NZ613467B2 - Pyrrole derivatives used as modulators of alpha7 nachr - Google Patents
Pyrrole derivatives used as modulators of alpha7 nachr Download PDFInfo
- Publication number
- NZ613467B2 NZ613467B2 NZ613467A NZ61346712A NZ613467B2 NZ 613467 B2 NZ613467 B2 NZ 613467B2 NZ 613467 A NZ613467 A NZ 613467A NZ 61346712 A NZ61346712 A NZ 61346712A NZ 613467 B2 NZ613467 B2 NZ 613467B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- optionally substituted
- benzenesulfonamide
- aryl
- group
- Prior art date
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- 150000003233 pyrroles Chemical class 0.000 title abstract description 3
- 230000000051 modifying Effects 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 153
- YIYZHARUXWKUEN-UHFFFAOYSA-N benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1.NS(=O)(=O)C1=CC=CC=C1 YIYZHARUXWKUEN-UHFFFAOYSA-N 0.000 claims abstract description 58
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- 239000011780 sodium chloride Substances 0.000 claims abstract description 12
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims abstract description 8
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims abstract description 8
- 210000004558 Lewy Bodies Anatomy 0.000 claims abstract description 7
- 230000001404 mediated Effects 0.000 claims abstract description 6
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 5
- -1 hereroaryl Chemical group 0.000 claims description 169
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- 239000000203 mixture Substances 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 63
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 27
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
- 125000003107 substituted aryl group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 19
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
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- 125000005842 heteroatoms Chemical group 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
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- VVQGCSOVWGVVLH-UHFFFAOYSA-N spiro[2H-1,4-benzodioxine-3,1'-cyclopropane] Chemical compound C1CC11OC2=CC=CC=C2OC1 VVQGCSOVWGVVLH-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drugs Drugs 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- GVCMFAGYMNVFSA-UHFFFAOYSA-N 1,4,4-trimethyl-3H-quinolin-2-one Chemical compound C1=CC=C2N(C)C(=O)CC(C)(C)C2=C1 GVCMFAGYMNVFSA-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
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- RYVOFIIYEQDJNG-UHFFFAOYSA-N 4-(2-methyl-3-propanoyl-5-spiro[3H-1,4-benzodioxine-2,1'-cyclopropane]-6-ylpyrrol-1-yl)benzenesulfonamide Chemical compound C=1C=C(S(N)(=O)=O)C=CC=1N1C(C)=C(C(=O)CC)C=C1C(C=C1OC2)=CC=C1OC12CC1 RYVOFIIYEQDJNG-UHFFFAOYSA-N 0.000 abstract 2
- RHBODKIUOLTNRO-UHFFFAOYSA-N 4-[5-(2,2-dimethyl-3,4-dihydrochromen-6-yl)-2-methyl-3-propanoylpyrrol-1-yl]benzenesulfonamide Chemical compound CC1=C(C(=O)CC)C=C(C=2C=C3CCC(C)(C)OC3=CC=2)N1C1=CC=C(S(N)(=O)=O)C=C1 RHBODKIUOLTNRO-UHFFFAOYSA-N 0.000 abstract 2
- XFJPMSKOQQJAKK-UHFFFAOYSA-N 4-[5-(2-acetyl-4,4-dimethyl-1,3-dihydroisoquinolin-6-yl)-2-methyl-3-propanoylpyrrol-1-yl]benzenesulfonamide Chemical compound CC1=C(C(=O)CC)C=C(C=2C=C3C(C)(C)CN(CC3=CC=2)C(C)=O)N1C1=CC=C(S(N)(=O)=O)C=C1 XFJPMSKOQQJAKK-UHFFFAOYSA-N 0.000 abstract 2
- FDQGQEPVQQEDDL-UHFFFAOYSA-N 4-[5-(2-acetyl-4,4-dimethyl-1,3-dihydroisoquinolin-7-yl)-2-methyl-3-propanoylpyrrol-1-yl]benzenesulfonamide Chemical compound CC1=C(C(=O)CC)C=C(C=2C=C3C(C(CN(C3)C(C)=O)(C)C)=CC=2)N1C1=CC=C(S(N)(=O)=O)C=C1 FDQGQEPVQQEDDL-UHFFFAOYSA-N 0.000 abstract 2
- VHWQGUPMLYQUEM-UHFFFAOYSA-N 4-[5-(4,4-dimethyl-2,3-dihydro-1H-isoquinolin-7-yl)-2-methyl-3-propanoylpyrrol-1-yl]benzenesulfonamide Chemical compound CC1=C(C(=O)CC)C=C(C=2C=C3C(C(CNC3)(C)C)=CC=2)N1C1=CC=C(S(N)(=O)=O)C=C1 VHWQGUPMLYQUEM-UHFFFAOYSA-N 0.000 abstract 2
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Abstract
This disclosure relates to a family of pyrrole derivatives of formula I, wherein R1, R2, R3 and R4 are as disclosed in the specification. The family also include its tautomeric forms, stereoisomers and pharmaceutically acceptable salts. The disclose also relates to their use in preventing or treating a disease or disorder mediated by nicotinic acetylcholine receptors. These conditions include attention deficit hyperactivity disorders, schizophrenia, Alzheimer's disease, Parkinson's dementia, vascular dementia or dementia associated with Lewy bodies and traumatic brain injury. Examples of compounds include: 4-(5-(2,2-dimethylchroman-6-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(5-(8-fluoro-4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl-1H-pyrrol-lyl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]-7-yl)-1H-pyrrol-1-yl)benzenesulfonamide; 4-(2-methyl-3-propionyl-5-(3 H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]-6-yl)-1H-pyrrol-1-yl)benzenesulfonamide; g a disease or disorder mediated by nicotinic acetylcholine receptors. These conditions include attention deficit hyperactivity disorders, schizophrenia, Alzheimer's disease, Parkinson's dementia, vascular dementia or dementia associated with Lewy bodies and traumatic brain injury. Examples of compounds include: 4-(5-(2,2-dimethylchroman-6-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(5-(8-fluoro-4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl-1H-pyrrol-lyl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; 4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]-7-yl)-1H-pyrrol-1-yl)benzenesulfonamide; 4-(2-methyl-3-propionyl-5-(3 H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]-6-yl)-1H-pyrrol-1-yl)benzenesulfonamide
Description
PYRROLE DERIVATIVES USED AS MODULATORS OF ALPHA'7 NACHR
Field of the Invention:
The present invention is related to novel compounds of the general formula I,
R3 R2
SOzNHz
their tautomeric forms, their stereoisomers, their analogs, their prodrugs, their
isotopes, their metabolites, their pharmaceutically acceptable salts, polymorphs,
solvates, optical s, clathrates, co-crystals, ations With suitable
medicament, pharmaceutical compositions containing them, methods of making of
the above compounds and their use as nicotinic choline or (:17 subunit
(d7 nAChR) modulator.
ound of the invention:
Cholinergic neurotransmission, mediated primarily through the neurotransmitter
acetylcholine (ACh), is a predominant regulator of the physiological functions of the
body via the central and autonomic nervous system. ACh acts on the synapses of
the neurons present in of all the autonomic ganglia, uscular junctions and
the central nervous system. Two distinct s of ACh target receptors viz.
muscarinic s) and the nicotinic (nAChRs) have been identified in brain,
forming a significant component of receptors carrying its mnemonic and other vital
physiological functions.
Neural nicotinic ACh receptors (NNRs) belong to the class of ligand-gated ion
channels (LGIC) comprising of five ts (c12-c110, [32-84) arranged in
heteropentameric ((31482) or homopertameric (d7) configuration (Paterson D et al.,
Prog. Neurobiol., 2000, Q, 75-1 1 1). (21482 and C17 nAChR constitute the
predominant subtypes expressed in the mammalian brain. (:17 nAChR has attained
prominence as a therapeutic target due to its abundant expression in the learning
and memory centers of brain, hippocampus and the cerebral cortex (Rubboli F et
al., Neurochem. Int., 1994, 2_5, 69-71). Particularly, C17 nAChR is characterized by
a high Ca2+ ion permeability, Which is responsible for ransmitter release and
consequent modulation of excitatory and inhibitory neurotransmission don
M et al., Eur. J. Pharmacol., 2000, @, 59-67; Dajas-Bailador F et al., Trends
col. Sci., 2004, 2_5, 317-324). Furthermore, high Ca2+ ion influx also has
implications on the long-term potentiation of memory via alterations in gene
expression (Bitner RS et al., J. Neurosci., 2007, 2_7, 10578-10587; McKay BE et al.,
Biochem. Pharmacol., 2007, E, 1 120-1 133).
Several recent studies have confirmed the role of C17 nAChR in neural processes
like attention, memory and cognition (Mansvelder HD et al., Psychopharmacology
(Berl), 2006, m, 292-305; Chan WK et al., Neuropharmacology, 2007, 5_2, 1641-
1649; Young JW et al., Eur, sychopharmacol,, 2007, g, 145-155). Gene
polymorphisms associated With the C17 nAChR protein CHRNA7 have been
ated in the genetic ission of schizophrenia, related neurophysiological
sensory gating deficits and ant cognitive impairment (Freedman R et al., Biol.
Psychiatry, 1995, @, 22-33; Tsuang DW et al., Am. J. Med. Genet., 2001, £5,
662-668). Also, preclinical studies in c1 7 nAChR knock-out and anti-sense
oligonucleotide treated mice have demonstrated impaired attention and defective
cognition underscoring the prominent role of C17 nAChR in ion (Curzon P et
al., Neurosci. Lett., 2006, 4—10, 15-19; Young JW et al., sychopharmacology,
2004, Q, 891-900). Additionally, pharmacological blockade of C17 nAChR impairs
memory and its activation enhances same in preclinical rodent models implicating
C17 nAChR as target for cognitive enhancement moto K et al., Biol.
Psychiatry, 2008, Q, 92—97).
Pathological brain on in sensory-deficit disorders has been associated With
nicotinic cholinergic ission particularly through (:17 receptors (Freedman R
et al., Biol. Psychiatry, 1995, E, 22-33; Tsuang DW et al., Am. J. Med. Genet.,
2001, 1—05, 662-668; Carson R et al., Neuromolecular, 2008, Med 10, 4;
Leonard S et al., Pharmacol. Biochem. Behav., 2001, 7_0, 561-570; Freedman R et
al., Curr. atry Rep., 2003, Q, 155-161; Cannon TD et al., Curr. Opin.
Psychiatry, 2005, Q, 135-140). A defective pre-attention sing of sensory
information is tood to be the basis of cognitive fragmentation in
schizophrenia and related sychiatric disorders (Leiser SC et al., Pharmacol.
Ther., 2009, Q, 302-31 1). Genetic linkage studies have traced sharing of the (:17
gene locus for several affective, attention, anxiety and psychotic disorders (Leonard
S et al., Pharmacol. Biochem. Behav., 2001, 7_0, 561-570; Suemaru K et al.,
Nippon. Yakurigaku. Zasshi., 2002, Q, 295-300). Modulation of the nicotinic
cholinergic receptors, particularly (:17 may provide for efficacy in a range of
cognitive states, right from pre-attention to ion and subsequently working,
reference and recognition memory. Accordingly, this ion may find application
in the treatment and prophylaxis of multitude of disease ions including,
either one or combinations of, schizophrenia, schizophreniform disorder, cognitive
deficits in schizophrenia, brief psychotic disorder, delusional disorder,
schizoaffective disorder, shared psychotic er, paranoid personality disorder,
schizoid personality disorder, schizotypal ality disorder, attention deficit
disorder, attention deficit hyperactivity disorder (ADHD), depression, maniac
depression, major depressive disorder, posttraumatic stress disorder, generalized
anxiety disorder, tourette’s syndrome, cyclothymic disorder, dysthymic disorder,
agoraphobia, panic disorder (With or t agoraphobia), phobias (including
social phobia) and bipolar disorders en MS et al., Curr. Pharm. Des. 2010,
1_6, 323-343; Peng ZZ et al., Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008, E, 154-
158; Young JW et al., Eur. Neuropsychopharmacol. 2007, H, 145-155; Martin LF
et al., Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007, w, 611-614; Martin
LF et al., Psychopharmacology (Berl), 2004, m, 54-64; Feher A et al., Dement.
Geriatr. Cogn. Disord. 2009, E, 56-62; Wilens TE et al., Biochem. Pharmacol.
2007, fl, 1212-1223; Verbois SL et al., harmacology, 2003, g, 224-233;
Sanberg PR et al., Pharmacol. Ther. 1997, E, . Cholinergic system,
WO 04782
particularly through (:17 nAChR seems to have implications in traumatic brain
injury-induced psychosis. Chronic ne treatment has shown to ate
same. Thus, this invention may also find application in the treatment of deficits in
cholinergic C17 nAChR following traumatic brain injury (Bennouna M et al.,
Encephale, 2007, @, 616-620; Verbois SL et al., Neuropharmacology, 2003, g,
Perturbations in the cholinergic and glutamatergic homeostasis, has long been
implicated as causative s for host of neurological disease, including
ia(s) (Nizri E et al., Drug News Perspect. 2007, @, 421-429). Dementia is a
severe, progressive, multi-factorial ive disorder affecting memory, attention,
language and problem solving. Nicotinic ACh receptor, particularly the interaction
of C17 receptor to A8142 is implicated as an up-stream pathogenic event in
Alzheimer’s disease, a major causative factor for dementia (Wang HY et al., J.
Neurosci., 2009, Q, 10961-10973). Moreover, gene polymorphisms in CHRNA7
have been implicated in dementia with Lewy bodies (DLB) and Pick’s disease (Feher
A et al., Dement. Geriatr. Cogn. Disord. 2009, E, 56-62). tion of nicotinic
ACh receptors, particularly the C17 subtype could help ment the down-
regulated cholinergic or expression and transmission as in dementia(s), and
also slowing disease progression by reduction of c17-A[31,42 complexation and
internalization in AD and Down’s syndrome (Nordberg A et al., Neurotox. Res.
2000, 2, 157-165; Haydar SN et al., Bioorg. Med. Chem., 2009, fl, 5247-5258;
Deutsch 81 et al., Clin. Neuropharmacol., 2003, E, 277-283). Appropriately, this
invention may find application in the ent and laxis of multitude of
disease conditions including, either one or combinations of, dementia(s) due to
mer’s disease, ia with Lewy bodies, Down’s syndrome, head trauma,
Stroke, hypoperfusion, Parkinson’s disease, Huntington’s disease, Prion diseases,
progressive supranuclear palsy, radiation therapy, brain tumors, normal-pressure
hydrocephalus, subdural hematoma, human immunodeficiency virus (HIV)
infection, vitamin deficiency, hypothyroidism, drugs, alcohol, lead, mercury,
aluminium, heavy metals, syphilis, Lyme disease, viral encephalitis, fungal
infection and cryptococcosis (Zhao X et al., Ann N Y Acad. Sci., 2001, 939, 179-
186; Perry E et al., Eur. J. Pharmacol., 2000, 393, 215-222; Harrington CR et al.,
Dementia, 1994, Q, 215-228; Wang J et al., J. Neurosci. Res., 2010, &, 807—815).
Disease cation potential of nAChRs particularly the C17 receptor has
application for disease-modification of Alzheimer ’s e (AD) and Parkinson’s
disease (PD) by enhancing neuron survival and preventing neurodegeneration
(Wang et al. 2009; Nagele RG et al., Neuroscience, 2002, E, 199-211;
Jeyarasasingam G et al., Neuroscience, 2002, w, 275-285). onally, C17
nAChR induced activation of anti-apoptotic (BCL—2) and anti-inflammatory
pathways in brain could have neuroprotective effects in neurodegenerative diseases
(Marrero MB et al., Brain Res., 2009, 1256, 1-7). Thus, this ion may find
application in the prophylaxis and preventive measures immediately after early-
stage fication of neurodegenerative disease like Alzheimer’s disease and
Parkinson’s e.
Dopamine containing neurons of l tegmental area (VTA) and laterodorsal
tegmental nucleus (LDT) are known to express nicotinic ACh receptors, particularly
C14, C13, [32, [33, [34 subunits (Kuzmin A et al., Psychopharmacology , 2009,
&, 99-108). Nicotinic ACh receptors, (21482 and C1384 have been identified With
candidate-gene approach to have strong mechanistic link for nicotine addiction
(Weiss RB et al., PLoS Genet 2008, 4, e1000125). C17 nAChR has particularly been
studied for a putative role in cannabis addiction (Solinas M et al., J. Neurosci.,
2007, 2_7, 5615-5620). Varenicline, a partial agonist at (31482, has demonstrated
better efficacy in reducing the smoking addiction and relapse prevention in
comparison to buproprion (Ebbert JO et al., Patient Prefer Adherence, 2010, 4,
355-362). tion of nicotinic ACh receptors particularly c1482, (31384 and (:17
may have implications in the development of ies for nicotine, cannabis
addiction and relapse prevention. Accordingly, this invention may find application
in the prophylaxis or therapy of nicotine addiction, cannabis addiction, relapse
prevention of nicotine or cannabis addiction. onally, this invention may also
provide for an alternative therapy for sponding ion patients, patients
having intolerable side-effects with iction therapies or those requiring long-
term maintenance therapies.
Presence of a high-affinity nicotine g site at (21482 nAChR, in the descending
inhibitory pathways from brainstem has sparked interest in the antinociceptive
properties of nicotinic ACh receptor agonists like epibatidine (Decker MW et al.,
Expert. Opin. Investig. Drugs, 2001, 1_0, 1819-1830). Several new developments
have opened the area for use of nicotinic modulators for therapy of pain
(Rowbotham MC et al., Pain,, 2009, £6, 245-252). riate modulation of the
nicotinic ACh receptors could provide for remedial approach to pain related states.
Thus, this invention may find application in the ent and prophylaxis of
multitude of pain conditions including, either one or combinations of, pain arising
from, peripheral nervous system (PNS), post-diabetic neuralgia (PDN), post-herpetic
neuralgia (PHN), multiple sclerosis, Parkinson’s disease, low-back pain,
fibromyalgia, post-operative pain, acute pain, chronic pain, mononeuropathy,
y lateral sclerosis, pseudobulbar palsy, ssive muscular palsy,
progressive bulbar palsy, postpolio syndrome, diabetes induced polyneuropathy,
acute inating uropathy (Guillain-Barre syndrome), acute spinal
muscular y (Werdnig-Hoffman disease) and secondary neurodegeneration
(Donnelly-Roberts DL et al., J. Pharmacol. Exp. Ther., 1998, E, 777-786; Rowley
TJ et al., Br. J. Anaesth., 2010, £5, 201-207; Bruchfeld A et al., J. Intern. Med.,
2010, &, 94-101).
Another key role of the C17 nAChR is the ability to modulate the production of pro-
inflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha (TNF-oc),
and high mobility group box (HMGB-l) in the central nervous system.
Consequently, an nflammatory and antinociceptive effect in pain disorders
have been demonstrated (Damaj MI et al., Neuropharmacology, 2000, Q, 2785-
2791). Additionally, nergic anti-inflammatory pathway’ is proposed to be a
regulatory of local and systemic inflammation and neuro-immune interactions
through neural and humoral pathways (Gallowitsch-Puerta M et al., Life Sci. 2007,
&, 2325-2329; itsch-Puerta and Pavlov 2007; Rosas-Ballina M et al., Mol.
Med. 2009, 1_5, 195-202; Rosas-Ballina M et al., J. Intern. Med. 2009, E, 663—
679). Selective modulators of nic ACh receptors, particularly (:17 type, like
GTS—21, attenuate cytokine production and IL—lB after endotoxin exposure.
Furthermore, (:17 nAChR are understood to have a central role in arthritis
pathogenesis and potential therapeutic strategy for treatment of joint ation
(Westman M et al., Scand J. Immunol. 2009, 7_0, 136-140). A putative role for (:17
nAChR has also been implicated in severe , endotoxemic shock and systemic
inflammation (Jin Y et al. (2010) Int. J. Immunogenet. Liu C et al., Crit. Care Med.
2009, g, 634-641). This invention may thus find application in the treatment and
laxis of plethora of inflammation and pain related states involving TNF-d
and thus ing symptomatic relief in either any one or combination of,
rheumatoid arthritis, bone resorption diseases, atherosclerosis, inflammatory
bowel disease, Crohn’s disease, inflammation, cancer pain, muscle degeneration,
osteoarthritis, osteoporosis, ulcerative colitis, rhinitis, pancreatitis, spondylitis,
acute respiratory distress me (ARDS), joint inflammation, anaphylaxis,
ischemia reperfusion injury, multiple sis, cerebral malaria, septic shock,
tissue rejection of graft, brain trauma, toxic shock me, herpes virus infection
(HSV—l & HSV—2), herpes zoster infection, sepsis, fever, myalgias, asthma, tis,
contact dermatitis, obesity-related disease and endotoxemia (Giebelen IA T et al.,
Shock, 2007, 2_7, 443-447; Pena G et al., Eur. J. Immunol., 2010, fl, 2580—2589).
Angiogenesis, is a critical logical process for the cell survival and
pathologically important for cancer proliferation; several non-neural nicotinic ACh
receptors, particularly C17, C15, C13, [32, [34, are involved (Arias HR et al., Int. J.
Biochem. Cell Biol., 2009, fl, 1441-1451; Heeschen C et al., J. Clin. Invest., 2002,
1—10, 527-536). A role of nicotinic ACh receptors in the pment of cervical
cancer, lung carcinogenesis and paediatric lung disorders in smoking-exposed
population has also been studied ja-Macias IE et al., Int. J. Cancer, 2009,
12—4, 1090-1096; Schuller HM et al., Eur. J. Pharmacol., 2000, @, 265-277). It is
thus, imperative for the modulators of nicotinic ACh receptors, to have a
tory role in angiogenesis and cancer cell survival. Thus, this invention may
find application in the ent and prophylaxis of multitude of cancerous
conditions including, one or combination of, acute or chronic myelogenous
ia, multiple myeloma, tumor growth inhibition, angiogenesis and cancer
associated-cachexia.
Several C17 nAChR agonists, partial agonists, have been characterized for their
efficacy in clinical and preclinical studies. EVP-6124, an agonist at (:17 nAChR, has
demonstrated significant ement in sensory processing and cognition
biomarkers in Phase Ib study with patients suffering from schizophrenia o
Pharmaceuticals press e 2009, Jan 12). GTS-21 (DMXB-Anabaseine), an (:17
nAChR agonist, in the P 11 clinical trials, has shown efficacy in improving cognitive
deficits in schizophrenia and inhibition of xin-induced TNF-d release (Olincy
A et al., Biol. Psychiatry, 2005, 5718, Suppl.], Abst 44; Olincy A et al., Arch. Gen.
Psychiatry, 2006, Q, 630-638; ein R et al., Acad. Emerg. Med., 2007, fl
1152 Suppl. 1], Abst. 474). CP-810123, a C17 nAChR agonist, exhibits protection
against the scopolamine-induced dementia and inhibition of amine-induced
auditory evoked potentials in preclinical studies (O'Donnell CJ et al., J. Med.
Chem., 2010, fl, 1222-1237). SSR—180711A, also an (:17 nAChR agonist, enhances
ng and memory, and protects against /Scopolamine-induced memory
loss and prepulse inhibition in preclinical studies (Redrobe JP et al., Eur. J.
Pharmacol., 2009, @, 58-65; Dunlop J et al., J. Pharmacol. Exp. Ther., 2009,
%, 766-776; Pichat P et al., Neuropsychopharmacology, 2007, Q, 17-34). SEN-
12333, protected against scopolamine-induced amnesia in e avoidance test
in preclinical studies (Roncarati R et al., J. Pharmacol. Exp. Ther., 2009, @, 459—
468). AR—R—17779, an agonist at (:17 nAChR, exhibits improvement in the social
recognition task performed in rats (Van KM et al., Psychopharmacology (Berl),
2004, m, 375-383). ABBF, an agonist at (:17 nAChR, improves social recognition
memory and working memory in Morris maze task in rats (Boess FG et al., J.
Pharmacol. Exp. Ther., 2007, 32—1, 716-725). TC-5619, a selective C17 nAChR
agonist has demonstrated efficacy in animal models of positive and negative
symptoms and cognitive dysfunction in schizophrenia (Hauser TA et al., Biochem.
col., 2009, 7_8, 803-812).
An alternative strategy to rce or potentiate the endogenous cholinergic
neurotransmission of ACh Without directly stimulating the target receptor is the
positive allosteric modulation (PAM) of C17 nAChR (Albuquerque EX et al., Alzheimer
Dis. Assoc. Disord., 2001, 15 Suppl 1, S19-S25). l PAMs have been
characterized, albeit in the preclinical stages of discovery. A-86774, C17 nAChR
PAM, improves sensory gating in DBA/2 mice by significantly reducing the T:C
ratio in a preclinical model of schizophrenia (Faghih R et al., J. Med. Chem., 2009,
5_2, 3377—3384). XY—4083, an (:17 nAChR PAM, normalizes the sensorimotor gating
deficits in the DBA/2 mice and memory acquisition in 8-arm radial maze Without
altering the receptor desensitization kinetics (Ng HJ et al., Proc. Natl. Acad. Sci. U.
S. A., 2007, M, 8059—8064). Yet r PAM, PNU-120596, ndly alters C17
nAChR desensitization kinetics and simultaneously protecting t the
tion of prepulse inhibition by MK-801. NS-1738, another PAM, has exhibited
efficacy in-vivo in the animal models of social recognition and spatial memory
acquisition in the Morris maze task (Timmermann DB et al., J. Pharmacol. Exp.
Ther., 2007, @, 294-307). In addition, several patents/applications published are
listed below - US20060 142349, US20070 142450, US2009025369 1,
WO200703 1440, WO2009 1 1 5547, WO2009 135944, WO2009 127678,
WO2009127679, WO2009043780, 043784, US7683084, US7741364,
WO2009 145996, US20 100240707, W020 1 1064288, US20100222398,
US20100227869, EP1866314, WO2010130768, WO2011036167, 0190819
disclose efficacy of eric modulators of nicotinic ACh receptors and
underscoring their therapeutic potential.
Following are the abbreviations used and meaning thereof in the specification:
ACh: Acetylcholine.
AD: Alzheimer ’s disease.
ADC: AIDS dementia x.
ADHD: attention deficit hyperactivity disorder.
AIDS: Acquired immunodeficiency syndrome.
ARDS: acute respiratory ss syndrome.
DCC: 1,3-dicyclohexylcarbodiimide.
DCE: dichloroethane.
DCM: dichloromethane.
DLB: dementia with Lewy bodies.
DMF: N,N-dimethylformamide.
EDCI: 1-(3-dimethylaminopropyl)ethylcarbodimide hloride.
FLIPR: Fluorometric Imaging Plate Reader.
HBSS: Hanks balanced salt solution.
HEPES: 4-(2-hydroxyethyl)piperazineethanesulfonic acid.
HMGB: high mobility group box.
HOAT: 1-hydroxyazabenzotriazole.
HOBT: hydroxybenzotriazole hydrate.
HPLC: High mance liquid chromatography.
IL: interleukins.
LDT: laterodorsal tegmental nucleus.
LGIC: -gated ion channels.
MCI: mild cognitive impairment.
NBS: N-bromosuccinamide.
NCS: N-chlorosuccinamide.
NIS: N-iodosuccinamide
NNRs: Neural nicotinic ACh receptors.
PAM: positive allosteric modulation.
PD: Parkinson’s disease.
PDN: iabetic neuralgia.
PHN: post-herpetic neuralgia.
PMBO: p-methoxy benzyloxy.
PNS: peripheral nervous system.
TBI: traumatic brain injury.
THF: Tetrahydrofuran.
TLC: Thin layer tography.
TMS: tetramethylsilane.
TNF-oc: tumor necrosis factor alpha.
VTA: ventral tegmental area.
(:17 nAChR: nicotinic acetylcholine receptor (:17 subunit.
Objective of the Invention:
The main objective of the present invention is therefore to provide novel
compounds of the general formula 1, their tautomeric forms, their stereoisomers,
their pharmaceutically acceptable salts, pharmaceutical compositions containing
them, s and intermediates for the preparation of the above said nds
Which have (:17 nAChR modulatory activity.
Summary of the Invention
According to one aspect of the present ion there is provided compounds
represented by the general a 1, its tautomeric forms, its stereoisomers, its
analogs, its prodrugs, its isotopes, its metabolites, its pharmaceutically able
salts, its rphs, its solvates, its optical isomers, its clathrates, its co-crystals,
their combinations With suitable medicament and pharmaceutical compositions
containing them.
In yet another aspect, the present invention provides a process for the preparation
of the compounds of the general formula I.
A further aspect of the present ion is to provide novel intermediates, a
process for their preparation and their use in methods of making compounds of the
general formula 1.
ed Description of the ion:
The present invention relates to a compound of the general formula 1, its
tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its
metabolites, its pharmaceutically able salts, its polymorphs, its solvates, its
optical isomers, its clathrates, its co-crystals, their combinations With suitable
medicament and pharmaceutical compositions containing them.
wherein,
R1 is selected from hydrogen, halogen, optionally substituted alkyl, perhaloalkyl,
optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted
heterocyclyl, optionally substituted heteroaryl;
R2 is selected from optionally substituted alkyl, ally substituted heteroalkyl,
ally substituted aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, or —NR5(R6), -A1R5, -N(R5)OR6;
R3 is ed from hydrogen, optionally substituted alkyl, halo, optionally
tuted cycloalkyl, optionally tuted aryl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, cyano, nitro or —NR5(R6), -OR5;
R4 is
[R7]m
JEEP/w1”
n, phenyl ring ‘D’ is fused With ring "E, Which is a non-aromatic five to eight
member ring inclusive of ‘Y’ group(s);
2012/050442
Y is independently selected at each repetition from -O-, PM; K
-S—, -NH-, or
, 1c],
where q = 1 - 4; wherein when Y is selected as —NH- or lb, it is optionally
substituted by [R8]n;
wherein, R5 and R6 are ndently selected from hydrogen, optionally
substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted cycloalkyl, ally
substituted heterocyclyl, R93C(=A1)-;
R7 is selected independently at each occurrence from the group consisting of
halogen, optionally substituted alkyl, optionally substituted cycloalkyl;
R8 is independently ed at each occurrence from the group consisting of
optionally substituted alkyl, R9A1-, R9aC(=A1)-;
p=Oto4;
wherein, R9 wherever it appears, is selected from hydrogen, optionally substituted
C16 alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted
heterocyclyl; and A1 is selected from O and S;
R981 wherever it appears, is selected from ally substituted C16 alkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
aryl, optionally substituted cycloalkyl, and optionally substituted
heterocyclyl;
wherein,
the term "optionally substituted alky ", means a alkyl group optionally substituted
With 1 to 6 tuents selected independently from the group comprising of oxo,
halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, Z-, R10A1-, RIOaOC(=O)-,
R108C(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R10aC(=O)N(H)-, (R10)(H)N-,
(R1°)(alky1)N-, (R1°)(H)NC(=A1)N(H)-, (R1°)(alky1)NC(=A1)N(H)-;
the term “optionally substituted heteroalky ” means a heteroalkyl group optionally
substituted With 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl.
the term “optionally tuted cycloalkyl" means a cycloalkyl group optionally
substituted With 1 to 6 substituents selected independently from the group
sing of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R103C(=O)-,
RIOaSOT, R10A1-, RIOaOC(=O)-, R103C(=O)O-, (R10)(H)NC(=O)-, alkyl)NC(=O)-,
RIOaC(=O)N(H)-, (R1°)(H)N-, (RIONalkyllNa (R1°)(H)NC(=A1)N(H)-,
(R10)(a1kyl)NC(=A1)N(H)-;
the term "optionally tuted aryl" means (i) an aryl group optionally substituted
With 1 to 3 substituents selected ndently from the group comprising of
halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl
, perhaloalkyl, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-,
alkyl-N(H)C(=O)-, H2NC(=O)-, alkyl-N(alkyl)802-, N(H)802-, H2NSOg-, 3 to 6
membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S
optionally tuted With alkyl or alkyl-C(=O)-, (ii) an aryl ring ally fused
With cycloalkane or heterocycle across a bond optionally substituted With oxo, alkyl
or alkyl—C(=O)-;
the term “optionally substituted heterocyclyl" means a (i) heterocyclyl group
optionally substituted on ring carbons With 1 to 6 tuents selected
independently from the group sing of oxo, halogen, nitro, cyano, aryl,
hereroaryl, alkyl, R10A1-, RIOaOC(=O)-, R108C(=O)O-, (R10)(H)NC(=O)-,
(R1°)(alky1)NC(O)-, R1°aC(=O)N(H)-, (R1°)(H)N-, (R1°)(alky1)N-, (R1°)(H)NC(=A1)N(H)-,
(R10)(alkyl)NC(=A1)N(H)-; (ii) heterocyclyl group optionally substituted on ring
nitrogen(s) with tuents selected from the group comprising of aryl,
hereroaryl, alkyl, R108C(=O)-, RIOaSOZ-, R10a0C(=O)-, (R10)(H)NC(=O)-,
(R1°)(alky1)NC(=O)-;
the term "optionally substituted heteroary" means a heteroaryl group optionally
substituted with 1 to 3 substituents selected independently from the group
comprising of halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1
to C6 oalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-,
alkyl-SOT, perhaloalkyl-SOT, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-
N(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H2NC(=O)-, alkyl-N(alkyl)802-, alkyl-N(H)802-,
H2NSOz-, 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from
N, O and S optionally substituted with alkyl or C(=O)-;
wherein R10 is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl; and A1 is selected from S and O; and R1081 is selected from alkyl,
oalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
Other aspect of the invention of the present invention is compound of formula I as
described above wherein when p is selected as 0 then n is selected from the
integers ranging between 1 and 4.
Preferred embodiment of the present invention is compound of formula I as d
herein above, wherein R1 is ed from methyl.
Other red ment of the present invention is compound of formula I as
defined above, wherein, R2 is selected from ethyl and .
r preferred embodiment of the present invention is compound of formula I
as defined hereinabove, wherein, R3 is selected from hydrogen and methyl.
Yet another preferred embodiment of the present invention is compound of formula
I as defined hereinabove, wherein, R4 is selected from following groups:
(R7)m (R )m,7 O N (Ra)n
! (R7)m! H (R7)m
(R7)m
O|\fil‘% R8,
HN \HL‘II ()\ \H‘si ms)” (0 \E'Il
L 4/0 \3'772
x., /L I L I \| 8/ I
o x N x m x K0 ,,
(R )m. H
(R8)n (R7)mg (R7)m! (R7)m or (R7)m_
Further preferred embodiment of the present invention is compound of formula I as
defined hereinabove, wherein R1 is selected from methyl; R2 is selected from ethyl
and ethoxy; R3 is selected from hydrogen and ; and R4 is selected from
following groups:
(Rm (R8)n H (R8)n H
b a; \ of; W
0 \(R7)m (R5)n 11% War“;
(R7)m (R7)m O (R3)n
, N \1R7) (R7)m
(R3)n (R8),,
E0 \ H
I HNfi/Ez \ \ E (R8) (0 \ H, 40 \ E‘s
m (R4L ' “\
O \(R7)m l
x [30/ (Rm/\U
N #0 O
’ \(R7)m
~ /, or \(R7)m
General terms used in formula can be defined as s; however, the meaning
stated hereinbelow should not be interpreted as limiting the scope of the term per
The term "alkyl", as used herein, means a ht or ed chain hydrocarbon
containing from 1 to 20 carbon atoms. The term as defined herein also includes
unsaturated chains containing 2 to 20 carbon atoms and one or more
unsaturations (double or triple bonds) as in alkenyl and alkynyl groups. Preferably
the alkyl chain may contain 1 to 10 carbon atoms, and alkenyl and alkynyl chains
may contain 2 to 10 carbons. More preferably alkyl chain may contain up to 6
carbon atoms. Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert—butyl, n-
pentyl, isopentyl, neopentyl, allyl, vinyl, acetylene, and n-hexyl.
2012/050442
Alkyl as defined hereinabove may be optionally substituted with one or more
substituents selected independently from the group comprising of oxo, halogen,
nitro, cyano, aryl, hereroaryl, cycloalkyl, RIOaSOT, R10A1-, R10a0C(=O)-, R10aC(=O)O-
, (R10)(H)NC(=O)-, (R1°)(a1ky1)NC(=O)-, =O)N(H)-, (R1°)(H)N-, (R1°)(a1ky1)N-,
(R10)(H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; wherein R10 is selected from
hydrogen, alkyl, aryl, aryl, cycloalkyl or heterocyclyl; and A1 is selected from
S and O; and R1081 is selected from alkyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl.
The term “perhaloalkyl” used herein means an alkyl group as defined hereinabove
wherein all the hydrogen atoms of the said alkyl group are substituted with
halogen. The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl
and the like.
The term “heteroalkyl” as used herein means an ‘alkyl’ group wherein one or
more of the carbon atoms replaced by —O-, -S—, -S(02)-, , -N(Rm)-, Si(Rm)Rn-
wherein, Rm and Rn are independently selected from hydrogen, alkyl, aryl,
aryl, cycloalkyl, and heterocyclyl.
The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, or tricyclic
non-aromatic ring system containing from 3 to 14 carbon atoms, preferably
monocyclic cycloalkyl ring ning 3 to 6 carbon atoms. The ring may contain
one or more unsaturations (double or triple . Examples of monocyclic ring
systems include ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. Bicyclic ring systems are also exemplified by a d monocyclic ring
system in which two non-adjacent carbon atoms of the monocyclic ring are linked
by an alkylene bridge. Representative examples of bicyclic ring systems e,
but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, o[3.2.2]nonane, bicyclo[3.3. 1]nonane, and
bicyclo [4.2. 1]nonane, bicyclo [3.3.2] decane, bicyclo[3. 1 .O]hexane,
bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-lH-indene. Tricyclic ring
systems are also exemplified by a bicyclic ring system in which two non-adjacent
carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge.
Representative examples of tricyclic-ring s include, but are not limited to,
tricyclo[3.3.1.03-7]nonane and tricyclo[3.3.1.13-7]decane (adamantane). The term
cycloalkyl also include spiro s wherein one of the ring is annulated on a
single carbon atom such ring systems are exemplified by spiro[2.5]octane,
spiro[4.5]decane, spiro[bicyclo[4. 1 .O]heptane-2, 1 '-cyclopentane], hexahydro-2'H-
spiro[cyclopropane- 1 1 '-pentalene].
cycloalkyl as defined hereinabove may be optionally substituted With one or more
substituents selected independently from the group comprising of oxo, halogen,
nitro, cyano, aryl, hereroaryl, alkyl, =O)-, RIOaSOT, R10A1-, R10a0C(=O)-,
=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R10aC(=O)N(H)-, (R10)(H)N-,
(R10)(alkyl)N-, H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; wherein R10 is selected
from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and A1 is selected
from S and O; and R10a is selected from alkyl, perhaloalkyl, aryl, heteroaryl,
cycloalkyl or heterocyclyl.
The term "aryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic
arbon ring system. Examples of aryl groups include but not limited to
phenyl, yl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The said
aryl group also includes aryl rings fused With heteroaryl or heterocyclic rings such
as 2,3-dihydro-benzo[1,4]dioxin-6—yl; hydro-benzo[1,4]dioxin-5—yl; 2,3-
dihydro-benzofuran-5—yl; 2,3-dihydro-benzofuran-4—yl; 2,3-dihydro-benzofuran-6—
yl; 2,3-dihydro-benzofuranyl; 2,3-dihydro-1H-indol-5—yl; 2,3-dihydro-1H-indol-
4-yl; 2,3-dihydro-1H-indol-6—yl; 2,3-dihydro-1H-indolyl; benzo[1,3]dioxol-4—yl;
benzo[1,3]dioxol-5—yl; 1 ,2,3,4—tetrahydroquinolinyl; 1 -tetrahydroisoquinolinyl;
2,3-dihydrobenzothien-4—yl, 2-oxoindolinyl.
Aryl as d hereinabove may be optionally substituted With one or more
substituents selected independently from the group comprising of halogen, nitro,
cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, alkyl-O-,
perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SOT, perhaloalkyl,
alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-, alkyl-N(H)C(=O)-,
H2NC(=O)-, alkyl-N(alkyl)802-, alkyl-N(H)802-, H2NSOz-, 3 to 6 membered
heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally
substituted with alkyl or alkyl-C(=O)-.
The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic
ring system having 1-4 ring atoms selected from O, N, or S, and the
der ring atoms being carbon (with appropriate hydrogen atoms unless
otherwise indicated), wherein at least one ring in the ring system is aromatic.
Heteroaryl groups may be optionally substituted with one or more substituents. In
one embodiment, O, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be
substituted by a substituent. Examples of heteroaryl groups e but not
limited to pyridyl, pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl,
imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,
pyrimidinyl, pyrazinyI, nyl. triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl,
benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl, benzoxadiazolyl, indolyl, olyl, imidazopyridyl, quinazolinyl,
purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 2,3-
thiadiazolyl, 1H-pyrazolo[5,1-c ]-1,2,4—triazolyl, pyrrolo[3,4—d]-1,2,3-triazolyl,
cyclopentatriazolyl, rolo[3,4—c] isoxazolyl and the like.
heteroaryl as defined hereinabove may be optionally substituted with one or more
substituents selected independently form the group comprising of halogen, nitro,
cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, alkyl-O-,
perhaloalkyl-O-, alkyl-N(alkyl)-, N(H)-, H2N-, alkyl-SOT, perhaloalkyl,
alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, N(alkyl)C(=O)-, alkyl-N(H)C(=O)-,
H2NC(=O)-, alkyl-N(alkyl)802-, alkyl-N(H)802-, H2NSOz-, 3 to 6 membered
heterocycle containing 1 to 2 heteroatoms selected from N, O and S ally
tuted with alkyl or alkyl-C(=O)-.
The term "heterocycle" or "heterocyclic" as used herein, means a ‘cycloalkyl’ group
wherein one or more of the carbon atoms replaced by —O-, -S—, -, -S(O)-, -
2012/050442
N(Rm)-, -Si(Rm)Rn-, wherein, Rm and Rn are independently selected from en,
alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. The heterocycle may be
connected to the parent molecular moiety through any carbon atom or any
nitrogen atom contained Within the cycle. Representative es of
monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl,
aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
olidinyl, morpholinyl, oxadiazolinyl. oxadiazolidinyl, oxazolinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl. pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,
thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone).
thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle include,
but are not limited to nzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro-1,4—
benzodioxinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-
dihydro-l H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also
e bridged heterocyclic systems such as yclo[3.2.1]octane,
azabicyclo[3.3.1]nonane and the like.
Heterocyclyl group may optionally be substituted on ring carbons With one or more
substituents selected independently from the group comprising of oxo, n,
nitro, cyano, aryl, hereroaryl, alkyl, R10A1-, RIOaOC(=O)-, =O)O-,
(R1°)(H)NC(=O)-, a1ky1)NC(O)-, RIOaC(=O)N(H)-, (R1°)(H)N-, (R1°)(alky1)N-,
(R10)(H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; wherein R10 is selected from
en, alkyl, aryl, aryl, cycloalkyl or heterocyclyl; and A1 is selected from
S and O; and R1081 is selected from alkyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl.
Heterocyclyl group may further optionally be substituted on ring nitrogen(s) With
substituents selected from the group comprising of aryl, hereroaryl, alkyl,
R108C(=O)-, T, RIOaOC(=O)-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-; wherein R10
is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and
R1081 is selected from alkyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
A compound its stereoisomers, racemates, pharmaceutically acceptable salt and
pharmaceutical composition thereof as described hereinabove wherein the
compound of general a I is selected from:
1. 4- (5- (4,4-dimethylchromanyl)methylpropionyl- 1H—pyrrol
yl)benzenesulfonamide.
. 4- (5-(2,3-dihydrobenzo [b] [ 1 ,4]dioxinyl)methylpropionyl- 1H-pyrrol
zenesulfonamide.
. 4- (2-(2,3-dihydrobenzo [b] [ 1 ,4]dioxin-6—yl)-3, 5-dimethyl-4—propionyl- 1H-
pyrrol- 1 nzenesulfonamide.
Ethyl 5-(2,3-dihydrobenzo[b][1,4]dioxinyl)-2,4—dimethyl (4-
sulfamoylphenyl)- 1H-pyrrolecarboxylate
. 4- (5-(2,3-dihydro- 1H-inden-4—yl)methylpropionyl- 1 H-pyrrol
yl)benzenesulfonamide.
. 4- (5-(2,2-dimethylchromanyl)methylpropionyl- 1H-pyrrol
yl)benzenesulfonamide.
. 4- (5-(8-fluoro-4,4—dimethylchromanyl)methylpropionyl- 1H-pyrrol
yl)benzenesulfonamide.
. 4-(5-(2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolinyl)methyl
propionyl- 1 H-pyrrolyl)benzenesulfonamide.
. 4-(5-(2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolinyl)methyl
nyl- 1 H-pyrrolyl)benzenesulfonamide.
1 O. 4- 4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolinyl)methylpropionyl-
1 H-pyrrolyl)benzenesulfonamide.
1 1.4-(2-methy1—3-propiony1-5—(3H-spiro[benzo[b][1,4]dioxine-2, 1 '-cyclopropan]-
7-y1) - 1 H-pyrrol- 1 nzenesulfonamide.
1 2. 4- (2-methy1—3-propiony1- 5- (3H-spiro[benzo [b] [ 1 ,4] dioxine-2, 1 opropan]-
6-y1) - 1 H-pyrroly1)benzenesulfonamide.
1 3. 4- (5—( 1 -acety1—4,4—dimethy1— 1 -tetrahydroquinolin-6—y1)methy1—3-
propionyl- 1 oly1)benzenesulfonamide.
1 4. 4- (5—( 1 -acety1—4,4—dimethy1— 1 ,2,3,4—tetrahydroquinoliny1)methy1—3-
propionyl- 1 H-pyrroly1)benzenesulfonamide.
1 5. 4- (5—(4,4—dimethy1- 1 ,2 ,3,4-tetrahydroquinoliny1)methy1—3-propiony1-
1 H-pyrroly1)benzenesulfonamide.
1 6. 4- (5—(4,4—dimethy1- 1 ,2 ,3,4-tetrahydroquinoliny1)methy1—3-propiony1-
1 H-pyrrol- 1 nzenesulfonamide.
1 7. 4- (5—(4,4—dimethy1oxo- 1 ,2,3,4-tetrahydroquinolin-6—y1)methy1—3-
propionyl- 1 H-pyrroly1)benzenesulfonamide.
1 8. 4- (5—(4,4—dimethy1oxo- 1 ,2,3,4—tetrahydroquinoliny1)methy1—3-
propionyl- 1 H-pyrroly1)benzenesulfonamide.
1 9. 4- (2-methy1—3-propiony1-5— ( 1 ,4,4—trimethy1—2-oxo- 1,2,13,4-
tetrahydroquinoliny1)- 1 H-pyrroly1)benzenesulfonamide.
. 4- (2-methy1—3-propiony1- 5- (5,6, 7,8-tetrahydronaphthaleny1)- 1 H-pyrrol
y1)benzenesu1fonamide.
According to another aspect of the present invention, the compounds of general
formula I where all the symbols are as defined earlier were prepared by method
described below in scheme 1. r, the invention may not be limited to these
WO 04782 2012/050442
methods; the compounds may also be prepared by using procedures described for
structurally related compounds in the literature.
R3—?H—COX1
X1Vl o o f‘"
o o WHLO’AK R3 o
3 —> 3 —>
R4H _’ R4JK/R R
R4 R4
R3-CH2-COX1 'V x1 o R1
I” VIII
0 NH2
JR2 /|
XIII \\
R1 802NH2
R3 R2 0 O 10‘}
HNR5(R6),HA1R5, R3 OH R3 0
R2 / \ 6
R3 O—>RNR1I()4 HNR OR5 R4/\1‘ R4/\1
N R N R
R4 2
0 /
1 / I / /
XIV \ \\so NH2 2 \\| \\|
SO2NH2 SO2NH
IX 302NH2 I
RZng1 l X=|,where Rzis-O-Ak
o ,0—
R4Hi/N\
SCHEME1
SOZN |
XII \\/N\
Compound of the formula I can be prepared starting from compounds represented
by general formulae II and III by subjecting them to Friedal—Crafts reaction in the
presence of Lewis acid as described in the ture EP 2168959 to give the
Compounds of formula IV. Friedal Craft on can be carried out under different
conditions well known in the art.
Alternatively, nd of formula IV can be prepared according to the
appropriate procedure given in literature such as US 6313107, U85037825 and
Journal of Med. Chemistry, 2006, @,478 or the like.
Compound of the formula IV where symbols R4 is same as defined earlier in general
formula and R3 is hydrogen, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl,
optionally substituted heteroaryl, -OR6 where R6 is not selected as hydrogen
undergo for halogenation to provide the nds of formula V. Halogenation can
be carried out under a ion adopting ure generally used in the
synthetic c chemistry using bromine, , N-halosuccinamide, sufuryl
chloride, cupric chloride, cupric bromide or cupric iodide preferably bromine and
cupric chloride using a solvent such as ethyl acetate, dichloromethane, methanol,
THF, 1,4—dioxane and the like. Preferably dichloromethane or methanol are used.
Alternatively, Compounds of formula V can be prepared starting from compounds
represented by general formulae II by reacting it with compound VI under Friedal—
Crafts condition in the presence of Lewis acid such as AlClg and the like as
described in the ture EP 9 to give the nd of formula V. Friedal
Craft reaction can be carried out under different conditions well known in the art.
Compound of formula V where symbols R3 and R4 are same as defined for
compound IV, and X1 is halogen when treated with base such as potassium
carbonate, sodium hydride, preferably pulverized sodium under room temperature
to heated conditions in a solvent such as THF, an aromatic hydrocarbon such as
benzene, toluene and the like. ably toluene and compound of the formula VII
where R1 is optionally tuted alkyl, perhaloalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl,
optionally substituted heteroaryl, e diketo ester compound VIII.
nd of the formula VII can be prepared according to the ure given in
literature such as Chem. Pharm. Bull. 1982, 30, 2590 and J. of Med. Chem., 1997,
Q, 547.
Compound VIII where symbols R1, R3, R4 are same as d earlier was treated
with substituted aniline of formula IX under heating conditions in a t such
as acetic acid and the like to obtain compound of the formula X.
The compounds of the a X when R3 = H can be functionalized by
electrophilic reagents such as but not limited to 12, HNOZ, HCHO which would
further lead to the formation of compounds of formula X having R3 = aryl, nitro,
amino, amino alkyl, halo, hydroxy or cyano by using common functional group
transformation procedure well known in the art.
Ester hydrolysis of compound of the formula X gave compound of formula XI. Ester
hydrolysis may be carried out using standard procedure lly used in
synthetic organic chemistry or well known in the art with reagents such as sodium
hydroxide, potassium hydroxide, lithium hydroxide or the like in solvents such as
alcohol, THF or the like. Preferably, aqueous on of sodium hydroxide and
ethanol were used for this reaction.
Compound of formula XI where R1, R3, R4 are same as defined earlier was further
converted to its corresponding acid chloride using rd procedure known in
synthetic organic chemistry or ably by reaction with oxalyl chloride in
dichloromethane along with DMF followed by reaction with NO—
ylhydroxylamine hydrochloride and triethylamine in dichloromethane to
provide compound of formula XII.
Compound of the formula XII was treated with Grignard reagent R2MgX1 where R2
selected from optionally substituted alkyl, optionally substituted heteroalkyl,
optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl or optionally substituted heterocyclyl, and X1 is halogen gave compound
of formula I, where R2 is optionally substituted alkyl, optionally substituted
heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl or optionally substituted heterocyclyl. The
reaction may be carried out as per the procedure given in literature such as J.
Med. Chem., 2009, 52,3377.
Compound of formula XI was alternatively reacted with HNR5(R6), HA1R5,
OR6 where R5, R6and A1 are same as defined under the general a I to
provide compound of the formula I where R2 is —NR5(R6), -A1R5, OR6. The
reaction was carried out according to the conditions known in converting
carboxylic acids to amides and esters as known to one skilled in the art. The
reaction may be carried out in the presence of solvents, for example DMF, THF, a
halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic
hydrocarbon such as xylene, benzene, toluene, or the like, in the presence of
suitable base such as triethylamine, diisopropylethylamine, pyridine or mixtures
thereof or the like at a ature between O-50°C using reagents such as 1-(3-
dimethylaminopropyl)ethylcarbodimide hydrochloride (EDCI), 1 ,3-
dicyclohexylcarbodiimide (DCC), auxillary reagents such as 1-hydroxy
azabenzotriazole (HOAT), ybenzotriazole hydrate (HOBT) or the like.
Alternatively, the compounds of the formula I where R3 = H; R2 is selected from
optionally tuted alkyl, optionally substituted heteroalkyl, ally
substituted aryl, optionally substituted heteroaryl, optionally substituted lkyl
or optionally substituted heterocyclyl; R1 is optionally substituted alkyl,
oalkyl, optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heterocyclyl, optionally substituted heteroaryl; and R4 is
same as defined earlier was prepared from compound of the formula V where R3 is
H, R4 is same as defined under generic formula I, and X1 is n by reacting it
with compound of the formula XIII where R1 is same as defined r and R2 is
same as defined earlier excluding NR5R6, -A1R5, -N(R5)OR6 to give the compound
XIV where R3 is H; R2 is optionally tuted alkyl, optionally substituted
heteroalkyl, optionally substituted aryl, ally tuted heteroaryl,
optionally substituted cycloalkyl or optionally substituted heterocyclyl; R1 and R4
are same as defined earlier in the generic formula I. The reaction may be carried
out in the presence of base such as potassium ate, sodium hydride,
ably pulverized sodium in a solvent such as THF, an aromatic hydrocarbon
such as benzene, toluene or the like, preferably toluene is used.
Cyclization of compound of formula XIV With substituted aniline of a IX
under heating conditions in a t such as acetic acid or the like gave
compound of formula I.
Compound of the formula XIII was be ed according to the procedure given in
literature such as J. Amer. Chem. Soc. 1945, Q, 9, 1510-1512.
Compound of the formula I Where R1 is hydrogen, R2, R3 and R4 are same as defined
earlier can be synthesized by adopting the chemistry bed in Tetrahedron
Letters, 1982, 23, 37, 3765-3768 and Helvetica Chimica Acta, 1998, 81, 7, 1207-
1214.
Compound of the formula I Where R1 = H, R2, R3 and R4 are same as defined earlier
can be converted to compound of the formula I Where R1 is Halogen, R2, R3 and R4
are same as defined r by halogenation. Halogenation can be carried out under
a ion according to a procedure generally used in the synthetic organic
chemistry using bromine, iodine, NCS, NBS, NIS, sufuryl chloride, cupric chloride,
cupric bromide or cupric iodide preferably bromine and cupric chloride using a
solvent such as ethyl acetate, dichloromethane, methanol, THF, 1,4 dioxane and
preferably romethane or methanol.
Compound of formula II Where R4 is same as defined under compound I can be
prepared using process reported in the literature such as J.Med. Chem, 1985, Q,
1, 116-124, Monatshefte fur chemie, 1996, 127, 275-290, J.Med. Chem,, 1997, 4_0,
16, 2445-2451, US 4808597 and Eur. J. of Med. Chem., 2008, Q, 8, 1730 —
1736, or the like.
Process for synthesis of some of the typical intermediates of formula II is provided
below in scheme 2.
HOW01) 0 0 O
—> HoYVO _.
0 0
X1 X133% X1
xv XVII R4-H
HN N
XVIII R‘H
PMBOjg
PMBO PMBO
I) o
. 9,51 1:a a H0510
AK 0 we
AK’ 0 XXIII
Br XXI
XIX xx
SCHEME 2
Compound XVII was prepared starting from compounds represented by general
a XV where X1 is halo, by esterification of carboxylic acid with alcohol in the
presence of nic acid such as but not limited to catalytic H2804 under room
temperature to heated condition as bed in the ture like Journal of the
American Chemical Society, 1944, 66, 914-17 to obtain the Compounds of
formula XVI. The compounds of the formula XVI was treated with Grignard reagent
l) to provide the compounds of formula XVII. The reaction may be carried
out but not limited to the procedure given in literature such as J.Med. Chem,
2009, 52, 3377. The compound XVII was converted to compound of formula II
where symbols R4 are same as defined for compound I by subjecting them to
Friedal—Crafts reaction in the presence of Lewis acid as described in the literature
(J.Med. Chem, 1985, 28, 1, 116 — 124).
The compounds of formula II where symbols R4 are same as defined for compound I
was prepared from nd XVIII by ating using base such as but not
limited to triethyl amine and acetyl chloride as described in J. Med. Chem, 2000,
43, 236-249.
The compound XXIII can be prepared starting from compounds represented by
general formulae XIX by treatment of substituted phenol with alkyl 2,4-
dibromobutanoate in the presence of base such as K2C03 under room temperature
to heated condition as bed in the literature such as U82010076027 to give
the nd of the formula XX. The compound of formula XX was converted to
compound of formula XXI by cyclopropane ring formation using base such as but
not limited to potassium t—butoxide as described in the literature such as
U82010076027. The compound of formula XXI can be ted into compound of
formula XXII using reducing reagent such as but not limited to LiAlH4 as described
in the ture edron, 1994, 50, 15, 431 1-4322; which was de-protected by
method using reagents such as ceric ammonium nitrate, Trifluoromethane
sulfonate BFg-etherate but preferably by hydrogenation using catalytic palladium
on carbon to give compound of formula XXIII. The compound XXIII was converted
to compound of formula II where symbols R4 are same as defined for nd I
by subjecting them to mitsunobu reaction in the ce of reagent such as but
not limited to Diethyl azo dicarboxylate as described in the literature (Bioorganic &
Medicinal Chemistry Letters, 2009, 19(3), 854 — 859).
The intermediates and the compounds of the present invention are ed in
pure form in a manner known per se, for example by distilling off the solvent in
vacuum and re-crystallizing the e obtained from a suitable solvent, such as
pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate,
acetone or their combinations or subjecting it to one of the purification methods,
such as column chromatography (eg. flash chromatography) on a suitable support
material such as alumina or silica gel using eluent such as dichloromethane, ethyl
acetate, hexane, methanol, e and their combinations. ative LC-MS
method is also used for the purification of molecules described herein.
Salts of compound of formula I are obtained by dissolving the compound in a
suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride
or chloroform or a low molecular weight aliphatic alcohol, for e, ethanol or
isopropanol, which was then treated with the d acid or base as described in
Berge SM. et al. ”Pharmaceutical Salts, a review article in Journal of
Pharmaceutical sciences volume 66, page 1-19 (1977)” and in ok of
pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland
Camille G.wermuth , Wiley- VCH (2002).
The stereoisomers of the compounds of formula I of the present invention may be
prepared by stereospecific syntheses or resolution of the achiral compound using
an optically active amine, acid or complex forming agent, and separating the
reomeric omplex by fractional crystallization or by column
tography.
The present invention further provides a pharmaceutical composition, containing
the compounds of the general formula (I) as defined above, its tautomeric forms, its
stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its
pharmaceutically acceptable salts, its polymorphs, its solvates, its optical s,
its clathrates and its co-crystals in ation with the usual pharmaceutically
employed carriers, diluents and the like are useful for the treatment and/or
prophylaxis of diseases or disorder or ion such as Alzheimer's disease (AD),
mild cognitive impairment (MCI), senile dementia, vascular dementia, dementia of
Parkinson’s disease, attention deficit disorder, ion deficit hyperactivity
disorder (ADHD), dementia associated with Lewy bodies, AIDS dementia complex
(ADC), Pick's disease, dementia associated with Down's syndrome, gton's
disease, cognitive deficits associated with traumatic brain injury (TBI), ive
and sensorimotor gating deficits associated with schizophrenia, cognitive deficits
associated with bipolar disorder, cognitive ments associated with depression,
acute pain, post-surgical or post-operative pain, chronic pain, inflammation,
inflammatory pain, neuropathic pain, smoking ion, need for new blood vessel
growth associated with wound healing, need for new blood vessel growth associated
with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid
arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory
bowel disease, celiac disease, ontitis, sarcoidosis, pancreatitis, organ
transplant rejection, acute immune disease associated with organ transplantation,
chronic immune disease associated with organ transplantation, septic shock, toxic
shock syndrome, sepsis syndrome, depression, and rheumatoid spondylitis.
The present invention also es a pharmaceutical composition, containing the
compounds of the l formula (I) as defined above, its tautomeric forms, its
stereoisomers, its analogs, its gs, its isotopes, its metabolites, its
pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers,
its clathrates and its co-crystals in combination with the usual pharmaceutically
employed carriers, diluents and the like are useful for the treatment and/or
laxis of diseases or disorder or condition classified or diagnosed as major or
minor neurocognitive disorders, or disorders arising due to neurodegeneration.
The present invention also provide method of administering a compound of a
I, as defined hereinabove in combination with or as adjunct to medications used in
the ent of attention deficit ctivity disorders, phrenia, and other
cognitive disorders such as Alzheimer's disease, Parkinson’s dementia, vascular
ia or dementia associated with Lewy bodies, traumatic brain injury.
The present invention also e method of administering a compound of formula
I, as defined hereinabove in combination with or as an adjunct to
acetylcholinesterase tors, disease modifying drugs or biologics for
neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an
atypical antipsychotic.
Accordingly, compound of formula I is useful for preventing or treating a disorder
mediated by nicotinic acetylcholine receptors. Such compounds can be
administered to a subject having such a disorder or susceptible to such disorders
in a therapeutically effective amount. The compounds are particularly useful for a
method of treating a mammal having a condition where modulation of nicotinic
acetylcholine receptor activity is of therapeutic benefit, n the method is
accomplished by administering a eutically effective amount of a compound of
formula I to a subject having, or susceptible to, such a disorder. The term ‘subject’
used herein can be defined as any living organism capable of expressing 0c7
t of nic acetylcholine receptor including mammals.
The following examples are provided to further illustrate the present invention and
therefore should not be construed to limit the scope of the t invention. All
1HNMR spectra were determined in the ts indicated and chemical shifts are
ed in 8 units downfield from the internal standard tetramethylsilane (TMS)
and interproton coupling constants are reported in Hertz (Hz).
Example 1: Preparation of 4,4-dimethylchromanyl)methyl
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide .
"'3C CH3 / \
SOzNHz
Step 1: 2-Bromo(4,4-dimethylchromanyl)ethanone
To a stirred on of 1-(4,4—dimethylchromanyl)ethanone (prepared according
to the procedure reported in J.Med. Chem,1985, E, 1, 116-124, 2.0g ,
9.80
mmol) in ol (30 ml.) was added bromine (1.57g, 0.5 ml, 9.80 mmol) in a
dropwise manner at 100C. The resulting mixture was stirred at room temperature
for 2 hr. The completion of reaction was monitored by TLC. Water (10 ml) was
added to it and resultant mixture was stirred for 45 s at room temperature.
Solvent was evaporated at reduced pressure. Residue so obtained was taken in
ehyl acetate (100 ml), washed with water (25 ml) followed by brine (25 ml).
Combined organic layer was dried over ous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate
in hexanes as an eluent to yield the title compound (2.3 g, 83%)
MS: m/z 283 (M+1)
1HNMR (CDClg, 4-00 MHZ): 5 7.98 (d, J=2.4HZ, 1H), 7.70 (dd, J=8.4,2.4 HZ, 1H),
6.82 (d, J=8.4HZ, 1H), 4.38 (s, 2H), 4.26 (dt, J=4.4, 1.2 HZ, 2H), 1.85 (dt, J=4.4, 1.2
Hz, 2H), 1.37 (s, 6H).
Step 2: 3-Acetyl(4,4-dimethylchromanyl)hexane- 1 ,4—dione
To the stirred solution of pulverized sodium (0.2g in toluene (40 ml)
, 8.63 mmol)
was added hexane-2,4—dione (prepared according to the ure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.894g, 7.85 mmol) at 00C and
reaction mixture was stirred at room ature for 2 hr. To this was added
solution of 2-bromo(4,4—dimethylchromanyl)ethanone (step 1, 2.0g , 7.07
mmol) in toluene (10 ml) and reaction e was heated at 600C for 2 hr under
stirring. The completion of reaction was monitored by TLC. To this reaction mixture
was added cold water (15 ml) and extracted with ethyl acetate (2x100 ml) and the
combined organic layer was dried over anhydrous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate
in hexanes as an eluent to yield the title compound (1.4g, 62.78%).
MS: m/z 317 (M+1)
1HNMR (CDClg, 400 MHZ): 5 7.90 (d, Z, 1H), 7.68 (dd, J=8.4,2.4 HZ, 1H),
6.79 (d, J=8.4HZ, 1H), 4.3 (t, J=6.8HZ, 1H), 4.25 (dt, J=4.4, 1.2 HZ, 2H), 3.52 (d,
Z, 2H), 2.67 (q, J=7.2HZ, 2H), 2.31 (s, 3H), 1.84 (dt, J=4.4, 1.2 HZ, 2H), 1.33
(s, 6H), 1.08 (t, J=7.2HZ, 3H).
Step 3: 4-(5-(4,4-dimethylchromanyl)methylpropionyl- 1H—pyrrol
yl)benzenesulfonamide
H3C CH3 / \
SOZNHZ
A mixture of 3-acetyl(4,4-dimethylchromanyl)hexane-1,4—dione (step 2,
1.3g ,
4.1 1 mmol) and 4-aminobenzenesulfonamide (0.7g, 4.1 1mmol) in acetic acid (5 ml)
was heated at 1 100 C for 3 hr. The completion of reaction was monitored by TLC.
Solvent was ated at reduced pressure. Residue so obtained was taken in
solution of ammonia in chloroform (20 ml) and stirred for 10 minutes. Reaction
mixture was again concentrated at reduced pressure. Ethyl acetate (100 ml) was
added to the residue, washed with water (10 ml). ed organic layer was dried
over anhydrous Na2804. The solvent was evaporated under reduced re to
obtain a crude product; which was purified by column chromatography over silica
gel (100-200 mesh) using 4% methanol in dichloromethane as an eluent to yield
the title compound (0.460 g, 24.8%)
MS: m/z 453 (M+1)
1HNMR (CDClg, 400 MHZ): 8 7.95 (d, J=8.8Hz, 2H), 7.26 (d, J=8.8,HZ, 2H), 6.89
(dd, J=8.4, 2.0 Hz, 1H), 6.64 (m, 3H), 5.07 (bs, exchanged with D20 2H), 4.09 (t,
J=5.2Hz, 2H), 2.85 (q, J=7.2Hz, 2H), 2.41 (s, 3H), 1.70 (t, J= 5.2 Hz, 2H), 1.19 (t,
J=7.2Hz, 3H), 1.00 (s, 6H).
Example 2: Preparation of 4-(5-(4,4-dimethylchromanyl)methyl
propionyl-1H-pyrrolyl)benzenesulfonamide [Alternative Method]
Step 1: Ethyl 2-acetyl(4,4-dimethylchroman-6—yl)oxobutanoate
COOC2H5
H3C CH3
To the stirred solution of pulverized sodium , 15.61 mmol) in toluene (40 ml)
was added ethyloxobutanoate (3.05g, 2.97 ml, 23.46 mmol) at 00C and reaction
mixture was d at room ature for 2 hr. To this was added solution of 2-
bromo(4,4-dimethylchromanyl)ethanone (4.41 g , 15.61 mmol) in toluene
(25ml) and reaction mixture was stirred at room temperature for 2 hr . The
completion of reaction was monitored by TLC. To this reaction e was added
cold water (30 ml) and extracted with ethyl acetate (2x250 ml) and the combined
organic layer was dried over anhydrous Na2804. The t was evaporated under
reduced pressure to obtain a crude product; which was purified by column
chromatography over silica gel (100-200 mesh) using DCM as an eluent to yield the
title compound (3.5g, 67.3%).
MS: m/z 333 (M+1)
Step 2: Ethyl 5-(4,4—dimethylchromanyl)methyl (4-sulfamoylphenyl)- 1 H-
pyrrolecarboxylate
H30 002H5
CH3 / \
SOZNHZ
A mixture of ethyl 2-acetyl-4—(4,4-dimethylchroman-6—yl)-4—oxobutanoate (Step 1,
3.5g, 10.53 mmol) and 4-aminobenzenesulfonamide (2.18g, 12.64 mmol) in
acetic acid (35 ml) was heated at 1 100 C for 15 hr. The completion of reaction was
monitored by TLC. on mixture was concentrated at reduced pressure. Ethyl
acetate (250 ml) was added to the residue, washed with water (1x 30 ml). Organic
layer was dried over anhydrous Na2804. The solvent was ated under reduced
pressure to obtain a crude product; which was purified by column tography
over silica gel (100-200 mesh) using 0.1% methanol in dichloromethane as an
eluent to yield the title compound (2.5 g, 50.80%)
2012/050442
MS: m/z 469 (M+1)
Step 3: 5- (4,4-dimethylchromanyl)methyl (4-sulfamoylphenyl)- 1H—pyrrole-
3-carboxylic acid
H3C CH3 / \
SOZNHZ
Ethyl 5- (4,4—dimethylchromanyl)methyl (4-sulfamoylphenyl)- 1 H—pyrrole
carboxylate (Step 2, 2.5g 5.34 mmol) was suspended in ethanol (100 ml) and ,
treated with 2M solution of NaOH (25 ml) at 0°C. the reaction mixture was refluxed
for 3 hr. The completion of reaction was monitored by TLC. Reaction mixture was
concentrated at reduced pressure. Residue was diluted with water (10 ml) and
neutralized with 10 % HCl upto pH7, aqueous layer was extracted with ethyl
acetate (2 x 100 ml). ed c layer was dried over anhydrous .
The solvent was evaporated under reduced pressure to obtain a product. (1.7g,
72.3%)
MS: m/z 441 (M+1)
Step 4: 1 - (4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-5—(4,4—
dimethylchromanyl)-N—methoxy-N,2-dimethyl- 1H—pyrrolecarboxamide
Oxalyl chloride (0.98g, 0.65ml, 7.72 mmol) was added dropwise at 00C to a
solution of 5-(4,4—dimethylchromanyl)methyl famoylphenyl)- 1 H-
pyrrolecarboxylic acid (step 3,1.7g, 3.86 mmol) in dichloromethane (100 m1)and
DMF (0.56g, 0.59 ml,7.72 m mol). e was allowed to come at room
temperature and stirred for 2 hr. under nitrogen here. The completion of
on was monitored by TLC. The mixture was concentrated under reduced
pressure and used directly for further reaction.
To this residue was added N, O—dimethylhydroxylamine hydrochloride (0.75g, 7.72
mmol) in dry dichloromethane (50 ml) at 00C followed by the addition of
ylamine (1.56g, 2.05 ml, 15.44 mmol,) under stirring. The reaction
mixture was stirred at room temperature for 2 hr. The completion of reaction was
monitored by TLC. The solvent was removed under reduced pressure. The residue
so obtained was taken in dichloromethane (100 ml) washed with water (2x 10 ml.)
and organic layers separated were dried over anhydrous sodium sulphate, ed
and concentrated at reduced pressure to get a crude product. This crude product
was ed by column chromatography over silica gel (100-200 mesh) using 0.2%
methanol in dichloromethane as an eluent to yield the title compound (1.67g,
80.6%).
MS: m/z 539 (M+1)
Step 5: 4-(5—(4,4-dimethylchromanyl)methylpropionyl- 1H—pyrrol
yl)benzenesulfonamide
SOZNHZ
To a solution of 1(N-((dimethylamino)methylene)sulfamoyl)phenyl)(4,4-
dimethylchroman-6—yl)-N—methoxy-N,2-dimethyl-1H—pyrrolecarboxamide (Step
4, 1.67g in anhydrous THF (25 ml) at 00C, Grignard reagent
, 3.10 mmol) [ethyl
magnesium bromide, 2.06g ,
.5 ml (1 M soln. in THF), 15.52 mmol] was added
dropwise and reaction mixture was heated to reflux for 30 minutes. The
completion of reaction was monitored by TLC. After cooling, on mixture was
quenched by on of solution of saturated ammonium chloride (20 ml) and
extracted with ethyl acetate (2 x100 ml) . Combined organic layer was dried over
anhydrous Na2804. The solvent was evaporated under reduced pressure to obtain a
crude product; which was purified by column chromatography over silica gel (100-
200 mesh) using 0.1% methanol in dichloromethane as an eluent to yield the title
compound which was y purified by preparative HPLC (0.100g, 7.1 %)
MS: m/z 453 (M+1)
1HNMR , 400 MHZ): 8 7.95 (d, J=8.8Hz, 2H), 7.27 (d, J=8.8,HZ, 2H), 6.90
(dd, J=8.4, 2.0 Hz, 1H), 6.65 (m, 3H), 4.90 (bs, exchanged with D20 2H), 4.11 (t,
J=5.2HZ, 2H), 2.86 (q, J=7.2Hz, 2H), 2.44 (s, 3H), 1.71 (t, J: 5.2 HZ, 2H), ,
J=7.2Hz, 3H) , 1.02 (s, 6H).
Example 3: Following compounds of the t inventions were prepared using a
process analogous to Example 1 and 2 by appropriately changing the reactants
required.
4- (5- (2,3-dihydrobenzo [b] [ 1 ,4]dioxiny1)methy1—3-propiony1- 1H-pyrrol
y1)benzenesu1fonamide
/ \
SOzNHg
MS: m/z 427 (M+1),
1HNMR (CDC13, 400 MHZ): 8 7.96 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4,Hz, 2H), 6.64-
6.66 (rn, 2H), 6.58 (d, J=2.0 HZ, 1H), 6.40 (dd, J=8.4, 2.0 Hz, 1H), 4.87 (bs,
exchanged With D20 2H), 4.19-4.22 (rn, 4H), 2.86 (q, J=7.2Hz, 2H), 2.42 (s, 3H),
1.20 (t, J=7.2Hz, 3H).
4- (2- (2,3-dihydrobenzo [b] [ 1 ,4]dioxin-6—y1)-3,5-dimethy1-4—propiony1— 1 ol
y1)benzenesu1fonamide
SOzNHz
MS: m/z 441 (M+1);
1HNMR (CDClg, 400 MHZ): 5 7.87 (d, J=8.4-HZ, 2H), 7.19 (d, J=8.4-,HZ, 2H), 6.67 (d,
J=8.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.39 (dd, J=8.0, 2.0 Hz, 1H), 4.88 (bs,
ged with D20 2H), 4.13-4.22 (m, 4H), 2.86 (q, J=7.2Hz, 2H), 2.33 (s, 3H),
2.24- (s, 3H), 1.20 (t, J=7.2HZ, 3H).
Ethyl 5- (2 , 3—dihydrobenzo [b] [ 1 ,4] dioxin-6—y1)-2 ,4—dimethy1— 1 - (4-su1famoy1phenyl) -
1 H-pyrrole-3—carboxylate
/ \
E N CH3
SOzNHg
MS: m/z 457 (M+1),
1HNMR (CDClg, 400 MHZ): 5 7.87 (d, J=8.4-HZ, 2H), 7.17 (d, J=8.4-,HZ, 2H), 6.65 (d,
J=8.4 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.39 (dd, J=8.4, 2.0 Hz, 1H), 4.95 (bs,
exchanged with D20 2H), 4.22 (q, J=6.8Hz, 2H), 4.14-4.20 (m, 4H), 2.35 (s, 3H),
2.22 (s, 3H), 1.36 (t, J=6.8Hz, 3H).
4— (2-methy1—3—propionyl (5,6,7,8-tetrahydronaphthaleny1)- rol
yl)benzenesu1fonamide.
0346N CH3
SOZNH2
MS: m/z 423 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.95 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4,HZ, 2H), 6.80-
6.83 (m, 2H), 6.67 (s, 1H), 6.59 (dd, J=8.0, 2.0 Hz, 1H), 4.99 (bs, exchanged with
D20 2H), 2.87 (q, Z, 2H), 2.60-2.68 (m, 4H), 2.42 (s, 3H), 1.72-1.75 (m, 4H),
1.20 (t, J=7.2HZ, 3H).
Example 4: Preparation of 2,3-dihydro-1H-indenyl)methyl
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
/ \
N CH3
802NH2
Step 1: 2-bromo- 1-(2,3-dihydro- 1H-inden-4—yl)ethanone
To a stirred on of 1-(2,3-dihydro-1H-inden-4—yl)ethanone (prepared according
to the procedure reported in Monatshefte fur chemie 1996, 127, 0, 0.8 gm,
.00 mmol) in diethyl ether (8 ml) were added A1C13 (0.73 gm, 5.5 mmol) and
bromine (0.96 gm, 0.31 ml, 6.00 mmol) in a drop wise manner at 00C. The
resulting mixture was stirred at room temperature for 1 hr. The completion of
reaction was monitored by TLC. Reaction mixture was poured into cold water (10
ml). Aqueous layer was extracted with ethyl acetate (2 x 30 ml). Organic layers
separated were dried over anhydrous sodium sulphate, filtered and concentrated at
reduced pressure to get a crude t; which was purified by column
chromatography using 1% ethyl acetate in hexanes as an eluent to yield the title
compound (0.76 gm, 63.8%).
MS: m/z 240 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.66 (d, J=7.2 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.23-
7.27 (m, 1H), 4.49 (s, 2H), 3.25 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.08
(quintet, J=7.6 Hz, 2H).
Step 2: 3-acetyl- 1-(2,3-dihydro- en-4—yl)hexane- 1 ,4—dione
To the stirred solution of pulverized sodium (0.046 gm, 2.00 mmol) in toluene (5
ml) was added hexane-2,4—dione (prepared according to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.21 gm, 1.85 mmol) at 00C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo(2,3-dihydro-1H-indenyl)ethanone (step 1, 0.4 gm, 1.67
mmol) in toluene (5 ml) and reaction mixture was heated at 60°C for 2 hr under
stirring. The completion of on was monitored by TLC. To this reaction mixture
was added cold water (5 ml) and extracted with ethyl acetate (2x30 ml) and the
ed organic layer was dried over ous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column chromatography using 10% ethyl acetate in hexanes as an eluent to
yield the title compound (0.196 gm, 39.12%).
MS: m/z 273 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.72 (d, J=7.2 HZ, 1H), 7.41 (d, J=7.2 HZ, 1H), 7.23-
7.26 (m, 1H), 4.36 (t, J=7.2 HZ, 1H), 3.56 (d, J=7.2 HZ, 2H), 3.23 (t, J=7.6 HZ, 2H),
2.91 (t, J=7.6 Hz, 2H), 2.69 (q, J=7.6 Hz, 2H), 2.31 (s, 3H), 2.07 et, J=7.2 Hz,
2H), 1.08 (t, J=7.2 Hz, 3H).
Step 3: 4- (5- (2,3-dihydro- 1 H-indenyl)methylpropionyl- 1H-pyrrol
yl)benzenesulfonamide
/ \
802NH2
To the solution of 3-acetyl(2,3-dihydro-1H-inden-4—yl)hexane-1,4-dione (step 2,
0.18 gm, 0.68 mmol) in acetic acid (5 ml) was added 4-aminobenzenesulfonamide
(0.12 gm, 0.68 mmol) at room temperature. Reaction mixture was heated at 1 100 C
for 3 hr. The completion of reaction was monitored by TLC. Solvent was evaporated
at reduced pressure. e so obtained was taken in solution of ammonia in
chloroform (10 ml) and stirred for 10 minutes. Reaction mixture was again
concentrated at reduced re. Ethyl acetate (30 ml) was added to the residue,
washed with water (5 ml). Combined organic layer was dried over anhydrous
Na2804. The solvent was evaporated under reduced pressure to obtain a crude
t; which was purified by column chromatography using 5% methanol in
DCM as an eluent to yield the title compound (0.041 gm, 14.8%).
MS: m/z 409 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.80 (d, J=8.4 Hz, 2H), 7.48 (bs-exchanges with D20,
2H), 7.41 (d, J=8.4 Hz, 2H), 7.07 (d, J=7.6 Hz, 1H), 6.93 (t, J=7.6 Hz, 1H), 6.79 (s,
1H), 6.64 (d, J=7.6 Hz, 1H), 2.77-2.85 (m, 6H), 2.34 (s, 3H), 1.91 (quintet, J=7.2
Hz, 2H), 1.08 (t, J=7.2 Hz, 3H).
Example 5: ation of 4-(5-(2,2-dimethylchromanyl)methyl
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
/ \
N CH3
SOZNHZ
Step 1: 2-bromo(2,2-dimethylchromanyl)ethanone
To a stirred solution of 1-(2,2-dimethylchromanyl)ethanone (prepared according
to the ure reported in J.Med. Chem,, 1997, Q, 16, 451, 2.5 gm,
12.25 mmol) in methanol (25 ml) was and e (1.96 gm, 0.63ml, 12.25 mmol)
in a drop wise manner at 00C. The resulting mixture was stirred at room
temperature for 2 hr. The completion of reaction was monitored by TLC. Reaction
mixture was concentrated at reduced pressure and dissolved in DCM (100 ml).
Organic layer was washed with water (2X 25 ml), dried over anhydrous sodium
sulphate, filtered and concentrated at reduced pressure to get a crude product;
which was purified by column chromatography using 1% ethyl acetate in hexanes
as an eluent to yield the title compound (1.50 gm, 43.22%).
MS: m/z 284 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.71—7.76 (m, 2H), 6.80 (d, J=8.4 HZ, 1H), 4.35 (s, 2H),
2.82 (t, J=6.8 HZ, 2H), 1.84 (t, J=6.8 HZ, 2H), 1.35 (s, 6H).
Step 2: 3-acetyl- 1-(2,2-dimethylchromanyl)hexane- 1 ,4—dione
To the stirred solution of pulverized sodium (0.37 gm, 16.08 mmol) in toluene (10
ml) was added -2,4—dione (prepared according to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, at 00C and
, 1510-1512, 1.82 gm, 15.96 mmol)
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo(2,2-dimethylchromanyl)ethanone (step 1, 3.0 gm, 10.60
mmol) in toluene (10 ml) and reaction e was heated at 600C for 2 hr under
stirring. The completion of reaction was monitored by TLC. To this reaction e
was added cold water (15 ml) and extracted with ethyl acetate (2x 100 ml) and the
ed organic layer was dried over anhydrous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column chromatography using 5% ethyl acetate in hexanes as an eluent to yield
the title compound (1.00 gm, 29.9%).
MS: m/z 317 (M+1),
1HNMR (CDClg, 4-00 MHZ): 8 7.67—7.77 (m, 2H), 6.72-6.79 (m, 1H), 4.36 (t, J=6.8
HZ, 1H), 3.51 (d, J=6.8 HZ, 2H), 2.72—2.85 (m, 4-H), 2.31 (s, 3H), 1.82 (q, J=7.2 HZ,
2H), 1.35 (s, 6H), 1.06 (t, J=7.2 HZ, 3H).
Step 3: 4-(5- (2 , 2-dimethylchromanyl)methylpropionyl- 1H-pyrrol
yl)benzenesulfonamide
/ \
SOZNHZ
To the solution of 3-acetyl(2,2-dimethylchromanyl)hexane-1,4—dione (step 2,
0.33 gm, 1.05 mmol) in acetic acid (5 ml) was added 4-aminobenzenesulfonamide
(0.22 gm, 1.25 mmol) at room temperature. Reaction mixture was heated at 1 100 C
for 3 hr. The completion of reaction was monitored by TLC. Solvent was evaporated
at reduced pressure. Residue so obtained was taken in solution of ammonia in
chloroform (10 ml) and stirred for 10 minutes. Reaction mixture was again
concentrated at reduced pressure. Ethyl acetate (30 ml) was added to the residue,
washed with water (5 ml). ed organic layer was dried over anhydrous
. The solvent was evaporated under d pressure to obtain a crude
product; which was purified by column chromatography using 5% ol in
DCM as an eluent to yield the title compound (0.10 gm, 21.27%).
MS: m/z 453 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.87 (d, J=8.4 Hz, 2H), 7.50 (bs-exchanges with D20,
2H), 7.44 (d, J=8.4 Hz, 2H), 6.93 (d, J=2.0 Hz, 1H), 6.78 (s, 1H), 6.57 (dd, J=8.4,
2.0 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 2.82 (q, J=7.2 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H),
2.31 (s, 3H), 1.70 (t, J=6.8 Hz, 2H), 1.22 (s, 6H), 1.07 (t, J=7.2 Hz, 3H).
Example 6: Preparation of 4-(5-(8-fluoro-4,4-dimethylchromanyl)methyl-
3-propionyl-1H-pyrrolyl)benzenesulfonamide.
/ \
SOzNHz
Step 1: Methyl uorophenoxy)propanoate
H3CO
.2109
To a stirred solution of 3-(2-fluorophenoxy)propanoic acid (prepared according to
the procedure reported in WO20lOOl3794, 14.0 gm, 76.08 mmol) in methanol (140
ml) was added thionyl chloride (13.57 gm, 8.5 ml, 114.12 mmol) in a drop wise
manner at 00C. The resulting mixture was stirred at room temperature for 2 hr.
The completion of on was monitored by TLC. Reaction mixture was
concentrated at reduced re and dissolved in Ethyl acetate (300 ml). Organic
layer was washed with water (2X 50 ml), dried over ous sodium sulphate,
filtered and concentrated at reduced pressure to get a crude product; which was
purified by column chromatography using 20% ethyl acetate in hexanes as an
eluent to yield the title compound (12.9 gm, 85.66%).
MS: m/z 221 (M+23),
1HNMR (CDClg, 400 MHZ): 5 6.88 — 7.09 (m, 4H), 4.32 (t, J=6.4 HZ, 2H), 3.72 (s,
3H), 2.84 (t, J=6.4 HZ, 2H).
Step 2: 4-(2-fluorophenoxy)methylbutanol
To a stirred on of methyl 3-(2-fluorophenoxy)propanoate 1, 12.0 gm,
60.60 mmol) in THF (25 ml) was added methyl magnesium bromide (21.67 gm,
60.72 ml 3M solution in diethyl ether, 181.80 mmol) in a drop wise manner at 00C
under nitrogen atmosphere. The resulting mixture was stirred at 900C for 2 hr. The
completion of reaction was monitored by TLC. Reaction mixture was quenched by
addition of saturated NH4Cl solution (100 ml). Aquous layer was extracted with
ethyl acetate (2x 200 ml). Organic layers was washed with water (2x 50 ml), dried
over anhydrous sodium sulphate, ed and concentrated at reduced pressure to
get a crude product; which was purified by column tography using 12%
ethyl acetate in hexanes as an eluent to yield the title compound (8.60 gm,
71.66%).
MS: m/z 221 (M+23),
1HNMR (CDClg, 400 MHZ): 5 6.88 — 7.09 (m, 4H), 4.24 (t, J=6.4 HZ, 2H), 2.35 (bs,
ges with D20 1H), 2.02 (t, J=6.4 Hz, 2H), 1.31 (s, 6H).
Step 3: 8-fluoro-4,4-dimethylchroman
To a stirred solution of A1C13 (8.67 gm, 65.05 mmol) in nitromethane (50 ml) was
added solution of 4-(2-fluorophenoxy)methylbutanol (Step-2, 8.5 gm, 43.36
mmol) in nitromethane (20 ml) in a drop wise manner at 00C. The resulting mixture
was stirred at room temperature for 3 hr. The completion of on was
monitored by TLC. Reaction mixture was quenched with 2N HCl (50 ml) at 00C.
Aqueous layer was extracted with ethyl acetate (2 x 100 ml). c layers
separated were dried over ous sodium sulphate, filtered and concentrated at
reduced pressure to get a crude product; which was d by column
chromatography using 1% ethyl acetate in hexanes as an eluent to yield the title
compound (5.80 gm, 74.35%).
MS: m/z No ionization,
1HNMR (CDClg, 400 MHZ): 5 7.03 — 7.76 (dt, J=1.6 HZ, 8.0 HZ, 1H), 6.85 — 6.88 (m,
1H), 6.77 — 6.8 (m, 1H), 4.24-4.26 (m, 2H), 1.85-1.87 (m, 2H), 1.33 (s, 6H).
Step 4: 2-bromo(8-fluoro-4,4-dimethylchromanyl)ethanone
To a stirred solution of A1C13 (4.88 gm, 36.73 mmol) in DCE (60 ml) was added
solution of 8-fluoro-4,4-dimethylchroman (Step-3, 5.8 gm, 32.22 mmol) in DCE (20
ml) and 2-bromoacetyl bromide (7.80 gm, 3.35 ml, 38.66 mmol) in a drop wise
manner at 0°C. The ing mixture was stirred at room temperature for 3 hr.
The completion of reaction was monitored by TLC. Reaction mixture was quenched
with water (70 ml) at 0°C. Aqueous layer was ted with ethyl acetate (2 x 100
ml). Organic layers washed with 1N HCl (50 ml), water (50 ml). Organic layer
separated was dried over anhydrous sodium sulphate, filtered and concentrated at
reduced pressure to get a crude t; which was purified by column
chromatography using 6% ethyl acetate in hexanes as an eluent to yield the title
compound (6.20 gm, 64.18%).
MS: m/z 301 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.75 — 7.76 (m, 1H), 7.28 (d, J=1l.2 HZ, 2 HZ, 1H),
4.33 -4.35 (m, 4H), 1.89 (dd, J=6.0, 5.6 HZ, 2H), 1.37 (s, 6H).
Step 5: 3-acetyl (8-fluoro-4,4-dimethylchromanyl)hexane- 1 ,4—dione
To the stirred solution of pulverized sodium (0.057 gm, 2.49 mmol) in toluene (5
ml) was added -2,4—dione (prepared according to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.23 gm, 1.99 mmol) at 00C and
on mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo(8-fluoro-4,4-dimethylchromanyl)ethanone (step 4, 0.5
gm, 1.66 mmol) in toluene (5 ml) and reaction e was heated at 60°C for 2 hr
under stirring. The completion of reaction was monitored by TLC. To this reaction
e was added cold water (10 ml) and extracted with ethyl acetate (2x 30 ml)
and the ed organic layer was dried over anhydrous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column chromatography using 20% ethyl acetate in hexanes as an eluent to
yield the title compound (0.32 gm, 60.37%).
MS: m/z 373 (M+39),
1HNMR(CDC13, 400 MHZ): 5 7.34-7.43 (m, 1H), 7.12-7.21 (m, 1H), 5.12-5.15(m,
1H), 4.12-4.34- (m, 4-H), 2.04 (s, 3H), 1.84-1.91 (m, 4-H), 1.35 (s, 6H), 1.21 (t, J=7.2
Hz, 3H).
Step 6: 4-(5-(8-fluoro-4,4-dimethylchromanyl)methylpropionyl-1H-pyrrol-
1 -yl)benzenesulfonamide
/ \
802NH2
To the on of 3-acetyl(8-fluoro-4,4-dimethylchromanyl)hexane-1,4—dione
(step 2, 0.30 gm, 0.94 mmol) in acetic acid (10 ml) was added 4-
aminobenzenesulfonamide (0.24 gm, 1.41 mmol) at room temperature. Reaction
mixture was heated at 1 100 C for 24 hr. The completion of reaction was monitored
by TLC. Solvent was evaporated at reduced pressure. Residue so obtained was
taken in solution of ammonia in form (10 ml) and stirred for 10 minutes.
on e was again concentrated at reduced pressure. Ethyl acetate (30
ml) was added to the residue, washed with water (5 ml). Combined organic layer
was dried over anhydrous . The solvent was evaporated under reduced
pressure to obtain a crude product; which was purified by column chromatography
using 30% ethyl acetate in hexanes as an eluent to yield the title compound (0.54
gm, 12.27%).
MS: m/z 471 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.99 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 6.74
(dd, J=11.6, 2.0 Hz, 1H), 6.66 (s, 1H), 6.42 (t, J=2.0 Hz, 1H), 5.02 (bs—exchanges
with D20, 2H), 4.19 (t, J=5.2 HZ, 2H), 2.86 (q, J=7.2 HZ, 2H), 2.43 (s, 3H), 1.75 (t,
J=5.2 HZ, 2H), 1.21 (t, J=7.2 HZ, 3H), 1.02 (s, 6H).
Example 7: Preparation of
4-(5-(2-acetyl-4,4-dimethyl- 1 , 2, 3,4-tetrahydroisoquinolinyl)methyl
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
£0 / \
SOZNHZ
4-(5-(2-acetyl-4,4-dimethyl- 1 , 2, 3,4-tetrahydroisoquinolinyl)methyl
propionyl- rol- 1-yl)benzenesulfonamide.
/ \
N CH3
\n/N
SOZNHZ
Step 1: 1-(4,4—dimethyl-3,4—dihydroisoquinolin-2(1H)-yl)ethanone
To a stirred solution of methyl-1,2,3,4-tetrahydroisoquinoline (prepared
according to the procedure reported in W020050037214 A2, 4.0 gm , 24.84
mmol) in DCM (100 ml.) was added triethyl amine (2.76 gm, 3.9 ml, 27.32 mmol)
in a dropWise manner at 00C followed by addition of acetyl chloride (2.14 gm, 1.9
ml, 27.32 mmol). The resulting mixture was stirred at room temperature for 2 hr.
The tion of reaction was monitored by TLC. Reaction mixture was diluted
with DCM (100 ml), washed with water (2x 25 ml) ed by brine (25 ml).
Combined organic layer was dried over anhydrous Na2804. The solvent was
ated under reduced pressure to obtain a crude product; which was purified
by column chromatography over silica gel (100-200 mesh) using 2.5% methanol in
DCM as an eluent to yield the title compound (4.9 g, 97%)
MS: m/z 204 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.04—7.36 (m, 4H), 4.76 (s, 2H), 3.42 (s, 2H), 2.18 (s,
3H), 1.30 (s, 3H), 1.27 (s, 3H).
Step 2: Mixture of 1-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)
bromoethanone
O O
A Br
1 - (2-acetyl-4,4-dimethyl- 1 ,2 bromoethanone
, 3,4-tetrahydroisoquinolinyl)
0
To a stirred solution of A1C13 (1.84 gm, 13.79 mmol) in DOE (30 ml) was added
on of 1-(4,4-dimethyl-3,4—dihydroisoquinolin-2(1H)-yl)ethanone (Step-1, 2.0
gm, 9.85 mmol) in DOE (10 ml) and 2-bromoacetyl bromide (2.60 gm, 1.13 ml,
12.80 mmol) in a drop wise manner at 0°C. The resulting mixture was stirred at
room temperature for 2 hr. The completion of reaction was monitored by TLC.
Reaction mixture was poured into cold water (50 ml). Aqueous layer was extracted
with DCM (2 x 100 ml). Organic layers separated were dried over anhydrous
sodium sulphate, ed and concentrated at reduced pressure to get a crude
product; which was ed by column chromatography over silica gel (100-200
mesh) using 2.5% methanol in DCM as an eluent to yield mixture of cetyl-
4,4—dimethyl-1,2,3,4-tetrahydroisoquinolinyl) bromoethanone and 1-(2-
acetyl-4,4—dimethyl-1,2,3,4-tetrahydroisoquinolinyl)bromoethanone (2.1 gm,
65.83%)
Step 3: Mixture of 3-acetyl(2-acetyl-4,4—dimethyl-1,2,3,4—tetrahydroisoquinolin-
7-yl)hexane- 1 ,4—dione
3-acetyl (2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolinyl)hexane- 1 ,4-
dione
To the stirred solution of pulverized sodium (0.22 gm in toluene (40
, 9.42 mmol)
ml) was added hexane-2,4—dione (prepared according to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.98 gm, 8.56 mmol) at 00C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
2012/050442
solution of mixture of the 1-(2-acetyl-4,4—dimethyl-1,2,3,4-tetrahydroisoquinolin
yl)bromoethanone and 1-(2-acetyl-4,4—dimethyl-1,2,3,4-tetrahydroisoquinolin
bromoethanone (step 2, 2.5 gm in toluene (10 ml) and reaction
, 7.71 mmol)
mixture was heated at 600C for 2 hr under stirring. The completion of on was
monitored by TLC. To this reaction mixture was added cold water (15 ml) and
extracted with ethyl e (2x100 ml) and the combined organic layer was dried
over anhydrous Na2804. The solvent was evaporated under d pressure to
obtain a crude product; which was purified by column chromatography over silica
gel (100-200 mesh) using 2.5% methanol in DCM as an eluent to yield mixture of
3-acetyl (2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolinyl)hexane- 1 ,4-
dione and 3-acetyl (2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolin
yl)hexane-1,4—dione (1.45 gm, 47.5%).
Step 4: 4-(5-(2-acetyl-4,4—dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methyl
propionyl- 1 H-pyrrolyl)benzenesulfonamide
SOZNHZ
4- (5- (2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolin-6—yl)methyl
propionyl- 1 H-pyrrolyl)benzenesulfonamide
/ \
SOZNHZ
To the solution of the mixture of yl(2-acetyl-4,4—dimethyl-1,2,13,4-
tetrahydroisoquinolinyl)hexane- 1 ,4—dione and 3-acetyl (2-acetyl-4,4—dimethyl-
1,2,3,4-tetrahydroisoquinolinyl)hexane-1,4—dione (step 3, 1.4 gm in
, 3.92 mmol)
acetic acid (5 ml) was added obenzenesulfonamide (0.68 gm, 3.92 mmol) at
room ature. Reaction mixture was heated at 1 100 C for 3 hr. The completion
of reaction was monitored by TLC. Solvent was evaporated at reduced pressure.
Residue so obtained was taken in solution of ammonia in chloroform (20 ml) and
stirred for 10 minutes. Reaction mixture was again trated at reduced
pressure. Ethyl acetate (100 ml) was added to the e, washed with water (10
ml). Combined organic layer was dried over anhydrous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column tography over silica gel (100-200 mesh) using 50 % ethyl acetate
in hexanes as an eluent to yield mixture of the 4-(5—(2-acetyl-4,4—dimethyl-1,2,13,4-
tetrahydroisoquinolinyl)methylpropionyl- 1 H-pyrrol
yl)benzenesulfonamide and 4- (5-(2-acetyl-4,4—dimethyl- 1,2,13,4-
tetrahydroisoquinolinyl)methylpropionyl 1 H-pyrrol
yl)benzenesulfonamide. The e was separated by preparative HPLC to yield
the first title compound (0.31 gm, 16.0%) and second title compound (0.21 gm,
10.89%).
First title compound: 4- (5- (2-acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroisoquinolin- 7-
yl)methylpropionyl- 1H-pyrrolyl)benzenesulfonamide
302NH2
MS: m/z 494 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.89-7.92 (m, 2H), 7.54 (bs—exchanges with D20, 2H),
7.49 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.01 (s, 1H), 6.92 (d, J=2.4 Hz, 1H),
6.72-6.74 (m, 1H), 4.56 (s, 2H), 3.42 (s, 2H), 2.84 (q, J=7.2 Hz, 2H), 2.30 (s, 3H),
2.05 (s, 3H), 1.17 (s, 3H), 1.11 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).
Second title compound: 4- (5- ty1—4,4—dimethy1— 1 ,2,3,4-tetrahydroisoquinolin-
6-y1) methy1propiony1- 1H-pyrroly1)benzenesulfonamide
MN CH3 CH3
0 ©
SOZNHZ
MS: m/z 494 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.89 (d, J=8.4 Hz, 2H), 7.51 (bs—exchanges with D20,
2H), 7.48 (d, J=8.4 Hz, 2H), 7.05-7.12 (m, 2H), 6.94 (s, 1H), 6.78-6.81 (m, 1H), 4.57
(s, 2H), 3.17 (s, 2H), 2.85 (q, J=7.2 Hz, 2H), 2.34 (s, 3H), 2.04 (s, 3H), 1.08 (t, J=7.2
Hz, 3H), 0.94 (s, 3H), 0.89 (s, 3H).
2012/050442
Example 8: Preparation of 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin
yl)methy1propionyl-1H-pyrrolyl)benzenesulfonamide.
/ \
HN N CH3
SOZNHZ
To the solution of the 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin
yl)methylpropionyl-1H-pyrrolyl)benzenesulfonamide (First title compound
of step 4 in Example-7, 0.2 gm, 0.40 mmol) in acetonitrile (8 ml) was 6M HCl (10
ml) at room temperature. Reaction mixture was heated at 800 C for 15 hr. The
completion of reaction was monitored by TLC. Solvent was evaporated at d
pressure. e so obtained was taken in solution of ammonia in chloroform (20
ml) and stirred for 10 minutes. on e was again concentrated at
reduced pressure. Ethyl acetate (50 ml) was added to the residue, washed with
water (10 ml). Combined organic layer was dried over anhydrous Na2804. The
solvent was evaporated under reduced pressure to obtain a crude product; which
was purified by preparative HPLC to yield the title compound (0.060 gm, 32.96%).
MS: m/z 452 (M+1),
1HNMR (DMSO, 400 MHZ): 8 8.23 (bs-exchanges with D20, 1H), 7.89 (d, J=8.4 Hz,
2H), 7.57 (bs-exchanges with D20, 2H), 7.19 (d, J=8.4 Hz, 2H), 6.88 (s, 1H), 6.85
(d, J=2.0 Hz, 1H), 6.76 (dd, J=8.4, 2.0 Hz, 2H), 3.81 (s, 2H), 2.84 (q, J=7.2 Hz, 2H),
2.78 (s, 2H), 2.30 (s, 3H), 1.17 (s, 6H), 1.05 (t, J=7.2 HZ, 3H).
Example 9: Preparation of 4-(2-methylpropionyl(3H-
spirofbenzo[b][1 ,4]dioxine-2, lopropan]yl)-1H-pyrrol
yl)benzenesulfonamide.
AEO / \
N CH3
SOZNHZ
4-(2-methylpropionyl(3H-spiro[benzo[b][1 xine-Z, 1'-cyclopropan]
yl)-1H-pyrrolyl)benzenesu1fonamide.
/ \
I: N CH3
SOZNHZ
Step 1: Methyl 4—bromo(2-((4—methoxybenzyl)oxy)phenoxy)butanoate
H3COOC 0
To a stirred solution of 2-((4—methoxybenzyl)oxy)phenol (prepared according to the
procedure reported in JOC, 1994, 5—9, 22, 6567-6587, 10.0 gm in
, 43.48 mmol)
DMF (100 ml) were added K2C03 (7.81 gm, 56.52 mmol) and methyl 2,4-
dibromobutanoate (14.58 gm, ml, 56.52 mmol) at 250C. The resulting mixture was
stirred at 1500C for 3 hr. The completion of reaction was monitored by TLC.
Reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x 50
ml) followed by brine (25 ml). Combined organic layer was dried over anhydrous
Na2804. The t was evaporated under reduced pressure to obtain a crude
product; which was purified by column chromatography over silica gel (100-200
mesh) using 10% ethyl acetate in hexanes as an eluent to yield the title compound
(10.0 g, )
MS: m/z 410 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.34 (d, J=8.4 HZ, 2H), 6.90-6.98 (m, 6H), 5.00-5.07
(m, 2H), 4.78 (dd, J=8.8. 4.0 HZ, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.53-3.57 (m, 2H),
2.39-2.52 (m, 2H).
Step 2: Methyl 1-(2-((4-methoxybenzyl)oxy)phenoxy)cyclopropanecarboxylate
choocyoPMBOD
To a stirred solution of methyl 4-bromo(2-((4-
methoxybenzyl)oxy)phenoxy)butanoate (Step-1, 8.0 gm, 19.60 mmol) in THF (100
ml) was added ium t-butoxide (2.41 gm, 21.56 mmol) at 0°C under nitrogen
atmosphere. The resulting mixture was d at room temperature for 3 hr. The
completion of reaction was monitored by TLC. Excess of reagent was quenched
with saturated NH4Cl solution (20 ml) at 00C. Aqueous layer was extracted with
ethyl acetate (2 x 150 ml). Organic layers separated were dried over ous
sodium sulphate, filtered and concentrated under reduced pressure to get a crude
product; which was purified by column chromatography over silica gel (100-200
mesh) using 25% ethyl acetate in hexanes as an eluent to yield the title compound
(2.5 g, 38.88%)
MS: m/z 351 (M+23),
1HNMR (CDClg, 400 MHZ): 8 7.34 (d, J=8.4 HZ, 2H), 6.84-6.97 (m, 6H), 5.06 (s, 2H),
3.77 (s, 3H), 3.69 (s, 3H), 1.59 (t, J=4.4 HZ, 2H), 1.25 (t, J=4.4 HZ, 2H).
Step 3: (1-(2-((4-methoxybenzyl)oxy)phenoxy)cyclopropyl)methanol
To a stirred solution of methyl 1 - (2- ( (4-
methoxybenzyl)oxy)phenoxy)cyclopropanecarboxylate (Step-2, 2.4 gm, 7.31 mmol)
in THF (50 ml) was added LAH (0.41 gm, 10.97 mmol) at 00C under nitrogen
atmosphere. The ing mixture was stirred at room temperature for 3 hr. The
tion of reaction was red by TLC. Excess of reagent was ed
with saturated NH4Cl solution (10 ml) at 00C. Reaction mixture was filtered
through bed of Na2804; washed with ethyl acetate (2 x 50 ml). Filtrate was dried
over anhydrous sodium sulphate and concentrated under reduced pressure to get
a crude product; which was purified by column chromatography over silica gel
(100-200 mesh) using 35% ethyl acetate in hexanes as an eluent to yield the title
compound (2.0 g, 91.3%)
MS: m/z 323 (M+23),
1HNMR (CDClg, 400 MHZ): 8 7.36 (d, J=8.4 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.88-
6.97 (m, 5H), 5.04 (s, 2H), 3.80 (s, 3H), 3.66 (d, J=6.0 Hz, 2H), 2.60 (t-exchanges
with D20, J=6.0 HZ, 1H), 1.14 (t, J=6.4 HZ, 2H), 0.79 (t, J=6.4 HZ, 2H).
Step 4: 2-(1-(hydroxymethyl)cyclopropoxy)phenol
Hoflo
To a stirred solution of 10% palladium on carbon (1.5 gm) in methanol (25 ml), was
added solution of (1-(2-((4-methoxybenzyl)oxy)phenoxy)cyclopropyl)methanol (Step-
3, 1.5 gm, 5.00 mmol) in methanol (25 ml). To this mixture ammonium formate
(12.60 gm, 200.00 mmol) was added at 25°C under nitrogen atmosphere. The
resulting mixture was d at 600C for 3 hr. The completion of reaction was
monitored by TLC. Reaction mixture was cooled to room temperature and filtered
through bed of celite; washed with DCM (2 x 50 ml). Filtrate was concentrated
under reduced pressure to get a crude product; which was purified by again it
dissolved in DCM (100 ml) and resulting solid was ed. Filtrate was
trated under reduced pressure to yield the title nd (0.85 g, 94.4%)
MS: m/z 203 (M+23),
1HNMR (CDClg, 400 MHZ): 8 7.02 (d, J=8.4 Hz, 1H), 6.89-6.93 (m, 2H), 6.76-6.81
(m, 1H), 3.78 (s, 2H), 2.30 (bs-exchanges with D20, 2H), 1.08 (t, J=6.4 Hz, 2H),
0.82 (t, J=6.4 Hz, 2H).
Step 5: 3H-spiro [benzo [b] [ 1 ,4]dioxine-2, 1 '-cyclopropane]
$0OD
To a stirred solution of hydroxymethyl)cyclopropoxy)phenol (Step-4, 1.2 gm
6.66 mmol) in DCM (30 ml.) was added triphenyl phospine (1.92 gm, 7.32 mmol) at
0°C ed by addition of diethyl azodicarboxylate (1.39 gm, 1.26 ml, 7.99 mmol)
under en atmosphere. The resulting mixture was stirred at room temperature
for 2 hr. The completion of reaction was monitored by TLC. Reaction mixture was
diluted with DCM (50 ml), washed with water (2x 20 ml) followed by brine (20 ml).
Combined organic layer was dried over anhydrous Na2804. The solvent was
evaporated under d pressure to obtain a crude product; which was purified
by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate
in hexanes as an eluent to yield the title nd (0.91 g, 84.2%)
MS: m/z No Ionization,
1HNMR (CDClg, 400 MHZ): 5 6.78-6.93 (m, 4H), 4.14 (s, 2H), 1.09 (t, J=6.4 HZ, 2H),
0.79 (t, J=6.4 HZ, 2H).
Step 6: mixture of 2-bromo(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]
anone
to)”
2-bromo (3H-spiro[benzo [b] [ 1 ,4] dioxine-2, 1 '-cyclopropan]yl)ethanone
VEOOfiK/Br
To a stirred solution of A1C13 (0.88 gm, 6.66 mmol) in C82 (5 ml) was added solution
of 3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropane] (Step-5, 0.9 gm, 5.55 mmol) in
C82 (5 ml) and oacetyl bromide (1.35 gm, 0.58 ml, 6.66 mmol) in a drop
wise manner at 00C. The resulting mixture was stirred at room temperature for 2
hr. The completion of reaction was monitored by TLC. on mixture was
quenched by addition of cold water (10 ml). Aqueous layer was extracted with DCM
(2 x 50 ml). Organic layers separated were dried over ous sodium sulphate,
filtered and concentrated at reduced pressure to get a crude product; which was
purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl
acetate in hexanes as an eluent to yield mixture of 2-bromo(3H-
spiro[benzo [b] [ 1 ,4] dioxine-2, 1 '-cyclopropan]yl)ethanone and o (3H-
spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]yl)ethanone (0.4 gm, 25.47%)
Step 7: Mixture yl(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]
yl)hexane- 1 ,4—dione
0 O
3-acetyl(3H-spiro[benzo[b][1,4]dioxine-2, 1 '-cyclopropan] -6—yl)hexane- 1 ,4—dione
0 0
$0 0
To the stirred solution of pulverized sodium (0.034 gm, 1.47 mmol) in toluene (5
ml) was added hexane-2,4—dione (prepared ing to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.15 gm, 1.36 mmol) at 00C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of e of 2-bromo(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]-
7-yl)ethanone and 2-bromo(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]
anone (step 6, 0.35 gm, 1.23 mmol) in toluene (5 ml) and reaction mixture
was heated at 600C for 2 hr under stirring. The completion of reaction was
monitored by TLC. To this reaction mixture was added cold water (5 ml) and
extracted with ethyl acetate (2x 30 ml) and the combined organic layer was dried
over anhydrous Na2804. The t was evaporated under reduced pressure to
obtain a crude product; which was purified by column chromatography over silica
gel (100-200 mesh) using 25% ethyl e in hexanes as an eluent to yield
e of 3-acetyl(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan]yl)hexane-
1 ,4—dione and 3-acetyl (3H-spiro[benzo [b] [ 1 ,4] dioxine-2, 1 '-cyclopropan] -6—
yl)hexane-1,4—dione (0.23 gm, 58.9%).
Step 8: 4- (2-methylpropionyl (3H-spiro[benzo [b] [ 1 ,4]dioxine-2, 1 '-
cyclopropan] - 7-yl) - 1 H-pyrrolyl)benzenesulfonamide
/ \
AEO N CH3
SOZNHZ
And
4- (2-methylpropionyl (3H-spiro[benzo [b] [ 1 ,4] dioxine-2, 1 opropan] -6—yl)-
1 H-pyrrolyl)benzenesulfonamide
/ \
E N CH3
SOZNHZ
To the solution of the mixture of 3-acetyl(3H-spiro[benzo[b][1,4]dioxine-2,1'-
cyclopropan]yl)hexane-1,4—dione and 3-acetyl(3H-spiro[benzo[b][1,4]dioxine-
yclopropan]-6—yl)hexane-1,4—dione (step 7, 0.2 gm, 0.63 mmol) in
toluene:acetic acid (5205 ml) was added obenzenesulfonamide (0.13 gm,
0.75 mmol) at room temperature under nitrogen atmosphere. To this reaction
mixture p—toluene sulphonic acid (0.015 gm, 0.09 mmol) was added and heated at
1100 C for 3 hr. The completion of on was monitored by TLC. Solvent was
evaporated at reduced pressure. Residue so obtained was taken in on of
ammonia in chloroform (10 ml) and stirred for 10 minutes. Reaction mixture was
again concentrated at reduced pressure. Ethyl acetate (50 ml) was added to the
residue, washed with water (10 ml). Combined organic layer was dried over
anhydrous Na2804. The solvent was ated under reduced pressure to obtain a
crude product; which was purified by column chromatography over silica gel (100-
200 mesh) using 40 % ethyl acetate in hexanes as an eluent to yield mixture of the
4- (2-methylpropionyl iro [benzo [b] [ 1 ,4] e-2, 1 '-cyclopropan] yl)-
1 H-pyrrolyl)benzenesulfonamide and 4- (2-methylpropionyl (3H-
spiro[benzo [b] [ 1 ,4] dioxine-2, 1 '-cyclopropan]yl)- 1 H-pyrrol
yl)benzenesulfonamide. The mixture was separated by preparative HPLC to yield
the first title compound (0.035 gm, 12.2%) and second title compound (0.05 gm,
17.48%).
First title compound: 4- (2-methylpropionyl (3H-spiro[benzo [b] [ 1 ,4]dioxine-2, 1 '-
cyclopropan] - 7-yl) - 1 H-pyrrolyl)benzenesulfonamide
AEO / \
N CH3
SOZNHZ
MS: m/z 453 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.88 (d, J=8.4 Hz, 2H), 7.52 (bs—exchanges with D20,
2H), 7.44 (d, J=8.4 Hz, 2H), 6.80 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.55 (d, J=2.0 Hz,
1H), 6.47 (dd, J=8.4, 2.0 Hz, 1H), 4.14 (s, 2H), 2.81 (q, J=7.2 Hz, 2H), 2.29 (s, 3H),
1.05 (t, J=7.2 HZ, 3H), 0.94 (t, J=5.6 Hz, 2H), 0.80 (t, J=5.6 Hz, 2H).
Second title compound: 4-(2-methy1—3-propiony1—5-(3H-spiro[benzo[b][1,4]dioxine-
2, 1 '-cyclopropan] - 1H-pyrroly1)benzenesulfonamide
[ N CH3
SOZNHZ
MS: m/z 453 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.89 (d, J=8.4 Hz, 2H), 7.53 (bs—exchanges with D20,
2H), 7.47 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.70 (d, J=2.0 Hz, 1H), 6.61 (d, J=8.4 Hz,
1H), 6.42 (dd, J=8.4, 2.0 Hz, 1H), 4.13 (s, 2H), 2.82 (q, J=7.2 Hz, 2H), 2.29 (s, 3H),
1.06 (t, J=7.2 HZ, 3H), 0.96 (t, J=5.6 Hz, 2H), 0.85 (t, J=5.6 Hz, 2H).
Example 10: Preparation of 4-(5-(1-acetyl-4,4-dimethyl-1 ,2,3,4-
tetrahydroquinolinyl)methylpropionyl- 1H-pyrrol- 1-
yl)benzenesulfonamide.
/ \
N CH3
SOzNHz
4-(5-(1-acetyl-4,4-dimethyl- 1 , 2, 3,4-tetrahydroquinolinyl)methyl
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
SOzNHz
Step 1: e of 1-(1-acety1-4,4—dimethy1-1,2,3,4—tetrahydroquinolin-B-yl)
bromoethanone
And
1 -( 1 -acety1-4,4—dimethyl- 1 ,2, 3,4—tetrahydroquinoliny1)bromoethanone
Y 0
To a stirred solution of AlClg (1.31 gm, 6.40 mmol) in DOE (30 ml) was added
solution of 1-(4,4—dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (prepared
according to the procedure reported in US 4808597, 1.2 gm, 5.91 mmol) in DOE
(10 ml) and 2-bromoacetyl bromide (0.94 gm, 0.41 ml, 7.00 mmol) in a drop wise
manner at 00C. The resulting mixture was d at room temperature for 2 hr.
The completion of reaction was red by TLC. Reaction e was poured
into cold water (30 ml). Aqueous layer was extracted with DCM (2 x 50 ml). Organic
layers separated were dried over anhydrous sodium sulphate, filtered and
concentrated at reduced pressure to get a crude product; which was ed by
column chromatography using 30% ethyl acetate in hexanes as an eluent to yield
the mixture of 1 - ( 1 -acetyl-4,4-dimethyl- 1 ,2,3,4-tetrahydroquinolin-6—yl)
bromoethanone and 1-(1-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)
bromoethanone (0.80 gm, 42.10%).
Step 2: Mixture of 3-acetyl(1-acetyl-4,4-dimethyl-1,2,3,4—tetrahydroquinolin
yl)hexane- 1 ,4-dione
3-acetyl ( 1 l-4,4-dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)hexane- 1 ,4-dione
To the stirred on of pulverized sodium (0.085 gm, 3.69 mmol) in toluene (10
ml) was added hexane-2,4—dione (prepared according to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.30 gm, 2.71 mmol) at 00C and
reaction mixture was stirred at room ature for 2 hr. To this was added
solution of mixture of 1-(1-acetyl-4,4—dimethyl-1,2,3,4-tetrahydroquinolinyl)
bromoethanone and 1-(1-acetyl-4,4—dimethyl-1,2,3,4—tetrahydroquinolinyl)
bromoethanone (step 1, 0.80 gm, 2.47 mmol) in toluene (10 ml) and reaction
mixture was heated at 600C for 2 hr under ng. The completion of reaction was
monitored by TLC. To this reaction mixture was added cold water (10 ml) and
extracted with ethyl acetate (2x 50 ml) and the combined organic layer was dried
over anhydrous Na2804. The solvent was evaporated under reduced pressure to
obtain a crude product; which was ed by column tography using 35%
ethyl acetate in hexanes as an eluent to yield mixture of 3-acetyl(1-acetyl-4,4—
dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)hexane- 1 ,4—dione and 3-acetyl( 1 -
acetyl-4,4—dimethyl-1,2,3,4—tetrahydroquinolinyl)hexane-1,4—dione (0.60 gm,
54.5%).
Step 3: 4-(5-( 1 -acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)methyl
propionyl- 1 H-pyrrolyl)benzenesulfonamide
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/ \
N CH3
SOzNHz
4- (5- ( 1 -acetyl-4,4—dimethyl- 1 ,2,3,4—tetrahydroquinolinyl)methylpropionyl-
1 H-pyrrolyl)benzenesulfonamide
802NH2
To the solution of the mixture of yl(1-acetyl-4,4—dimethyl-1,2,13,4-
tetrahydroquinolinyl)hexane- 1 ,4—dione and 3-acetyl ( 1 -acetyl-4,4—dimethyl-
1,2,3,4—tetrahydroquinolinyl)hexane-1,4—dione (step 2, 0.25 gm in
, 0.70 mmol)
acetic acid (5 ml) was added 4-aminobenzenesulfonamide (0.24 gm, 1.40 mmol) at
room temperature. Reaction mixture was heated at 1 100 C for 3 hr. The completion
of reaction was monitored by TLC. Solvent was evaporated at reduced re.
Residue so obtained was taken in solution of ammonia in chloroform (10 ml) and
stirred for 10 minutes. Reaction mixture was again concentrated at reduced
pressure. Ethyl acetate (50 ml) was added to the e, washed with water (10
ml). Combined organic layer was dried over anhydrous Na2804. The solvent was
evaporated under reduced pressure to obtain a crude product; which was purified
by column chromatography over silica gel (100-200 mesh) using 50 % ethyl e
in hexanes as an eluent to yield mixture of the 4-(5—(1-acetyl-4,4—dimethyl-1,2,13,4-
WO 04782
tetrahydroquinolinyl)methylpropionyl- 1H-pyrrolyl)benzenesulfonamide
and 4-(5- ( 1 -acetyl-4,4-dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)methyl
propionyl-1H-pyrrolyl)benzenesulfonamide. The mixture was ted by
preparative HPLC to yield the first title compound (0.045 gm, 13.0%) and second
title compound (0.030 gm, 8.69%).
First title compound: 4- (5- ( 1 -acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)-
2-methylpropionyl- 1 H-pyrrolyl)benzenesulfonamide
N CH3
SOzNHz
MS: m/z 494 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.90 (d, J=8.4 HZ, 2H), 7.47-7.53 (m, 5H), 7.05 (d,
J=8.0 HZ, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 3.62 (t, J=5.6 HZ, 2H), 2.85 (q, J=7.2 HZ,
2H), 2.34 (s, 3H), 2.08 (s, 3H), 1.60 (t, J=5.6 HZ, 2H), 1.08 (t, J=7.2 HZ, 3H), 0.92 (s,
6H).
Second title compound: 4-(5-(1-acetyl-4,4-dimethyl- 1 ,2,3,4-tetrahydroquinolin
yl)methylpropionyl- 1H-pyrrolyl)benzenesulfonamide
802NH2
MS: m/z 494 (M+1),
1HNMR (DMSO, 400 MHZ): 8 7.89 (d, J=8.4 HZ, 2H), 7.48-7.54 (m, 4H), 7.29 (d,
J=8.0 HZ, 1H), 6.86-6.94 (m, 3H), 3.63 (t, J=6.0 HZ, 2H), 2.85 (q, J=7.2 HZ, 2H),
2.50 (s, 3H), 2.30 (s, 3H), 1.65 (t, J=6.0 HZ, 2H), 1.18 (s, 6H), 1.06 (t, J=7.2 HZ, 3H).
e 11: Preparation of 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin
yl)methylpropionyl-1H-pyrrolyl)benzenesulfonamide.
N CH3
802NH2
And
4-(5-(4,4-dimethyl-1 ,2,3,4-tetrahydroquinolinyl)methylpropionyl-1H-
pyrrolyl)benzenesu1fonamide.
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ZI \ /
802NH2
To the stirred solution of mixture of the 4-(5-(1-acetyl-4,4—dimethyl-1,2,13,4-
tetrahydroquinolinyl)methylpropionyl- 1H-pyrrol- 1 nzenesulfonamide
and 4-(5- ( 1 -acetyl-4,4—dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)methyl
propionyl-1H-pyrrolyl)benzenesulfonamide (step 3 in Example-8, 0.1 gm, 0.20
mmol) in acetonitrile (5 ml) was GM HCl (10 ml) at room temperature. Reaction
mixture was heated at 1000 C for 4 hr. The completion of reaction was monitored
by TLC. Solvent was evaporated at reduced pressure. Residue so obtained was
taken in solution of ammonia in chloroform (20 ml) and stirred for 10 s.
Reaction mixture was again concentrated at reduced pressure. Ethyl acetate (30
ml) was added to the residue, washed with water (10 ml). Combined organic layer
was dried over anhydrous Na2804. The t was evaporated under reduced
pressure to obtain a crude t; which was purified by column chromatography
using 55% ethyl acetate in hexanes as an eluent to yield the first title compound
(0.035 gm, 38.46%) and second title compound (0.025 gm, ).
First title compound: 4- (5-(4,4—dimethyl- 1 ,2,3,4-tetrahydroquinolinyl)methyl-
3-propionyl- 1H-pyrrolyl)benzenesulfonamide
N CH3
802NH2
MS: m/z 452 (M+1),
1HNMR (CD013, 400 MHz): 8 7.96 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 6.79
(dd, J=8.0, 2.0 HZ, 1H), 6.60 (s, 1H), 6.58 (d, J=2.0 HZ, 1H), 6.31 (d, J=8.0 Hz, 1H),
4.87 (bs—exchanges with D20, 2H), 3.24 (t, J=5.6 Hz, 2H), 2.85 (q, J=7.2 Hz, 2H),
2.44 (s, 3H), 1.62 (t, J=5.6 Hz, 2H), 1.59 (bs—exchanges with D20, 1H), 1.21 (t,
J=7.2 Hz, 3H), 0.98 (s, 6H).
Second title compound: 4-(5-(4,4-dimethy1— 1 ,2,3,4—tetrahydroquinoliny1)-2—
methyl-3—propiony1— 1H-pyrroly1)benzenesulfonamide
ZI /\
N CH3
SO2NH2
MS: m/z 452 (M+1),
1HNMR (CDClg, 400 MHZ): 5 7.95 (d, J=8.4 HZ, 2H), 7.29 (d, J=8.4 HZ, 2H), 6.93 (d,
J=8.0 HZ, 1H), 6.65 (s, 1H), 6.19 (d, J= 2.0 Hz, 1H), 6.16 (dd, J=8.0, 2.0 Hz, 1H),
4.99 changes with D20, 2H), 3.25 (t, J=5.6 Hz, 2H), 2.84 (q, J=7.2 Hz, 2H),
2.40 (s, 3H), 1.68 (t, J=5.6 Hz, 2H), 1.66 changes with D20, 1H), 1.22 (s, 6H),
1.20 (t, J=7.2 HZ, 3H).
Example 12: Preparation of 4-(5-(4,4-dimethyloxo-1 ,2,3,4-
tetrahydroquinolinyl)methylpropionyl- 1H-pyrrol- 1-
yl)benzenesulfonamide.
WO 04782
/ \
SOZNHZ
4-(5-(4,4-dimethyloxo-1,2,3,4-tetrahydroquinolinyl)methyl
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
0“ /\
N CH3
SOZNHZ
Step 1: Mixture of 6-(2-bromoacetyl)-4,4—dimethyl-3,4-dihydroquinolin-2(1H)-one
7-(2-bromoacety1)-4,4-dimethyl-3,4—dihydroquinolin-2( 1H)-one
To a stirred solution of AlClg (7.50 gm, 56.25 mmol) in C82 (30 ml) was added
solution of 4,4-dimethyl-3,4—dihydroquinolin-2(1H)-one (prepared according to the
ure reported in US 4808597, 2.5 gm, 14.20 mmol) in C82 (20 ml) and 2-
bromoacetyl bromide (4.32 gm, 1.88 ml, 21.70 mmol) in a drop wise manner at
00C. The resulting mixture was stirred at reflux temperature for 3 hr. The
completion of reaction was monitored by TLC. Reaction mixture was poured into
cold 2N HCl (30 ml). Aqueous layer was extracted with ethyl e (2 x 100 ml).
Organic layers ted were dried over anhydrous sodium sulphate, ed and
concentrated at reduced pressure to get a crude product; which was purified by
column chromatography using 35% ethyl acetate in hexanes as an eluent to yield
the mixture of 6-(2-bromoacetyl)-4,4—dimethyl-3,4—dihydroquinolin-2(1H)-one and
romoacetyl)-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (2.00 gm, 47.4%).
Step 2: Mixture of 3-acetyl(4,4-dimethyloxo-1,2,3,4-tetrahydroquinolin-6—
yl)hexane- 1 ,4-dione
3-acetyl (4,4—dimethyloxo- 1 ,2,3,4-tetrahydroquinolinyl)hexane- 1 ,4—dione
To the stirred solution of pulverized sodium (0.184 gm, 8.00 mmol) in toluene (15
ml) was added hexane-2,4—dione red according to the procedure given in J.
Amer. Chem. Soc., 1945, Q, 9, , 1510-1512, 0.77 gm, 6.70 mmol) at 00C and
reaction mixture was d at room temperature for 2 hr. To this was added
solution of mixture of 6-(2-bromoacetyl)-4,4—dimethyl-3,4—dihydroquinolin-2(1H)-
one and 7-(2-bromoacetyl)-4,4-dimethyl-3,4—dihydroquinolin-2(1H)-one (step 1,
2.00 gm, 6.70 mmol) in toluene (15 ml) and reaction e was heated at 600C
for 2 hr under ng. The completion of reaction was monitored by TLC. To this
reaction mixture was added cold water (20 ml) and extracted with ethyl acetate (2x
100 ml) and the combined organic layer was dried over anhydrous Na2804. The
solvent was evaporated under reduced pressure to obtain a crude product; which
was purified by column chromatography using 35% ethyl acetate in hexanes as an
eluent to yield mixture of 3-acetyl (4,4—dimethyloxo- 1,2,13,4-
tetrahydroquinolinyl)hexane- 1 ,4—dione and 3-acetyl (4,4—dimethyloxo-
1,2,3,4—tetrahydroquinolinyl)hexane-1,4—dione (1.30 gm, 58.55%).
Step 3: 4- (5- imethyloxo- 1 ,2,3,4-tetrahydroquinolin-6—yl)methyl
propionyl- 1 H-pyrrolyl)benzenesulfonamide
/ \
302NH2
4- (5- imethyloxo- 1 ,2,3,4—tetrahydroquinolinyl)methylpropionyl- 1H-
pyrrolyl)benzenesulfonamide
SOZNHZ
To the solution of the mixture of 3-acetyl(4,4—dimethyloxo-1,2,3,4—
tetrahydroquinolinyl)hexane- 1 ,4—dione and 3-acetyl (4,4—dimethyloxo-
1,2,3,4-tetrahydroquinolinyl)hexane-1,4—dione (step 2, 1.30 gm, 3.95 mmol) in
acetic acid (20 ml) was added 4-aminobenzenesulfonamide (1.35 gm, 7.90 mmol)
at room temperature. Reaction mixture was heated at 1 100 C for 3 hr. The
completion of reaction was monitored by TLC. Solvent was evaporated at reduced
re. Residue so obtained was taken in solution of a in chloroform (30
ml) and d for 10 minutes. Reaction mixture was again trated at
d pressure. Ethyl acetate (100 ml) was added to the residue, washed with
water (30 ml). Combined organic layer was dried over anhydrous Na2804. The
solvent was evaporated under reduced pressure to obtain a crude product; which
was purified by column chromatography over silica gel (100-200 mesh) using 50 %
ethyl acetate in hexanes as an eluent to yield mixture of the 4-(5-(4,4—dimethyl
oxo- 1 ,2,3,4-tetrahydroquinolinyl)methylpropionyl- 1H-pyrrol
yl)benzenesulfonamide and 4-(5-(4,4—dimethyloxo-1,2,3,4—tetrahydroquinolin
methylpropionyl-1H-pyrrolyl)benzenesulfonamide (0.6 gm, 32.78%).
0.150 gm of the mixture was separated by preparative HPLC to yield the first title
compound (0.035 gm, 23.33%) and second title compound (0.025 gm, 16.66%).
First title compound: 4- (5- (4,4—dimethyloxo- 1 ,2,3,4-tetrahydroquinolinyl)
methylpropionyl- 1H-pyrrolyl)benzenesulfonamide
/ \
SOZNHZ
MS: m/z 466 (M+1),
1HNMR (DMSO, 400 MHZ): 8 10.46 changes with D20, 1H), 7.99 (d, J=8.4 Hz,
2H), 7.56-7.72 (m, 6H), 6.97 (d, J=8.4 Hz, 1H), 6.21 (s, 1H), 2.44 (s, 2H), 2.30 (q,
J=7.2 Hz, 2H), 2.21 (s, 3H), 1.27 (s, 6H), 1.01 (t, J=7.2 Hz, 3H).
Second title compound: 4- (5-(4,4—dimethyloxo- 1 ,2,3,4-tetrahydroquinolin- 7-y1)-
2-methy1—3-propionyl- 1 H-pyrroly1)benzenesulfonamide
SOZNHZ
MS: m/z 466 (M+1),
1HNMR (DMSO, 400 MHZ): 8 10.13 (bs—exchanges with D20, 1H), 7.89 (d, J=8.4 Hz,
2H), 7.46-7.51 (m, 4H), 7.03 (dd, J=8.0, 2.0 Hz, 1H), 6.87 (s, 1H), 6.71-6.74 (m,
2H), 2.83 (q, J=7.2 Hz, 2H), 2.33 (s, 3H), 2.21 (s, 2H), 1.07 (t, J=7.2 Hz, 3H), 0.94
(s, 6H).
Example 13: Preparation of 4-(2-methylpropionyl(1,4,4-trimethyloxo-
1 , 2, 3,4-tetrahydroquinolin-G-yl)- 1H-pyrrol- 1-yl)benzenesulfonamide.
/ \
N CH3
SOZNHZ
Step 1: 6-(2-bromoacetyl)-1,4,4-trimethyl-3,4—dihydroquinolin-2(1H)-one
To a stirred solution of A1C13 (2.36 gm, 17.7 mmol) in C82 (30 ml) was added
solution of 1,4,4—trimethyl-3,4—dihydroquinolin-2(1H)-one, red according to
the procedure reported in European Journal of Medicinal Chemistry, 2008, Q, 8,
1730 - 1736, 2.8 gm, 14.80 mmol) in C82 (20 ml) and oacetyl bromide (3.26
gm, 1.42 ml, 16.20 mmol) in a drop wise manner at 00C. The resulting mixture
was stirred at reflux temperature for 4 hr. The completion of reaction was
monitored by TLC. Reaction mixture was poured into cold water (50 ml). Aqueous
layer was extracted with ethyl acetate (2 x 100 ml). c layers separated were
dried over anhydrous sodium sulphate, filtered and trated at reduced
pressure to get a crude product; which was purified by column chromatography
using 45% ethyl acetate in s as an eluent to yield the title compound (2.00
gm, 43.57%).
MS: m/z 311 (M+1),
WO 04782
Step 2: 3-acetyl(1,4,4—trimethyloxo- 1 ,2,3,4-tetrahydroquinolinyl)hexane-
1 ,4—dione
To the stirred on of pulverized sodium (0.220 gm, 9.56 mmol) in toluene (15
ml) was added hexane-2,4—dione (prepared according to the ure given in J.
Amer. Chem. Soc., 1945, Q, 9, 7.60 mmol) at 00C and , 1510-1512, 0.87 gm,
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 6-(2-bromoacetyl)-1,4,4—trimethyl-3,4—dihydroquinolin-2(1H)-one (step
1, 2.00 gm, 6.40 mmol) in toluene (15 ml) and reaction mixture was heated at 600C
for 2 hr under stirring. The completion of reaction was monitored by TLC. To this
reaction e was added cold water (20 ml) and ted with ethyl acetate (2x
100 ml) and the combined organic layer was dried over anhydrous Na2804. The
solvent was evaporated under reduced pressure to obtain a crude product; which
was purified by column chromatography using 35% ethyl acetate in hexanes as an
eluent to yield title compound (0.72 gm, 32.57%).
MS: m/z 344 (M+1),
Step 3: 4-(2-methylpropionyl-5—(1,4,4—trimethyloxo- 1,2,13,4-
tetrahydroquinolinyl) - 1 H-pyrrolyl)benzenesulfonamide
/ \
SOZNHZ
To the on of the yl(1,4,4-trimethyloxo-1,2,3,4-tetrahydroquinolin-
6-yl)hexane-1,4-dione (step 2, 0.70 gm, 2.04 mmol) in acetic acid (15 ml) was
added 4-aminobenzenesulfonamide (0.70 gm, 4.08 mmol) at room temperature.
Reaction mixture was heated at 1100 C for 3 hr. The completion of reaction was
monitored by TLC. Solvent was evaporated at reduced pressure. Residue so
ed was taken in solution of ammonia in chloroform (30 ml) and stirred for 10
minutes. Reaction mixture was again trated at reduced pressure. Ethyl
acetate (100 ml) was added to the residue, washed with water (30 ml). Combined
organic layer was dried over anhydrous Na2804. The solvent was evaporated under
reduced pressure to obtain a crude product; which was purified by preparative
HPLC to yield the title compound (0.1 10 gm, 1 1.2%).
MS: m/z 480 (M+1),
1HNMR (CDClg, 400 MHZ): 8 7.99 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.03
(dd, J=8.4, 2.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.73 (s, 1H),
4.98 (bs-exchanges with D20, 2H), 3.33 (s, 3H), 2.89 (q, J=7.2 Hz, 2H), 2.46 (s, 3H),
2.41 (s, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.07 (s, 6H).
Example 14: Pharmacological ing
Compounds were tested in a cell-based ime kinetic assay in human IMR—32
cells with native expression of oc7nAChR. The increase in intracellular Ca2+ levels
was measured in a Fluorometric Imaging Plate Reader (FLIPR). Test compound and
agonist solutions were made in assay buffer (HBSS, pH 7.4, 20 mM HEPES, and 10
mM CaClg). Briefly, cells were plated into Poly-D-Lysine coated back-walled clear-
bottom 96-well microplates at a y of 80,000 to 100,000 cells/well and
ted at 37°C/5% C02 for 40-48 h prior to the experiment. For evaluation of
compound mediated potentiation of agonist response, growth media was removed
from the wells and 200 pl of FLIPR calcium 4 dye (Molecular Devices), reconstituted
in assay buffer, and was added to the wells. After dye loading, microplates were
incubated for 30 min at 370C and 30 min at room temperature and then directly
transferred to the FLIPR. Baseline fluorescence was monitored for the first 10 to 30
s followed by the addition of 25 pl of test compound solution and subsequent
monitoring of fluorescence changes for up to 10 min. This was followed by addition
of 25 pl of t 82987, 10 M) solution and measurement of fluorescence
for 4 min. (Faghih R. et al. 2009, J. Med. Chem 52, 3377 — 84.)
The compound induced fold increase in agonist response (fold PAM activity) was
computed by dividing the maximum effect (Max-Min fluorescence) obtained with
test compound in presence of agonist with the agonist-alone effect. EC5o of the
nd was calculated using GraphPad Prism software version 5.0, by plotting
compound trations against fold PAM activity.
The compounds of the present ion showed 2 to 30 fold activation at 1 ”M
concentration.
FPAA2730PCT
Claims (15)
1. A compound of the general formula I, its tautomeric forms, its stereoisomers and its 5 pharmaceutically acceptable salts; wherein, R1 is selected from hydrogen, n, optionally tuted alkyl, perhaloalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted 10 heterocyclyl, optionally substituted heteroaryl; R2 is selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, ally substituted cycloalkyl, ally substituted cyclyl, or –NR5(R6), -A1R5, -N(R5)OR6; R3 is ed from hydrogen, optionally substituted alkyl, halo, optionally substituted 15 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, cyano, nitro or –NR5(R6), -OR5; R4 is [ R 7 ]m [ R 8 ]n D E [Y] P FPAA2730PCT wherein, phenyl ring ‘D’ is fused with ring ‘E’, which is a non-aromatic five to eight member ring inclusive of ‘Y’ group(s); Y is independently selected at each repetition from -O-, -S-, -NH-, , or [ ]q , where q = 1 - 4; wherein when Y is selected as –NH- or [ ]q , it is optionally 5 substituted by [R8]n; wherein, R5 and R6 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkyl, optionally tuted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, R9aC(=A1)-; 10 R7 is selected independently at each occurrence from the group consisting of halogen, optionally substituted alkyl, optionally substituted cycloalkyl; R8 is independently selected at each occurrence from the group consisting of optionally substituted alkyl, R9A1-, R9aC(=A1)-; m = 0 to 2; 15 n = 0 to 3; p = 0 to 4; such that, when p = 0 then n 0; wherein, R9 wherever it appears, is ed from hydrogen, optionally substituted C1- 6 alkyl, ally substituted heteroalkyl, optionally tuted aryl, optionally 20 substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; and A1 is selected from O and S; 30PCT R9a wherever it appears, is selected from ally substituted C1-6 alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; wherein, 5 "optionally substituted alkyl", means a alkyl group optionally tuted with 1 to 6 substituents ed independently from the group ting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO2-, R10A1-, R10aOC(=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R10aC(=O)N(H)-, (R10)(H)N-, (R10)(alkyl)N-, (R10)(H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; 10 “optionally substituted heteroalkyl” means a heteroalkyl group optionally substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, lkyl. “optionally substituted cycloalkyl" means a cycloalkyl group optionally substituted with 1 to 6 substituents selected independently from the group consisting of oxo, 15 halogen, nitro, cyano, aryl, aryl, alkyl, R10aC(=O)-, R10aSO2-, R10A1-, (=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R10aC(=O)N(H)-, (R10)(H)N-, (R10)(alkyl)N-, H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; "optionally substituted aryl" means (i) an aryl group optionally substituted with 1 to 20 3 tuents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SO2-, perhaloalkyl-SO2-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H2NC(=O)-, alkyl-N(alkyl)SO2-, alkyl-N(H)SO2-, H2NSO2-, 3 to 6 membered 25 heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally substituted with alkyl or alkyl-C(=O)-, (ii) an aryl ring optionally fused with FPAA2730PCT cycloalkane or heterocycle across a bond optionally substituted with oxo, alkyl or alkyl-C(=O)-; “optionally substituted heterocyclyl" means a (i) heterocyclyl group optionally substituted on ring carbons with 1 to 6 substituents selected independently from the 5 group consisting of oxo, halogen, nitro, cyano, aryl, aryl, alkyl, R10A1-, (=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(O)-, R10aC(=O)N(H)-, (R10)(H)N-, (R10)(alkyl)N-, (R10)(H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; (ii) heterocyclyl group optionally substituted on ring en(s) with substituents selected from the group consisting of aryl, hereroaryl, alkyl, R10aC(=O)-, R10aSO2-, 10 R10aOC(=O)-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-; "optionally substituted heteroaryl" means a heteroaryl group optionally substituted with 1 to 3 substituents selected ndently from the group consisting of n, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, N(H)-, H2N-, alkyl-SO2-, 15 perhaloalkyl-SO2-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-, N(H)C(=O)-, H2NC(=O)-, alkyl-N(alkyl)SO2-, alkyl-N(H)SO2-, H2NSO2-, 3 to 6 membered cycle containing 1 to 2 heteroatoms selected from N, O and S optionally substituted with alkyl or alkyl-C(=O)-; wherein R10 is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or 20 heterocyclyl; and A1 is selected from S and O; and R10a is selected from alkyl, perhaloalkyl, aryl, heteroaryl, lkyl or heterocyclyl.
2. The compound of formula I as claimed in claim 1, wherein R1 is selected as methyl.
3. The compound of formula I as claimed in claim 1, wherein R2 is selected from ethyl and ethoxy. 25
4. The compound of formula I as claimed in claim 1, wherein R3 is selected from hydrogen and methyl. FPAA2730PCT
5. The compound of formula I as claimed in claim 1, wherein R4 is selected from , , , , , , or .
6. The nd of formula I as claimed in claim 1, wherein R1 is selected from methyl, R2 is selected from ethyl and , R3 is selected from hydrogen and methyl, and R4 is selected from , , , , , , or .
7. The compound of formula I as claimed in claim 1, wherein the compound is selected from- 4-(5-(4,4-dimethylchromanyl)methylpropionyl-1H-pyrrol yl)benzenesulfonamide; 4-(5-(2,3-dihydrobenzo[b][1,4]dioxinyl)methylpropionyl-1H- pyrrolyl)benzenesulfonamide; 4-(2-(2,3-dihydrobenzo[b][1,4]dioxinyl)-3,5-dimethylpropionyl- 15 rolyl)benzenesulfonamide; Ethyl 5-(2,3-dihydrobenzo[b][1,4]dioxinyl)-2,4-dimethyl(4- FPAA2730PCT sulfamoylphenyl)-1H-pyrrolecarboxylate; 4-(5-(2,2-dimethylchromanyl)methylpropionyl-1H-pyrrol yl)benzenesulfonamide; 4-(5-(8-fluoro-4,4-dimethylchromanyl)methylpropionyl-1H- pyrrolyl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methyl- 10 3-propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methyl- ionyl-1H-pyrrolyl)benzenesulfonamide; 15 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(2-methylpropionyl(3H-spiro[benzo[b][1,4]dioxine-2,1'- cyclopropan]yl)-1H-pyrrolyl)benzenesulfonamide; ethylpropionyl(3H-spiro[benzo[b][1,4]dioxine-2,1'- cyclopropan]yl)-1H-pyrrolyl)benzenesulfonamide; 4-(5-(1-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methyl 25 propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(1-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 30 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 30PCT 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(4,4-dimethyloxo-1,2,3,4-tetrahydroquinolinyl)methyl 5 propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(4,4-dimethyloxo-1,2,3,4-tetrahydroquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 10 4-(2-methylpropionyl(1,4,4-trimethyloxo-1,2,3,4- tetrahydroquinolinyl)-1H-pyrrolyl)benzenesulfonamide.
8. A pharmaceutical composition comprising a compound of claim 1 and a 15 pharmaceutically acceptable carrier.
9. Use of a therapeutically effective amount of a compound of claim 1 in the manufacture of a medicament for ting or treating a disease or its symptoms or a disorder mediated partially or completely by nicotinic acetylcholine receptors.
10. Use of therapeutically ive amount of a compound of formula I in the manufacture 20 of a medicament for treating a disease or er or condition, wherein, FPAA2730PCT R1 is selected from hydrogen, halogen, optionally substituted alkyl, perhaloalkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heterocyclyl, optionally substituted heteroaryl; R2 is selected from optionally substituted alkyl, optionally substituted heteroalkyl, 5 ally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or –NR5(R6), -A1R5, -N(R5)OR6; R3 is selected from hydrogen, optionally substituted alkyl, halo, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted cyclyl, ally substituted heteroaryl, cyano, nitro or –NR5(R6), -OR5; 10 R4 is [ R 7 ]m [ R 8 ]n D E [Y] P wherein, phenyl ring ‘D’ is fused with ring ‘E’, which is a non-aromatic five to eight member ring inclusive of ‘Y’ group(s); Y is independently ed at each repetition from -O-, -S-, -NH-, , or [ ]q , 15 where q = 1 - 4; wherein when Y is selected as –NH- or [ ]q , it is ally substituted by [R8]n; wherein, R5 and R6 are independently selected from hydrogen, optionally tuted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted 20 heterocyclyl, R9aC(=A1)-; FPAA2730PCT R7 is selected independently at each occurrence from the group consisting of halogen, optionally substituted alkyl, ally substituted cycloalkyl; R8 is ndently selected at each ence from the group ting of optionally substituted alkyl, R9A1-, R9aC(=A1)-; 5 m = 0 to 2; n = 0 to 3; p = 0 to 4; wherein, R9 wherever it appears, is selected from hydrogen, optionally substituted C1- 6 alkyl, optionally substituted alkyl, optionally substituted aryl, optionally 10 substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; and A1 is selected from O and S; R9a wherever it appears, is selected from optionally substituted C1-6 alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; 15 wherein, "optionally tuted alkyl", means an alkyl group optionally substituted with 1 to 6 substituents ed independently from the group ting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO2-, R10A1-, R10aOC(=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R10aC(=O)N(H)-, (R10)(H)N-, alkyl)N-, 20 (R10)(H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; “optionally substituted heteroalkyl” means a alkyl group optionally substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl. “optionally substituted cycloalkyl" means a cycloalkyl group optionally substituted FPAA2730PCT with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R10aC(=O)-, R10aSO2-, R10A1-, R10aOC(=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R10aC(=O)N(H)-, (R10)(H)N-, (R10)(alkyl)N-, (R10)(H)NC(=A1)N(H)-, 5 (R10)(alkyl)NC(=A1)N(H)-; "optionally substituted aryl" means (i) an aryl group optionally substituted with 1 to 3 tuents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SO2-, perhaloalkyl-SO2-, 10 alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H2NC(=O)-, N(alkyl)SO2-, alkyl-N(H)SO2-, H2NSO2-, 3 to 6 membered heterocycle ning 1 to 2 heteroatoms selected from N, O and S optionally substituted with alkyl or alkyl-C(=O)-, (ii) an aryl ring optionally fused with cycloalkane or heterocycle across a bond optionally substituted with oxo, alkyl or 15 alkyl-C(=O)-; nally substituted heterocyclyl" means a (i) heterocyclyl group optionally substituted on ring carbons with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R10A1-, R10aOC(=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(O)-, R10aC(=O)N(H)-, 20 (R10)(H)N-, (R10)(alkyl)N-, (R10)(H)NC(=A1)N(H)-, (R10)(alkyl)NC(=A1)N(H)-; (ii) heterocyclyl group optionally substituted on ring nitrogen(s) with substituents ed from the group consisting of aryl, aryl, alkyl, R10aC(=O)-, R10aSO2-, R10aOC(=O)-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-; "optionally tuted heteroaryl" means a heteroaryl group optionally substituted 25 with 1 to 3 substituents ed independently from the group consisting of halogen, nitro, cyano, hydroxy, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 oalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, SO2-, perhaloalkyl-SO2-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-, FPAA2730PCT alkyl-N(H)C(=O)-, O)-, alkyl-N(alkyl)SO2-, alkyl-N(H)SO2-, H2NSO2-, 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally substituted with alkyl or alkyl-C(=O)-; 5 wherein R10 is selected from hydrogen, alkyl, aryl, heteroaryl, lkyl or heterocyclyl; and A1 is selected from S and O; and R10a is selected from alkyl, perhaloalkyl, aryl, aryl, cycloalkyl or heterocyclyl.
11. The use of claim 10, wherein the compounds are selected from, 10 4-(5-(4,4-dimethylchromanyl)methylpropionyl-1H-pyrrol yl)benzenesulfonamide; 4-(5-(2,3-dihydrobenzo[b][1,4]dioxinyl)methylpropionyl-1H-pyrrol zenesulfonamide; 4-(2-(2,3-dihydrobenzo[b][1,4]dioxinyl)-3,5-dimethylpropionyl-1H-pyrrol- 1-yl)benzenesulfonamide; Ethyl 5-(2,3-dihydrobenzo[b][1,4]dioxinyl)-2,4-dimethyl(4- 20 sulfamoylphenyl)-1H-pyrrolecarboxylate; 4-(5-(2,3-dihydro-1H-indenyl)methylpropionyl-1H-pyrrol yl)benzenesulfonamide; 25 4-(5-(2,2-dimethylchromanyl)methylpropionyl-1H-pyrrol yl)benzenesulfonamide; 4-(5-(8-fluoro-4,4-dimethylchromanyl)methylpropionyl-1H-pyrrol yl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methyl FPAA2730PCT propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinolinyl)methylpropionyl- 1H-pyrrolyl)benzenesulfonamide; 4-(2-methylpropionyl(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan] 10 yl)-1H-pyrrolyl)benzenesulfonamide; 4-(2-methylpropionyl(3H-spiro[benzo[b][1,4]dioxine-2,1'-cyclopropan] yl)-1H-pyrrolyl)benzenesulfonamide; 15 4-(5-(1-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methyl nyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(1-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methyl propionyl-1H-pyrrolyl)benzenesulfonamide; 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methylpropionyl-1H- pyrrolyl)benzenesulfonamide; 4-(5-(4,4-dimethyl-1,2,3,4-tetrahydroquinolinyl)methylpropionyl-1H- 25 pyrrolyl)benzenesulfonamide; 4-(5-(4,4-dimethyloxo-1,2,3,4-tetrahydroquinolinyl)methylpropionyl- 1H-pyrrolyl)benzenesulfonamide; 30 4,4-dimethyloxo-1,2,3,4-tetrahydroquinolinyl)methylpropionyl- 1H-pyrrolyl)benzenesulfonamide; FPAA2730PCT 4-(2-methylpropionyl(1,4,4-trimethyloxo-1,2,3,4-tetrahydroquinolin -pyrrolyl)benzenesulfonamide; 4-(2-methylpropionyl(5,6,7,8-tetrahydronaphthalenyl)-1H-pyrrol 5 yl)benzenesulfonamide.
12. The use of claim 10, n the disorder or condition or disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senile dementia, vascular ia, dementia of Parkinson’s disease, attention deficit disorder, attention deficit ctivity disorder, dementia associated with Lewy bodies, AIDS 10 dementia complex, Pick's disease, dementia associated with Down's syndrome, Huntington's disease, cognitive deficits associated with traumatic brain , cognitive and imotor gating deficits associated with schizophrenia, cognitive ts associated with bipolar disorder, cognitive impairments associated with depression, acute pain, post-surgical or post-operative pain, chronic pain, 15 inflammation, inflammatory pain, neuropathic pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth ated with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, s disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, 20 organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock me, sepsis syndrome, depression, and rheumatoid spondylitis.
13. The use of claim 10, wherein the e or disorder or condition is selected from the group classified or diagnosed as major or minor neurocognitive disorders, or disorders 25 arising due to neurodegeneration.
14. The use of claim 10, wherein the medicament is adapted for administration in ation with or as adjunct to medications used in the treatment of attention deficit hyperactivity disorders, schizophrenia, and other cognitive disorders such as FPAA2730PCT Alzheimer's disease, Parkinson’s dementia, vascular ia or dementia associated with Lewy bodies, tic brain injury.
15. The use of claim 10, wherein the medicament is adapted for administration in combination with or as an adjunct to acetylcholinesterase inhibitors, disease ing 5 drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an atypical antipsychotic.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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IN151KO2011 | 2011-02-03 | ||
IN151/KOL/2011 | 2011-02-03 | ||
PCT/IB2012/050442 WO2012104782A1 (en) | 2011-02-03 | 2012-01-31 | Pyrrole derivatives used as modulators of alpha7 nachr |
Publications (2)
Publication Number | Publication Date |
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NZ613467A NZ613467A (en) | 2015-03-27 |
NZ613467B2 true NZ613467B2 (en) | 2015-06-30 |
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