Note: Descriptions are shown in the official language in which they were submitted.
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TETRAHYDROQUINOLINONES AND THEIR USE AS MODULATORS OF
METABOTROPIC GLUTAMATE RECEPTORS
FIELD OF THE" INVENTION
[0001] The present invention is concerned with novel metabotropic glutamate
receptor (mGluR) modulators, methods for their synthesis and the treatment
and/or prevention of neurological disorders by administration of such
substances.
BACKGROUND OF THE INVENTION
[0002] Neuronal stimuli are transmitted by the central nervous system (CNS)
through the interaction of a neurotransmitter released by a neuron, which
neurotransmitter has a specific effect on a neuroreceptor of another neuron.
[0003] L-glutamic acid is considered to be the major excitatory
neurotransmitter in the mammalian CNS, consequently playing a critical role
in a large number of physiological processes. Glutamate-dependent stimulus
receptors are divided into two main groups. The first group comprises ligand-
controlled ion channels whereas the second comprises metabotropic
glutamate receptors (mGluR). Metabotropic glutamate receptors are a
subfamily of G-protein-coupled receptors (GPCR). There is increasing
evidence for a peripheral role of both ionotropic and metabotropic glutamate
receptors outside of the CNS e.g., in chronic pain states.
[0004] At present, eight different members of these mGluRs are known. On
the basis of structural parameters such as sequence homology, the second
messenger system utilized by these receptors and their different affinity to
low-molecular weight compounds, these eight receptors can be divided into
three groups: mGluRl and mGluR5 belong to group I which couple to
phospholipase C and their activation leads to intracellular calcium-ion
mobilization. Both mGluR2 and mGluR3 belong to group II and mGluR4,
mGluR6, mGluR7 and mGluR8 belong to group III, which couple to adenyl
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cyclase with their activation causing a reduction in second messenger cAMP
and as such a dampening of the neuronal activity.
[0005] Group I mGluR modulators have been shown to modulate the effects of
the presynaptically released neurotransmitter glutamate via postsynaptic
mechanisms. Moreover, as these modulators can be both positive and/or
negative Group I mGIuR moduiators, such modulators may increase or inhibit
the effects of these metabotropic receptors. Since a variety of
pathophysiological processes and disease states affecting the CNS are
thought to be related to abnormal glutamate neurotransmission and group I
mGluRs are shown to be expressed in several areas of the CNS, modulators
of these receptors could be therapeutically beneficial in the treatment of CNS
diseases.
[0006] Therefore, group I mGluR modulators may be administered to provide
neuroprotection in acute and chronic pathological conditions such as: AIDS-
related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine
spongiform encephalopathy (BSE) or other prion related infections, diseases
involving mitochondrial dysfunction, diseases involving f3-amyloid and/or
tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's
disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS),
multiple sclerosis (MS), olivoponto-cerebellar atrophy, post-operative
cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild
cognitive impairment, dementia pugilisitca, vascular and frontal lobe
dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma,
retinopathy, macular degeneration), head and spinal cord injuries / trauma,
hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from
cardiac
arrest, stroke, bypass operations or transplants), convulsions, glioma and
other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-
dopa-induced and tardive dyskinesias.
[0007] Other indications in this context include a symptomatological effect on
the following conditions: addiction (nicotine, alcohol, opiate, cocaine,
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amphetamine, obesity and others), amyotrophic lateral sclerosis (ALS),
anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD),
restless leg syndrome and hyperactive children, autism, convulsions /
epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular
dementia, HIV infections), major depressive disorder or depression (including
that resulting from Borna virus infection) and bipolar manic-depressive
disorder, drug tolerance e.g. to opioids, movement disorders, dystonia,
dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in Huntington's
disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome
(IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute,
e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive
pain), Parkinson's disease, post traumatic stress disorder, schizophrenia
(positive and negative symptoms), spasticity, tinnitus, Tourette's syndrome,
urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep
disorders, micturition disorders, neuromuscular disorder in the lower urinary
tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter
(LES), functional gastrointestinal disorders, dyspepsia, regurgitation,
respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g.
reflux-related asthma), lung disease, eating disorders, obesity and obesity-
related disorders.
[0008] Yet further indications for Group I mGluR modulators include those
indications wherein a particular condition does not necessarily exist but
wherein a particular physiological parameter may be improved through
administration of the instant compounds, for example cognitive enhancement.
[0009] Positive modulators may be particularly useful in the treatment of
positive and negative symptoms in schizophrenia and cognitive deficits in
various forms of dementia and mild cognitive impairment.
[0010] Among the Group I mGluR modulators, those which exhibit a
modulatory effect on mGluR5 receptors and thus may affect conditions or
diseases associated with the function of those mGluR5 receptors are of
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particular interest. In addition to the utility of mGIuR5 modulators in
preventing
and/or treating the conditions and/or diseases mentioned above, mGluR5
positive modulators or agonists may be particularly useful for preventing
and/or treating conditions or diseases that are associated with an
insufficient
stimulation or activity of mGIuR5 receptors. mGIuR5 modulators and
especially mGluR5 positive modulators or agonists may be particularly useful
for preventing and/or treating addiction, neuropathic pain, L-dopa-induced and
tardive dyskinesias, ALS, fragile-X syndrome, Parkinson's disease, anxiety
disorders, epilepsy, positive and/or negative symptoms of schizophrenia,
cognitive impairment, or for cognitive enhancement and neuroprotection.
THE PRESENT INVENTION
[0011] We have determined that certain ethynyl-substituted
tetrahydroquinolones within the genus of compounds disclosed in our
copending International Patent Application No. PCT/GB2005/000717 are
Group I mGIuR modulators and in particular mGluR5 modulators. Therefore,
these substances may be therapeutically beneficial in the treatment of
conditions which involve abnormal glutamate neurotransmission or in which
modulation of Group I mGluR receptors results in therapeutic benefit. These
substances are preferably administered in the form of a pharmaceutical
composition, wherein they are present together with one or more
pharmaceutically acceptable diluents, carriers, or excipients.
OBJECTS OF THE INVENTION
[0012] It is an object of the present invention to provide novel
pharmaceutical
compounds which are tetrahydroquinolone Group I mGIuR modulators and
pharmaceutical compositions thereof. It is a further object of the invention
to
provide a novel method of treating, eliminating, alleviating, palliating, or
ameliorating undesirable CNS disorders which involve abnormal glutamate
neurotransmission by employing a compound of the invention or a
pharmaceutical composition containing the same. An additional object of the
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invention is the provision of a process for producing the tetrahydroquinolone
active principles. Yet additional objects will become apparent hereinafter,
and
still further objects will be apparent to one skilled in the art.
SUMMARY OF THE INVENTION
[0013] What we therefore believe to be comprised by our invention may be
summarized inter alia in the following words:
[0014] A compound of Formula I
2 O
R3 ~ORI
wherein
R' represents aryl or heteroaryl;
R2 and R3, which may be the same or different, represent hydrogen or
C1_salkyl;
R4 and R5, which may be the same or different, represent hydrogen or
C1_salkyl;
it being understood that:
aryl represents an unsubstituted phenyl ring or a phenyl ring that is
substituted with 1, 2, 3, 4 or 5 substituents, that may be the same of
different, which substituents are selected from the group consisting of
C1_6alkyl, which is optionally substituted with one or more fluorine,
chlorine or bromine atoms, C1_6alkoxy, which is optionally substituted
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with one or more fluorine, chlorine or bromine atoms, cycloC3_12alkyl,
hydroxyl, F, Cl, Br, I, CN, nitro, di-C1_6alkylamino,
N-cycloC3_12alkyl-N-CI_6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, 4-C1_6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring
having from 1 to 4 heteroatoms said heteroatoms being independently
selected from oxygen, nitrogen and sulfur, wherein said ring is
unsubstituted or substituted with 1, 2 or 3 substituents, that may be the
same or different, which substituents are selected from the group
consisting of C1_6alkyl, which is optionally substituted with one or more
fluorine, chlorine or bromine atoms, C1_6alkoxy, which is optionally
substituted with one or more fluorine, chlorine or bromine atoms,
cycloC3_12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Cl_salkylamino,
N-cycloC3_12alkyl-N- Cl_salkylamino, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, 4-Cl_6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
and that the compounds of Formula I may not represent:
2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one
2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile
2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
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2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-
one
2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-
one
2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-
benzonitrile
7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one or
2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates
and polymorphs thereof.
[0015] Such a compound of Formula I, wherein
R2 and R3, which may be the same or different, represent methyl, ethyl,
n-propyl, 2-propyl, n-butyl or tert-butyl and
R4 and R5 represent hydrogen.
[0016] Such a compound of Formula I, wherein
R2 and R3 represent hydrogen and
R4 and R5, which may be the same or different, represent methyl, ethyl,
n-propyl, 2-propyl, n-butyl or tert-butyl.
[0017] Such a compound of Formula I, wherein
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R2, R3, R4 and R5, which may be the same or different, represent
hydrogen, methyl or ethyl.
[0018] Such a compound of Formula I, wherein
R' represents aryl;
it being understood that:
aryl represents unsubstituted phenyl or phenyl that is mono- or di-
substituted with the same or different substituents that are selected
from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl,
tert-butyl, hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
tert-butoxy, CF3, CH2F, CH2F, C2F5, OCF3, OC2F5, F, CI, Br, CN,
piperidinyl, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl,
thiazolyl, imidazolyl, oxadiazolyi, pyridinyl, pyrimidyl and phenyl.
[0019] Such a compound of Formula I, wherein aryl represents unsubstituted
phenyl or a phenyl ring that is mono- or di-substituted with the
substituent(s)
in the meta-position.
[0020] Such a compound of Formula I, wherein the phenyl ring is di-
substituted in the meta-position and the substituents are different.
[0021] Such a compound of Formula I, wherein the substituents are selected
from F, CN, pyridinyl, tetrazolyl and unsubstituted phenyl.
[0022] Such a compound of Formula I, wherein
R' represents heteroaryl;
it being understood that:
heteroaryl represents pyridin-2-yi, pyridin-3-yl, pyridin-4-yl, oxazol-5-yl,
thiazol-5-yl, wherein each of these rings may be unsubstituted or mono
or di-substituted with phenyl, methyl, ethyl, n-propyl, 2-propyl, n-butyl,
tert-butyl, hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
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tert-butoxy, CF3, CH2F, CH2F, C2F5, OCF3, OC2F5, F, Cl, Br, CN,
piperidinyl, morpholinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl,
thiazolyl, imidazolyl, oxadiazolyl, pyridinyl or pyrimidyl.
[0023] Such a compound of Formula I, wherein
heteroaryl represents unsubstituted heteroaryl or an heteroaryl ring that is
mono- or di-substituted with the substituent(s) in the meta-position.
[0024] Such a compound of Formula I, wherein the heteroaryl ring is di-
substituted in the meta-position and the substituents are different.
[0025] Such a compound of Formula I, wherein the substituents are selected
from F, CN, pyridinyl, tetrazolyl and unsubstituted phenyl.
[0026] Moreover, a method-of-treating a living animal, including a human, for
a condition or a disease associated with abnormal glutamate
neurotransmission or in which modulation of Group I mGluR receptors results
in therapeutic benefit comprising the step of administering to the living
animal,
including a human, an amount of a Group I mGIuR modulator selected from
those of Formula I
R2 O
R3
R4
R5 N
R
wherein
R' represents aryl or heteroaryl;
R2 and R3, which may be the same or different, represent hydrogen or
C1_6alkyl;
R4 and R5, which may be the same or different, represent hydrogen or
C1_6alkyl;
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it being understood that:
aryl represents an unsubstituted phenyl ring or a phenyl ring that is
substituted with 1, 2, 3, 4 or 5 substituents, that may be the same of
different, which substituents are selected from the group consisting of
C1_6alkyl, which is optionally substituted with one or more fluorine,
chlorine or bromine atoms, C1_6alkoxy, which is optionally substituted
with one or more fluorine, chlorine or bromine atoms, cycloC3_12alkyl,
hydroxyl, F, Cl, Br, I, CN, nitro, di-CI_6alkylamino, N-cycloC3_12alkyl-N-
C1_6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-
CI_6alkyl-piperazinyl, tetrazolyl, oxazolyi, furyl, pyrrolyl, thiophenyl,
isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and
phenyl;
heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring
having from 1 to 4 heteroatoms said heteroatoms being independently
selected from oxygen, nitrogen and sulfur, wherein said ring is
unsubstituted or substituted with 1, 2 or 3 substituents, that may be the
same or different, which substituents are selected from the group
consisting of C1_6alkyl, which is optionally substituted with one or more
fluorine, chlorine or bromine atoms, Cl_6alkoxy, which is optionally
substituted with one or more fluorine, chlorine or bromine atoms,
cycloC3_12alkyl, hydroxyl, F, Cl, Br, 1, CN, nitro, di-C1_6alkylamino,
N-cycloC3_12alkyl-N- CI_6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, 4-CI_6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
and optical isomers, pharmaceutically acceptable salts, hydrates,
solvates, and polymorphs thereof;
which is effective for alleviation of the condition or disease or for
enhancing cognition.
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[0027] Such a method wherein the condition associated with abnormal
glutamate neurotransmission, or wherein modulation of mGluR receptors
results in therapeutic benefit, is selected from: AIDS-related dementia,
Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform
encephalopathy (BSE) or other prion related infections, diseases involving
mitochondrial dysfunction, diseases involving f3-amyloid and/or tauopathy
such as Down's syndrome, hepatic encephalopathy, Huntington's disease,
motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple
sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive
deficit
(POCD), Parkinson's disease, Parkinson's dementia, mild cognitive
impairment, dementia pugilisitca, vascular and frontal lobe dementia,
cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy,
macular degeneration), head and spinal cord injuries / trauma,
hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from
cardiac
arrest, stroke, bypass operations or transplants), convulsions, glioma and
other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-
dopa-induced and tardive dyskinesias, addiction (nicotine, alcohol, opiate,
cocaine, amphetamine, obesity and others), anxiety and panic disorders,
attention deficit hyperactivity disorder (ADHD), restless leg syndrome and
hyperactive children, autism, convulsions / epilepsy, dementia (e.g. in
Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections),
major depressive disorder or depression (including that resulting from Borna
virus infection) and bipolar manic-depressive disorder, drug tolerance e.g. to
opioids, movement disorders, dystonia, dyskinesia (e.g. L-Dopa-induced,
tardive dyskinesia or in Huntington's disease), fragile-X syndrome,
Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple
sclerosis, muscle spasms, pain (chronic and acute, e.g. inflammatory pain,
neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's
disease, post traumatic stress disorder, schizophrenia (positive and negative
symptoms), spasticity, Tourette's syndrome, urinary incontinence and
vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition
disorders, neuromuscular disorder in the lower urinary tract,
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gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES),
functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory
tract
infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related
asthma), lung disease, eating disorders, obesity and obesity-related
disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive
disorder, panic disorder, posttraumatic stress disorder, social phobia,
substance-induced anxiety disorder, delusional disorder, schizoaffective
disorder, schizophreniform disorder, substance-induced psychotic disorder,
delirium, or for cognitive enhancement or neuroprotection.
[0028] Such a method wherein the compound is administered in the form of a
pharmaceutical composition thereof comprising the compound of Formula I in
combination with one or more pharmaceutically-acceptable diluents,
excipients, or carriers.
[0029] Further, the use of at least one compound of Formula I
R2 0
R3
R4 t ~ I
R5
R
wherein
R' represents aryl or heteroaryl;
R2 and R3, which may be the same or different, represent hydrogen or
C1_6alkyl;
R4 and R5, which may be the same or different, represent hydrogen or
CI_6alkyl;
it being understood that:
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aryl represents an unsubstituted phenyl ring or a phenyl ring that is
substituted with 1, 2, 3, 4 or 5 substituents, that may be the same of
different, which substituents are selected from the group consisting of
CI-6alkyl, which is optionally substituted with one or more fluorine,
chlorine or bromine atoms, C1-6alkoxy, which is optionally substituted
with one or more fluorine, chlorine or bromine atoms, cycloC3-12alkyl,
hydroxyl, F, Cl, Br, I, CN, nitro, di-C1-6alkylamino, N-cycloC3-12alkyl-N-
Cl-6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1-6
alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl,
isoxazolyl, thiazolyl, imidazolyi, oxadiazolyl, pyridinyl, pyrimidyl and
phenyl;
heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring
having from 1 to 4 heteroatoms said heteroatoms being independently
selected from oxygen, nitrogen and sulfur, wherein said ring is
unsubstituted or substituted with 1, 2 or 3 substituents, that may be the
same or different, which substituents are selected from the group
consisting of C1_6alkyl, which is optionally substituted with one or more
fluorine, chlorine or bromine atoms, C1-6alkoxy, which is optionally
substituted with one or more fluorine, chlorine or bromine atoms,
cycloC3-12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C1-6alkylamino,
N-cycloC3_12alkyl-N- C1-6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, 4-C1_6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
and optical isomers, pharmaceutically acceptable salts, hydrates,
solvates, and polymorphs thereof;
for the manufacturing of a medicament for the prevention and/or
treatment of a condition or disease in an animal including a human
being which condition or disease is affected or facilitated by the
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modulatory effect of Group I mGluRl modulators and in particular of
mGIuR5 modulators.
[0030] The compounds of Formula I used according to the present invention
for the manufacturing of a medicament have been found to be modulators of
Group I mGluR receptors. In particular, these compounds are modulators of
mGIuR5 receptors. Surprisingly it has been found that they show at least
partially agonistic or positive modulatory effects on the mGIuR5 receptors.
[0031] Consequently, one aspect of the present invention is the use of one or
more compounds of formula I
2 O
R \
R ~ ~
R5 N
R
wherein
R' represents aryl or heteroaryl;
R2 and R3, which may be the same or different, represent hydrogen or
C1_6alkyl;
R4 and R5, which may be the same or different, represent hydrogen or
C1_6alkyl;
it being understood that:
aryl represents an unsubstituted phenyl ring or a phenyl ring that is
substituted with 1, 2, 3, 4 or 5 substituents, that may be the same of
different, which substituents are selected from the group consisting of
C1_6alkyl, which is optionally substituted with one or more fluorine,
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chlorine or bromine atoms, C1_6alkoxy, which is optionally substituted
with one or more fluorine, chlorine or bromine atoms, cycloC3_12alkyl,
hydroxyl, F, Cl, Br, I, CN, nitro, di-C1_6alkylamino, N-cycloC3_12alkyl-N-
C1_6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1_6
alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl,
isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and
phenyl;
heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring
having from I to 4 heteroatoms said heteroatoms being independently
selected from oxygen, nitrogen and sulfur, wherein said ring is
unsubstituted or substituted with 1, 2 or 3 substituents, that may be the
same or different, which substituents are selected from the group
consisting of C1_6alkyl, which is optionally substituted with one or more
fluorine, chlorine or bromine atoms, C1_6alkoxy, which is optionally
substituted with one or more fluorine, chlorine or bromine atoms,
cycloC3_12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Cl_6alkylamino,
N-cycloC3_12alkyl-N-C1_6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, 4-Cl_6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
and optical isomers, pharmaceutically acceptable salts, hydrates,
solvates, and polymorphs thereof;
for the manufacturing of a medicament for the prevention and/or
treatment of AIDS-related dementia, Alzheimer's disease, Creutzfeld-
Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other
prion related infections, diseases involving mitochondrial dysfunction,
diseases involving 9-amyloid and/or tauopathy such as Down's
syndrome, hepatic encephalopathy, Huntington's disease, motor
neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple
sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive
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deficit (POCD), Parkinson's disease, Parkinson's dementia, mild
cognitive impairment, dementia pugilisitca, vascular and frontal lobe
dementia, cognitive impairment, eye injuries or diseases (e.g.
glaucoma, retinopathy, macular degeneration), head and spinal cord
injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia
(e.g. resulting from cardiac arrest, stroke, bypass operations or
transplants), convulsions, glioma and other tumours, inner ear insult
(e.g. in tinnitus, sound or drug-induced), L-dopa-induced and tardive
dyskinesias, addiction (nicotine, alcohol, opiate, cocaine,
amphetamine, obesity and others), anxiety and panic disorders,
attention deficit hyperactivity disorder (ADHD), restless leg syndrome
and hyperactive children, autism, convulsions / epilepsy, dementia (e.g.
in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV
infections), major depressive disorder or depression (including that
resulting from Borna virus infection) and bipolar manic-depressive
disorder, drug tolerance e.g. to opioids, movement disorders, dystonia,
dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in Huntington's
disease), fragile-X syndrome, Huntington's chorea, irritable bowel
syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain
(chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia,
hyperalgesia, nociceptive pain), Parkinson's disease, post traumatic
stress disorder, schizophrenia (positive and negative symptoms),
spasticity, Tourette's syndrome, urinary incontinence and vomiting,
pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders,
neuromuscular disorder in the lower urinary tract, gastroesophageal
reflux disease (GERD), lower esophageal sphincter (LES), functional
gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract
infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related
asthma), lung disease, eating disorders, obesity and obesity-related
disorders, agoraphobia, generalized anxiety disorder, obsessive-
compulsive disorder, panic disorder, posttraumatic stress disorder,
social phobia, substance-induced anxiety disorder, delusional disorder,
schizoaffective disorder, schizophreniform disorder, substance-induced
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psychotic disorder, delirium, or for cognitive enhancement or
neuroprotection.
[0032] Such a medicament wherein the medicament is for the prevention
and/or treatment of addiction, neuropathic pain, L-dopa-induced and tardive
dyskinesias, ALS, fragile-X syndrome, Parkinson's disease, anxiety disorders,
epilepsy, positive and/or negative symptoms of schizophrenia, cognitive
impairment, or for cognitive enhancement and neuroprotection.
[0033] Further, a pharmaceutical composition comprising, together with one or
more pharmaceutically acceptable excipients or vehicles, a compound of
Formula I
R2 O
R3
R4
R5 N
R~
wherein
R' represents aryl or heteroaryl;
R2 and R3, which may be the same or different, represent hydrogen or
C1_6alkyl;
R4 and R5, which may be the same or different, represent hydrogen or
C1_6alkyl;
it being understood that:
aryl represents an unsubstituted phenyl ring or a phenyl ring that is
substituted with 1, 2, 3, 4 or 5 substituents, that may be the same of
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different, which substituents are selected from the group consisting of
C1_6alkyl, which is optionally substituted with one or more fluorine,
chlorine or bromine atoms, C1.6alkoxy, which is optionally substituted
with one or more fluorine, chlorine or bromine atoms, cycloC3_12alkyl,
hydroxyl, F, Cl, Br, I, CN, nitro, di-C1.6alkylamino, N-cycloC3_12alkyl-N-
C1.6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Cl_
6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl,
isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and
phenyl;
heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring
having from 1 to 4 heteroatoms said heteroatoms being independently
selected from oxygen, nitrogen and sulfur, wherein said ring is
unsubstituted or substituted with 1, 2 or 3 substituents, that may be the
same or different, which substituents are selected from the group
consisting of C1_6alkyl, which is optionally substituted with one or more
fluorine, chlorine or bromine atoms, CI_6alkoxy, which is optionally
substituted with one or more fluorine, chlorine or bromine atoms,
cycloC3.12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-C1.6alkylamino,
N-cycloC3_12alkyl-N- CI.6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl, 4-Cl.6alkyl-piperazinyl, tetrazolyl, oxazolyi, furyl, pyrrolyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
and that the compounds of Formula I may not represent:
2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one
2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
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2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
3-(5-Oxo-5,6,7, 8-tetrahyd ro-quinolin-2-yiethynyl)-benzonitri le
2-Thiazol-5-ylethynyl-7,8-dihyd ro-6H-quinolin-5-one
2-Oxazol-5-ylethynyl-7, 8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-
one
2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-
one
2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahyd ro-quinolin-2-ylethynyl)-
benzonitrile
7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihyd ro-6H-qu inolin-5-one
7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one or
2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates,
and polymorphs thereof.
[0034] Specific compounds of Formula I within the present invention include
but are not limited to:
6,6-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Chloro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Methoxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(3-Hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile
6,6-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-(3-piperidin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
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7,7-Dimethyl-2-(3-piperidin-1-yi-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(3-Piperidin-1-yl-phenylethynyi)-7,8-dihydro-6H-quinolin-5-one
2-(3-Morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-
one
6,6-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-
one
6,6-Dimethyl-2-[3-(1 H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-
one
7,7-Dimethyl-2-[3-(1 H-tetrazol-5-yi)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-
one
2-[3-(1 H-Tetrazol-5-yi)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one
2-[3-Fluoro-5-(1 H-tetrazol-5-yi)-phenylethynyl]-6,6-dimethyl-7,8-dihydro-6H-
quinolin-5-one
2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-7,7-dimethyl-7,8-dihydro-6H-
quinolin-5-one
2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinoiin-5-one
2-(3-Trifluoromethyi-phenylethynyi)-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-(3-trifluoromethyi-phenylethynyi)-7,8-dihydro-6H-quinolin-5-
one
6,6-Dimethyl-2-(3-trifluoromethyi-phenylethynyi)-7,8-dihydro-6H-quinolin-5-
one
7,7-Dimethyl-2-phenylethynyi-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(4-Methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-(4-methyl-thiazol-2- ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(4-Fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(4-Fluoro-thiazol-2-ylethynyl)-7, 7-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(4-Fluoro-thiazol-2-ylethynyl)-6, 6-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(5-Fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
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3-Fluoro-5-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-qu inolin-2-ylethynyl)-
benzonitrile
2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-
quinolin-5-one
2-(4-Fluoro-5-pyrid in-3-yl-oxazol-2-ylethynyl)-6,6-d imethyl-7,8-dihyd ro-6H-
quinolin-5-one
7,7-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-Pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(4-Fluoro-5-pyridin-3-y1-1 H-imidazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
2-(4-Fluoro-5-pyridin-3-yi-1 H-imidazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-
6H-quinolin-5-one
2-(4-Fluoro-5-pyridin-3-yi-1 H-imidazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-
6H-quinolin-5-one
6,6-Dimethyl-2-(4-pyridin-3-yi-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
7,7-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
2-(4-Pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-Thiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-[1,3,4]Thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-[1,3,4]Oxadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
2-(1 H-Tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-(1 H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-(1 H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
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2-Oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
6, 6-Dimethyl-2-oxazol-2-ylethynyl-7, 8-dihydro-6H-q uinolin-5-one
7 ,7-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-q u inolin-5-one
'6,6-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one
7,7-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
6,6-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
7, 7-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-d ihydro-6H-q uinolin-5-one
6,6-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
2-(5-Fluoro-pyridin-3-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
2-(5-Fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
3-Fluoro-5-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile
3-(6, 6-D i methyl-5-oxo-5, 6, 7, 8-tetra hyd ro-q u i n ol i n-2-ylethynyl )-
5-fl u o ro-
benzonitrile
2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,7-d imethyl-7,8-d ihydro-6H-
quinolin-5-one
2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-
quinolin-5-one
6,6-Dimethyl-2-(5-pyrid in-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-
quinolin-5-one
7,7-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-
quinolin-5-one
2-(5-Pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates,
and polymorphs thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0035] For the purpose of the present invention, the carbon atom content of
various hydrocarbon-containing moieties is indicated by a prefix designating
the minimum and maximum number of carbon atoms in the moiety, i.e., the
prefix C;_j indicates a moiety of the integer "i" to the integer "j" carbon
atoms,
inclusive. Thus, for example, (C1.3)alkyl refers to alkyl of one to three
carbon
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atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and
branched forms thereof.
[0036] As used herein, the term "C1_6alkyl" comprises straight or branched
chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Said alkyl groups
may be unsubstituted and include, e.g., methyl, ethyl, n-propyl, 2-propyl, n-
butyl, tert-butyl. Further, these alkyl groups may optionally be substituted
by
one or more fluorine, chlorine and/or bromine atoms; examples of these
halogenated alkyl moieties include -CF3, -C2F5, -CBr3, and -CCI3. The term
"Cl_6alkoxy" comprises straight or branched chain -O-C1_6alkyl groups
wherein "CI_6alkyl" is defined as given hereinbefore. Examples of "C1_6alkoxy"
include methoxy, ethoxy, n-propoxy, i-propoxy. A C1_6alkoxy group optionally
may be substituted by one or more fluorine, chlorine and/or bromine atoms
thereby forming, for instance, -OCF3, -OC2F5, -CBr3. The term "cycloC3_12
alkyl" represents monocyclic, bicyclic or tricyclic alkyl groups having 3, 4,
5, 6,
7, 8, 9, 10, 11 or 12 carbon atoms and includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantyl. A cycloC3_12alkyl
group optionally may be substituted with one or more fluorine, chlorine and/or
bromine atoms. In the context of the present invention the term "di-
C1_6alkylamino" refers to an amino moiety in which the nitrogen atom of the
amino group is substituted with two C1_6alkyl groups, that may be the same or
different, as defined above. Examples of di-C1_6alkylamino groups include
dimethylamino, diethylamino and N-methyl-N-isopropylamino. The term
"N-cycloC3_12alkyl-N-Cl_6alkylamino" comprises amino groups in which the
nitrogen atom of the amino group is substituted by one C1_6alkyl group and
one- N-cycloC3_12alkyl group. Both the C1_6alkyl group and the N-
cycloC3_12alkyl
group are defined as given hereinbefore. The term "4-C1_6alkyl-piperazinyl"
comprises piperazinyl radicals bearing a C1_6alkyl moiety at the nitrogen atom
in 4-position of the piperazine ring, said "Cl_6alkyl" having the same meaning
as given hereinbefore. The term "(hetero)aromatic 5-, 6- or 7-membered ring"
refers to heterocyclic rings having up to 4 oxygen, nitrogen and/or sulfur
atoms in the ring that comprises 5, 6 or 7 carbon and hetero atoms, said
heterocyclic ring being an aromatic ring system. Examples of such
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(hetero)aromatic 5-, 6- or 7-membered rings include unsubstituted or
appropriately substituted pyrroles, oxazoles, thiophens, furans, isoxazoles,
imidazoles, oxazoles, oxadiazoles, thiazoles, imidazolines, pyrazoles,
oxazolidines, isoxazolidines, thiazolidines, pyridines, pyridazines,
pyrimidines,
pyrazines, azepines. The term "halogen" represents fluorine, chlorine,
bromine and iodine.
[0037] The compounds of the present invention are named according to the
IUPAC or CAS nomenclature system. Abbreviations which are well known to
one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for
methyl, "Et" for ethyl, "h" for hour or hours, and "rt" for room temperature).
[0038] The term "analog" or "derivative" is used herein in the conventional
pharmaceutical sense, to refer to a molecule that structurally resembles a
reference molecule (such as 7,8-dihydro-6H-quinolin-5-one), but has been
modified in a targeted and controlled manner to replace one or more specific
substituents of the referent molecule with an alternate substituent, thereby
generating a molecule which is structurally similar to the reference molecule.
Synthesis and screening of analogs (e.g., using structural and/or biochemical
analysis), to identify slightly modified versions of a known compound which
may have improved or biased traits (such as higher potency and/or selectivity
at a specific targeted receptor type, greater ability to penetrate mammalian
blood-brain barriers, fewer side effects, etc.) is a drug design approach that
is
well known in pharmaceutical chemistry.
[0039] In addition, using methods known to those skilled in the art, analogs
and derivatives of the compounds of the invention can be created which have
improved therapeutic efficacy in controlling dementia, i.e., higher potency
and/or selectivity at a specific targeted receptor type, either greater or
lower
ability to penetrate mammalian blood-brain barriers (e.g., either higher or
lower blood-brain barrier permeation rate), fewer side effects, etc.
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[0040] The phrase "pharmaceutically acceptable", as used in connection with
compositions of the Invention, refers to molecular entities and other
ingredients of such compositions that are physiologically tolerable and do not
typically produce untoward reactions when administered to a mammal (e.g.,
human). Preferably, as used herein, the term "pharmaceutically acceptable"
means approved by a regulatory agency of the Federal or a state government
or listed in the U.S. Pharmacopeia or other generally recognized
pharmacopeia for use in mammals, and more particularly in humans.
[0041] Compounds of the present invention may be in the form of
pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers
to those salts which possess the biological effectiveness and properties of
the
parent compound and which are not biologically or otherwise undesirable.
The nature of the salt or isomer is not critical, provided that it is non-
toxic and
does not substantially interfere with the desired pharmacological activity.
[0042] It will be appreciated by those skilled in the art that compounds of
the
invention having a chiral center may exist in and be isolated in optically
active
and racemic forms. Some compounds may exhibit polymorphism. It is to be
understood that the present invention ecompasses any racemic, optically-
active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof,
of
a compound of the invention, which possesses the useful properties
described herein.
[0043] The following Scheme I describes the preparation of compounds of
Formula I of the present invention. All of the starting materials are prepared
by procedures described in the scheme, by procedures well known to one of
ordinary skill in organic chemistry or can be obtained commercially. All of
the
final compounds of the present invention are prepared by procedures
described in this chart or by procedures analogous thereto, which would be
well known to one of ordinary skill in organic chemistry. All of the variables
used in the scheme are as defined below or as in the claims.
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[0044] A synthetic procedure toward 2-substituted-ethynyl-7,8-dihydro-6H-
quinolin-5-ones with the general Formula I is given in Scheme 1. The reaction
of appropriately functionalized cyclohexane-1,3-dione derivatives 1 with
ammonium acetate / acetic acid in benzene gave the corresponding 3-amino-
cyclohex-2-enone derivatives 2. Compound 2 were then reacted with alkyl
propiolate and cyclization was achieved at elevated temperatures to form the
quinoline-2,5-dione 3. Subsequent reaction with phosphoryl chloride gave the
2-chloro-substituted quinolin-5-one derivative 4. Substitution of the chloro-
substituent with appropriate acetylene derivative under palladium (0)
catalysis
in the presence of base yielded compounds of Formula I.
Scheme I Synthesis of 2-substituted-ethynyl-7,8-dihydro=6H-quinolin-5-
ones
R2 O R2 O
R3 NH4OAc R3 COOAIk
4 R4
R5 O R5 NH2
1 2
R2 O R2 O
R3 POCI3 3
R4 R4 I --;
R H O R5 N CI
3 4
R2 O
R~ g
4 I i
R N
R
[0045] It will be apparent to those skilled in the art that the described
synthetic
procedures are merely representative in nature and that alternative synthetic
processes are known to one of ordinary skill in organic chemistry.
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EXPERIMENTAL PART
[0046] The compounds and their preparation of the present invention will be
better understood in connection with the following examples, which are
intended as an illustration of and not a limitation upon the scope of the
invention.
[0047] Hereinafter, "DMF" is defined as N,N-dimethylformamide, "HCI" as
hydrochloric acid, "DMSO" as dimethylsulfoxide and "TMS" as
tetramethylsilane.
Preparation I
3-Amino-5,5-dimethylcyclohex-2-en-1-one
0
NH2
A
[0048] The title compound was prepared according to (Baraldi, P. G.; Simoni,
D.; Manfredini, S.; Synthesis 1983, (11) 902-903.) as a colorless solid in 76%
yield.
Preparation 2
7,7-Dimethyl-7,8-dihydro-1 H,6H-quinoline-2,5-dione
0
~
N O
H
[0049] In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org.
Chem.
1968, 33 (3) 1089-1092.), 3-amino-5,5-dimethylcyclohex-2-en-l-one was
reacted with ethyl propiolate to give the title compound as a light brown
solid
in 78.5% yield.
Physical characteristics are as follows:
'H NMR (CDCI3, TMS) S: 1.14, 2.42, 2.82, 6.47, and 8.04.
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Preparation 3
2-Chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
Ici
N 5 [0050] In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V.
V.;
Granik, V. G. Khim. Geterotsiki. Soedin. 1991, (1) 86-92.) 7,7-dimethyl-7,8-
dihydro-1 H,6H-quinoline-2,5-dione was treated with phosphoryl chloride
(POCI3) to give the title compound as a gray solid in 60% yield.
Physical characteristics are as follows:
'H NMR (CDCI3, TMS) 8: 1.11, 2.54, 3.01, 7.30, and 8.30.
Preparation 4
3-Amino-5-ethylcyclohex-2-en-1 -one
0
ANHZ
[0051] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.;
Synthesis 1983, (11) 902-903) 5-ethylcyclohexane-1,3-dione was reacted with
ammonium acetate to give the title compound.
Physical characteristics are as follows:
'H NMR (CDCI3, TMS) b: 0.93 (t, 6.5 Hz, 3H); 1.42 (m, 2H); 1.88 - 2.44 (m,
5H); 4.62 (br s, 2H) and 5.23 ppm (s, I H).
Preparation 5
3-Ami no-6-propylcyclohex-2-en-l-one
0
. I 25 NH2
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[0052] In close analogy to (Baraidi, P. G.; Simoni, D.; Manfredini, S.;
Synthesis 1983, (11) 902-903) 4-propylcyclohexane-1,3-dione was reacted
with ammonium acetate to give the title compound as a colorless solid.
Physical characteristics are as follows:
'H NMR (CDCI3, TMS) S: 0.91 (t, 7 Hz, 3H); 1.25 - 1.90 (m, 5H); 1.98 - 2.18
(m, 2H); 2.35 (t, 6 Hz, 2H); 4.50 (br s, 2H) and 5.19 ppm (s, 1 H).
Preparation 6
3-Amino-5-isopropylcyclohex-2-en-l-one
0
NH2
Y(:!l
[0053] In analogy to (Baraidi, P. G.; Simoni, D.; Manfredini, S.; Synthesis
1983, (11) 902-903) 5-isopropylcyclohexane-1,3-dione was reacted with
ammonium acetate to give the title compound as a colorless solid.
Physical characteristics are as follows:
'H NMR (CDCI3, TMS) S: 0.91 (d, 6.5 Hz); 1.48 - 1.65 (m, 1 H); 1.84 - 2.39
(m, 5H); 5.04 (br s, 2H) and 5.22 ppm (s, I H).
Preparation 7
3-Amino-6,6-dimethylcyclohex-2-en-l-one
0
NH2
[0054] In analogy to (Baraidi, P. G.; Simoni, D.; Manfredini, S.; Synthesis
1983, (11) 902-903) 4,4-dimethylcyclohexane-1,3-dione was reacted with
ammonium acetate to give the title compound as a colorless solid.
Physical characteristics are as follows:
Mp 153-154 C; 1 H NMR (DMSO-D6, TMS) S: 0.94 (s, 6H); 1.64 (t, 6.5 Hz,
2H); 2.28 (t, 6.5 Hz, 2H); 4.79 (s, 1 H) and 6.58 ppm (br s, 2H).
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Preparation 8
3-Amino-6-ethyl-6-methylcyclohex-2-en-l-one
0
-)()",NH2
[0055] In analogy to (Baraidi, P. G.; Simoni, D.; Manfredini, S.; Synthesis
1983, (11) 902-903) 4-ethyl-4-methylcyc(ohexane-1,3-dione was reacted with
ammonium acetate to give the title compound as a colorless solid.
Physical characteristics are as follows:
-'H NMR (CDCI3, TMS) S: 0.83 (t, 6.5 Hz, 3H); 1.06 (s, 3H); 1.40 - 1.80 (m,
3H); 1.85 - 2.00 (m, 1 H); 2.35 (t, 6.5 Hz, 2H); 4.31 (br s, 2H) and 5.14 ppm
(s,
1 H).
Mp 99-100 C; 'H NMR (CDCI3, TMS) 8: 1.08, 1.73, 2.45, 2.79, 3.91, and
8.33; Anal. Found (C17H21 N30) (%): C, 71.6; H, 7.5; N, 14.4
Preparation 9
2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one
0
[0056] To a solution of 2-chloro-7,8-dihydro-6H-quinolin-5-one (0.2 g, 1.1
mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an
argon atmosphere was added tetrakis (triphenylphosphine) palladium (0.02 g,
0.062 mmol). The mixture was heated at reflux for 3 h. Then it was
concentrated under reduced pressure and the residue was purified by column
chromatography on silica gel to give the title compound (0.04 g, 15%).
Physical characteristics are as follows:
Mp 121-122 C; 'H NMR (CDCI3, TMS) 8: 2.20 (2H); 2.68 (2H); 3.17 (2H);
7.22-7.38 (3H); 7.46 (1 H); 7.60 (2H); 8.24 (1 H); MS 248 (M+1).
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Preparation 10
2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
[0057] In analogy to the procedure described in Preparation 9, the title
compound was obtained in moderate yield (120 mg, 15%, MP: 120-122.1 C).
Preparation 11
7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
[0058] In analogy to the procedure described in Preparation 9, the title
compound was obtained in moderate yield (50 mg, 12 %, MP: 108-109.2 C).
Preparation 12
2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one
0
\N ~
[0059] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 13
2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
N
OH
[0060] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 14
2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
[JLTfl
N
"lO
[0061] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 15
2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
~N
F
[0062] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 16
2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
Ci
[0063] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 17
2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
/I
Br
[0064] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 18
3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile
0
/I
[0065] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 19
2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
\N \
s
N
[0066] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 20
2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
CN
O
N
[0067] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 21
2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
O
N
[0068] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 22
2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
i I
C S
[0069] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 23
7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one
O
N~z
[0070] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 24
2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
OH
[0071] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 25
2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
[0072] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 26
2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
F
[0073] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 27
2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
CI
[0074] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 28
2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
Br
[0075] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 29
3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-
benzonitrile
0
N
N
[0076] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Preparation 30
7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N S
N
[0077] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Preparation 31
7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N O
N
[0078] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example I
6,6-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N
[0079] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 2
6,6-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N
N
[0080] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 3
6,6-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one
0
\N \
[0081] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield
Example 4
2-(3-Methoxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
[0082] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 5
2-(3-Fluoro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
\N \
F
[0083] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 6
2-Thiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N
S
N-'/
[0084] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 7
2-(4-Methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
N
S
N ,
[0085] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 8
7,7-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
nN
N
[0086] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 9
6,6-Dimethyl-2-(4-methyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
I
N S
I /
N
[0087] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 10
2-(4-Fluoro-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
N
S
N-
F
[0088] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 11
2-(4-Fluoro-thiazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-
5-one
0
4 ~N
S
N-
F
[0089] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 12
2-(4-Fluoro-thiazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-
one
0
'N \ S
N- (
F
[0090] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 13
2-(5-Fluoro-pyridin-3-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
\N \ / F
[0091] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 14
3-Fluoro-5-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-
benzonitrile
0
N F
N
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[0092] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 15
2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
"~N _
O
N / \ ~
F
[0093] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 16
2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
\N 0 _ N
N
F
[0094] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 17
2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-
6H-quinolin-5-one
0
N 0 -N
N
F
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[0095] In analogy to the procedure described in Preparation 9, the titie
compound is obtained in moderate yield.
Example 18
2-(4-Fluoro-5-pyridin-3-yl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-
6H-quinolin-5-one
0
*~N 0 N
N
F
[0096] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 19
7, 7-D i m ethyl-2-pyri d i n-2-yl ethynyl-7, 8-d i hyd ro-6 H-q u i n o i i n-
5-o ne
0
\N ~
[0097] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 20
2-Pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
[0098] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 21
2-(3-Chloro-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
cl
[0099] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 22
2-(3-Hydroxy-phenylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one
0
N
oH
[00100] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 23
3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-
benzonitrile
0
N
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[00101] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 24
6,6-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
\N ~
s
N
[00102] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 25
6,6-Dimethyl-2-(3-piperidin-1-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-
5-one
O
N N
[00103] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 26
7,7-Dimethyl-2-(3-piperidin-l-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-
5-one
0
N \ N~
[00104] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 27
2-(3-Piperidin-l-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
N \ N~
[00105] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 28
2-(3-Morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
~
~N p
[00106] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 29
7,7-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
N
rp
\ \/
[00107] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 30
6,6-Dimethyl-2-(3-morpholin-4-yl-phenylethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
i I
~N O
[00108] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 31
6,6-Dimethyl-2-[3-(1 H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-
quinolin-5-one
O
H,
N N-NN
\ / I ~N
[00109] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 32
7,7-Dimethyl-2-[3-(1 H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-
quinolin-5-one
O
H.
N N-NN
N.
[00110] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 33
2-[3-(1 H-Tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-one
0
N HNNN
\ / I N=
[00111] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 34
2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-6,6-dimethyl-7,8-dihydro-
6H-quinolin-5-one
0
H,
~N \ N NN
/ I N
[00112] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 35
2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-7,7-dimethyl-7,8-dihydro-
6H-quinolin-5-one
0
H'N-N
%
N =N
N
F
[00113] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 36
2-[3-Fluoro-5-(1 H-tetrazol-5-yl)-phenylethynyl]-7,8-dihydro-6H-quinolin-5-
one
0
~N I \ H'N-
NNN
[00114] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 37
2-(3-Trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
'N F
F
F
[00115] -In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 38
7,7-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
\N ~ F
F F
[00116] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 39
6,6-Dimethyl-2-(3-trifluoromethyl-phenylethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
F
F
F
[00117] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 40
2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
"'N
S
N
[00118] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 41
6,6-Dimethyl-2-pyridin-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
O
i I
N
N
(00119] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 42
6,6-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
N O
N
I ~,
[00120] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 43
7,7-Dimethyl-2-(4-methyl-oxazol-2-ylethynyl)-7,8-dihydro-6H-qu i noi in-5-
one
0
O
N
[00121] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 44
2-(4-Fluoro-5-pyridin-3-y1-1 H-imidazol-2-yiethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
I
N
N
N J ~ l
F
[00122] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 45
2-(4-Fluoro-5-pyridin-3-y1-1 H-imidazol-2-ylethynyl)-7,7-dimethyl-7,8-
dihydro-6H-quinolin-5-one
0
N N
N
F
[00123] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 46
2-(4-Fluoro-5-pyridin-3-yi-1 H-imidazol-2-ylethynyl)-6,6-dimethyl-7,8-
dihydro-6H-quinolin-5-one
0
\N N _N
N
F
[00124] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 47
6,6-Dimethyl-2-(4-pyridin-3-yi-imidazol-l-ylethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
I
\N \ -N
[00125] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 48
7,7-Dimethyl-2-(4-pyridin-3-yl-imidazol-1-ylethynyl)-7,8-dihydro-6H-
quinolin-5-one
0
N N
L-~
N
[00126] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 49
2-(4-Pyridin-3-yl-imidazol-l-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
~I
L~
N
[00127] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 50
2-[1,3,4]Thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
CJLfl
N
S
N'N
[00128] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 51
2-[1,3,4]Oxadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N
O
N'N
[00129] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 52
2-(1 H-Tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
i I
N \ N
N
N_N
[00130] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 53
6,6-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-
one
0
N
s
N-
N
[00131] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 54
7,7-Dimethyl-2-[1,3,4]thiadiazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-
one
0
~N
N-N
[00132] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 55
7,7-Dimethyl-2-(1 H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
N N
N'N
[00133] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 56
6,6-Dimethyl-2-(1 H-tetrazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one
0
N N
N_NN
[00134] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 57
6,6-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
N
O
N
[00135] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 58
2-Oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
~N
O
N
[00136] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 59
6,6-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
Hn
N \
O
IJ/
N
[00137] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 60
7,7-Dimethyl-2-oxazol-2-ylethynyl-7,8-dihydro-6H-quinolin-5-one
0
~I
7': \N ~
O
N
[00138] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 61
7,7-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
7' N p
N
[00139] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 62
6,6-Dimethyl-2-(2-phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
N p i O'-/Y
N
[00140] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 63
7,7-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
4~N S
N
[00141] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 64
6,6-Dimethyl-2-(5-phenyl-thiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
N
[00142] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 65
2-(5-Fluoro-pyridin-3-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-
one
0
N
N
[00143] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
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Example 66
3-Fluoro-5-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile
0
~I
\ F
N
N
[00144] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 67
3-(6,6-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-5-fluoro-
benzonitrile
0
i I
N F
N
[00145] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 68
2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-7,7-dimethyl-7,8-dihydro-6H-
quinolin-5-one
0
N
O
N
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[00146] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 69
2-(4-Fluoro-5-phenyl-oxazol-2-ylethynyl)-6,6-dimethyl-7,8-dihydro-6H-
quinolin-5-one
0
i I
N
O
N
F
[00147] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 70
6,6-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-
6H-quinolin-5-one
0
1~I
\N O N
N_/
N
[00148] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 71
7,7-Dimethyl-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-
6H-quinolin-5-one
0
rN 0 N
N-~
N
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[00149] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 72
2-(5-Pyridin-3-yl-[1,3,4]oxadiazol-2-ylethynyl)-7,8-dihydro-6H-quinolin-5-
one
0
i N N
O
N_/
N
[00150] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
Example 73
7,7-Dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one
0
I
N
[00151] In analogy to the procedure described in Preparation 9, the title
compound is obtained in moderate yield.
[00152] Pure stereoisomeric forms of the compounds and the
intermediates of this invention may be obtained by the application of art-
known procedures. Diastereomers may be separated by physical separation
methods such as selective crystallization and chromatographic techniques,
e.g. liquid chromatography using chiral stationary phases. Enantiomers may
be separated from each other by selective crystallization of their
diastereomeric salts with optically active acids. Alternatively, enantiomers
may
be separated by chromatographic techniques using chiral stationary phases.
Said pure stereoisomeric forms may also be derived from the corresponding
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pure stereoisomeric form of appropriate starting materials, provided that the
reaction occurs stereoselectively. Stereoisomeric forms of Formula I are
obviously intended to be included within the scope of this invention.
ADDITION SALTS
[00153] For therapeutic use, salts of the compounds of Formula I are
those wherein the counterion is pharmaceutically acceptable. However, salts
of acids and bases which are non-pharmaceutically acceptable may also find
use, for example, in the preparation and purification of pharmaceutically
acceptable compounds. All salts whether pharmaceutically acceptable or not
are included within the ambit of the present invention. The pharmaceutically
acceptable salts as mentioned above are meant to comprise the
therapeutically active non-toxic salt forms which the compounds of Formula I
are able to form. The latter can conveniently be obtained by treating the base
form with such appropriate acids as inorganic acids, e.g. hydrohalic acids
such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;
phosphoric acid and the like; or organic acids such as acetic, propanoic,
hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic,
maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic,
methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,
cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the
like acids. Conversely, the salt form can be converted by treatment with
alkali
into the free base form.
PHARMACEUTICAL COMPOSITIONS
[00154] The active ingredients of the invention, together with one or
more conventional adjuvants, carriers, or diluents, may be placed into the
form of pharmaceutical compositions and unit dosages thereof, and in such
form may be employed as solids, such as coated or uncoated tablets or filled
capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or
capsules filled with the same, all for oral use; in the form of suppositories
or
capsules for rectal administration or in the form of sterile injectable
solutions
for parenteral (including intravenous or subcutaneous) use. Such
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pharmaceutical compositions and unit dosage forms thereof may comprise
conventional or new ingredients in conventional or special proportions, with
or
without additional active compounds or principles, and such unit dosage forms
may contain any suitable effective amount of the active ingredient
commensurate with the intended daily dosage range to be employed. Tablets
containing one (1) to one hundred (100) milligrams of active ingredient or,
more broadly, zero point five (0.5) to five hundred (500) milligrams per
tablet,
are accordingly suitable representative unit dosage forms.
[00155] The term "carrier" applied to pharmaceutical compositions of the
invention refers to a diluent, excipient, or vehicle with which an active
compound is administered. Such pharmaceutical carriers can be sterile
liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous
glycerol solutions, and oils, including those of petroleum, animal, vegetable
or
synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and
the like. Suitable pharmaceutical carriers are described in "Remington's
Pharmaceutical Sciences" by E.W. Martin, 18 th Edition.
METHOD OF TREATING
[00156] Due to their high degree of activity and their low toxicity, together
presenting a most favorable therapeutic index, the active principles of the
invention may be administered to a subject, e.g., a living animal (including a
human) body, in need thereof, for the treatment, alleviation, or amelioration,
palliation, or elimination of an indication or condition which is susceptible
thereto, or representatively of an indication or condition set forth elsewhere
in
this application, preferably concurrently, simultaneously, or together with
one
or more pharmaceutically-acceptable excipients, carriers, or diluents, espe-
cially and preferably in the form of a pharmaceutical composition thereof,
whether by oral, rectal, or parental (including intravenous and subcutaneous)
or in some cases even topical route, in an effective amount. Suitable dosage
ranges are 1-1000 milligrams daily, preferably 10-500 milligrams daily, and
especially 50-500 milligrams daily, depending as usual upon the exact mode
of administration, form in which administered, the indication toward which the
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administration is directed, the subject involved and the body weight of the
subject involved, and the preference and experience of the physician or
veterinarian in charge.
[00157] The term "therapeutically effective" applied to dose or amount
refers to that quantity of a compound or pharmaceutical composition that is
sufficient to result in a desired activity upon administration to a living
animal
body in need thereof.
[00158] The active agents of the present invention may be administered
orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation,
or
rectally) in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers. It is usually desirable to use the oral
route. The active agents may be administered orally in the form of a capsule,
a tablet,' or the like (see Remington: The Science and Practice of Pharmacy,
20th Edition (2000), Philadelphia, PA). The orally administered medicaments
may be administered in the form of a time-controlled release vehicle,
including
diffusion-controlled systems, osmotic devices, dissolution-controlled
matrices,
and erodible/degradable matrices.
[00159] For oral administration in the form of a tablet or capsule, the
active drug component can be combined with a non-toxic, pharmaceutically
acceptable excipients such as binding agents (e.g., pregelatinized maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.,
lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-
reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium
hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica,
steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and
the like); disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents,
gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth
or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol,
waxes,
and the like. For oral administration in liquid form, the drug components can
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be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g.,
ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose
derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin
or
acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or
fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-
hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as
antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can
also
be added to stabilize the dosage forms.
[00160] The tablets can be coated by methods well known in the art.
The compositions of the invention can be also introduced in microspheres or
microcapsuies, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
Liquid preparations for oral administration can take the form of, for example,
solutions, syrups, emulsions or suspensions, or they can be presented as a
dry product for reconstitution with water or other suitable vehicle before
use.
Preparations for oral administration can be suitably formulated to give
controlled or postponed release of the active compound.
[00161] The active drugs can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles and multilamellar vesicles. Liposomes can be formed
from a variety of phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines, as is well known.
[00162] Drugs of the invention may also be delivered by the use of
monoclonal antibodies as individual carriers to which the compound
molecules are coupled. Active drugs may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include polyvinyl-
pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol,
polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine
substituted with paimitoyl residues. Furthermore, active drug may be coupled
to a class of biodegradable polymers useful in achieving controlled release of
a drug, for example, polylactic acid, polyglycolic acid, copolymers of
polylactic
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and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid,
polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-
linked or amphipathic block copolymers of hydrogels.
[00163] For administration by inhalation, the therapeutics according to
the present invention can be conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the use of a
suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case
of
a pressurized aerosol, the dosage unit can be determined by providing a
valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin
for use in an inhaler or insufflator can be formulated containing a powder mix
of the compound and a suitable powder base such as lactose or starch.
[00164] The formulations of the invention can be delivered parenterally,
i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous
(s.c.),
intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal
(i.d.)
administration, by direct injection, via, for example, bolus injection or
continuous infusion. Formulations for injection can be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an added
preservative. The compositions can take such forms as excipients,
suspensions, solutions, or emulsions in oily or aqueous vehicles, and can
contain formulatory agents such as suspending, stabilizing and/or dispersing
agents. Alternatively, the active ingredient can be in powder form for
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,
before
use.
[00165] Compositions of the present invention can also be formulated for
rectal administration, e.g., as suppositories or retention enemas (e.g.,
containing conventional suppository bases such as cocoa butter or other
glycerides).
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[00166] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient and/or may contain different dosage levels to
facilitate dosage titration. The pack may, for example, comprise metal or
plastic foil, such as a blister pack. The pack or dispenser device may be
accompanied by instructions for administration. Compositions of the invention
formulated in a compatible pharmaceutical carrier may also be prepared,
placed in an appropriate container, and labeled for treatment of an indicated
condition.
[00167] As disclosed herein, the dose of the components in the
compositions of the present invention is determined to ensure that the dose
administered continuously or intermittently will not exceed an amount
determined after consideration of the results in test animals and the
individual
conditions of a patient. A specific dose naturally varies depending on the
dosage procedure, the conditions of a patient or a subject animal such as
age, body weight, sex, sensitivity, feed, dosage period, drugs used in
combination, seriousness of the disease. The appropriate dose and dosage
times under certain conditions can be determined by the test based on the
above-described indices but may be refined and ultimately decided according
to the judgment of the practitioner and each patient's circumstances (age,
general condition, severity of symptoms, sex, etc.) according to standard
clinical techniques.
[00168] Toxicity and therapeutic efficacy of the compositions of the
invention can be determined by standard pharmaceutical procedures in
experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of
the population) and the ED50 (the dose therapeutically effective in 50% of the
population). The dose ratio between therapeutic and toxic effects is the
therapeutic index and it can be expressed as the ratio ED50/LD50=
Compositions that exhibit large therapeutic indices are preferred.
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EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS
[00169] With the aid of commonly used solvents, auxiliary agents and
carriers, the reaction products can be processed into tablets, coated tablets,
capsules, drip solutions, suppositories, injection and infusion preparations,
and the like and can be therapeutically applied by the oral, rectal,
parenteral,
and additional routes. Representative pharmaceutical compositions follow.
(a) Tablets suitable for oral administration which contain the active
ingredient may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for
incorporation thereinto by usual procedure of the active ingredient, such as a
polyethyleneglycol which is a solid at normal room temperature but which
melts at or about body temperature.
(c) For parental (including intravenous and subcutaneous) sterile
solutions, the active ingredient together with conventional ingredients in
usual
amounts are employed, such as for example sodium chloride and double-
distilled water q.s., according to conventional procedure, such as filtration,
aseptic filling into ampoules or IV-drip bottles, and autoclaving for
sterility.
[00170] Other suitable pharmaceutical compositions will be immediately
apparent to one skilled in the art.
FORMULATION EXAMPLES
[00171] The following examples are again given by way of illustration
only and are not to be construed as limiting.
EXAMPLE 1
Tablet Formulation
A suitable formulation for a tablet containing 10 milligrams of active
ingredient
is as follows:
mg
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Active Ingredient 10
Lactose 61
Microcrystalline Cellulose 25
Talcum 2
Magnesium stearate 1
Colloidal silicon dioxide 1
EXAMPLE 2
Tablet Formulation
Another suitable formulation for a tablet containing 100 mg is as follows:
mg
Active Ingredient 100
Polyvinylpyrrolidone, crosslinked 10
Potato starch 20
Polyvinylpyrrolidone 19
Magnesium stearate I
Microcrystalline Cellulose 50
Film coated and colored.
The film coating material consists of:
Hypromellose 10
Microcryst. Cellulose 5
Talcum 5
Polyethylene glycol 2
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Color pigments 5
EXAMPLE 3
Capsule Formulation
A suitable formulation for a capsule containing 50 milligrams of active
ingredient is as follows:
mg
Active Ingredient 50
Corn starch 26
Dibasic calcium phosphate 50
Talcum 2
Colloidal silicon dioxide 2
filled in a gelatin capsule.
EXAMPLE 4
Solution for injection
A suitable formulation for an injectable solution is as follows:
Active Ingredient mg 10
Sodium chloride mg q.s.
Water for Injection mL add 1.0
EXAMPLE 5
Liquid oral formulation
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A suitable formulation for 1 liter of a an oral solution containing
2,milligrams of
active ingredient in one milliliter of the mixture is as follows:
mg
Active Ingredient 2
Saccharose 250
Glucose 300
Sorbitol 150
Orange flavor 10
Colorant q.s.
Purified water add 1000 mL
EXAMPLE 6
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 20
milligrams of active ingredient in one milliliter of the mixture is as
follows:
G
Active Ingredient 20.00
Tragacanth 7.00
Glycerol 50.00
Saccharose 400.00
Methylparaben 0.50
Propylparaben 0.05
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Black currant-flavor 10.00
Soluble Red color 0.02
Purified water add 1000 mL
EXAMPLE 7
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 2
milligrams of active ingredient in one milliliter of the mixture is as
follows:
G
Active Ingredient 2
Saccharose 400
Bitter orange peel tincture 20
Sweet orange peel tincture 15
Purified water add 1000 mL
EXAM'PLE 8
Aerosol formulation
180 g aerosol solution contain:
G
Active Ingredient 10
Oleic acid 5
Ethanol 81
Purified Water 9
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Tetrafluoroethane 75
15 ml of the solution are filled into aluminum aerosol cans, capped with a
dosing valve, purged with 3.0 bar.
EXAMPLE 9
TDS formulation
100 g solution contain:
G
Active Ingredient 10.0
Ethanol 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0
Hydroxyethylcellulose 0.4
Purified water 19.6
1.8 ml of the solution are placed on a fleece covered by an adhesive backing
foil. The system is closed by a protective liner which will be removed before
use.
EXAMPLE 10
Nanoparticle formulation
10 g of polybutylcyanoacrylate nanoparticies contain:
G
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Active Ingredient 1.00
Poloxamer 0.10
Butylcyanoacrylate 8.75
Mannitol 0.10
Sodium chloride 0.05
Polybutylcyanoacrylate nanoparticies are prepared by emulsion
polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation
medium. The nanoparticles in the suspension are finally lyophilized under
vacuum.
PHARMACOLOGY - SUMMARY
[00172] The active principles of the present invention, and
pharmaceutical compositions thereof and method of treating therewith, are
characterized by unique and advantageous properties, rendering the "subject
matter as a whole", as claimed herein, unobvious. The compounds and
pharmaceutical compositions thereof exhibit, in standard accepted reliable
test procedures, the following valuable properties and characteristics:
METHODS
BINDING ASSAYS FOR THE CHARACTERIZATION OF MGLUR5
ANTAGONIST PROPERTIES
[3H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to
transmembrane allosteric modulatory sites ' of mGIuR5 receptors in
cortical membranes
Preparation of rat cortical membranes:
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[00173] Male Sprague-Dawley rats (200-250 g) are decapitated and their
brains are removed rapidly. The cortex is dissected and homogenized in 20
volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The
homogenate is centrifuged at 1000xg for 10 min. The pellet is discarded and
the supernatant centrifuged at 20,000xg for 20 min. The resulting pellet is re-
suspended in 20 volumes of distilled water and centrifuged for 20 min at
8000xg. Then the supernatant and the buffy coat are centrifuged at 48,000xg
for 20 min in the presence of 50 mM Tris-HCI, pH 8Ø The pellet is then re-
suspended and centrifuged two to three more times at 48,000xg for 20 min in
the presence of 50 mM Tris-HCI, pH 8Ø All centrifugation steps are carried
out at 4 C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0 the
membrane suspension is frozen rapidly at -80 C.
[00174] On the day of assay the membranes are thawed and washed
four times by resuspension in 50 mM Tris-HCI, pH 8.0 and centrifugation at
48,000xg for 20 min. and finally re-suspended in 50 mM Tris-HCI, pH 7.4. The
amount of protein in the final membrane preparation (250-500 pg/mI) is
determined according to the method of Lowry (Lowry O. H. et al., 1951. J.
Biol. Chem. 193, 256-275).
[3H]MPEP Assay
[00175] Incubations are started by adding (3H)-MPEP (50.2 Ci/mmol,
5nM, Tocris) to vials with 125-250pg protein (total volume 0.5 ml) and various
concentrations of the agents. The incubations are continued at room
temperature for 60 min (equilibrium was achieved under the conditions used).
Non-specific binding is defined by the addition of unlabeled MPEP (10 pM).
Incubations are terminated using a Millipore filter system. The samples are
rinsed twice with 4 ml of ice cold assay buffer over glass fibre filters
(Schleicher & Schuell) under a constant vacuum. Following separation and
rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold) and
radioactivity retained on the filters is determined with a conventional liquid
scintillation counter (Hewlett Packard, Liquid Scintillation Analyser).
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Characterization
[00176] Specific binding is extremely high i.e. normally > 85% and
essentially independent of buffer (Tris or HEPES oth 50 mM) and pH (6.8-
8.9). There is a clear saturable protein dependence and the chosen protein
concentration used for subsequent assays (250-500 pg/mi) is within the linear
portion of this dependence. Cold MPEP displaces hot ligand with an IC50 of
18.8 4.1 nM. The Kd of (3H)-MPEP of 13.6 nM is determined by Scatchard
analysis and used according to the Cheng Prussoff relationship to calculate
the affinity of displacers as Kd values (IC50 of cold MPEP equates to a Ki of
13.7 nM). Bmax was 0.56 pm / mg protein. Compounds of the present
invention exhibit specific affinity for transmembrane modulatory sites of
mGLuR5 receptors in cortical/cerebellar membrane preparations.
FUNCTIONAL ASSAY OF MGLUR5 RECEPTORS
Materials and Methods
Astrocyte culture
[00177] Primary astrocyte cultures were prepared from cortices of
newborn rats as described by Booher and Sensenbrenner (1972). Briefly,
Sprague-Dawley rat pups (2 - 4 d old) were decapitated and neocortices were
dissected, disintegrated with a nylon filter (poresize 80 pm) and carefully
triturated. The cell suspension was plated on poly-D-lysine precoated flasks
(Costar) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM,
InVitrogen) supplemented with 10% heat inactivated fetal calf serum (FCS;,
Sigma), 4 mnn glutamine (Biochrom) and 50 pg/mL gentamycin (Biochrom) at
37 C in a humidified atmosphere of 5% C02/95% air for 7 d with exchanging
the medium at day 2.
[00178] After 7 DIV, cells were shaken overnight at 250 rpm to remove
oligodendrocytes and microglia. The next day, astrocytes were rinsed twice
with CMF-PBS, trypsinized and subplated on poly-D-lysine precoated 96-well
plates (Becton Dickinson #6516 or #6640) at a density of 40,000 - 45,000
cells/well. 24 h after establishing the secondary culture the astrocytes were
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rinsed with PBS++ and fed with astrocyte-defined medium (ADM) consisting of
DMEM containing 1x G5-supplement (InVitrogen), 0.5 pg/mL heparan sulfate
(Sigma), and 1.5 pg/ mL fibronectin (Sigma) (Miller et al., 1993). 3 d later
the
medium was exchanged and the cells incubated for another 2-3 d, so that at
the time of experiments astrocytes were 14-15 DIV.
lmmunocytochemistry
[00179] Immunostaining was performed to confirm the presence of
classical astrocytic markers such as GFAP as well the expression of mGIuR5
receptors.
Accumulation of [3H]-Inositol Phosphates
[00180] After astrocytes were cultured for 12 d ADM was removed and
inositol-free QMEM (MP Biomedicals) supplemented with [3H]myo-inositol (0.5
pCi I well; Perkin Elmer), and the ADM chemicals was added. After 48 h the
medium was replaced with 100 pL Locke's buffer (plus 20 mnn Li+, pH 7.4) and
incubated for 15 min at 37 C before replacement with agonists / antagonists
in Locke's buffer. The incubation (45 min at 37 C) was terminated by
replacing the Locke's solutions with 100 pL 0.1 nn HCI (10 min on ice). The 96
well plates can be frozen at -20 C at this stage until further analysis. Home
made resin exchange columns (AG1-X8 Biorad, 140-14444) were used to
separate labeled inositol phosphates by elution with I mL of I nn ammonium
formate / 0.1 nn formic acid into 24-well visiplates (Perkin Elmer).
Scintillation
liquid (UltimaFlow AF, Perkin Elmer) was added, the plate sealed and
vortexed before radioactivity was determined by conventional liquid
scintillation counting (Microbeta,Perkin Elmer) as disintegration per minute
(DPM).
Calcium FLIPR studies
[00181] Cultured astrocytes expressed mGIuR5 receptors as shown by
immunostaining. The increase of intracellular calcium after stimulation with
the
mGIuR5 agonist DHPG or L-quisqualate was measured using the fluorometric
imaging plate reader (FLIPR) and the Ca-Kit (both Molecular Devices, CA).
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Prior to addition of agonist or antagonist the medium was aspirated and cells
were loaded for 2 h at RT with 150 pL of loading buffer consisting of Ca-
sensitive dye (MD # R8033) reconstituted in sodium chloride (123 mnn),
potassium chloride (5.4 mnn), magnesium chloride (0.8 mnn), calcium chloride
(1.8 mnn), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently,
plates were transferred to FLIPR to detect calcium increase with the addition
of DHPG (300 pnn) or L-quisqualate (100 nM) measured as relative
fluorescence units (RFU). If antagonists were tested, these compounds were
pre-incubated for 10 min at RT before addition of the respective agonist.
[00182] For positive modulators, concentration-response curves for
quisqualate were performed in the presence and absence of 10 pM modulator
to determine the extent of potentiation / agonist potency increase.
Thereafter,
concentration-response curves for the positive modulator were performed in
the presence of a fixed concentration of quisqualate showing the biggest
window for potentiation (normally 10-30 nM).
Data analysis
[00183] The fluorescence signal increase after addition of agonist
reflects the increase of intracellular calcium. Inconsistencies in the amount
of
cells per well were normalised by using the spatial uniformity correction of
the
FLIPR software. The mean of replicated temporal data (n=5) was calculated
and used for graphical representation. For the evaluation of the
pharmacology, the calcium changes in response to different concentrations of
agonist or antagonist were determined using a maximum minus minimum
(MaxMin) calculation.
[00184] All responses (DPM- or RFU-values) were determined as
percentage of control (= maximum response at 100 nM quisqualate).
EC50 and IC50 were calculated according the logistic equation using GraFit 5.0
(Erithacus Software).
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Chemicals
[00185] Unless otherwise stated all chemicals were purchased from
Sigma.
References
Booher and Sensenbrenner (1972) Neurobiology 2(3):97-105
Miller et al., (1993) Brain Res. 618(1):175-8
[00186] Compounds of the present invention have an EC50 range of
about 0.5 nM to about 100 M.
CONCLUSIONS
[00187] In conclusion, from the foregoing, it is apparent that the present
invention provides novel, valuable, and unpredictable applications and uses of
the compounds of the present invention, which compounds comprise the
active principle according to the present invention, as well as novel
pharmaceutical compositions thereof and methods of preparation thereof and
of treating therewith, all possessed of the foregoing more specifically-
enumerated characteristics and advantages.
[00188] The high order of activity of the active agent of the present
invention and compositions thereof, as evidenced by the tests reported, is
indicative of utility based on its valuable activity in human beings as well
as in
lower animals. Clinical evaluation in human beings has not been completed,
however. It will be clearly understood that the distribution and marketing of
any compound or composition falling within the scope of the present invention
for use in human beings will of course have to be predicated upon prior
approval by governmental agencies, such as the U.S. Federal Food and Drug
Administration, which are responsible for and authorized to pass judgment on
such questions.
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[00189] The instant ethynyl-substituted tetrahydroquinolinone derivatives
represent a novel class of Group I mGluR modulators. They are especially
useful as mGluR 5 positve modulators or agonists. In view of their potency,
they will be useful therapeutics in a wide range of CNS disorders which
involve abnormal glutamate induced excitation.
[00190] These compounds accordingly find application in the treatment
of the following disorders of a living animal body, especially a human: AIDS-
related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine
spongiform encephalopathy (BSE) or other prion related infections, diseases
involving mitochondrial dysfunction, diseases involving 9-amyloid and/or
tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's
disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS),
multiple sclerosis (MS), olivoponto-cerebellar atrophy, post-operative
cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild
cognitive impairment, dementia pugilisitca, vascular and frontal lobe
dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma,
retinopathy, macular degeneration), head and spinal cord injuries / trauma,
hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from
cardiac
arrest, stroke, bypass operations or transplants), convulsions, glioma and
other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-
dopa-induced and tardive dyskinesias.
[00191] These compounds also find application in the treatment of the
following disorders of a living animal body, especially a human: addiction
(nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others),
amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention
deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive
children, autism, convulsions / epilepsy, dementia (e.g. in Alzheimer's
disease, Korsakoff syndrome, vascular dementia, HIV infections), major
depressive disorder or depression (including that resulting from Borna virus
infection) and bipolar manic-depressive disorder, drug tolerance e.g. to
opioids, movement disorders, dystonia, dyskinesia (e.g. L-Dopa-induced,
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tardive dyskinesia or in Huntington's disease), fragile-X syndrome,
Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple
sclerosis, muscle spasms, pain (chronic and acute, e.g. inflammatory pain,
neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's
disease, post traumatic stress disorder, schizophrenia (positive and negative
symptoms), spasticity, tinnitus, Tourette's syndrome, urinary incontinence and
vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition
disorders, neuromuscular disorder in the lower urinary tract,
gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES),
functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory
tract
infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related
asthma), lung disease, eating disorders, obesity and obesity-related
disorders.
[00192] These compounds also find application in the treatment of
indications in of a living animal body, especially a human, wherein a
particular
condition does not necessarily exist but wherein a particular physiological
parameter may be improved through administration of the instant compounds,
including cognitive enhancement.
[00193] The method-of-treating a living animal body with a compound of
the invention, for the inhibition of progression or alleviation of the
selected
ailment therein, is as previously stated by any normally-accepted
pharmaceutical route, employing the selected dosage which is effective in the
alleviation of the particular ailment desired to be alleviated.
[00194] Use of the compounds of the present invention in the
manufacture of a medicament for the treatment of a living animal for
inhibition
of progression or alleviation of selected ailments or conditions, particularly
ailments or conditions susceptible to treatment with a Group I mGIuR
modulator, in particular an mGluR 5 modulator, especially an mGluR 5
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positive modulator or agonist, is carried out in the usual manner comprising
the step of admixing an effective amount of a compound of the invention with
a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-
of-treating, pharmaceutical compositions, and use of a compound of the
present invention in the manufacture of a medicament.
[00195] Representative pharmaceutical compositions prepared by
admixing the active ingredient with a suitable pharmaceutically-acceptable
excipient, diluent, or carrier, include tablets, capsules, solutions for
injection,
liquid oral formulations, aerosol formulations, TDS formulations, and
nanoparticle formulations, thus to produce medicaments for oral, injectable,
or
dermal use, also in accord with the foregoing.
*****
[00196] The present invention is not to be limited in scope by the specific
embodiments described herein. Indeed, various modifications of the invention
in addition to those described herein will become apparent to those skilled in
the art from the foregoing description.
[00197] All patents, applications, publications, test methods, literature,
and other materials cited herein are hereby incorporated by reference.
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