Note: Descriptions are shown in the official language in which they were submitted.
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CHROMENONES AND THEIR USE AS MODULATORS OF
METABOTROPIC GLUTAMATE RECEPTORS
FIELD OF THE INVENTION
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
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.
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 fffe_ 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.
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 I1 and mGIuR4,
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.
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 mGluR modulators, 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.
Therefore, group I mGluR modulators may be administered to provide
neuroprotection in acute and chronic pathologica( 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 pugilistica, vascular and
frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
glaucoma, retinopathy, macular degeneration), head and brain and spinal
cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia
(e.g. resulting from cardiac arrest, stroke, bypass operations or
transplants),
convulsions, epilepsy, temporal lope epilepsy, glioma and other tumours,
inner ear insult (e.g. in tinnitus, sound- or drug-induced), L-Dopa-induced
and tardive dyskinesias.
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Other indications in this context include a symptomatological effect on the
following conditions: abuse and 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, hyperactivity in children, autism, convulsions,
epileptic convulsions, epilepsy, temporal lobe 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, chorea, Huntington's chorea, irritable bowel syndrome (IBS),
migraine, multiple sclerosis (MS), 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 , vomiting, pruritic conditions
(e.g.
pruritis), sleep disorders, micturition disorders, neuromuscular disorder in
the
--lower urinary_ _-tract,- gastroesophageal reflux disease (GERD), iower
esophageal sphincter (LES) disease, functional gastrointestinal disorders,
dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa,
chronic
laryngitis, asthma (e.g. reflux-related asthma), lung disease, eating
disorders, obesity, obesity-related disorders, binge eating disorders,
agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder,
panic disorder, anxiety disorder, posttraumatic stress disorder, social
phobia,
substance-induced anxiety disorder, delusional disorder, schizoaffective
disorder, schizophreniform disorder, substance-induced psychotic disorder
and delirium.
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
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administration of the instant compounds, for example cognitive
enhancement.
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.
THE PRESENT INVENTION
We have determined that certain chromenones are Group I mGluR
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 mGIuR 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
_
-- t-is - arr object of- the- present- invention to provide- novel -
pharmaceutical
compounds which are chromenone Group I mGluR 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
invention is the provision of a process for producing the chromenone 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
What we therefore believe to be comprised by our invention may be
summarized inter alia in the following words:
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A compound of Formula I
R3
R4 ~ O~O
I ~ 1
R R
R6 R2
I
5 wherein
R1 represents hydrogen, C1_6alkyl, aryl, heteroaryl or -C(=0)-R1o
R2 represents hydrogen, C1-6alkyl, aryl, heteroaryl, aryIC1-6 alkyl,
heteroarylCT_6alkyl, cyano, nitro, halogen, hydroxy or C2-6 alkoxy;
or R1 and R2 together represent -W1-X1-Y1-Z1-,
wherein
-W1 represents-a-single-bond; -oxygen;-sulfur, -NR7--or--CR$R9-,_and
X1, Y1 and Z1 each independently represents oxygen, sulfur, -NR'- or
-CR$R9-;
R3 represents hydrogen, C1-6alkyl, aryl, heteroaryl, nitro, amino, C1-6
alkoxy, halogen, hydroxy, -C(=O)-R10, -N(R11)-C(=O)-R10,
-N(R11)S02-R10, -N(R11)C(=O)OR11, -C(=O)N(R11)2, -C1_6alkylene-
C(=O)N(R11)2, -N(R11)C(=S)N(R11)2, -N(R11)C(=O)N(R11)2,
C1-6alkylamino, di-C1-6 alkylamino, cycloC3-12alkylamino, cycloC3-12
alkylaminoCl-6alkyl, cycloC3-12alkyl-C1-6alkylamino, di-C1_s
alkylaminoC1-6alkyl, C1-6alkoxy-C2-6 alkylamino, arylamino, aryIC1-6
alkylamino, N-cycloC3-12 aJkyl-N-C1-6 alkylamino, N-aryl-N-C1-6
alkylamino, N-aryIC1-6alkyl-N-C1_6 alkylamino, pyrrolidino, piperidino,
4-arylpiperidino, 4-heteroarylpiperidino, morpholino, morpholinoCl-s
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alkyl, piperazino, 4-CI-6alkylpiperazino, 4-arylpiperazino,
hexamethyleneimino, heteroarylamino or heteroarylC1.6 alkylamino;
R4 represents hydrogen, halogen, nitro, amino, hydroxy, -OR12,
-SO3CF3, CI.6alkyl, cycloC3.12alkyl, cycloC3.12alkyl-CI-6alkyl, C2.6
alkenyl, C2-6alkynyl, aryl, biaryl, aryIC1-6alkyl, aryIC2.6alkenyl, aryIC2-6
alkynyl, heteroaryl, heteroarylC1.6aIkyl, heteroarylC2-6alkenyl,
heteroarylthio, 2,3-dihydro-1 H-indenyl, C1-6alkoxyC1-6alkyl,
aryloxyarylC1.6alkoxy, C1.6alkylthio, C4-6 alkenylthio, cycIoC3.12
alkylthio, cycloC3.12alkyl-C1-6alkylthio, cycloC3-1Z alkyl-C3.6alkenylthio,
C1-6alkoxyC1-6alkylthio, Cl-6alkoxyC3.6alkenylthio, aryIC3.6alkenylthio,
heteroarylC1.6alkylthio, Cl-6alkylsulfonyl, cycloC3.12 alkyl-Cl.6
alkylsulfonyl, aryIC1.6alkylsulfonyl, C1.6alkylamino, di-C1-6 alkylamino,
cycloC3_12alkylamino, CI-6alkoxycycloC3.12alkylamino,
cycloC3.12 alkylCI-6 alkylamino, di-C1.6alkylaminoC1-6alkyl, C1-6alkoxy-
C2-6 alkylamino, arylamino, aryIC1-6alkylamino, N-cycloC3.12alkyl-N-
C1-6alkylamino, N-aryI-N-C1-6alkylamino, N-aryIC1.6alkyl-N-C1-6
alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4-
arylpiperidino, 4-heteroary_Ipiperidino, morpholino, piperazino, 4-C1-6
alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl,
1,3-dihydro-2H-isoindol-2-yi, heteroarylC1.6alkoxy, heteroarylamino,
heteroarylC1.6 alkylamino, -N(R")C(=O)-Rlo, -N(R'1)SO2-R10,
-N(R")C(=O)OR", -C(=O)N(R")2, -C1.6alkylene-C(=O)N(R'1)2,
-S-C(=O)N(R'1)2 or -O-C(=O)-Rlo;
R5 represents hydrogen, halogen, nitro, amino, hydroxy, C1.6alkoxy,
C1.6 alkyl, C1.6alkylamino, hydroxyCj-6alkoxy, aryl, heteroaryl, OCF3,
-N(R")C(=O)-R10, -N(R1')SO2-R1O, -N(R")C(=O)OR", -C(=O)N(R")2,
-C1.6alkylene-C(=0)N(R11)2, -N(R")C(=S)N(R'1)2,
-N(R")C(=O)N(R")2, -O-S02R10 or-C(=O)RlO;
R6 represents hydrogen, C1_6alkyl, aryl, heteroaryl, halogen, hydroxy
or Cl-6alkoxy;
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R7 represents hydrogen, C1_6alkyl, aryl, heteroaryl, aryIC1_6 alkyl, C1_6
alkoxy, halogen, hydroxy, cyano, nitro, hydroxyC,_6alkyl, CYCIOC3-12
alkoxy, C1_6alkylamino, di-C1_6alkylamino, cycloC3_12alkylamino,
cycloC3_12alkyl-C1_6alkylamino, di-Cl.6alkylaminoC1_6alkyl, arylamino,
aryIC1_6alkyl, N-aryI-N-C1_6alkylamino, pyrrolidino, piperidino, 4-C1_6
alkylpiperazino, morpholino, hexamethyleneimino, pyrrolidinylC1_6
alkyl, piperidinylC1_6alkyl, morpholinylC1_6alkyl, C1_6alkylsulfonyl, Cl_s
alkylthio, C1_6alkylaminosulfonyl or di-Cl_6alkylaminosu(fonyl;
R 8 and R9 each independently represent hydrogen, C1_6alkyl, aryl,
heteroaryl, aryIC1_6 alkyl, C1_6alkoxy, halogen, hydroxy, cyano, nitro,
amino or cycloC3_12alkyl;
R10 represents hydrogen, C1_6alkyl, cycloC3_12alky! (e.g. adamantyl),
aryl, heteroaryl or carboxyC1_6alkyl;
R" represents hydrogen, C1_6alkyl, cycloC3_12alkyl (e.g. adamantyl),
a ry_I, heteroary_I, carboxyC1_6aikyl or C1_6aikyicarbonyl;
R12 represents C1_6alkyl optionally substituted by one or more (e.g. 1,
2, 3, 4 or more) substituents selected from hydroxy, cycloC3_12alkyl,
C1_6 alkylamino, di-C1_6alkylamino, morpholino, halogen, arylamino
and -C(=O)R13; heteroaryl; CYCIOC3-12 alkyl; C1_6alkoxycycloC3_12alkyl;
aryICI.6 alkyl; aryloxyarylC1_6alkyl and C2_6 alkenyl; and
R13 represents amino, pyrrolidino or piperidino;
or if R' and R2 represent -W'-X'-Y'-Zl- and Wl does not represent a
single bond,
R3 and R4, R4 and R5 or R5 and R6 together with the carbon
atoms to which they are attached may form a 5-6 membered
ring which may be saturated or unsaturated, wherein the ring
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may optionally have 1 to 4 heteroatoms selected from oxygen,
sulfur and nitrogen, and wherein the ring may be optionally
substituted by one or more (e.g. 1, 2, 3, 4 or more) substituents
selected from hydrogen, C1-6 alkyl, cycloC3-12 alkyl, aryl,
heteroaryl, aryIC1_6alkyi, carboxyC1-6 alkyl, alkylcarbonyl,
arylcarbonyl, oxo, thioxo, C1-6alkoxy, C1-6 alkylthio, aryIC1-6
alkylthio, arylCl.6alkoxy, morpholino, C3-6 cycloalkylamino,
pyrrolidino, piperidino, hexamethyleneimino, piperazinyl, N-C1-6
alkylpiperazinyl and arylamino;
wherein the term "C1_6alkyl", unless otherwise specified, denotes
straight or branched chain groups which may be unsubstituted or
substituted by one or more (e.g. 1, 2, 3, 4 or more) fluorine, chlorine
and/or bromine atoms; the term "C1-6alkoxy" denotes straight or
branched chain groups which may be unsubstituted or substituted by
one or more (e.g. 1, 2, 3, 4 or more) fluorine, chlorine and/or bromine
atoms; the term "cycloC3-12 alkyl" denotes monocyclic, bicyclic or
tricyclic groups which may be unsubstituted or substituted by one or
more(e.g. 1,2, 3, 4 or more) fluorine, chlorine and/or bromine atoms;
the term "aryl" denotes phenyl or naphthyl or phenyl substituted by
one or more (e.g. 1, 2, 3, 4 or more) substituents, which may be the
same or different, selected from C1-6alkyl, C2-6aikenyl, C1-6alkoxy,
cycloC3-12alkyl, hydroxy, halogen, cyano, nitro, C1-6alkoxycarbonyl,
amino, C1-6alkylamino, di-C1_6alkylamino, N-cycloC3-12alkyl-N-
C1-6alkylamino, azetidinyl, pyrrolyl, piperidinyl, morpholinyl, 4-C1-6
alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl,
thiazolyi, imidazolyi, oxadiazolyl, pyridinyl, pyrimidyl and C1_6
alkylenedioxy; and the term "heteroaryl" denotes an aromatic 5-6
membered ring containing from one to four heteroatoms selected
from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6
membered ring containing from one to four heteroatoms selected
from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6
membered aromatic ring containing from one to four heteroatoms
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selected from oxygen, sulfur and nitrogen, wherein the heteroaryl
group may be optionally substitued by one or more (e.g. 1, 2, 3, 4 or
more) substituents, which may be the same or different, selected from
C1_6alkyl, C1_6alkoxy, cycloC3_12alkyl, hydroxy, halogen, cyano, nitro,
C1_6afkoxycarbonyl, amino, C1_6alkylamino, di-Cl.6alkylamino, N-
cycloC3_12alkyl-N-CI_6alkylamino, azetidinyl, pyrrolyl, piperazinyl,
morpholinyl, 4-C1_6alkylpiperazinyl, tetrazolyl, oxazolyl, furyl,
thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl,
pyrimidyl and phenyl;
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates,
and polymorphs thereof;
with the proviso that the compounds of Formula I do not include:
chromen-2-one,
2-ch lo ro-3-iso pro poxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
3-(2-chlorobenzyioxy)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-(2-chlorobenzyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-
6-one,
3-(1-phenylethoxy)benzo[c]chromen-6-one,
8-hexyl-7-methoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one,
2-ch lo ro-3-methoxy-7, 8, 9,10-tetra h yd ro be nzo [c] ch ro m e n-6-o ne,
3-hydroxy-4-piperidin-1-ylmethyl-7,8,9,10-
tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-hydroxy-9-methyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one,
6-chloro-7-hyd roxy-4-trifluoromethylchromen-2-one,
2-chforo-3-hydroxy-4-morpholin-4-ylmethyl-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one,
2-chloro-4-dimethylaminomethyl-3-hyd roxy-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one,
2-ethyl-3-hydroxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
2 ,3-dimethoxy-7,8, 9,10-tetrahydrobenzo[c]chromen-6-one,
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2-hyd roxy-3-methoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-(2-methylallyloxy)-7,8, 9,10-tetrahyd robenzo [c]chromen-6-
one,
3-allyloxy-2-chloro-7, 8,9,10-tetrahyd robenzo[c]chromen-6-one,
2-chloro-3-hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-hexyl-3-methoxy-7,8, 9,10-tetrahyd robenzo[c]chromen-6-one,
8-chloro-7-isopropoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one,
8-chloro-7-hydroxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one,
3-(adamantane-1-carbonyl)-6-methoxychromen-2-one,
3-(adamantane-1 -carbonyl)-6-bromochromen-2-one,
3-(adamantane-1-carbonyl)chromen-2-one,
3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-(3-methylbut-2-enyloxy)-7, 8,9,10-
tetrahydrobenzo[c]chromen-6-one,
8-isopropoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one,
3-amino-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
3-isopropylamino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
3-amino-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]ch romen-6-one,
6-chloro-3-imidazo[1,2-a]pyridin-2-yichromen-2-one,
3-pyridin-2-yI-3,4,7,8,9,10-hexahydro-2H-1,5-dioxa-3-azachrysen-6-
one or
6-chloro-3-imidazo[1,2-a]pyridin-2-ylchromen-2-one.
Such a compound of Formula I wherein R' represents hydrogen or
-C(=O)-R'o
Such a compound of Formula I wherein R10 represents adamantyl.
Such a compound of Formula I wherein R2 represents hydrogen, aryl,
heteroaryl or C1_6alkyl.
Such a compound of Formula I wherein R2 represents phenyl or pyridyl.
Such a compound of Formula I wherein R' and R2 together represent
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-Wl-X1-Yl-Z1-,
wherein
W1 represents a single bond or -CR8R9-, and Xl, Y', and Z1 each
independently represent -CR8R9-, wherein R8 and R9 are each
independently selected from hydrogen, C1_6alkyl, aryl and heteroaryl.
Such a compound of Formula I wherein R 8 represents hydrogen and R9
represents hydrogen, C1_6alkyl, aryl or heteroaryl.
Such a compound of Formula I wherein R9 represents hydrogen, methyl,
ethyl, trifluoromethyl, t-butyl, phenyl or pyridyl.
Such a compound of Formula I wherein R9 represents hydrogen, methyl or
trifluoromethyl.
Such a compound of Formula I wherein R3 represents hydrogen, C1-6 alkyl,
morpholinoCl-6alkyl, amino, nitro, -N(R11)C(=O)N(R'1)2, -N(R11)SO2-R10, C1-6
alkylamino or -N(R11)C(=O)-R10.
Such a compound of Formula I wherein R4 represents halogen, hydroxy,
OR12, -S-C(=O)N(R")2, -C(=O)N(R11)2, C1-6alkylthio, C1-6 alkylsulfonyl,
morpholino, pyrrolidino, arylC1-6alkylamino, -N(R11)C(=O)-R10, heteroarylthio,
-O-C(=O)-R10, di-Cl-6alkylamino or heteroaryl.
Such a compound of Formula I wherein R4 represents halogen, OR12,
-S-C(=O)N(R11)2, -C(=O)N(R11)2, C1-6alkylthio or di-C1.6 alkylamino.
Such a compound of Formula 1 wherein R12 represents C1-6alkyl optionally
substituted by one or more substituents selected from hydroxy, di-C1-6
alkylamino, morpholino, halogen, cycloC3-12alkyl, arylamino and -C(=0)R13
(e.g. as in CF3 or CHF2); cycloC3-12alkyl; Cl-6alkoxycycloC3-12alkyl or
heteroaryl.
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Such a compound of Formula 1 wherein R4 represents bromo, methoxy, iso-
propoxy, -C(=O)N(R")2, isopropylsulfanyl, difluoromethoxy, dimethylamino
or diethylamino.
Such a compound of Formula I wherein R" represents hydrogen or Cl.6
alkyl.
Such a compound of Formula I wherein R" represents methyl.
Such a compound of Formula 1 wherein R5 represents hydrogen, nitro,
halogen, C1.6alkyl, hydroxy CI.6alkoxy, -C(=O)-R10, -N(R")S02-R'0,
-N(R")C(=0)-Rl0 or C1_6alkylamino.
Such a compound of Formula I wherein R5 represents hydrogen, nitro,
chloro or ethyl.
Such a compound-of Formula t wherein R6 represents hydrogen or C1.6 alkyl.
Such a-compound of_Formula I wherein R 3 and R together with the carbon
atoms to which they are attached form a 5-6 membered ring which may be
saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected
from oxygen and nitrogen and may optionally be substituted by one or more
substituents selected from C1.6alkyl, C1_6alkylthio, CI.salkoxy, oxo, aryIC1.6
alkyl, aryl, arylCI_salkylthio and morpholino.
Such a compound of Formula I wherein R4 and R5 together with the carbon
atoms to which they are attached form a 5-6 membered ring which may be
saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected
from oxygen and nitrogen and may optionally be substituted by one or more
substituents selected from heteroaryl, piperazinyl, N-CI.6alkylpiperazinyl,
arylamino, aryIC1_6alkylthio, morpholino, C1.6alkylthio, oxo, thioxo,
arylcarbonyl, aryl, CI.salkoxy, aryIC1.6alkyl and cycloC3_12alkyl.
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Such a compound of Formula I wherein R5 and R6 together with the carbon
atoms to which they are attached form a 5-6 membered ring which may be
saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected
from oxygen and nitrogen and may optionally be substituted by one or more
substituents selected from heteroaryl, oxo, thioxo, aryl, C1.6alkyl and C1_6
alkoxy.
Such a compound of Formula I selected from:
N-acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-
benzo[c]chromen-4-yl)acetamide,
N-(2-chloro-3-isopro pxy-6-oxo-7,8,9,10-tetrahydro-6 H-benzo[c]chromen-
4-yl)benzamide,
N-(3-isopropxy-6-oxo-7,8,9,10-tetrahyd ro-6 H-benzo[c]chromen-2-
yl)isobutyramide,
N-(2-ch lo ro-3-iso pro pxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-
4-yl)formamide,
N-(2-chlo ro-3-isopropoxy-6-oxo-7,8,9,10-tetrahyd ro-6H-
benzo[c]chromen-4-yl)succinamic acid,
dimethylthiocarbamic acid 6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl ester,
S-( N, N-d imethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10-
tetrahyd robenzo[c]ch romen-6-one,
2-chloro-3-(pyrid i n-2-ylsulfanyl)-7,8,9,10-tetrahyd robenzo[c]chromen-6-
one,
S-(N,N-dimethylcarbamoyl)-8-ethyl-2-chloro-6-oxo-3-thio-7,8,9,10-
tetrahydro-6H-benzo[c]chromen-6-one, and
12-ch lo ro-16-i so p ro pyl s u lfa nyl-1, 2, 3, 4-tetra h yd ro-7,17-d ioxa-
15-
azacyclopenta[a]phenanthren-6-one.
Such a compound of Formula I selected from:
3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one,
3-(adamantane-1 -carbonyl)-7-dimethylaminochromen-2-one,
3-(adamantane-1 -carbonyl)-7-d iethylaminochromen-2-one,
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3-(adamantane-1 -carbonyl)-7-bromochromen-2-one,
2-ch lo ro-3-iso propoxy-9-methyl-7,8, 9,10-tetrahydrobenzo[c]chromen-6-
one,
2-ch loro-3-isopropoxy-8-trifluoromethyl-7, 8, 9,10-
tetrahydrobenzo[c]chromen-6-one,
dimethylfihiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10-
tetrahydro-6H-benzo[c]chromen-3-yl) ester,
dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl) ester,
3-isopropoxy-2-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-isopropylsulfanyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-ethyl-3-i so pro poxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
2-ch(oro-3-difluoromethoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, and
2-chloro-3-isopropoxy-7-methyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one.
Moreover, a compound of Formula I as hereinbefore defined or an optical
isomer, pharmaceutically_ acceptable salt, ester, hydrate, solvate or
polymorph thereof, subject to the modified proviso that the compound of
Formula I may additionally be 2-chloro-3-methoxy-7,8,9,1 0-
tetrahydrobenzo[c]chromen-6-one, 2-chlo ro-3-isopropoxy-7,8,9,10-
tetrahydrobenzo[c]chromen-6-one or 8-chloro-7-isopropoxy-2,3-dihydro-1 H-
cyclopenta[c]chromen-4-one, for use as a medicament.
Moreover, a pharmaceutical composition comprising as active ingredient a
compound of the invention as hereinbefore defined, together with one or
more pharmaceutically acceptable excipients or vehicles.
Moreover, use of a compound of the invention as hereinbefore defined but
not subject to the foregoing proviso to Formula I as or in the manufacture of
a medicament for prevention and/or treatment of a condition associated with
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abnormal glutamate neurotransmission or in which modulation of Group I
mGluR receptors results in therapeutic benefit or for enhancing cognition.
Furthermore, a method for treating or preventing a condition or disease
associated with abnormal glutamate neurotransmission or a method for
modulating Group I mGluR receptors to achieve therapeutic benefit, or a
method for enhancing cognition, such method comprising administering to a
living animal, including a human, a therapeutically effective amount of a
compound of the invention as hereinbefore defined but not subject to the
foregoing proviso to Formula I.
Such a use or 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 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), oiivoponto-cerebeliar atrophy, post-operative cognitive
deficit
(POCD), Parkinson's disease, Parkinson's dementia, mild cognitive
impairment, dementia pugilistica, vascular and frontal lobe dementia,
cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy,
macular degeneration), head and brain and spinal cord injuries / trauma,
hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from
cardiac arrest, stroke, bypass operations or transplants), convulsions,
epileptic convulsions, epilepsy, temporal lobe epilepsy, glioma and other
tumours, inner ear insult (e.g. in tinnitus, sound- or drug-induced), L-Dopa-
induced and tardive dyskinesias, abuse and addiction (nicotine, alcohol,
opiate, cocaine, amphetamine, obesity and others), anxiety and panic
disorders, attention deficit hyperactivity disorder (ADHD), restless leg
syndrome, hyperactivity in children, autism, convulsions / epilepsy,
dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular
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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, 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, 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) disease, 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, binge eating disorders, agoraphobia, generalized anxiety disorder,
obsessive-compulsive disorder, panic disorder, anxiety 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 and/or neuroprotection.
Such a use or method wherein the condition associated with abnormal
glutamate neurotransmission, or wherein modulation of mGluR receptors
results in therapeutic benefit, is selected from: 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/or neuroprotection.
Such a use or method wherein the condition associated with abnormal
glutamate neurotransmission, or wherein modulation of mGluR receptors
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results in therapeutic benefit, is selected from: neuropathic pain, diabetic
neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis,
inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's
disease, anxiety disorders, Huntington's chorea and/or epilepsy.
Such a use or 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.
Such a use or method wherein the compound of Formula I is selected from:
3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one,
3-(adamantane-1-carbonyl)-7-dimethyiaminochromen-2-one,
3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one,
3-(adamantane-1-carbonyl)-7-bromochromen-2-one,
2-ch loro-3-iso pro poxy-9-methyl-7,8, 9,1 0-tetrahydrobenzo[c]chromen-6-
one,
2-chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one,
dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10-
tetrahydro-6H-benzo[c]chromen-3-yl) ester,
dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl) ester,
3-isopropoxy-2-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-isopropylsulfanyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-ethyl-3-iso pro poxy-7, 8, 9,10-tetra hyd ro benzo [c]ch romen-6-one,
2-chloro-3-d ifluoromethoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one,
2-chloro-3-isopropoxy-7-methyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one,
2-chloro-3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-methoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one, and
8-chloro-7-isopropoxy-2,3-dihydro-1 H-cyciopenta[c]chromen-4-one.
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Specific compounds of Formula I within the present invention include but are
not limited to:
6-chloro-7-(4-fluorobenzyloxy)-4-phenylchromen-2-one,
7-(3-phenoxybenzyloxy)-4-phenylchromen-2-one,
7-(4-fluorobenzyloxy)-4-phenylchromen-2-one,
6-chloro-7-isopropoxy-4-trifluoromethylchromen-2-one,
6-ch lo ro-7-hyd roxy-4-pyrid i n-2-yl ch ro m e n-2-o n e,
6-chloro-7-hydroxy-4-pyridin-3-ylchromen-2-one,
6-chloro-7-hydroxy-4-pyridin-4-ylchromen-2-one,
6-chloro-7-isopropoxy-4-pyrid in-4-ylch romen-2-one,
6-ch lo ro-7-iso pro poxy-4-pyrid i n-2-ylch ro men-2-one,
6-chloro-7-isopropoxy-4-pyrid in-3-ylchromen-2-one,
3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one,
3-(adamantane-1 -carbonyl)-7-di methylami nochromen-2-one,
3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one,
3-(adamantane-1-carbonyl)-7-oxazof-2-ylchromen-2-one,
_ ___ _ 3-(adamantane-l-carbonyl)-7-bromochromen-2-one,
3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
3-hydroxy-2-nitro-7, 8,9,10-tetrahydrobenzo[c]chromen-6-one,
3-isopropoxy-2-nitro-7, 8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-a mino-3-i so pro poxy-7,8,9,1 0-tetrahyd robe nzo [c]ch ro men-6-o ne,
2,2-dimethylpropionic acid 6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-
3-yl ester,
2-chloro-3-(2-oxo-2-pyrrolidin-1 -yiethoxy)-7,8,9,10-
tetrahydrobenzo[c]chromen-6-onene,
2-ch lo ro-3-(2-oxo-2-p i pe rid i n-1-yl ethoxy)-7, 8, 9,10-
tetrahydrobenzo[c]chromen-6-onene,
2-chloro-3-isopropoxy-9-methyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-hydroxy-8-trifluoromethyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one,
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2-chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,1 0-tetrahyd robenzo[c]chro men-
6-one,
2-chloro-3-(2-hyd roxyethoxy)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10-tetrahydro-
6H-benzo[c]chromen-3-yl) ester,
2-c h lo ro-3-(2-d i meth y!a m i noeth oxy)-7, 8, 9,10-tetra hyd ro benzo [c]
ch ro m en-6-
one,
dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl) ester,
2-chloro-3-isopropylsulfanyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-methylsuffanyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-methanesulfonyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-ch lo ro-3-(2-hyd roxy-3-mo rp h o l i n-4-yl p ro poxy)-7, 8, 9,10-tetra h
yd ro-
benzo[c]chromen-6-one,
2-chloro-3-isopropoxy-4-morpholin-4-ylmethyl-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one,
2-ch lo ro-3-( 3-d i methyl a m i no-2-hyd roxyp ro poxy)-7, 8, 9,10-tetra hyd
ro-
benzo[c]chromen-6-one,
2-chloro-3-(3-diethyla_mino-2-hydroxypropoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one,
2-chloro-3-(2-hydroxy-3-isopropylaminopropoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one,
2-chloro-3-cyclobutylmethoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-ethyl-3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-(2-hydroxyethoxy)-3-methoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
4-amino-3-isopropoxy-7, 8, 9,10-tetrahydrobenzo[c]chromen-6-one,
2-methoxy-3-isopropoxy-7,8,9,1 0-tetrahydro-6H-benzo[c]ch romen-6-one,
2-chloro-3-(2-hydroxy-3-isopropylaminopropoxy)-7,8, 9,10-
tetrahydrobenzo[c]chromen-6-one hydrochloride,
2-chloro-3-hydroxy-4-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-(3-chloro-2-hydroxypropoxy)-7,8,9,10-
tetrahydrobenzo[c]chromen-6-one,
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1-(3-isopropoxy-6-oxo-7, 8,9,10-tetrahyd ro-6H-benzo[c]chromen-4-yl)-3-
phenylurea,
2-ch lo ro-3-(2-hyd roxy-3-p henyla m i no pro poxy)-7,8,9,1 0-tetrahyd ro-
benzo[c]chromen-6-one hydrochloride,
1 -(2,4-d ichlorophenyi)-3-(3-isopropoxy-6-oxo-7, 8,9,10-tetrahyd ro-6H-
benzo[c]chromen-4-yl)thiourea,
3-isopropoxy-4-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
N-tosyl-4-amino-3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-isopropoxy-4-n itro-7,8,9,10-tetrahyd 0-tetrahydrobenzo[c]chromen-6-
one,
4-amino-2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
2-d ifluoromethoxy-3-methoxy-7,8, 9,10-tetrahyd robenzo[c]chromen-6-one,
2-chloro-3-d ifluoromethoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
trifluoromethanesulfonic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl ester,
3-benzyl-8-isopropoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one,
2-acetyl-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
3-isopropoxy-4-methylamino-7,8, 9,10-tefirahyd 0-tetrahydrobenzo[c]chromen-6-
one,
N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-yl) -
methanesulfonamide
N-acetyl-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-
yl)acetamide,
2-ch(oro-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-
yl)acetamide,
N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-
yl)methanesulfonamide,
N-(3-isopropoxy-6-oxo-7, 8,9,10-tetrahyd ro-6H-benzo[c]chromen-2-yl )-4-
methylbenzenesulfonamide,
3-i so p ro po xy-4-n itro-7, 8, 9,10-tetra hyd ro be nzo [c] ch ro m en-6-o n
e,
N-acetyl-N-(3-isopro poxy-6-oxo-7, 8,9,10-tetrahyd ro-6H-benzo[c]chromen-2-
yl)acetamide,
N-acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)acetamide,
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2-ch lo ro-N-(3-iso pro poxy-6-oxo-7,8,9,1 0-tetrahyd robenzo[c]cromen-2-
yI)acetamide,
1-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-yl)-3-
phenylurea,
N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-
yI)succinamic acid,
N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-
yI)formamide,
3-isopropoxy-2-methylamino-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-morpholin-4-yI-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
3-benzylamino-2-chloro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-2-
yI)benzamide,
N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-4-
yI)benzamide,
N-(2-ch lo ro-3-iso pro pxy-6-oxo-7, 8, 9,10-tetrahyd ro-6 H-benzo [c]ch ro
men-4-
yI)benzamide,
N-(3-iso propoxy-6-oxo-7, 8, 9,10-tetra hyd ro-6 H-benzo [c]ch ro men-2-
yi)isobutyramide,
N-isobutyryl-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-2-yl)isobutyramide,
N-(3-iso pro poxy-6-oxo-7, 8, 9,10-tetra hyd ro-6 H-benzo [c]ch ro men-4-
yl)isobutyramide,
N-( 2-ch l o ro-3-i so p ro poxy-6-oxo-7, 8, 9,10-tet ra hyd ro-6 H-be nzo [c]
ch ro m e n-4-
yi)formamide,
N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahyd ro-6H-benzo[c]chromen-4-
yI)-4-methylbenzesulfonamide,
N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-
yI)succinamic acid,
N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-
yI)-acetamide,
2-chloro-3-pyrrolidin-1-yI-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
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dimethylthiocarbamic acid 6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-
yl ester,
acetic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl
ester,
2-chloro-3-ethoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-propoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-(2-chloro-6-oxo-7, 8, 9,10-tetra hydro-6H-benzo[c]chromen-3-
yloxy)acetamide,
N-(2-chloro-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-3-yl)acetamide,
S-(N,N-dimethylcarbamoyl)-8-tert-butyl-2-chloro-6-oxo-3-thio-7,8,9,10-
tet ra h yd ro-6 H-b e n zo [c] c h ro m e n-6-o n e,
S-(N,N-dimethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10-
tetrahydrobenzo[c]chromen-6-one,
3-methoxy-2-pyridin-2-yl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
3-(pyridin-2-yloxy)-7,8,9,1 0-tetrahyd robe nzo [c]ch ro men-6-o ne,
2-chloro-3-(pyridin-2-ylsulfanyl)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one,
S-(N, N-d imethylcarbamoyl)-8-ethyl-2-chloro-6-oxo-3-thio-7,8,9,10-
tetrahyd ro-6H-benzo[c]chro men-6-one,
S-(N, N-dimethyfcarbamoyl)-10-methyl-2-chloro-6-oxo-3-thio-7, 8,9,10-
tetra hyd ro-6 H-be nzo [c]ch ro men-6-o ne,
12-chloro-1 6-thioxo-1,2,3,4,15,16-hexahydro-7,1 7-dioxa-1 5-
azacyclo penta [a]phena nth ren-6-one,
2-chloro-3-(4-methoxycyclohexyloxy)-7,8,9,10-tetrahydrobenzo[c]chromen-
6-one, mixture of cis and trans isomers,
2,2-dimethylpropionic acid 6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-
3-yl ester,
12-chloro-1 6-isopropylsulfanyl-1,2,3,4-tetrahyd ro-7,17-d ioxa-l5-
azacyclopenta[a]phenanthren-6-one,
12-chloro-1 6-methylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-l5-
azacyclopenta[a]phenanthren-6-one,
12-ch lo ro-16-ethyl-1, 2, 3, 4-tetrahyd ro-7,17-d ioxa-l5-
azacyclopenta[a]phenanthren-6-one,
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12-ch lo ro-16-methyl-1, 2, 3,4-tetrahyd ro-7,17-d ioxa-l5-
azacyclopenta[a]phenanthren-6-one,
15-benzyl-1,2,3,4-tetrahyd ro-15H-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6,16-d ione,
15-isopropyl-1,2, 3,4-tetrahydro-15H-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6,16-dione,
15-methyl-1,2,3,4-tetrahyd ro-15 H-7,17-d ioxa-l5-
azacyclopenta[a]phenanthren-6,16-d ione,
16-phenyl-1,2, 3,4-tetrahyd ro-7,17-d ioxa-15-azacyclopenta[a]phenanthren-6-
one,
16-efihyl-1,2,3,4-tetrahyd ro-7,17-d ioxa-l5-azacyclopenta[a]phenanthren-6-
one,
1,2,3,4-tetrahydro-15H-7,17-dioxa-15-azacyclopenta[a]phenanthrene-6,16-
dione,
1, 2,3,4-tetrahyd ro-7,17-dioxa-15-azacyclopenta[a]phenanthren-6-one,
16-benzyisulfanyl-1 2-chloro-1,2,3,4-tetrahydro-7,17-dioxa-1 5-
azacyclo penta[a]phena nth ren-6-one,
12-chloro-16-morpholin-4-yl -1,2,3,4-tetrahydro-7,17-dioxa-15-
- - azacyclopenta[a]phenanthren-6-one,
9-(6-hydroxypyridin-3y1)-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one,
9-(4-methylpiperazin-1 -yl-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one,
9-piperazin-1-y1-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyciopenta[b]phenanthren-5-one,
9-phenylamino-1,2,3,4-tetrahydro-6,8-dioxa-l0-
azacyclopenta[b]phenanthren-5-one,
9-benzylsu Ifanyl-1,2,3,4-tetrahyd ro-6, 8-d ioxa-10-
azacyclopenta[b]phenanthren-5-one,
9-morpholin-4-y1-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one,
9-pyrid in-3-y1-1,2,3, 4-tetrahyd ro-6, 8-d ioxa-l0-azacyclo pe nta[b]phen
anth ren-
5-one,
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9-pyridin-4-yl-1,2,3,4-tetrahydro-6,8-dioxa-10-azacyclopenta[b]phenanthren-
5-one,
9- m eth yl s u l fa n yl-1, 2, 3, 4-tetra h yd ro-6 , 8-d io xa-10-
azacyclopenta[b]phenanthren-5-one,
10-thiophen-2-yl-1,2,3,4-tetrahydro-6,8-dioxa-l1-azabenzo[a]anthracene-
5,9-dione,
9-isopropylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one,
9-benzoyl-1,2,3,4-tetrahydro-6,8-d ioxa-l0-azacyclopenta[b]phenanthren-5-
one,
9-thioxo-1,2,3,4,9,10-hexahydro-6,8-dioxa-10-azacyc(openta[b]phenanthren-
5-one,
9-i s o p ro pyl -1, 2, 3, 4-tet ra h yd ro-6, 8-d i oxa-l0-a za cycl o p e
nta [b] p h e n a nth re n-5-
one,
9-phenyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5-
one,
10-isopropyl-1,2,3,4-tetrahyd ro-10H-6,8-d ioxa-10-
azacyclopenta[b]phenanthrene-5,9-dione,
_ 1,2,3,4-tetrahydro-10H-6,8-dioxa-l0-azacycfopenta[b]phenanthrene-5,9-
dione,
9-ethyl-1, 2, 3, 4-tetrahyd ro-6, 8-d ioxa-10-azacyclopenta [b] phena nthren-5-
one,
9-methyl-1, 2, 3, 4-tetra hyd ro-6, 8-d ioxa-10-azacyclope nta[b] phenanth re
n-5-
one,
9-ethoxy-1,2, 3,4-tetrahyd ro-6,8-d ioxa-10-azacyclopenta[b]phenanthren-5-
one,
4-methoxy-2-thioxo-1,2,8,9,1 0,11 -hexahydro-3, 6-d ioxa-1-
azacyclopenta[c]phenanthren-7-one,
12-chloro -1,2,3,4-tetrahydro-7,17-dioxa-15-azacyclopenta[a]phenanthren-6-
one,
4-methoxy-2-phenyl- 8,9,10,11-tetrahydro-3,6-dioxa-1-
azacyclopenta[c]phenanthren-7-one,
5-methoxy-2-thiophen-2-yI-9,10,11,12-tetrahydro-4,7-dioxa-1-
azabenzo[c]phenanthrene-3,8-dione,
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4-methoxy-2-methyl- 8,9,10,11-tetrahydro-3,6-d ioxa-l-
azacyclopenta[c]phenanthren-7-one,
4-methoxy-8,9,1 0,11 -tetrahydro-1 H-3,6-dioxa-l-
azacyclopenta[c]phenanfihren-2,7-dione,
4-methoxy-2-methylsulfanyl- 8,9,10,11-tetrahydro-3,6-dioxa-l-
azacyclopenta[c]phenanthren-7-one,
2-ethoxy-4-methoxy- 8,9,10,11-tetrahydro-3,6-dioxa-l-
azacyclopenta[c]phenanthren-7-one,
2-ch I o ro-3-pyri d i n-2-y(-7, 8, 9,10-tetra hyd ro b e nzo [c]ch ro m e n-6-
o ne,
3-acetyl-2-chloro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyciopenta[c]chromen-4-one,
9-(4-dimethylaminobenzyl)-1,2,3,4-tetrahydro-6,8-dioxa-l0-aza-
cyc(openta[b]phenanthren-5-one,
4-methoxy-2-pyridin-2-yI-8,9,10,11-tetrahydro-3,6-dioxa-l-aza-
cyclopenta[c]phenanthren-7-one,
9-pyridin-2-yI-1,2,3,4-tetrahydro-6,8-d ioxa-10-aza-
cyclopenta[b]phenanthren-5-one,
2-chloro-3-isopropoxy-8-pyridin-2-yI-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one,
2-ch(oro-3-isopropoxy-8-pyridin-3-yI-7,8,9,10-tetrahydrobenzo[c]chrornen-6-
one,
10-(3,5-dif(uoropheny()-1,2,3,4-tetrahydro-6,8-dioxa-11-
azabenzo[a]anthracene-5,9-dione,
4-(5, 9-d ioxo-1, 3,4, 5-tetra hyd ro-2 H, 9 H-6, 8-d ioxa-11-aza benzo[a]a
nth ra cen-
10-yI)benzonitri(e,
9-phenyl-2,3-dihyd ro-1 H-5, 7-dioxa-10-azacyclopenta[a]anthracene-4,8-
dione,
10-phenyl-1,2,3,4-tetrahydro-6,8-dioxa-11-azabenzo[a]anthracene-5,9-
dione,
1 0-(4-m etho xyp he nyl )-1, 2, 3, 4-tetra h yd ro-6, 8-d i oxa-11-
azabenzo[a]anthracene-5,9-dione,
10-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 1 -aza-
benzo[a]anthracene-5,9-dione,
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10-(4-trifl uo ro methyl p he nyl )-1,2, 3, 4-tetrahyd ro-6, 8-d ioxa-11-aza-
benzo[a]anthracene-5,9-dione,
9-adamantan-1-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-aza-
cyclopenta[b]phenanthren-5-one,
10-(4-dimethylaminophenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 1 -aza-
benzo[a]a nth racene-5,9-d ione,
2-chloro-3-isopropoxy-7-methyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one,
2-chloro-3-isopropoxy-9-pyridin-2-yl-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one
and optical isomers, pharmaceutically acceptable salts, hydrates, solvates,
and polymorphs thereof.
DETAILED DESCRIPTION OF THE INVENTION
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_3alkyi _refers_to _alkyl _of_one to
three carbon
atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and
branched forms thereof.
As used herein, the following definitions are applicable unless otherwise
described. 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, -C2F5i -CBr3, and -CCI3; thus, for
example, groups such as R2, R4, R5 and R'-R" may represent e.g.
trifluoromethyl. The term "C1_6 alkoxy" comprises straight or branched chain
-O-C1_6alkyl groups wherein "C1_6 alkyl" is defined as given hereinbefore.
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Examples of "Cl_6alkoxy" include methoxy, ethoxy, n-propoxy, i-propoxy. A
CI_salkoxy group optionally may be substituted by one or more fluorine,
chlorine and/or bromine atoms thereby forming, for instance, -OCF3 and
-OC2F5. The term "cycloC3_12alkyl" 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_12aIkyl 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_6 alkyl
groups, which 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-C1_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
"C1_6alkyP" having the same meaning as given hereinbefore. The term aryl
represents phenyl or naphthyl or phenyl substituted by one or more
substituents, which may be the same or different, selected from C1_6alkyl,
which is optionally substituted with one or more fluorine, chlorine or bromine
atoms, C2_6alkenyl, C1_ealkoxy, which is optionally substituted with one or
more fluorine, chlorine or bromine atoms, cycloC3_12alkyl, hydroxy, halogen,
cyano, nitro, C1_6alkoxycarbonyl, amino, C1_6 alkylamino, di-C1_6 alkylamino,
N-cycloC3_12alkyl-N-C1_6alkylamino, azetidinyl, pyrrolyl, piperidinyl,
morpholinyl, 4-C1_6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl,
isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and C1_6
alkylenedioxy. The term "heteroaryl" represents an aromatic 5-6 membered
ring containing from one to four heteroatoms selected from oxygen, sulfur
and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing
from one to four heteroatoms selected from oxygen, sulfur and nitrogen
fused with a benzene ring or a 5-6 membered ring containing from one to
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four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the
heteroaryl group may be optionally substitued by one or more substituents,
which may be the same or different, selected from 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, hydroxy, halogen, cyano, nitro, Cl_6
alkoxycarbonyl, amino, C1_6alkylamino, di-C1_6alkylamino, N-cycloC3_12alkyl-
N-Cl_6alkylamino, azetidinyl, pyrrolyl, piperazinyl, morpholinyl, 4-C1_6alkyl-
piperazinyl, tetrazolyl, oxazolyi, furyl, thiophenyl, isoxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl. Representative
heteroaryl groups 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.
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).
The term "analog" or "derivative" is used herein in the conventional
pharmaceutical sense, to refer to a molecule that structurally resembles a
reference molecule, but has been modified in a targeted and controlled
manner to replace one or more specific substituents of the reference
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.
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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 neurological conditions including
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.
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.
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.
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.
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The following Schemes describe the preparation of compounds of Formula I
of the present invention. All of the starting materials are prepared by
procedures described in these schemes, by procedures well known to one of
ordinary skill in organic chemistry or may 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 schemes are as defined in the specification, below or as in the
claims.
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.
Chromenone 3A may be prepared by Pechmann condensation of a
resorcinol I with a substituted P-ketoester 2 according to Scheme 1.
Compound 4 may be prepared by Pechmann condensation of a mono O-
alky_I_ated resorcinol 5 _with asubstituted R-ketoester 2 or, alternatively,
by 0-
alkylation, arylation or acylation of chromenone 3A.
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Scheme I
R3 Ra
HO OH O O H2SO4 HO O O
+
R5 I/ RZ OEt Rs R
s R Rs 2
R
2 3A
iPrBr(CI), K2C03
or
iPrBr(CI), Pd(OAc)2
3 Y R3
R O O O
O OH O O H2SO4 I~
I + RZ~OEt R5 / q RI
R R~ Rs R2
Rs 2 4
5
5 Compound 6 may be prepared from compound 3B via reaction with an
amine derivative (e.g., morpholine) and formaldehyde under acidic
conditions_(Scheme 2). Alkylation of compound 6 at oxygen with an alkyl
bromide (e.g. isopropyl bromide) yields chromenone derivative 7.
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Scheme 2
ro
NJ N
HO O O iPrBr, Y
I CH2O , H v HO O O K2CO3 O O O
_~ I \
RVR R5 / R1
R6 Ra Rs / R~
R6 R2 R6 R2
3B 6
7
Nitration of compound 3B yields nitrochromenone 8 (Scheme 3). Alkylation
of nitro derivative 8 at oxygen yields compound 9. Reduction of the nitro
group of 9 provides aniline 10. The amino group of 10 may be mono- or bis-
alkylated, acylated, sulfonylated, and/or carbamoylated to yield compound
11. Alternatively, the nitro group in compound 8 may be reduced to yield
aniline 12 with a free hydroxy group, the amino group of which may be
mono- or bis- acylated, sulfonylated, and/or carbamoylated in the presence
of potassium carbonate to yield compound 11.
Scheme 3-
NOa NH2
HO O O HN03 _ HO O O H2, Pd/C HO O O
)C? RR R5 R~ R5 R
R6 RZ 6 R2 R6 Rz
3B iPrBr, 8 12
K2C03 Y NO2 NHZ Ra HN~H
O O O Hz, Pd/C 0 O O O \ O O
I \ I
R5 RI RS / / R~ R5 J / Ri
6 2 R6 R2 R6 RZ
9 10 11
Ra = H, iPr
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Nitration of compound 3C yields nitro chromenone 13 (Scheme 4).
Alkylation of nitro derivative 13 at oxygen yields compound 14, the nitro
group of which may be reduced to provide aniline 15. The amino group of
aniline 15 may be mono- or bis-alkylated, acylated, sulfonylated, and/or
carbamoylated to yield compound 16. Alternatively, the nitro group of
compound 13 may be reduced to yield aniline 17 with a free hydroxy group,
the amino group of which may be mono- or bis- acylated, sulfonylated,
and/or carbamoylated to yield compound 16.
Scheme 4
R 3 R3 R3
HO O O HNO3 HO O O H2, Pd/C HO I\ O O
R OaN R~ HZN / Rt
6 Rz Re 2 6 Ra
3C 13 17
iPrBr,
K2 C03
MeSO2Br(CI), K2C03
R3 ~ R3 Ra R3
\ O O O\ o O
H21 Pd/C \ O O
- ~- - -- - --- --,- ~--
_ _- -_ _-~ _ -
OzN / R H N R HN R
Rs RZ 2 Rs Ra /S~ O Rs RZ
O
14 15 16
Ra = H, iPr
Trifluorosulfonic acid ester 18 may be prepared from chromenone derivative
3A according to Scheme 5. Triflate 18 may be used to prepare stannyl
derivative 19 which may be utilized in a palladium catalyzed coupling
reaction with an aryl halide to prepare compound 20, or compound 19 may
be coupled with an acyl chloride to prepare compound 21.
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Scheme 5
R3 3 R Bu3SnSnBu3 R3
HO O O Tf20, Py Tf0 O O Pd(Ph3P)4 Bu3Sn O O
Re R~ Re R1 R5 qr Ri
R6 R 2 R 6 R2 Rs R2
3A 18 ArBr, 19 CH3C(O)CI
Pd(Ph3P)4 Pd 2(dba)3
R3
Ar ~ O O 0 R3
O O
Re ~ / X R~
I / / a
Ar = aryl or heteroaryl Rs R2 R e 2 R
R R
20 21
5 Palladium catalyzed arylation of an amine with triflate 18 yields compound
22. N-Benzyl derivative 22 may be deprotected to yield aniline 23 (Scheme
6).
Scheme 6
-- - ~
R3 R3 3
NH2 ~N O O
Tf0 0 O BINAP, Pd(OAc)Z H I~ H2, 10%Pd/C HZN O O
Rs I ~ R Re / / R R1 R5 R
R6 R2 R6 Rz Rs RZ
18 22 23
Treatment of 7-hydroxychromenone 3A with N,N-dimethylthiocarbamoyl
chloride provides compound 24 which may be subjected to thermal
rearrangement to provide carbamoyl protected thiol 25 (Scheme 7).
Cleavage of the carbamoyl group in compound 25 followed by alkylation or
arylation at sulfur yields compound 26. This compound may be oxidized to
sulfone 27.
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Scheme 7
R3 Dimethyl MezN,rS R3
thiocarbamoylchloride, O O O
HO O O Et3N I~ 2000C
R5 R~ R5 / / R~
z
R5 Rz R6 R
3A 24
MezNO R 3 ~ R3 ~ Ra
1. MeONa
s ~ O O 2.iPrBr S O O Oxone OzS ~ O O
R5 ~/ X R~ R5 R~ R R
6 Rz R6 Rz Rs Rz
25 26 27
5 Amino phenol 17 may be condensed with a carboxylic acid to prepare
oxazole 28 (Scheme 8). Condensation of amino phenol 17 with an a-keto
carboxylic acid ester yields compound 29. Treatment of amino phenol 17
with carbonyldiimidazole provides oxazolidinone 30 which may be alkylated
at nitrogen to give compound 31. Treatment of amino phenol 17 with
thiocarbonyidiimidazole provides oxazolidinethione 32 which may be
---alkylated--at sulfur-to give- compound 33. Replacement -of sulfur-with an
amine in thione 32 provides compound 34 (wherein R14 represents
hydrogen, C1_6alkyl, cycloC3_12alkyl, aryl, heteroaryl, carboxyC1_6alkyl,
aryIC1_6alkyl, alkylcarbonyl or CF3, and R15 represents hydrogen, CI_6alkyl,
cycloC3_12aIkyl, aryl, heteroaryl, aryIC1_6alkyl, carboxyC1_6alkyl,
alkylcarbonyl,
CF3, Cl_6alkyloxy, Cl_6alkylthio, arylCl_6alkylthio, arylCI_6alkyloxy,
morpholino, C1_6cycloamino, piperazinyl, N-Cl_6alkylpiperazinyl or arylamino).
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Scheme 8
R3
O O p
R'~
N )CX1
Rs Rz
28 R
O O \ O p
t RtsCpzH 0 oEt I/ X R
PPA ~ R R 6 R 2
Ri 29
R3 ~
HO O O
carbonyl 3
H N / Rz dilmidazole R
z ~ p \ p p
Rs R'
17 p I/ / ~ R14Br, KzC03
N R R 3
H s z
thiocarbonyl R R p I\ p O
diimidazole 30 p~N R
R1a Rs Rz
R3
O \ p R14Br, KZCO3 p \ p p 31
S~
S N I/ / Rt R14 'N I/ X R1
H Rs Rz Rs Rz
32 \R~aR~aNH 33
Rs
~~aa R'\ p \ p O
N
R1ap N ~ / X Rt
R. Rz
34
Amino phenol 12 may be condensed with a carboxylic acid to prepare
oxazole 35 (Scheme 9). Condensation of amino phenol 12 with an a-keto
carboxylic acid ester yields compound 36. Treatment of amino phenol 12
with carbonyldiimidazole provides oxazolidinone 37 which may be alkylated
at nitrogen to provide compound 38. Treatment of amino phenol 12 with
thiocarbonyldiimidazole provides oxazolidinethione 39 which may be
alkylated at sulfur to provide compound 40. Replacement of sulfur with an
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WO 2007/045876 PCT/GB2006/003888
amine in oxazolidinethione 39 yields compound 41 (wherein R14 and R15 are
as previously defined).
Scheme 9
R 15
N
Ra
:x
Rs Rz
R 15
O
N
R15C02H, PPA O O O
0 OEt R5 1
R
R, x0 R6 R2
NHZ 36
HO O O
Rs R1 carbonyl O
Rs R2 dilmidazole \\ H
12 O/y~ O O
\
s / T 1 R14Br, K2CO3 O R 14
thiocarbonyl R R N
diimidazole Rs Rz
O O O
37
Rs 2
S H R14 S Rs R1
N ~N 38
O I\ O O R14Br, K2C03 O 4(T O O
R Rs / R~
Rs R2 RR2
39 40
R 14
R:RiaNH Ria N
~N
O \ O O
Rs I / X Rz
Rs R1
41
5
37
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Trifluorosulfonic acid ester 42 may be prepared from chromenone derivative
3D (Scheme 10). Triflate 42 may be used to prepare stannyl derivative 43
which may be utilized for palladium catalyzed coupling with an aryl halide to
prepare compound 44, or compound 43 may be coupled with an acyl
chloride to prepare compound 45.
Scheme 10
R3 3 3
R4 O O 4 R Bu3SnSnBu3 4 R
TfzO, Py R I\ O O Pd(Ph3P)4 R O O
HO R' --~
Tf0 R' Bu3Sn / q R
R6 R2 Rs 2 Rs RZ
3D 42 PArBr, d Ph P 43 R10C(O)CI
( 3 )4 Pd2(dba)3
R3 R3
R4 I\ O O R4 O O
Ar = aryl or heteroaryl
Ar / R' 0 / R~
R6 R2 R10 Re R2
44 45
Nitration of compound 3E yields nitrochromenone 46 (Scheme 11).
Alkylation of nitro derivative 46 at oxygen yields compound 47, the nitro
group of which may be reduced to yield aniline 48. The amino group in
aniline 48 may be mono- or bis- alkylated, acylated, sulfonylated, and/or
carbamoylated to yield compound 49. Alternatively, the nitro group in
compound 46 may be reduced to give aniline 50 with a free hydroxy group,
the amino group of which may be mono- or bis- acylated, sulfonylated,
and/or carbamoylated to give compound 49.
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Scheme 11
R3 R3 R3
R4 ~ O O HNO3 Ra ~ O HZ, Pd/C ~ 0 R
R2 NOZ R~ NH2 Rz
3E iPrBr, 46 50
KZC03
R3
4 O O R3 R3
HZ, Pd/C 4 ~ O O R4 O
O R O I/ / R R~
~ O
NOZ R NHa R~ N\ Ra
47 48 49
Ra = H, iPr
Amino phenol 50 may be condensed with a carboxylic acid to prepare
oxazole 51 (Scheme 12). Condensation of amino phenol 50 with an a-keto
carboxylic acid ester yields compound 52. Treatment of amino phenol 50
with carbonyidiimidazole provides oxazolidinone 53 which may be alkylated
at nitrogen to give compound 54. Treatment of amino phenol 50 with
thiocarbonyldiimidazole provides oxazolidinethione 55 which may be
alkylated at sulfur to yield compound 56. Replacement of sulfur with an
amine in thione 55 yields compound 57 (wherein R14 and R15 are as
previously defined).
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Scheme 12
R3
R 4 O O
I
O R
N R 2
R 51
R3
a
R15C02H, PPA R O O
0 OEt
2
R3 R75 O N R
Ra )#, O R52
1 carbonyl
HO R diimidazole
Hz R3
4 p
O R R14Br, K2C03
thiocarbonyl NH Rz R
O ~a RQ O O
diimidazole 53
~
O R'
R3 0 R 0 0 N~R14Rz
a
R 0 R14Br, K2CO3
54
O-- - -- - - R - N
NH R 2 R14 S
s 55 56
R14R14NH Ra
R4 O 0
I Ra
0
-N Rz
Rt4 N
R14
57
3-Acylch ro me none derivative 60 may be prepared by piperidine catalysed
condensation of 2-acylphenol 58 with R-ketoester 59 (Scheme 13).
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Scheme 13
R3 R3
::IrIIIII1 + piperidin ~ R/ O R~oi~ OEt 58 59 60
EXPERIMENTAL PART
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.
Hereinafter, "DMF" is defined as N,N-dimethylformamide, "HCI" as
hydrochloric acid, "DMSO" as dimethylsulfoxide and "TMS" as
tetramethylsilane.
Preparation I
3-Hydroxy-7,8,9-,10-tetrahydro-benzo[c]ch romen-6-one
HO 0 0
A mixture of resorcinol (1.45 g, 10 mmol) and ethyl 2-oxocyclohexane
carboxylate (2.04 g, 12 mmol) is cooled in an ice bath and sulfuric acid (5
ml) is added dropwise. The reaction mixture is stirred for 2.5 h and diluted
with ice water (30 ml). The precipitate is collected on a filter and
recrystaf(ized from i-PrOH to give the title compound (1.44 g, 67% ) as
colorless crystals.
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Physical characteristics are as follows:
Mp 187-190 C; 'H NMR (DMSO-d6, TMS) 8: 1.71, 2.37, 2.72, 6.68, 6.77,
7.52, 10.34; MS: 216 (M+).
Example I
6-Ch loro-7-(4-fl,uoro-benzyloxy)-4-phe nyl-chrome n-2-one
F 101'~'O O 0
/
CI \ I ~
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 2
7-(3-Phenoxy-benzyloxy)-4-phenyl-chromen-2-one
i
--- - -_
O \ ~ ~
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 3
7-(4-Fluoro-benzyioxy)-4-phenyl-chromen-2-one
F(:
O 0 0
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 4
6-Chloro-7-isopropoxy-4-trifluoromethyi-chromen-2-one
Y
0 \ 0 0
ci~~
F
F F
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 5
6-Chioro-7-hydroxy-4-pyridin-2-yl-chromen-2-one
HO 0 0
CI
N
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 6
6-Chloro-7-hydroxy-4-pyridin-3-yl-chromen-2-one
HO O 0
ci
N
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 7
6-Chloro-7-hyd roxy-4-pyrid i n-4-yl-chromen-2-one
Ho o 0
ci
N
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 8
6-Chloro-7-isopropoxy-4-pyridin-4-yl-ch romen-2-one
O o O
ci
N
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Exampie 9
6-Chloro-7-isopropoxy-4-pyridin-2-yl-chromen-2-one
O o 0
ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 10
6-Chloro-7-isopropoxy-4-pyridin-3-yi-chromen-2-one
o o 0
ci
N
In analogy to the procedure described in Scheme 1, the title compound is
-
obtained-in moderate yield:
Example 11
3-(Adamantane-1-carbony!)-7-methoxy-chromen-2-one
0
i +
O \ O O
In analogy to the procedure described in Scheme 13, the title compound is
obtained in moderate yield.
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Example 12
3-(Adamantane-l-carbonyl)-7-dimethylamino-chromen-2-one
0
i
N~ I
1 0 O
In analogy to the procedure described in Scheme 13, the title compound is
obtained in moderate yield.
Example 13
3-(Adamantane-l-carbonyl)-7-diethylamino-chromen-2-one
0
~ ~
,~NI \ I O G
/
In analogy to the procedure-described in Scheme 13, the title compound is
obtained in moderate yield.
Example 14
3-(Adamantane-l-carbonyl)-7-oxazol-2-yl-chromen-2-one
0
o ~)
In analogy to the procedure described in Scheme 13, the title compound is
obtained in moderate yield.
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Example 15
3-(Adamantane-l-carbonyl)-7-bromo-chromen-2-one
O
~ ~
~ ~
Br O O
In analogy to the procedure described in Scheme 13, the title compound is
obtained in moderate yield.
Example 16
3-Hydroxy-2-nitro-7,8,9,1 0-tetrahyd robe nzo[c]ch romen-6-one
HO 0 O
O':~N
I I
O
3-Hydroxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one (Preparation 1) (1.0
g, 5.9 mmol) is dissolved in acetic acid (1.5 ml) and the mixture is cooled to
10 C. Concentrated HNO3 is added and the reaction mixture is stirred at r.t.
-
for 20 h an-d diluted with water (15 ml)-. The precipitate is-collected-on, a
filter--
and recrystallized twice from MeOH to give the title compound (145 mg,
10%) as red crystals.
Physical characteristics are as follows:
Mp 208-210 C; 1 H NMR (DMSO-d6, TMS) s: 1.74, 2.41, 2.76, 6.97, 8.19,
11.77.
Example 17
3-Isopropoxy-2-nitro-7,8,9,10-tetrahyd robe nzo[c]chromen-6-one
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O O O
il
2-Bromopropane (5 ml, 53 mmol) is added to a mixture of 3-Hydroxy-2-nitro-
7,8,9,1 0-tetrahyd robe nzo [c]ch romen-6-o ne (Example 16) (4.15 g, 13.55
mmol) and K2CO3 (5.6 g, 40 mmol) in DMFA (30 ml). The reaction mixture is
stirred at 50 C for 24 h, cooled to r.t. and diluted with water (50 ml). The
precipitate is collected on a filter and recrystallized from MeOH to give the
title compound (154 mg, 30%) as colorless crystals,
Physical characteristics are as follows:
Mp 166-168 C; 'H NMR (DMSO-d6, TMS) 5: 1.32, 1.73, 2.41, 2.76, 4.95,
7.41, 8.19.
Example 18
2-Amino-3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
y----- _
0 0 0
~ /
H2N ~
3-Isopropoxy-2-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one (Example
17) (1.0 g, 3.3 mmol) is dissolved in EtOH (30 ml) and 10% Pd/C (280 mg) is
added. Hydrogen pressure (7 bar) is applied for 6 h. The catalyst is filtered
off and the solvent removed in vacuo. The residue is purified by flash
chromatography on silica gel eluting with mixture of ethyl acetate and light
petroleum ether to give the title compound (0.68 g, 75%) as white crystals.
Physical characteristics are as follows:
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Mp 95-97 C; 'H NMR (DMSO-d6, TMS) 5: 1.30, 1.74, 2.38, 2.65, 4.69, 4.76,
6.85, 6.84.
Example 19
2,2-Dimethyl-propionic acid 6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl ester
o
0 0 / O
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 20
2-Chloro-3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-onene
O
O
- -
)t1,1-O 1016
CD
CI 15 I
n analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 21
2-Chloro-3-(2-oxo-2-pi perid i n-1-yl-ethoxy)-7,8,9,10-tetrahyd ro-
benzo[c]chromen-6-onene
O
)LI~ O CJNi7XC0 49
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In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 22
2-Chloro-3-isopropoxy-9-methyl-7,8,9,10-tetrahydro-benzo[c]chromen-
6-one
o ~ cx00
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 23
2-Chloro-3-hydroxy-8-trifl uoromethyl-7,8,9,10-tetrahyd ro-
benzo[c]chromen-6-one
HO ~ O CI
F
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 24
2-Chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one
o ~ O 0
ci I .~ ~
F
FF
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 25
2-Chloro-3-(2-hydroxy-ethoxy)-7,8,9,10-tetrahydro-benzo[c]chromen-6-
one
0
o I
0
CI
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 26
Dimethyl-thiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10-
tetrahydro-6H-benzo[c]chromen-3-yl) ester
I
0 y N",
S ~ O 0
~ /
Cf
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In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
Example 27
2-Chloro-3-(2-dimethytamino-ethoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one
0
N\
O
ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 28
Dimethyl-thiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yi) ester
oy N~
0 0
ci
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
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Example 29
2-Chloro-3-isopropylsulfanyl-7,8,9,10-tetrahydro-benzo[c]chromen-6-
one
Y
S o 0
CI i
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
Example 30
2-Chloro-3-methylsulfanyl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one
1
o 0
cl
In analogy to the procedure described in Scheme 7, the title compound is
obtained_ inmo_derateyield.
Example 31
2-Chloro-3-methanesulfonyl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-
one
o, ,o
~s O 0
CI
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
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Example 32
2-Chloro-3-(2-hydroxy-3-morphol i n-4-yi-propoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one
O OH
0 0
cl
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 33
2-Chloro-3-isopropoxy-4-morpholin-4-ylmethyl-7,8,9,1 0-tetrahydro-
benzo[c]chromen-6-one
O
N
"Y O O
ci
In analogy to the procedure described in Scheme 2, the title compound is
obtained in moderate yield.
Example 34
2-Chloro-3-(3-dimethylamino-2-hydroxy-propoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one
i OH
O
,-INO 1016
ci In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 35
2-Chloro-3-(3-diethylam ino-2-hydroxy-propoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one
OH
O O
,NO 1016
CI In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 36
2-Chloro-3-(2-hydroxy-3-isopropylamino-propoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one
OH
,,JO ~ O O
( /
CI
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 37
2-Chloro-3-cyclobutylmethoxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-
one
O o
Ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 38
2-Ethyl-3-isopropoxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one
0
o ~
o I
In analogy to the procedure described-in Scheme 1, the title compound is
obtained in moderate yield.
Example 39
2-(2-Hydroxy-ethoxy)-3-methoxy-7,8,9,10-tetrahydro-benzo[c]chromen-
6-one
O
O
0- -
O"'~OH
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 40
4-Amino-3-isopropoxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one
NH2
\/O O O
TI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 41
2-Methoxy-3-isopropoxy-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-6-
one
o O
o
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 42
2-Chloro-3-hydroxy-4-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
OI--N+.O
HO O O
cl
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 43
2-Chloro-3-(3-chloro-2-hydroxypropoxy)-7,8,9,10-
tetrahydrobenzo[c]chromen-6-one
OH
CI-_,~O O O
~
CI
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 44
1-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-yl)-3-
phenylurea
/~
HN ~ H\
O \ O O
I
/
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 45
2-Chloro-3-(2-hydroxy-3-phenylaminopropoxy)-7,8,9,10-tetrahydro-
benzo[c]chromen-6-one hydrochloride
OCC0Dr0Y0
ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 46
1-(2,4-Dichlorophenyl)-3-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)thiourea
c~
H
N CI
S
NH
O ~ O O
I / /
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In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 47
3-Isopropoxy-4-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
0 \N+~O
' O O O
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 48
N-Tosyl-4-am i no-3-isopropoxy-7,8,9,10-tetrahyd robenzo[c]chromen-6-
one
-_~----
os
HN II
~O O O
ld~
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 49
2-Chloro-3-isopropoxy-4-nitro-7,8,9,1 0-tetrahyd robe nzo[c]chromen-6-
one
O,Z~, N+A
O O O
CI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 50
4-Am i n o-2-ch l oro-3-isopropoxy-7, 8,9,10-tetra hyd robe nzo[c]ch rome n-6-
one
NH2
O O O
CI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 51
2-Difluoromethoxy-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-
one
/O O O
o
FF
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 52
2-Chloro-3-difluoromethoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
Fy F
0
\ O O
Ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 53
Trifluoromethanesulfonic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl ester
F
Fsl~-O
"/ I
O
OO la6
CI 10
In analogy to the procedure described in Scheme 5, the title compound is
obtained in moderate yield.
Example 54
3-Benzyl-8-isopropoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one
0
O I N I \
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 55
2-Acetyl-3-methoxy-7,8,9,10-tetrahydro-be nzo[c]chromen-6-one
I
o ~ o 0
o 1
In analogy to the procedure described in Scheme 5, the title compound is
obtained in moderate yield.
Example 56
3-Isopropoxy-4-methylamino-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one
HN
Yo O O
In_ analogy_to the_procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 57
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-yl)-
methanesulfonamide
\,O
ONH
'yo ~ O O
~ /
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 58
N-Acetyl-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)acetam ide
O O
~N)t"
10iI51I0
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 59
2-Chloro-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)acetamide
O
ci""~NH
~'Y O 1 O O
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 60
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-
yl)methanesulfonamide
Y
o ~ O O
~
HN
0
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In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 61
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-yl)-4-
methylbenzenesulfonamide
o o O
HN
I ~ S~O
O
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 62
N-Acetyl-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-2-yl)acetamide
Y
o ~ O o
i,
O J,, N ~
O~
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
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Example 63
N-Acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)acetamide
0 0
~N)t""
O ~ O O
71 I /
CI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 64
2-Chloro-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydrobenzo[c]cromen-2-
yl)acetamide
y
0
o 0
o
- -i _
H
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 65
1-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-yi)-3-
phenylurea
y
o cJNHIIX5
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In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 66
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-2-
yl)succinamic acid
Y
O O O
HN
HO
O
O
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 67
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahyd ro-6H-benzo[c]chromen-2-
yl)formam-ide
Y
0
O 'a6
~ N H H
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
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Example 68
3-Isopropoxy-2-methylam ino-7,8,9,10-tetrahydrobenzo[c]chromen-6-
one
Y
o
o 'C6
N H
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 69
2-Chloro-3-morphol i n-4-y1-7,8,9,10-tetrahydrobenzo[c]ch romen-6-one
0
~ O
CI
In analogy to the procedure described in Scheme 6, the title compound is
obtained in moderate yield.
Example 70
3-Benzylamino-2-chloro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
N ~ O 0
I /
CI
In analogy to the procedure described in Scheme 6, the title compound is
obtained in moderate yield.
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Example 71
N-(3-ilsopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]-ch romen-2-
yl)benzamide
y
o O 101 O
e N /
H
n analogy to the procedure described in Scheme 4, the title compound is
I
obtained in moderate yield.
Example 72
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-4-
yl)benzamide
/
O NH
-\ /O - - O 0
7I ~ \
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 73
N-(2-Chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)benzamide
O NH
O O O
CI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 74
N-(3-Isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]-chromen-2-
yl)isobutyramide
Y
O O O 0
N
H
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
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Example 75
N-Isobutyryl-N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-2-yl)isobutyramide
Y
O
O 0 0
N
O
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 76
N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]-chromen-4-
yI)isobutyramide
XH
,Y
-
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 77
N-(2-Chloro-3-isopropoxy-6-oxo-7,8,9,1 O-tetrahydro-6H-
benzo[c]chromen-4-yl)formamide
H
O1;1-~ NH
~5 In analogy to,the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 78
N-(2-Ch loro-3-isopropxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)-4-methylbenzesulfonamide
o
SN,NH
O 0 O
CI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 79
N-(2-Ch loro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)succinamic acid
O OH
O
NH
O O O
-y
CI
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
Example 80
N-(2-Ch ioro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-4-yl)-acetamide
OJI"NH
O O O
CI
I IC
In analogy to the procedure described in Scheme 3, the title compound is
obtained in moderate yield.
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Example 81
2-Chloro-3-pyrrolidin-l-yl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
ON O
CI
In analogy to the procedure described in Scheme 6, the title compound is
obtained in moderate yield.
Example 82
Dimethyl-thiocarbamic acid 6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yi ester
~
O'\/N~
~IS" O O
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
Example 83
Acetic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-
yl ester
OTO O
CI
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In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 84
2-Chloro-3-ethoxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one
O
0 0
ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 85
2-Chloro-3-propoxy-7,8,9,1 0-tetrahydro-be nzo[c]chromen-6-one
- - -
0
0 0
ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 86
2-(2-C h loro-6-oxo-7,8,9,10-tetrahyd ro-6H-benzo[c]chromen-3-yloxy)-
acetamide
O
O O O
H2N I
CI
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 87
N-(2-Ch Ioro-6-oxo-7,8,9,10-tetrahydro-6H-be nzo[c]ch romen-3-yl)-
acetamide
H
\ /N O O
IOI
CI
In analogy to the procedure described in Scheme 6, the title compound is
obtained in moderate yield.
Example 88
S-(N, N-Di m ethyl ca rbam oyl)-8-te rt-butyl-2-ch ioro-6-oxo-3-thio-7,8,9,10-
tetrahydro-6H-benzo[c]chromen-6-one
(
O'\/N~
~S ~ O O
CI I /
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In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
Example 89
S-(N,N-Dimethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10-
tetrahydrobenzo[c]chromen-6-one
I
Oy N~
S ~ O O
cl
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
Example 90
3-Methoxy-2-pyridin-2-yl-7,8,9,10-tetrahydro-benzo[c]chromen-6-one
o C:Ooo
N
In analogy to the procedure described in Scheme 10, the title compound is
obtained in moderate yield.
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Example 91
3-(Pyridin-2-yloxy)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one
N /
O ~ 0 0
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 92
2-Chloro-3-(pyrid i n-2-yisulfanyl)-7,8,9,10-tetrahyd robe nzo[c]ch rome n-6-
one
I ~
N /
s O
-- -- -
ci
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
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Example 93
S-( N, N-D i m ethyl ca rba m oyl )-8-ethyl-2-c h I o ro-6-oxo-3-th i o-7, 8,
9,10-
tetrahydro-6H-benzo[c]chromen-6-one
O'\
s ~ 0 0
I /
CI
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
Example 94
S-(N,N-Dimethylcarbamoyl)-10-methyl-2-chloro-6-oxo-3-thio-7,8,9,10-
tetrahydro-6H-benzo[c]chromen-6-one
OYN
s O
CI
In analogy to the procedure described in Scheme 7, the title compound is
obtained in moderate yield.
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Example 95
12-C h l o ro-l6-th i oxo-1, 2, 3, 4,15,16- h e x a h yd ro-7,17-d i oxa-15-
azacyclopenta[a]phenanthren-6-one
S /~ H
N
O O
I \
ci
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 96
2-Chloro-3-(4-methoxycyclohexyloxy)-7,8,9,1 0-tetrahydro-
benzo[c]chromen-6-one, mixture of cis and trans isomers
-O
O
0
o
ci
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 97
2,2-Dimethyl-propionic acid 6-oxo-7,8,9,10-tetrahydro-6H-
benzo[c]chromen-3-yl ester
o
O O o
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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Example 98
12-Chloro-l6-isopropylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-l5-
azacyclopenta[a]phenanthren-6-one
~-s
>'--N
O O
Ci
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 99
12-Chloro-16-methylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6-one
-s
O O
CI
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 100
12-Chloro-16-ethyl-1,2,3,4-tetrahydro-7,17-dioxa-l5-
azacyclopenta[a]phenanthren-6-one
\--0
}--N
O O O
I \
CI
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 101
12-Chloro-16-methyl-1,2,3,4-tetrahydro-7,17-dioxa-l5-
azacyclopenta[a]phenanthren-6-one
)--N
O O
-----
_--
CI
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 102
15-Benzyl-1,2,3,4-tetrahydro-15H-7,17-dioxa-l5-
azacyclopenta[a]phenanthren-6,16-dione
O 9,\-/"
~-N
O bz
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 103
15-Isopropyl-1,2,3,4-tetrahydro-1 5H-7,17-dioxa-1 5-
azacyclopenta[a]phenanthren-6,16-dione
o
)- N
O O O
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 104
15-Methyl-1,2,3,4-tetrahydro-15H-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6,16-dione
0
~-N
O 0 O
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 105
16-Phe nyl-1,2,3,4-tetrahyd ro-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6-one
--N
O
~ O
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 106
16-Ethyl-1,2,3,4-tetrahydro-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6-one
-)=N
O O
16, 5 In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 107
1,2,3,4-Tetrahydro-15H-7,17-dioxa-15-azacyclopenta[a]phenanthrene-
6,16-dione
0
~-N
O 0
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 108
1,2,3,4-Tetrahydro-7,17-dioxa-15-azacyclopenta[a] phenanthren-6-one
H
~-- N
O O
I
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 109
16-Benzylsulfanyl-l2-chloro-1,2,3,4-tetrahydro-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6-one
s
>='N
O Icoo
I
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 110
12-Chloro-16-morpholin-4-yi -1,2,3,4-tetrahydro-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6-one
o-
N
>-- N
O O O
CI
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
Example 111
9-(6-Hyd roxypyridi n-3y1)-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
o o 0
Fio / \ ~
N- -N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 112
9-(4-Methylpiperazin-1-y1-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
/-\ o O o
N\
N
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In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 113
9-Piperazin-1-y1-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
0
0 la6
H ~-N In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 114
9-Phenylamino-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
q0000
\
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 115
9-Benzylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-l0-
azacyclopenta[b]phenanthren-5-one
c\s<Jcro 87
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In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 116
9-Morpholin-4-yl-1,2,3,4-tetrahydro-6,8-dioxa-l0-
azacyclopenta[b]phenanthren-5-one
o ~ o 0
N~\ ~
\--, N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 117
9-Pyri d i n-3-yI-1, 2, 3, 4-tetra hyd ro-6, 8-d i oxa-10-
azacyclopenta[b]phenanthren-5-one
o ~ o 0
--- - -~ ~
N N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 118
9-Pyridin-4-y1-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
O
N~ ~ O ~
- N
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In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 119
9-Methylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-l0-
azacyclopenta[b]phenanthren-5-one
0 / O
~S\ I
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 120
10-Thiophen-2-y1-1,2,3,4-tetrahydro-6,8-dioxa-l1-
azabenzo[a]anthracene-5,9-dione
O O O
N
S
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 121
9-Isopropylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
0 O 89
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In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 122
9-Benzoyl-1,2,3,4-tetrahydro-6,8-dioxa-10-
azacyclopenta[b]phenanthren-5-one
O 0 O O
rN /
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 123
9-Th ioxo-1,2,3,4,9,10-hexahyd ro-6,8-d i oxa-10-
azacyclopenta[b]phenanthren-5-one
O
_
- O
S=<
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
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Example 124
9-Isopropyl-1,2,3,4-tetrahydro-6,8-dioxa-l0-
azacyclopenta[b]phenanthren-5-one
>cc0 5 In analogy to the procedure described in Scheme 8, the title compound
is
obtained in moderate yield.
Example 125
9-Phenyl-1,2,3,4-tetrahydro-6,8-dioxa-l0-azacyclopenta[b]phenanthren-
5-one
ecc0 In_ analogy_to the_procedure_described _in_Scheme 8, the title compound
is
obtained in moderate yield.
Example 126
10-Isopropyl-1,2,3,4-tetrahydro-10H-6,8-dioxa-10-
azacyclopenta[b]phenanthrene-5,9-dione
0 O O
O=<
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
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Example 127
1,2,3,4-Tetrahydro-10H-6,8-dioxa-10-azacyclopenta[b] phenanthrene-
5,9-dione
0 ~ O O
O I
N ~ /
H
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 128
9-Ethyl-1,2,3,4-tetrahydro-6,8-dioxa-10-azacyclopenta[b]phenanthren-5-
one
O ~ O
\ In_analogy to the procedure described inScheme 8, the title compound is
obtained in moderate yield.
Example 129
9-Methyl-1,2,3,4-tetrahydro-6,8-dioxa-10-azacyclopenta[b]phenanthren-
5-one
O O
\ I
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
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Example 130
9-Ethoxy-1,2,3,4-tetrahydro-6,8-dioxa-10-azacyclopenta[b]phenanthren-
5-one
o o
~'cI
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 131
4-Methoxy-2-thioxo-1,2,8,9,10,11-hexahydro-3,6-dioxa-l-
azacyclopenta[c]phenanthren-7-one
1-1O O O
o
H
s
In-analogy-to the procedure-described in Scheme-12, the title compound is
obtained in moderate yield.
Example 132
12-Chloro -1,2,3,4-tetrahydro-7,17-dioxa-15-
azacyclopenta[a]phenanthren-6-one
/=N
O O
cl
In analogy to the procedure described in Scheme 9, the title compound is
obtained in moderate yield.
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Example 133
4-Methoxy-2-phenyl- 8,9,10,11-tetrahydro-3,6-dioxa-1-
azacyclopenta[c]phenanthren-7-one
0
0
o
N
In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
Example 134
5-Methoxy-2-thiophen-2-y1-9,10,11,12-tetrahydro-4,7-dioxa-l-
azabenzo[c]phenanthrene-3,8-dione
0
0
o
iN
O
s
In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
Example 135
4-Methoxy-2-methyl- 8,9,10,11-tetrahydro-3,6-dioxa-l-
azacyclopenta[c]phenanthren-7-one
o 0
1-1o PN
o
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In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
Example 136
4-Methoxy-8,9,10,11-tetrahydro-1 H-3,6-dioxa-l-
azacyclopenta[c]phenanthren-2,7-dione
O O
/O P\N
O
O H
In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
Example 137
4-Methoxy-2-methylsulfanyl- 8,9,10,11-tetrahydro-3,6-dioxa-l-
azacyclopenta[c]phenanthren-7-one
~o--~ o-O-
~
o
-~=N
S/
In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
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Example 138
2-Ethoxy-4-methoxy- 8,9,10,11-tetrahydro-3,6-dioxa-l-
azacyclopenta[c]phenanthren-7-one
0
1-1o 0
o~
}=N
O
In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
Example 139
2-Chloro-3-pyridin-2-yI-7,8,9,10-tetrahydro-benzo[c]chromen-6-one
NI O O
I
CI
In_ analogy to the_ procedure_described in Scheme 5, the _title _compound is_
obtained in moderate yield.
Example 140
3-Acetyl-2-chloro-7,8,9,10-tetrahydro-benzo[c]chromen-6-one
0
~ o 0
cI~
6
In analogy to the procedure described in Scheme 5, the title compound is
obtained in moderate yield.
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Example 141
7-Isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one
"To ~ o 0
/
02N /
In analogy to the procedure described in Scheme 4, the title compound is
obtained in moderate yield.
Example 142
9-(4-Dimethylamino-benzyl)-1,2,3,4-tetrahydro-6,8-dioxa-10-aza-
cyclopenta[b]phenanthren-5-one
o o 0
N
-N
\
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 143
4-Methoxy-2-pyridin-2-y1-8,9,10,11-tetrahydro-3,6-dioxa-1-aza-
cyclopenta[c]phenanthren-7-one
1-11o 0 0
o
N
N-
~
97
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In analogy to the procedure described in Scheme 12, the title compound is
obtained in moderate yield.
Example 144
9-Pyridin-2-y1-1,2,3,4-tetrahydro-6,8-dioxa-10-aza-
cyclopenta[b]phenanthren-5-one
~ 0
-N N In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 145
2-Ch loro-3-isopropoxy-8-pyridi n-2-y1-7,8,9,10-tetrahyd ro-
benzo[c]chromen-6-one
y
o o
ci
N
~ \
/
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 146
2-Chloro-3-isopropoxy-8-pyridin-3-yl-7,8,9,1 0-tetrahydro-
benzo[c]chromen-6-one
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y
o 0 0
ci
N
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 147
10-(3,5-Difl uoro-phenyl)-1,2,3,4-tetrahyd ro-6,8-dioxa-1l-aza-
benzo[a]anthracene-5,9-dione
O O / O O
F I
I ~ N /
/
------------- ---
-
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 148
4-(5,9-Dioxo-1,3,4,5-tetrahydro-2H,9H-6,8-dioxa-l1-aza-
benzo[a]anthracen-10-y1)-benzonitrile
O O O O
N
N
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In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 149
9-Phenyl-2,3-dihydro-1 H-5,7-dioxa-10-aza-cyclopenta[a]anthracene-4,8-
dione
O O O O
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 150
10-Phenyl-1,2,3,4-tetrahydro-6,8-d ioxa-11-aza-benzo[a]anthracene-5,9-
_
dione
0 O / 0 0
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 151
10-(4-M ethoxy-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-l1-aza-
benzo[a]anthracene-5,9-dione
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O O O O
~ \
N
O
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 152
10-(3,4-Dimethoxy-phe nyl)-1,2,3,4-tetrahyd ro-6,8-dioxa-1l-aza-
benzo[a]anthracene-5,9-dione
O O O O O N
\ /
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 153
10-(4-Trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-11-aza-
benzo[a]anthracene-5,9-dione
O O O O
~
N
F
F
F
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In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 154
9-Adamantan-l-yl-1,2,3,4-tetrahydro-6,8-dioxa-l0-aza-
cyclopenta[b]phenanthren-5-one
o o 0
N
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
Example 155
10-(4-Dimethylamino-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1l-aza-
-benzo[a]anthracene-5,9-dione
O O / O O
~ ~ ~
I ~ N
N /
I
In analogy to the procedure described in Scheme 8, the title compound is
obtained in moderate yield.
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Example 156
2-Chloro-3-isopropoxy-7-methyl-7,8,9,10-tetrahydro-benzo[c]chromen-
6-one
Y
0 ~ 0 0
~
cI~
i
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
Example 157
2-Chloro-3-isopropoxy-9-pyrid i n-2-yl-7,8,9,10-tetrahyd ro-
benzo[c]chromen-6-one
Y
0 0 0
ci
N
In analogy to the procedure described in Scheme 1, the title compound is
obtained in moderate yield.
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
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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 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
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
The active ingredients of the invention, together with one or more
conventional adjuvants, carriers, or diluents, may be placed into the form of
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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
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 zero point five (0.5) to five hundred (500) milligrams per
tablet,
are accordingly suitable representative unit dosage forms.
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, 18th Edition.
METHOD OF TREATING
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, modulation, 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, optionally concurrently, simultaneously, or together with
one or more pharmaceutically-acceptable excipients, carriers, or diluents,
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and optionally 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, 10-500 milligrams daily, and 50-500
milligrams daily, depending as usual upon the exact mode of administration,
form in which administered, the indication toward which the administration is
directed, the subject involved and the body weight of the subject involved,
and the preference and experience of the physician or veterinarian in
charge.
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.
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.
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,
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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
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.
The tablets can be coated by methods well known in the art. The
compositions of the invention can be also introduced in microspheres or
microcapsules, 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.
The active drugs can also be administered in the form of liposome delivery
systems, such as small unilamellar vesicles, large uniiamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as
is well known.
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
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targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone,
pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-
ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with
palmitoyl 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 and
polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid,
polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and
cross-linked or amphipathic block copolymers of hydrogels.
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.
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.
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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).
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, optionally at various dosage levels to act as a titration
pack. 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.
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.
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
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it can be expressed as the ratio ED50/LD50. Compositions that exhibit large
therapeutic indices are preferred.
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL
COMPOSITIONS
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.
Other suitable pharmaceutical compositions will be immediately apparent to
one skilled in the art.
FORMULATION EXAMPLES
The following examples are again given by way of illustration only and are
not to be construed as limiting.
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EXAMPLE 1
Tablet Formulation
A suitable formulation for a tablet containing 10 milligrams of active
ingredient is as follows:
mg
Active Ingredient 10
Lactose 61
Microcrystalline Cellulose 25
Talcum 2
Magnesium stearate 1
Colloidal silicon dioxide 1
EXAMPLE 2
Tablet -For-mulation
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 1
Microcrystalline Cellulose 50
Film coated and colored.
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The film coating material consists of:
Hypromellose 10
Microcryst. Cellulose 5
Talcum 5
Polyethylene glycol 2
Color pigments 5
EXAMPLE 3
Capsule Formulation
A suitable formuiation 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.
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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
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:
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G
Active Ingredient 20.00
Tragacanth 7.00
Glycerol 50.00
Saccharose 400.00
Methylparaben 0.50
Propylparaben 0.05
Black currant-flavor 10.00
Soluble Red color 0.02
Purified water add 1000 mL
EXAMPLE 7
Liquid oral formulation
Another suitabie 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
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EXAMPLE 8
Aerosol formulation
180 g aerosol solution contain:
G
Active Ingredient 10
Oleic acid 5
Ethanol 81
Purified Water 9
Tetrafluoroethane 75
ml of the solution are filled into aluminum aerosol cans, capped with a
dosing valve, purged with 3.0 bar.
EXAMPLE 9
-10- T_DS-formulation
100 g solution contain:
G
Active Ingredient 10.0
Ethanol 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0
Hydroxyethyicellulose 0.4
Purified water 19.6
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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
g of polybutylcyanoacrylate nanoparticles contain:
G
Active Ingredient 1.00
Poloxamer 0.10
Butylcyanoacrylate 8.75
Mannitol 0.10
Sodium chloride 0.05
10---- Polybutylcyanoacrylate __nanoparticles. 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
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:
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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:
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
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.
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/mL) is determined
according to the method of Lowry (Lowry O. H. et al., 1951. J. Biol. Chem.
193, 256-275).
[3H]MPEP Assay
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 is achieved under the conditions used).
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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).
Characterization
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 lag/mL) 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 (lC50 of cold MPEP equates to a Ki of
13.7 nM). Bmax is 0.56 pm / mg protein.
FUNCTIONAL ASSAY OF MGLUR5 RECEPTORS
Materials and Methods
Astrocyte culture
Primary astrocyte cultures are prepared from cortices of newborn rats as
described by Booher and Sensenbrenner (1972). Briefly, Sprague-Dawley
rat pups (2 - 4 d old) are decapitated and neocortices are dissected,
disintegrated with a nylon filter (poresize 80 pm) and carefully triturated.
The
cell suspension is 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 (FCSi, Sigma), 4
mM 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.
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After 7 DIV, cells are shaken overnight at 250 rpm to remove
oligodendrocytes and microglia. The next day, astrocytes are 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 are
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 is exchanged and the cells incubated for another 2-3 d, so
that at the time of experiments astrocytes are 14-15 DIV.
Immunocytochemistry
Immunostaining is performed to confirm the presence of classical astrocytic
markers such as GFAP as well the expression of mGluR5 receptors.
Accumulation of [3H]-Inositol Phosphates
After astrocytes are cultured for 12 d ADM is removed and inositol-free
DMEM (MP Biomedicals) supplemented with [3H]myo-inositol (0.5 pCi / well;
PerkinElmer),and the ADM chemicals is added. After 48 h the medium is
replaced with 100 pL Locke's buffer (plus 20 mM 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) is terminated by replacing the
Locke's solutions with 100 pL 0.1 M 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) are used to separate
labeled inositol phosphates by elution with 1 mL of 1 M ammonium formate /
0.1 M formic acid into 24-well visiplates (Perkin Elmer). Scintillation liquid
(UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed
before radioactivity is determined by conventional liquid scintillation
counting
(Microbeta,Perkin Elmer) as disintegration per minute (DPM).
Alternatively, on the day of assay, columns are washed with 1 mL of 0.1 M
formic acid followed by 1 mL of distilled water. The contents of each assay
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well are then added to one column and washed with 1 mL distilled water
followed by 1 mL of 5 mM sodium tetraborate / 60 mM sodium formate. The
retained radioactive inositol phosphates are then eluted with 2 X 1 mL of I M
ammonium formate / 0.1 M formic acid into 24-well visiplates. Scintillation
liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed
before radioactivity is determined by conventional liquid scintillation
counting
(Microbeta,Perkin Elmer) as disintegration per minute (DPM).
Calcium FLIPR studies
Cultured astrocytes express mGIuR5 receptors as shown by
immunostaining. The increase of intracellular calcium after stimulation with
the mGluR5 agonist DHPG or L-quisqualate is measured using the
fluorometric imaging plate reader (FLIPR) and the Ca-Kit (both Molecular
Devices, CA). Prior to addition of agonist or antagonist the medium is
aspirated and cells are loaded for 2 h at RT with 150 pL of loading buffer
consisting of Ca-sensitive dye (MD # R8033) reconstituted in sodium
chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8
mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM),
---- pH_7.3. Subsequently, plates are transferred to FLIPR to detect calcium
increase with the addition of DHPG (300 taM) or L-quisqualate (100 nM)
measured as relative fluorescence units (RFU). If antagonists are tested,
these compounds are pre-incubated for 10 min at RT before addition of the
respective agonist.
For positive modulators, concentration-response curves for quisqualate are
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 are performed in
the presence of a fixed concentration of quisqualate showing the biggest
window for potentiation (normally 10-30 nM).
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Data analysis
The fluorescence signal increase after addition of agonist reflects the
increase of intracellular calcium. Inconsistencies in the amount of cells per
well are normalised by using the spatial uniformity correction of the FLIPR
software. The mean of replicated temporal data (n=5) is calculated and
used for graphical representation. For the evaluation of the pharmacology,
the calcium changes in response to different concentrations of agonist or
antagonist are determined using a maximum minus minimum (MaxMin)
calculation.
All responses (DPM- or RFU-values) are determined as percentage of
control (= maximum response at 100 nM quisqualate).
EC50 and IC50 are calculated according the logistic equation using GraFit 5.0
(Erithacus Software).
FUNCTIONAL ASSAY OF mGluRl RECEPTORS IN CEREBELLAR
GRANULE CELLS - RADIOACTIVE ASSAY FOR CHANGES IN IP3
LEVELS
Preparation of cerebellar granule cells
Cerebellar cortici are obtained from P8 postnatal Sprague Dawley rats,
mechanically disrupted into small pieces with forceps and then transferred to
Ca2+ and Mg2+ free Hank's buffered salt solution (HBSS-CMF) on ice. After
three washes in HBSS-CMF, the tissue pieces are incubated at 37 C for 8
minutes in the presence of 0.25% trypsin / 0.05% DNase. The enzymatic
reaction is stopped with 0.016% DNAase / 0.1% ovomucoid before
centrifugation at 800 rpm for 5 minutes. The supernatant is replaced twice
with NaHCO3/HEPES-buffered basal Eagle medium (BME) plus 20 mM KCI.
Cells are mechanically dissociated in 2 ml of BME by trituration through
three Pasteur pipettes of successively decreasing tip diameter and then
filtered through a 48 pM gauge filter. Cells are plated at a density of
150,000
cells in 50 pl in each well of poly-L-Lysin pre-coated 96 well plates
(Falcon).
The cells are nourished with BEM supplemented with 10% foetal calf serum,
2 mM glutamine (Biochrom), 20 mM KCI and gentamycin (Biochrom) and
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incubated at 36 C with 5% CO2 at 95% humidity. After 24 h, cytosine-l3-D-
arabinofuranoside (AraC, 10 pM) is added to the medium.
IP3 assay with [3H]myo-inositol
After 6 DIV the culture medium is replaced completely with inositol free
DMEM (ICN) containing [3H]myo-inositol (Perkin Elmer) at a final
concentration of 0.5 pCi / 100 pl / well and incubated for a further 48 hours.
The culture medium in each well is replaced with 100 pL Locke's buffer
(containing in (mM) NaCI (156), KCI (5.6), NaHCO3 (3.6), MgCl2 (1.0), CaCI2
(1.3), Glucose (5.6), HEPES (10)) with additional (20 mM Li+, pH 7.4) and
incubated for 15 min at 37 C. Locke's buffer is replaced with agonists /
antagonists / putative mGluRl ligands in Locke's buffer and incubated for 45
min. These solutions are then replaced by 100 pL 0.1 M HCI in each well and
incubated for a further 10 mins 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) are used to separate labeled inositol
phosphates. On the day of assay, columns are washed with 1 ml of 0.1 M
formic acid followed by 1 ml of distilled water. The contents of each assay
_well are_ then added to one column and washed with 1 ml distilled water
followed by I ml of 5 mM sodium tetraborate / 60 mM sodium formate. The
retained radioactive inositol phosphates are then eluted with 2 * 1 mI of 1 M
ammonium formate / 0.1 M formic acid into 24-well visiplates. Scintillation
liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed
before radioactivity is determined by conventional liquid scintillation
counting
(Microbeta,Perkin Elmer) as disintegration per minute (DPM).
Chemicals
Unless otherwise stated all chemicals are purchased from Sigma.
References
Booher and. Sensenbrenner (1972) Neurobiology 2(3):97-105
Miller et al., (1993) Brain Res. 698(1):175-8
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Compounds of the present invention have a potency (EC50 or IC50,
respectively) range of about 0.5 nM to about 100 M.
CONCLUSIONS
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.
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.
The instant chromenone derivatives represent a novel class of Group I
mGluR modulators. In view of their potency, they will be useful therapeutics
in a wide range of CNS disorders which involve abnormal glutamate induced
excitation.
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,
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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 pugilistica, vascular and
frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g.
glaucoma, retinopathy, macular degeneration), head and brain 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.
These compounds also find application in the treatment of the following
disorders of a living animal body, especially a human: abuse and 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, hyperactivity in
children, autism, convulsions I 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,
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)
disease, functional gastrointestinal disorders, dyspepsia, regurgitation,
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respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g.
reflux-related asthma), lung disease, eating disorders, obesity, 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 and/or
neuroprotection.
These compounds also find application in the treatment of indications in 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.
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.
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 mGluR modulator 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.
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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.
*****
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.
All patents, applications, publications, test methods, literature, and other
materials cited herein are hereby incorporated by reference.
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