.53, (LTV, ELSD) 98.3%, 95.3%.
7ah N ~l-~S-(4-Chlo~ophenoxy)-1,3-dimetlayl-IH pyrazol-4-ylmethylJ-2,3-dihydro-
IH iradol-S yl~-2-(4 fluo~ophenyl)-acetanaide.
LC/MS (rn/z) 503.3 ([M-1]+); RT = 2.55, (UV, ELSD) 92.3%, 90.5%.
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jai N jl-j6-(4-Cyanoplzenoxy) py~idin-3 ybnethylJ-2,3-dihydno-IH indol-5 ylJ-2-
(4-
fZuoropherzyl)-acetamide.
LC/MS (m/z) 479.1 ([M+1]+); RT = 2.81, (UV, ELSD) 84.1%, 87.1%.
7a12-(4-Fluorophenyl)-N j1 -(3-methyl-benzo jbJtlziophen-2 ylnzethyl)-2, 3-
dihydro-
IH indol-S ylJ-acetamide.
LC/MS (m/z) 431.2 ([M+1]+); RT = 3.34, (UV, ELSD) 60.2%, 88.8%.
lam N j1 -(6-Fluof°o-4H benzo j1, 3Jdioxin-8 ylrnethyl)-2, 3-dihydro-1
H indol-5 ylJ-2-
(4 fluoz°ophenyl)-acetamide.
LCIMS (m/z) 437.0 ([M+1]+); RT = 2.62, (UV, ELSD) 79.7%, 83.6%.
7ao 2-(4-Fluorophenyl)-N j1-(6 phenoxypynidin-3-ylmethyl)-2,3-dihydno-1H indol-
5-
ylJ-acetamide.
1s LC/MS (m/z) 454.3 ([M+1]+); RT = 2.81, (UV, ELSD) 77.9%, 83.1%.
jar N (I-BenzojbJthiophen-2 ylmethyl-2,3-dihyd~~o-IH indol-S yl)-2-(4-
fluoroplzenyl)-acetaznide.
LC/MS (m/z) 417.2 ([M+1]+); RT = 3.22, (UV, ELSD) 80.2%, 89.4%.
7as 2-(4-Fluorophenyl)-N jl-jl-(4 fluoroplzenyl)-5-methyl-IHpynazol-4
ylfzzethylJ-
2,3-dihydf°o-IH indol-5 yl~-acetamide.
LC/MS (m/z) 459.3 ([M+1]+); RT = 2.15, (W, ELSD) 91.5%, 88.7%.
7au 2-(4-Fluonophenyl)-N jl-(5-rnethylthiophen-~ ylmethyl)-2,3-dilzydno-IH
indol-S-
ylJ-acetamide.
LC/MS (m/z) 381.1 ([M+1]+); RT = 2.71, (UV, ELSD) 76.6%, 82.9%.
7av 2-(4-Fluorophenyl)-N j1-(4 p'~rt-ol-1 yl-benzyl)-2,3-dihydYO-IH indol-5
ylJ-
acetaznide.
LC/MS (m/z) 426.1 ([M+1]+); RT = 2.87, (UV, ELSD) 92.2%, 88.2%.
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Table 2. Aldehydes used in the preparation of compounds of the invention 7a -
7av
Compound
of the Aldehyde MW SupplierCatalog
invention
number
7a 4-CHLOROBENZALDEHYDE 140.568 Aldrich
7b 4-(TRIFLUOROMETHYL)- 174.12 Aldrich
BENZALDEHYDE
7c 4-ISOPROPYLBENZALDEHYDE 148.204 Aldrich
7d 3-FLUORO-4-(TRIFLUOROMETHYL)-192.111 ABCR AV20008
BENZALDEHYDE
7e 6-CHLOROPIPERONAL 184.577 ABCR AV13607
7f 3,5-DIMETHYL-1-PHENYLPYR.AZOLE- Acros 40852-0050
200.24
4-CARB OXALDEHYDE Organics
7g 2-CHLORO-5-(TRIFLUOROMETHYL)-208.566 Aldrich 37,682-5
BENZALDEHYDE
7h 5-(4-CHLOROPHENOXY)-1,3- 250.684 Bionet 11F-4315
DIMETHYL-1 H-PYRAZOLE-4- Research
CARBALDEHYDE
7j 6-(4-METHYLPHENOXY)- 213.235 Bionet SL-3555
NICOTINALDEHYDE Research
7k 6-[(4-CHLOROPHENYL)SULFANYL]-249.72 Bionet SL-3565
NICOT1NALDEHYDE Research
71 4-[(5-FORMYL-2-PYRIDINYL)OXY]- 224.218 Bionet 6L-3095
BENZENECARBONITRILE Research
7m 6-(TRIFLUOROMETHYL)PYRIDINE-3- 175.109 Fluoroche 9397
CARBOXALDEHYDE m
7p 3-METHYLBENZO[B]THIOPHENE-2- 176.238 ABCR AV11375
CARBOXALDEHYDE
7q 5-FLUORO-4H-1,3-BENZODIOXINE-5-182.149 Maybridge CC 01904
CARBALDEHYDE
7s 6-PHENOXYNICOTINALDEHYDE 199.208 Maybridge CC 19604
7u 3-METHYL-5-PHENYL-4- 187.197 Maybridge CC 20304
ISOXAZOLECARBALDEHYDE
7v 1-BENZOTHIOPHENE-2- 162.211 Specs 942!2503463
CARBALDEHYDE 9
7w 1-(4-FLUOROPHENYL)-5-METHYL-1H-204.203 Maybridge MO 00310
PYR.AZOLE-4-CARBALDEHYDE
7y 5-METHYL-2- 126.178 Aldrich M8,441-0
THIOPHENECARBOXALDEHYDE
7z 4-(1H-PYRROL-1-YL)BENZALDEHYDE Maybridge N/A
171.198
7aa 4-CHLOROBENZALDEHYDE 140.568 Aldrich
lab 4-(TR1FLUOROMETHYL)- 174.12 Aldrich
BENZALDEHYDE
7ac 4-ISOPROPYLBENZALDEHYDE 148.204 Aldrich
lad 3-FLUORO-4-(TRIFLUOROMETHYL)- 192.111 ABCR AV20008
BENZALDEHYDE
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7ae 6-CHLOROPIPERONAL 184.577 ABCR AV13607
7af 3,5-DIMETHYL-1-PHENYLPYR.AZOLE- 200.24 Acros 40852-0050
4-CARBOXALDEHYDE Organics
lag 2-CHLORO-5- 208.566 Aldrich 37,682-5
(TRIFLUOROMETHYL)BENZALDEHYD
E
7ah 5-(4-CHLOROPHENOXY)-1,3- 250.684 Bionet 11F-4315
DIMETHYL-1 H-PYRAZOLE-4- Research
CARBALDEHYDE
jai 4-[(5-FORMYL-2- 224.218 Bionet 6L-3095
PYRIDINYL)OXY]BENZENECARBONIT Research
RILE
7a1 3-METHYLBENZO[B]THIOPHENE-2- 176.238 ABCR AV11375
CARBOXALDEHYDE
lam 5-FLUORO-4H-1,3-BENZODIOXINE-5- 182.149Maybridge CC 01904
CARBALDEHYDE
7ao 6-PHENOXYNICOTINALDEHYDE 199.208 Maybridge CC 19604
jar 1-BENZOTHIOPHENE-2- 162.211 Specs 942/2503463
CARBALDEHYDE 9
7as 1-(4-FLUOROPHENYL)-5-METHYL-1H- 204.203Maybridge MO 00310
PYR AZOLE-4-CARBALDEHYDE
7au 5-METHYL-2- 126.178 Aldrich M8,441-0
THIOPHENECARBOXALDEHYDE
7av 4-(1H-PYRROL-1-YL)BENZALDEHYDE 171.198 Maybridge N/A
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In vitro and in vivo testing
The compounds of the invention have been tested and shown effect in one or
more of
the below models:
Relative efflux through the KCNQ2 channel.
This exemplifies a KCNQ2 screening protocol for evaluating compounds of the
present invention. The assay measures the relative efflux through the KCNQ2
channel, and was carned out according to a method described by Tang et al.
(Tang,
l0 W. et. al., J. Bioynol. Screen. 2001, 6, 325-331) for hERG potassium
channels with the
modifications described below.
An adequate number of CHO cells stably expressing voltage-gated KCNQ2 channels
were plated at a density sufficient to yield a mono-confluent layer on the day
of the
15 experiment. Cells were seeded on the day before the experiment and loaded
with 1
~Ci/ml [86Rb] over night. On the day of the experiment cells were washed with
a
HBSS-containing buffer. Cells were pre-incubated with drug for 30 minutes and
the
B~Rb+ efflux was stimulated by a submaximal concentration of 15 mM KCl in the
continued presence of drug for additional 30 minutes. After a suitable
incubation
2o period, the supernatant was removed and counted in a liquid scintillation
counter
(Tricarb). Cells were lysed with 2 mM NaOH and the amount of $6Rb+ was
counted.
The relative efflux was calculated ((CPMsuper/(CPMsuper+ CPM~eII))~mpa/
(CPMsupen/(CPMsuper+ CPM~eII))lsr~~cc1)*100-100.
25 The compounds of the invention have an ECSO of less than 20000nM, in most
cases
less than 2000 nM and in many cases less than 200 nM. Accordingly, the
compounds
of the invention are considered to be useful in the treatment of diseases
associated
with the KCNQ family potassium channels.
3o Electrophysiological patch-clamp recordings.
Voltage-activated KCNQ2 currents were recorded from mammalian CHO cells by use
of conventional patch-clamp recordings techniques in the whole-cell patch-
clamp
configuration (Hamill OP et.al. Pfliigers Arcla 1981; 391: 85-100). CHO cells
with
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stable expression of voltage-activated KCNQ2 channels were grown under normal
cell culture conditions in COZ incubators and used for electrophysiological
recordings
1-7 days after plating. KCNQ2 potassium channels were activated by voltage
steps up
to + 80 mV in increments of 5-20 mV (or with a ramp protocol) from a membrane
holding potential between -100 mV and - 40 mV (Tatulian L et al. JNeuroscience
2001; 21 (15): 5535-5545). The electrophysiological effects induced by the
compounds were evaluated on various parameters of the voltage-activated KCNQ2
current. Especially effects on the activation threshold for the current and on
the
maximum induced current were studied.
to
Some of the compounds of the invention have been tested in this test. A left-
ward
shift of the activation threshold or an increase in the maximum induced
potassimn
current is expected to decrease the activity in neuronal networks and thus
make the
compounds useful in diseases with increased neuronal activity - like
epilepsia.
Maximum electroshock
The test was conducted in groups of male mice using corneal electrodes and
administering a square wave current of 26mA for 0.4 seconds in order to induce
a
convulsion characterised by a tonic hind limb extension (Wlaz et al. Epilepsy
2o Research 1998, 30, 219-229).
Pilocarpine induced seizures
Pilocarpine induced seizures are induced by intraperitoneal injection of
pilocarpine
250mg/lcg to groups of male mice and observing for seizure activity resulting
in loss
of posture within a period of 30 minutes (Stan et al. Pharmacology
Biochemistry and
Behavior' 1993, 45, 321-325).
Electrical seizure -threshold test
A modification of the up-and-down method (Kimball et al. Radiatiofa Research
1957,
1-12) was used to determine the median threshold to induce tonic hind-limb
extension
in response to corneal electroshock in groups of male mice. The first mouse of
each
group received an electroshoclc at 14 mA, (0.4 s, 50 Hz) and was observed for
seizure
activity. If a seizure was observed the current was reduced by 1 mA for the
next
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mouse, however, if no seizure was observed then the current was increased by 1
mA.
This procedure was repeated for all 15 mice in the treatment group.
Chemical seizure -threshold test
The threshold dose of pentylenetetrazole required to induce a clonic
convulsion was
measured by timed infusion of pentylenetetrazole (Smg / mL at 0.5 mL/minute)
into a
lateral tail vein of groups of male mice (Nutt et al. JPharmacy and
Pharmacology
1986, 38, 697-698).
1o Amygdala kindling
Rats underwent surgery to implantation of tri-polar electrodes into the
dorsolateral
amygdala. After surgery the animals were allowed to recover before the groups
of rats
received either varying doses of test compound or the drug's vehicle. The
animals
were stimulated with their initial after discharge threshold + 25 p,A daily
for 3-5
15 weeks and on each occasion seizure severity, seizure duration, and duration
of
electrical after discharge were noted. (Racine. Electroencephalography and
Clinical
Neuf°ophysiology 1972, 32, 281-294).
Side effects
2o Central nervous system side-effects were measured by measuring the time
mice would
remain on rotarod apparatus (Capacio et al. Drug ayad Claemical Toxicology
1992, 15,
177-201); or by measuring their locomotor activity by counting the number of
infra-
red beams crossed in a test cage (Watson et al. Neuroplaarnaacology 1997, 36,
1369-
1375). Hypothermic actions on the animals core body temperature of the
compound
2s were measured by either rectal probe or implanted radiotelemetry
transmitters capable
of measuring temperature (Keeney et al. Physiology and Behaviour 2001, 74, 177-
184).
Pharmacokinetics
3o The pharmacolcinetic properties of the compounds were determined via. i.v.
and p.o.
dosing to Sprague Dawley rats, and, thereafter, drawing blood samples over 20
hours.
Plasma concentrations were determined with LC/MS/MS.
