PYRROLE DERIVATIVES USED AS MODULATORS OF ALPHA7 NACHR
Field of the Invention:
The present invention is related to s of the general formula I,
their tautomeric forms, their stereoisomers, their analogs, their prodrugs, their
isotopes, their metabolites, their pharmaceutically acceptable salts, polymorphs,
solvates, optical isomers, clathrates, co-crystals, combinations with suitable
medicament, pharmaceutical compositions containing them, methods of making of
the above compounds , and their use as nicotinic acetylcholine receptor a 7 subunit
(a7 nAChR) modulator.
Background 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, neuromuscular junctions and
the central nervous system. Two distinct classes of ACh target receptors viz.
muscarinic (mAChRs) 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 subunits (2-10, 2-4) arranged in
heteropentameric (42) or homopertameric (a7) configuration (Paterson D et al.,
Prog. Neurobiol., 2000, 61, 75-1 11). 42 and a7 nAChR constitute the
predominant subtypes expressed in the mammalian brain. a7 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, 25, 69-71). Particularly, a7 nAChR is characterized by
a high Ca2+ ion permeability, which is responsible for neurotransmitter release and
consequent modulation of excitatory and inhibitory neurotransmission (Alkondon
M et al., Eur. J . Pharmacol., 2000, 393, 59-67; Dajas-Bailador F et al., Trends
Pharmacol. Sci., 2004, 25, 317-324). Furthermore, high Ca + ion influx also has
implications on the long-term potentiation of memory via alterations in gene
expression (Bitner RS et al., J . Neurosci., 2007, 27, 10578-10587; McKay BE et al.,
Biochem. Pharmacol., 2007, 74, 1120-1 133).
Several recent studies have confirmed the role of a7 nAChR in neural processes
like attention, memory and cognition (Mansvelder HD et al., Psychopharmacology
(Berl), 2006, 184 292-305; Chan WK et al., Neuropharmacology, 2007, 52, 1641-
1649; Young JW et al., Eur, Neuropsychopharmacol,, 2007, 7, 145-155). Gene
polymorphisms associated with the a7 nAChR protein CHRNA7 have been
implicated in the genetic transmission of schizophrenia, related neurophysiological
sensory gating deficits and resultant cognitive impairment (Freedman R et al., Biol.
Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J . Med. Genet., 2001, 105,
662-668). Also, preclinical studies in a 7 nAChR knock-out and anti-sense
oligonucleotide treated mice have demonstrated impaired attention and defective
cognition underscoring the prominent role of a7 nAChR in cognition (Curzon P et
al., Neurosci. Lett., 2006, 410 , 15-19; Young JW et al., Neuropsychopharmacology,
2004, 29, 891-900). Additionally, pharmacological blockade of a7 nAChR impairs
memory and its activation enhances same in preclinical rodent models implicating
a7 nAChR as target for cognitive enhancement (Hashimoto K et al., Biol.
Psychiatry, 2008, 63, 92-97).
Pathological brain function in sensory-deficit disorders has been associated with
nicotinic cholinergic transmission particularly through a7 receptors (Freedman R
et al., Biol. Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J . Med. Genet.,
2001, 105, 662-668; Carson R et al., Neuromolecular, 2008, Med 10 , 377-384;
Leonard S et al., Pharmacol. Biochem. Behav., 2001, 70, 561-570; Freedman R et
al., Curr. Psychiatry Rep., 2003, 5, 155-161; Cannon TD et al., Curr. Opin.
Psychiatry, 2005, 8, 135-140). A defective pre-attention processing of sensory
information is understood to be the basis of cognitive fragmentation in
schizophrenia and related neuropsychiatric disorders (Leiser SC et al., Pharmacol.
Ther., 2009, 122, 302-31 1). Genetic linkage studies have traced sharing of the a7
gene locus for several affective, attention, anxiety and psychotic disorders (Leonard
S et al., Pharmacol. Biochem. Behav., 2001, 70, 561-570; Suemaru K et al.,
Nippon. Yakurigaku. Zasshi., 2002, H9, 295-300). Modulation of the nicotinic
cholinergic receptors, particularly a7 may provide for efficacy in a range of
cognitive states, right from pre-attention to attention and subsequently working,
reference and recognition memory. Accordingly, this invention may find application
in the treatment and prophylaxis of multitude of disease conditions including,
either one or combinations of, schizophrenia, schizophreniform disorder, cognitive
deficits in schizophrenia, brief psychotic disorder, delusional disorder,
schizoaffective disorder, shared psychotic disorder, paranoid personality disorder,
schizoid personality disorder, schizotypal personality 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 without agoraphobia), phobias (including
social phobia) and bipolar disorders (Thomsen MS et al., Curr. Pharm. Des. 2010,
16, 323-343; Peng ZZ et al., Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008, 25, 154-
158; Young JW et al., Eur. Neuropsychopharmacol. 2007, 7, 145-155; Martin LF
et al., Am. J . Med. Genet. B Neuropsychiatr. Genet. 2007, 144B, 6 11-614; Martin
LF et al., Psycho pharmacology (Berl), 2004, 174, 54-64; Feher A et al., Dement.
Geriatr. Cogn. Disord. 2009, 28, 56-62; Wilens TE et al., Biochem. Pharmacol.
2007, 74, 1212-1223; Verbois SL et al., Neuropharmacology, 2003, 44 224-233;
Sanberg PR et al., Pharmacol. Ther. 1997, 74, 21-25). Cholinergic system,
particularly through a 7 nAChR seems to have implications in traumatic brain
injury-induced psychosis. Chronic nicotine treatment has shown to attenuate
same. Thus, this invention may also find application in the treatment of deficits in
cholinergic a 7 nAChR following traumatic brain injury (Bennouna M et al.,
Encephale, 2007, 33, 616-620; Verbois SL et al., Neuropharmacology, 2003, 44,
224-233).
Perturbations in the cholinergic and glutamatergic homeostasis, has long been
implicated as causative factors for host of neurological disease, including
dementia(s) (Nizri E et al., Drug News Perspect. 2007, 20, 421-429). Dementia is a
severe, progressive, multi-factorial cognitive disorder affecting memory, attention,
language and problem solving. Nicotinic ACh receptor, particularly the interaction
of a 7 receptor to -42 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, 29, 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, 28, 56-62). Modulation of nicotinic
ACh receptors, particularly the a 7 subtype could help supplement the downregulated
cholinergic receptor expression and transmission as in dementia(s), and
also slowing disease progression by reduction of 7--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, 17, 5247-5258;
Deutsch SI et al., Clin. Neuropharmacol., 2003, 26, 277-283). Appropriately, this
invention may find application in the treatment and prophylaxis of multitude of
disease conditions including, either one or combinations of, dementia(s) due to
Alzheimer's disease, dementia 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, 5, 215-228; Wang J et al., J . Neurosci. Res., 2010, 88, 807-815).
Disease modification potential of nAChRs particularly the a 7 receptor has
application for disease-modification of Alzheimer 's disease (AD) and Parkinson's
disease (PD) by enhancing neuron survival and preventing neurodegeneration
(Wang et al. 2009; Nagele RG et al., Neuroscience, 2002, 110 , 199-21 1;
Jeyarasasingam G et al., Neuroscience, 2002, 109 , 275-285). Additionally, a 7
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 invention may find
application in the prophylaxis and preventive measures immediately after earlystage
identification of neurodegenerative disease like Alzheimer's disease and
Parkinson's disease.
Dopamine containing neurons of ventral tegmental area (VTA) and laterodorsal
tegmental nucleus (LDT) are known to express nicotinic ACh receptors, particularly
a4, a3, 2, 3, 4 subunits (Kuzmin A et al., Psychopharmacology (Berl), 2009,
203 , 99-108). Nicotinic ACh receptors, 4 2 and 34 have been identified with
candidate-gene approach to have strong mechanistic link for nicotine addiction
(Weiss RB et al., PLoS Genet 2008, 4 , el000125). a.7 nAChR has particularly been
studied for a putative role in cannabis addiction (Solinas M et al., J . Neurosci.,
2007, 27, 5615-5620). Varenicline, a partial agonist at 4 2, has demonstrated
better efficacy in reducing the smoking addiction and relapse prevention in
comparison to buproprion (Ebbert J O et al., Patient Prefer Adherence, 2010, 4,
355-362). Modulation of nicotinic ACh receptors particularly 4 2, 34 and .7
may have implications in the development of therapies 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. Additionally, this invention may also
provide for an alternative therapy for non-responding addiction patients, patients
having intolerable side-effects with de-addiction therapies or those requiring longterm
maintenance therapies.
Presence of a high-affinity nicotine binding site at 42 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, 10, 1819-1830). Several new developments
have opened the area for use of nicotinic modulators for therapy of pain
(Rowbotham MC et al., Pain,, 2009, 146, 245-252). Appropriate modulation of the
nicotinic ACh receptors could provide for remedial approach to pain related states.
Thus, this invention may find application in the treatment 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,
primary lateral sclerosis, pseudobulbar palsy, progressive muscular palsy,
progressive bulbar palsy, postpolio syndrome, diabetes induced polyneuropathy,
acute demyelinating polyneuropathy (Guillain-Barre syndrome), acute spinal
muscular atrophy (Werdnig-Hoffman disease) and secondary neurodegeneration
(Donnelly-Roberts DL et al., J . Pharmacol. Exp. Ther., 1998, 285, 777-786; Rowley
TJ et al., Br. J . Anaesth., 2010, 105, 201-207; Bruchfeld A et al., J . Intern. Med.,
2010, 268, 94-101).
Another key role of the a 7 nAChR is the ability to modulate the production of pro
inflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha (TNF-a),
and high mobility group box (HMGB-1) in the central nervous system.
Consequently, an anti-inflammatory and antinociceptive effect in pain disorders
have been demonstrated (Damaj MI et al., Neuropharmacology, 2000, 39, 2785-
2791). Additionally, 'cholinergic 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,
80, 2325-2329; Gallowitsch-Puerta and Pavlov 2007; Rosas-Ballina M et al., Mol.
Med. 2009, 15, 195-202; Rosas-Ballina M et al., J . Intern. Med. 2009, 265 , 663-
679). Selective modulators of nicotinic ACh receptors, particularly a7 type, like
GTS-21, attenuate cytokine production and IL- after endotoxin exposure.
Furthermore, a7 nAChR are understood to have a central role in arthritis
pathogenesis and potential therapeutic strategy for treatment of joint inflammation
(Westman M et al., Scand J . Immunol. 2009, 70, 136-140). A putative role for a7
nAChR has also been implicated in severe sepsis, endotoxemic shock and systemic
inflammation (Jin Y et al. (2010) Int. J . Immunogenet. Liu C et al., Crit. Care Med.
2009, 37, 634-641). This invention may thus find application in the treatment and
prophylaxis of plethora of inflammation and pain related states involving TNF-a
and thus providing 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 syndrome (ARDS), joint inflammation, anaphylaxis,
ischemia reperfusion injury, multiple sclerosis, cerebral malaria, septic shock,
tissue rejection of graft, brain trauma, toxic shock syndrome, herpes virus infection
(HSV-1 & HSV-2), herpes zoster infection, sepsis, fever, myalgias, asthma, uveititis,
contact dermatitis, obesity- related disease and endotoxemia (Giebelen IA T et al.,
Shock, 2007, 27, 443-447; Pena G et al., Eur. J . Immunol., 2010, 40, 2580-2589).
Angiogenesis, is a critical physiological process for the cell survival and
pathologically important for cancer proliferation; several non-neural nicotinic ACh
receptors, particularly a7, a5, a3, 2, 4, are involved (Arias HR et al., Int. J .
Biochem. Cell Biol., 2009, 41, 1441-1451; Heeschen C et al., J . Clin. Invest., 2002,
110, 527-536). A role of nicotinic ACh receptors in the development of cervical
cancer, lung carcinogenesis and paediatric lung disorders in smoking-exposed
population has also been studied (Calleja-Macias IE et al., Int. J . Cancer, 2009,
124, 1090-1096; Schuller HM et al., Eur. J . Pharmacol., 2000, 393, 265-277). It is
thus, imperative for the modulators of nicotinic ACh receptors, to have a
modulatory role in angiogenesis and cancer cell survival. Thus, this invention may
find application in the treatment and prophylaxis of multitude of cancerous
conditions including, one or combination of, acute or chronic myelogenous
leukemia, multiple myeloma, tumor growth inhibition, angiogenesis and cancer
associated-cachexia.
Several a 7 nAChR agonists, partial agonists, have been characterized for their
efficacy in clinical and preclinical studies. EVP-6124, an agonist at a7 nAChR, has
demonstrated significant improvement in sensory processing and cognition
biomarkers in Phase lb study with patients suffering from schizophrenia (EnVivo
Pharmaceuticals press release 2009, Jan 12). GTS-21 (DMXB-Anabaseine) , an a7
nAChR agonist, in the P II clinical trials, has shown efficacy in improving cognitive
deficits in schizophrenia and inhibition of endotoxin-induced TNF-a release (Olincy
A et al., Biol. Psychiatry, 2005, 57(8, Suppl.) , Abst 44; Olincy A et al., Arch. Gen.
Psychiatry, 2006, 63, 630-638; Goldstein R et al., Acad. Emerg. Med., 2007, 14
(15, Suppl. 1) , Abst. 474). CP-810123, a a 7 nAChR agonist, exhibits protection
against the scopolamine-induced dementia and inhibition of amphetamine-induced
auditory evoked potentials in preclinical studies (O'Donnell CJ et al., J . Med.
Chem., 2010, 53, 1222-1237). SSR-18071 1A, also an a 7 nAChR agonist, enhances
learning and memory, and protects against MK-801 /Scopolamine-induced memory
loss and prepulse inhibition in preclinical studies (Redrobe J P et al., Eur. J .
Pharmacol., 2009, 602, 58-65; Dunlop J et al., J . Pharmacol. Exp. Ther., 2009,
328, 766-776; Pichat P et al., Neuropsychopharmacology, 2007, 32, 17-34). SEN-
12333, protected against scopolamine-induced amnesia in passive avoidance test
in preclinical studies (Roncarati R et al., J . Pharmacol. Exp. Ther., 2009, 329 , 459-
468). AR-R- 17779, an agonist at a7 nAChR, exhibits improvement in the social
recognition task performed in rats (Van KM et al., Psychopharmacology (Berl),
2004, 172, 375-383). ABBF, an agonist at a7 nAChR, improves social recognition
memory and working memory in Morris maze task in rats (Boess FG et al., J .
Pharmacol. Exp. Ther., 2007, 321 , 716-725). TC-5619, a selective a 7 nAChR
agonist has demonstrated efficacy in animal models of positive and negative
symptoms and cognitive dysfunction in schizophrenia (Hauser TA et al., Biochem.
Pharmacol., 2009, 78, 803-812).
An alternative strategy to reinforce or potentiate the endogenous cholinergic
neurotransmission of ACh without directly stimulating the target receptor is the
positive allosteric modulation (PAM) of a 7 nAChR (Albuquerque EX et al., Alzheimer
Dis. Assoc. Disord., 2001, 15 Suppl 1, S19-S25). Several PAMs have been
characterized, albeit in the preclinical stages of discovery. A-86774, a7 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,
52, 3377-3384). XY-4083, an a 7 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, 104, 8059-8064). Yet another PAM, PNU- 120596, profoundly alters a7
nAChR desensitization kinetics and simultaneously protecting against the
disruption of prepulse inhibition by MK-801. NS-1738, another PAM, has exhibited
efficacy in-vlvo 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, 323 , 294-307). In addition, several patents/applications published are
listed below - US20060 142349, US20070142450, US20090253691,
WO2007031440, WO20091 15547, WO2009 135944, WO2009 127678,
WO2009 127679, WO2009043780, WO2009043784, US7683084, US7741364,
WO2009145996, US20 100240707, WO201 1064288, US20100222398,
US20 100227869, EP1866314, WO2010130768, WO201 1036167, US20100190819
disclose efficacy of allosteric 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 complex.
ADHD: attention deficit hyperactivity disorder.
AIDS: Acquired immunodeficiency syndrome.
ARDS: acute respiratory distress syndrome.
DCC: 1,3-dicyclohexylcarbodiimide.
DCE: dichloroethane.
DCM: dichlorome thane.
DLB: dementia with Lewy bodies.
DMF: N,N-dimethylformamide.
EDCI: l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride.
FLIPR: Fluorometric Imaging Plate Reader.
HBSS: Hank's balanced salt solution.
HEPES: 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid.
HMGB: high mobility group box.
HOAT: l-hydroxy-7-azabenzotriazole.
HOBT: hydroxybenzotriazole hydrate.
HPLC: High Performance liquid chromatography.
IL: interleukins.
LDT: laterodorsal tegmental nucleus.
LGIC: ligand-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: post-diabetic neuralgia.
PHN: post-herpetic neuralgia.
PMBO: p-methoxy benzyloxy.
PNS: peripheral nervous system.
TBI: traumatic brain injury.
THF: Tetrahydrofuran.
TLC: Thin layer chromatography.
TMS: tetramethylsilane.
TNF- : tumor necrosis factor alpha.
VTA: ventral tegmental area.
a7 nAChR: nicotinic acetylcholine receptor a7 subunit.
Objective of the Invention:
The main objective of the present invention is therefore to provide novel
compounds of the general formula I, their tautomeric forms, their stereoisomers,
their pharmaceutically acceptable salts, pharmaceutical compositions containing
them, process and intermediates for the preparation of the above said compounds
which have a7 nAChR modulatory activity.
Summary of the Invention
According to one aspect of the present invention there is provided compounds
represented by the general formula I, its tautomeric forms, its stereoisomers, its
analogs, its prodrugs, its isotopes, its metabolites, its pharmaceutically acceptable
salts, its polymorphs, 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 invention is to provide novel intermediates, a
process for their preparation and their use in methods of making compounds of the
general formula I.
Detailed Description of the invention:
The present invention relates to a compound of the general formula I, its
tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its
metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its
optical isomers, its clathrates, its co-crystals, their combinations with suitable
medicament and pharmaceutical compositions containing them.
I
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, optionally substituted heteroalkyl,
optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, or -NR (R6), -A¾5, -N(R )OR6;
R3 is selected from hydrogen, optionally substituted alkyl, halo, optionally
substituted cycloalkyl, optionally substituted aryl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, cyano, nitro or -NR (R6), -OR5;
R s
wherein, phenyl ring 'D' is fused with ring Έ ', which is a non-aromatic five to eight
member ring inclusive of Ύ ' group(s);
is independently selected at each repetition from -0-, -Swhere
q = 1 - 4 ; wherein when Y is selected as -NH- or it is optionally
substituted by [R ]n;
wherein, R5 and R6 are independently selected from hydrogen, optionally
substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, R aC(=A1)-;
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, -, R C(=A )-;
m = 0 to 2 ;
n = 0 to 3 ;
p = 0 to 4 ;
wherein, R9 wherever it appears, is selected from hydrogen, optionally substituted
Ci e 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;
R9 wherever it appears, is selected from optionally substituted Ci e alkyl, optionally
substituted heteroalkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted cycloalkyl, and optionally substituted
heterocyclyl;
wherein,
the term "optionally substituted alkyl", means a alkyl group optionally substituted
with 1 to 6 substituents selected independently from the group comprising of oxo,
halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO2- , R^A 1- , R10aOC(=O)-,
Rioac(=0)0-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-, R C(=O)N(H)-, R °)(H)N-,
(R o)(alkyl)N-, (R °)(H)NC(=A )N(H)-, (R 0)(alkyl)NC(=A )N(H)-;
the term "optionally substituted heteroalkyl" 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 substituted cycloalkyl" means a cycloalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R10aC(=O)-,
Rioa o 2- , R A - , R 0aOC(=O)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-,
R
ioaC(=0)N(H)-, (R o)(H)N-, R °)(alkyl)N-, R °)(H)NC(=A )N(H)-,
(R o)(alkyl)NC(=A )N(H)-;
the term "optionally substituted aryl" means (i) an aryl group optionally substituted
with 1 to 3 substituents selected independently from the group comprising of
halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C 3 to Ce cycloalkyl, Ci to Ce
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-S0 2-
, perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-,
alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-N(H)S0 2- , H2NS0 2- , 3 to 6
membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S
optionally substituted with alkyl or alkyl-C(=0)-, (ii) an aryl ring optionally fused
with cycloalkane or heterocycle across a bond optionally substituted with oxo, alkyl
or alkyl-C(=0)-;
the term "optionally substituted heterocyclyl" means a (i) heterocyclyl group
optionally substituted on ring carbons with 1 to 6 substituents selected
independently from the group comprising of oxo, halogen, nitro, cyano, aryl,
hereroaryl, alkyl, R °A - , R 0aOC(=O)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-,
(R o)(alkyl)NC(0)-, R C(=O)N(H)-, (R o)(H)N-, (R 0)(alkyl)N-, R °)(H)NC(=A )N(H)-,
(R 10)(alkyl)NC(=A1)N(H)-; (ii) heterocyclyl group optionally substituted on ring
nitrogen(s) with substituents selected from the group comprising of aryl,
hereroaryl, alkyl, R C(=O)-, R 0aSO2- , R 10aOC(=O)-, (R 0)(H)NC(=O)-,
the term "optionally substituted heteroaryl" means a heteroaryl group optionally
substituted with 1 to 3 substituents selected independently from the group
comprising of halogen, nitro, cyano, hydroxy, C i to C e alkyl, C 3 to C e cycloalkyl, C i
to C e perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-,
alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-
N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-N(H)S02- ,
H2NS0 2- , 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from
N, O and S optionally substituted with alkyl or alkyl-C(=0)-;
wherein R 10 is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl; and A1 is selected from S and O; and R 10a is selected from alkyl,
perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
Other aspect of the invention of the present invention is compound of formula I as
described hereinabove 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 defined
herein above, wherein R 1 is selected from methyl.
Other preferred embodiment of the present invention is compound of formula I as
defined hereinabove, wherein, R 2 is selected from ethyl and ethoxy.
Another preferred embodiment of the present invention is compound of formula I
as defined hereinabove, wherein, R 3 is selected from hydrogen and methyl.
Yet another preferred embodiment of the present invention is compound of formula
I as defined hereinabove, wherein, R 4 is selected from following groups:
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 methyl; and R4 is selected from
following groups:
General terms used in formula can be defined as follows; however, the meaning
stated hereinbelow should not be interpreted as limiting the scope of the term per
se.
The term "alkyl", as used herein, means a straight or branched 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, npentyl,
isopentyl, neopentyl, allyl, vinyl, acetylene, and n-hexyl.
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, R10aSO2- , R10Ai-,
(Rio)(H)N-, (R 0)(alkyl)N-,
R 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 "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, pentailuoroethyl
and the like.
The term "heteroalkyl" as used herein means an 'alkyl' group wherein one or
more of the carbon atoms replaced by -0-, -S-, -S(0 2)-, -S(O)-, -N(Rm)-, Si(Rm)R -
wherein, Rm and R are independently selected from hydrogen, alkyl, aryl,
heteroaryl, 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 containing 3 to 6 carbon atoms. The ring may contain
one or more unsaturations (double or triple bonds). Examples of monocyclic ring
systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. Bicyclic ring systems are also exemplified by a bridged 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 include,
but are not limited to, bicyclo[3. 1.1]heptane, bicyclo[2. 2.1]heptane,
bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, and
bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]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 systems 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 systems 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. 1.0]heptane-2, 1'-cyclopentane] , hexahydro-2'Hspiro
[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, R10aC(=O)-, R10aSO2- , R^A - , R 0 OC(=O)-,
R
ioac(=0)0-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-, R C(=O)N(H)-, (R io)(H)N-,
(R 0)(alkyl)N-, (R 0)(H)NC(=A )N(H)-, (R 0)(alkyl)NC(=A )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
hydrocarbon ring system. Examples of aryl groups include but not limited to
phenyl, naphthyl, 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[ l ,4]dioxin-6-yl; 2,3-dihydro-benzo[ l ,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-benzofuran-6-yl; 2,3-dihydro- lH-indol-5-yl; 2,3-dihydro- lH-indol-
4-yl; 2,3-dihydro- lH-indol-6-yl; 2,3-dihydro- lH-indol-7-yl; benzo[ l ,3]dioxol-4-yl;
benzo[ 1,3]dioxol-5-yl; 1,2,3,4-tetrahydroquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl;
2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl.
Aryl as defined hereinabove may be optionally substituted with one or more
substituents selected independently from the group comprising of halogen, nitro,
cyano, hydroxy, Ci to Ce alkyl, C3 to Ce cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-,
perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SCb-, perhaloalkyl-S0 2- ,
alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-N(H)C(=0)-,
H2NC(=0)-, alkyl-N(alkyl)S02- , alkyl-N(H)S02- , H2NS02- , 3 to 6 membered
heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally
substituted with alkyl or alkyl-C(=0)-.
The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic
ring system having 1-4 ring heteroatoms selected from O, N, or S, and the
remainder 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, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be
substituted by a substituent. Examples of heteroaryl groups include but not
limited to pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl,
imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl. triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl,
benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl,
purinyl, pyrrolo [2,3 ]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 2,3-
thiadiazolyl, lH-pyrazolo[5, 1-c ]-l,2,4-triazolyl, pyrrolo[3,4-d]-l,2,3-triazolyl,
cyclopentatriazolyl, 3H-pyrrolo[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, C i to C e alkyl, C 3 to C e cycloalkyl, C i to C e perhaloalkyl, alkyl-O-,
perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- ,
alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-N(H)C(=0)-,
H2NC(=0)-, alkyl-N(alkyl)S02- , alkyl-N(H)S02- , H2NS02- , 3 to 6 membered
heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally
substituted with alkyl or alkyl-C(=0)-.
The term "heterocycle" or "heterocyclic" as used herein, means a 'cycloalkyl' group
wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 2)-, -S(O)-, -
N(Rm)-, -Si(Rm)R - , wherein, Rm and R are independently selected from hydrogen,
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 heterocycle. Representative examples 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,
isoxazolidinyl, 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 1,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro- l ,4-
benzodioxinyl, 2,3-dihydro- l -benzofuranyl, 2,3-dihydro- l -benzothienyl, 2,3-
dihydro- 1 H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also
include bridged heterocyclic systems such as azabicyclo[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, halogen,
nitro, cyano, aryl, hereroaryl, alkyl, R °A - , R °aOC(=0)-, R10aC(=O)O-,
(R o)(H)NC(=0)-, (R o)(alkyl)NC(0)-, R 0 C(=O)N(H)-, (R o)(H)N-, (R ) (alkyl)N-,
(R o)(H)NC(=A )N(H)-, (R o) (alkyl)NC(=A )N(H)-; wherein R 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.
Heterocyclyl group may further optionally be substituted on ring nitrogen(s) with
substituents selected from the group comprising of aryl, hereroaryl, alkyl,
R
ioac(=0)-, R 0aSO2- , R10aOC(=O)-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-; wherein R
is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and
Ri° 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 formula I is selected from:
1. 4-(5-(4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide.
2. 4-(5-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-methyl-3-propionyl-lH-pyrrol-lyl)
benzenesulfonamide.
3. 4-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3,5-dimethyl-4-propionyl-lHpyrrol-
1-yl)benzenesulfonamide.
4. Ethyl 5-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2,4-dimethyl-l-(4-
sulfamoylphenyl)-lH-pyrrole-3-carboxylate
5. 4-(5-(2,3-dihydro- lH-inden-4-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide.
6. 4-(5-(2,2-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide.
7. 4-(5-(8-fluoro-4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide.
8. 4-(5-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
9. 4-(5-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
10.4-(5-(4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-propionyl-
1H-pyrrol- l-yl)benzenesulfonamide.
11.4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][ 1,4]dioxine-2, 1'-cyclopropan]-
7-yl) -1H-pyrrol- 1-yl)benzenesulfonamide .
12.4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropan]-
6-yl) -1H-pyrrol- 1-yl)benzenesulfonamide .
13.4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
14. 4-(5-( l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
15.4-(5-(4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-propionyl-
1H-pyrrol- 1-yl)benzenesulfonamide .
16.4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-propionyl-
1H-pyrrol- 1-yl)benzenesulfonamide .
17.4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
18.4-(5-(4,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide.
19.4-(2-methyl-3-propionyl-5-(l ,4,4-trimethyl-2-oxo- 1,2,3,4-
tetrahydroquinolin-6-yl)- lH-pyrrol- l-yl)benzenesulfonamide.
20.4-(2-methyl-3-propionyl-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-lH-pyrrol-lyl)
benzenesulfonamide.
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. However, the invention may not be limited to these
methods; the compounds may also be prepared by using procedures described for
structurally related compounds in the literature.
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 literature EP 2168959 to give the
Compounds of formula IV. Friedal Craft reaction can be carried out under different
conditions well known in the art.
Alternatively, compound of formula IV can be prepared according to the
appropriate procedure given in literature such as US 6313107, US5037825 and
Journal of Med. Chemistry, 2006, 49,478 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 compounds of formula V. Halogenation can
be carried out under a condition adopting procedure generally used in the
synthetic organic chemistry using bromine, iodine, N-halosuccinamide, sufuryl
chloride, cupric chloride, cupric bromide or cupric iodide preferably bromine and
cupric chloride using a solvent such as ethyl acetate, dichloro methane, 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 AICI3 and the like as
described in the literature EP 2168959 to give the compound 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. Preferably toluene and compound of the formula VII
where R1 is optionally substituted alkyl, perhaloalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl,
optionally substituted heteroaryl, provide diketo ester compound VIII.
Compound of the formula VII can be prepared according to the procedure given in
literature such as Chem. Pharm. Bull. 1982, 30, 2590 and J . of Med. Chem., 1997,
40, 547.
Compound VIII where symbols R1, R3, R4 are same as defined earlier was treated
with substituted aniline of formula IX under heating conditions in a solvent such
as acetic acid and the like to obtain compound of the formula X.
The compounds of the formula X when R3 = H can be functionalized by
electrophilic reagents such as but not limited to I2, HNO2, 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 generally 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 solution 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 standard procedure known in
synthetic organic chemistry or preferably by reaction with oxalyl chloride in
dichloromethane along with DMF followed by reaction with ,-
dimethylhydroxylamine hydrochloride and triethylamine in dichloromethane to
provide compound of formula XII.
Compound of the formula XII was treated with Grignard reagent R MgX 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 HNR (R6), HA R ,
HN(R5)OR6 where R5, R6and A1 are same as defined under the general formula I to
provide compound of the formula I where R2 is -NR (R6), -A R , -N(R )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 dichloro methane, 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 temperature between 0-50°C using reagents such as l-(3-
dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDCI), 1,3-
dicyclohexylcarbodiimide (DCC), auxiliary reagents such as l-hydroxy-7-
azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT) or the like.
Alternatively, the compounds of the formula I where R3 = H; R2 is selected from
optionally substituted alkyl, optionally substituted heteroalkyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl
or optionally substituted heterocyclyl; R1 is optionally substituted alkyl,
perhaloalkyl, 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 halogen by reacting it
with compound of the formula XIII where R1 is same as defined earlier and R2 is
same as defined earlier excluding NR R6, -A R , -N(R )OR6 to give the compound
XIV where R3 is H; R2 is optionally substituted alkyl, optionally substituted
heteroalkyl, optionally substituted aryl, optionally substituted 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 carbonate, sodium hydride,
preferably 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 formula IX
under heating conditions in a solvent such as acetic acid or the like gave
compound of formula I.
Compound of the formula XIII was be prepared according to the procedure given in
literature such as J . Amer. Chem. Soc. 1945, 67, 9, 1510-1512.
Compound of the formula I where R1is hydrogen, R2 R3 and R4 are same as defined
earlier can be synthesized by adopting the chemistry described 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 earlier by halogenation. Halogenation can be carried out under
a condition 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 dichloromethane 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, 28,
1, 116-124, Monatshefte fur chemie, 1996, 127, 275-290, J.Med. Chem,, 1997, 40,
16, 2445-2451, US 4808597 and Eur. J . of Med. Chem., 2008, 43, 8, 1730 -
1736, or the like.
Process for synthesis of some of the typical intermediates of formula II is provided
hereinbelow in scheme 2.
SCHEME 2
Compound XVII was prepared starting from compounds represented by general
formula XV where X1 is halo, by esterification of carboxylic acid with alcohol in the
presence of inorganic acid such as but not limited to catalytic H2SO4 under room
temperature to heated condition as described in the literature 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
(MeMgX1) 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 compound XVIII by acetylating 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 K2CO3 under room temperature
to heated condition as described in the literature such as US20 10076027 to give
the compound 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
US20 10076027. The compound of formula XXI can be converted into compound of
formula XXII using reducing reagent such as but not limited to L AlH as described
in the literature Tetrahedron, 1994, 50, 15, 431 1-4322; which was de-protected by
method using reagents such as eerie ammonium nitrate, Trifluoromethane
sulfonate BF3-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 compound I
by subjecting them to mitsunobu reaction in the presence 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 obtained in
pure form in a manner known per se, for example by distilling off the solvent in
vacuum and re- crystallizing the residue 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 dichlorome thane, ethyl
acetate, hexane, methanol, acetone and their combinations. Preparative 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 example, ethanol or
isopropanol, which was then treated with the desired acid or base as described in
Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of
Pharmaceutical sciences volume 66, page 1-19 (1977)" and in handbook 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
diastereomeric salt/complex by fractional crystallization or by column
chromatography.
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 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
prophylaxis of diseases or disorder or condition such as Alzheimer's disease (AD),
mild cognitive impairment (MCI), senile dementia, vascular dementia, dementia of
Parkinson's disease, attention deficit disorder, attention deficit hyperactivity
disorder (ADHD), dementia associated with Lewy bodies, AIDS dementia complex
(ADC), Pick's disease, dementia associated with Down's syndrome, Huntington's
disease, cognitive deficits associated with traumatic brain injury (TBI), cognitive
and sensorimotor gating deficits associated with schizophrenia, cognitive deficits
associated with bipolar disorder, cognitive impairments associated with depression,
acute pain, post-surgical or post-operative pain, chronic pain, inflammation,
inflammatory pain, neuropathic pain, smoking cessation, 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, periodontitis, 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 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 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
prophylaxis 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 formula
I, as defined hereinabove in combination with or as adjunct to medications used in
the treatment of attention deficit hyperactivity disorders, schizophrenia, and other
cognitive disorders such as Alzheimer's disease, Parkinson's dementia, vascular
dementia or dementia associated with Lewy bodies, traumatic brain injury.
The present invention also provide method of administering a compound of formula
I, as defined hereinabove in combination with or as an adjunct to
acetylcholinesterase inhibitors, disease modifying drugs or biologies 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, wherein the method is
accomplished by administering a therapeutically 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 7
subunit of nicotinic 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 present invention. All
H MR spectra were determined in the solvents indicated and chemical shifts are
reported in units downfleld from the internal standard tetramethylsilane (TMS)
and interproton coupling constants are reported in Hertz (Hz).
Example 1: Preparation of 4-(5-(4,4-dimethylchroman-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol-1-yljbenzenesulfonamide .
Step 1: 2-Bromo-l-(4,4-dimethylchroman-6-yl)ethanone
To a stirred solution of l-(4,4-dimethylchroman-6-yl)ethanone (prepared according
to the procedure reported in J.Med. Chem,1985, 28, 1, 116-124, 2.0g , 9.80
mmol) in methanol (30 ml.) was added bromine (1.57g, 0.5 ml, 9.80 mmol) in a
dropwise manner at 10°C. 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 minutes 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 anhydrous Na2S04. 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+l)
HNMR (CDCla, 400 MHz): 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-l-(4,4-dimethylchroman-6-yl)hexane-l,4-dione
To the stirred solution of pulverized sodium (0.2g , 8.63 mmol) in toluene (40 ml)
was added hexane-2,4-dione (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 0.894g, 7.85 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo-l-(4,4-dimethylchroman-6-yl)ethanone (step 1, 2.0g , 7.07
mmol) in toluene (10 ml) and reaction mixture was heated at 60°C 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 Na2S04. 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+l)
HNMR (CDC13, 400 MHz): 7.90 (d, J=2.4Hz, 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,
J=6.8Hz, 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-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide
A mixture of 3-acetyl-l-(4,4-dimethylchroman-6-yl)hexane-l,4-dione (step 2, 1.3g ,
4.1 1 mmol) and 4-aminobenzenesulfonamide (0.7g, 4. l lmmol) in acetic acid (5 ml)
was heated at 110° 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 concentrated at reduced pressure. Ethyl acetate (100 ml) was
added to the residue, washed with water (10 ml). Combined organic layer was dried
over anhydrous Na2S04. 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 4% methanol in dichloro methane as an eluent to yield
the title compound (0.460 g, 24.8%)
MS: m/z 453 (M+l)
HNMR (CDCI3, 400 MHz): 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-dimethylchroman-6-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide [Alternative Method]
Step 1: Ethyl 2-acetyl-4-(4,4-dimethylchroman-6-yl)-4-oxobutanoate
To the stirred solution of pulverized sodium (0.35g, 15.61 mmol) in toluene (40 ml)
was added ethyl-3-oxobutanoate (3.05g, 2.97 ml, 23.46 mmol) at 0°C and reaction
mixture was stirred at room temperature for 2 hr. To this was added solution of 2-
bromo-l-(4,4-dimethylchroman-6-yl)ethanone (4.41g , 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 mixture was added
cold water (30 ml) and extracted with ethyl acetate (2x250 ml) and the combined
organic layer was dried over anhydrous Na2S04. 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 DCM as an eluent to yield the
title compound (3.5g, 67.3%).
MS: m/z 333 (M+l)
Step 2 : Ethyl 5-(4,4-dimethylchroman-6-yl)-2-methyl-l-(4-sulfamoylphenyl)-lHpyrrole-
3-carboxylate
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 110° C for 15 hr. The completion of reaction was
monitored by TLC. Reaction mixture was concentrated at reduced pressure. Ethyl
acetate (250 ml) was added to the residue, washed with water (lx 30 ml). Organic
layer was dried over anhydrous Na2S04. 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 (2.5 g, 50.80%)
MS: m/z 469 (M+l)
Step 3 : 5-(4,4-dimethylchroman-6-yl)-2-methyl- l-(4-sulfamoylphenyl)- lH-pyrrole-
3-carboxylic acid
Ethyl 5-(4,4-dimethylchroman-6-yl)-2-methyl- l-(4-sulfamoylphenyl)- lH-pyrrole-3-
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 reiluxed
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 % HC1 upto pH7, aqueous layer was extracted with ethyl
acetate (2 x 100 ml). Combined organic layer was dried over anhydrous Na2S04.
The solvent was evaporated under reduced pressure to obtain a product. (1.7g,
72.3%)
MS: m/z 441 (M+l)
Step 4 : 1-(4- (N- ((dimethylamino)methylene)sulfamoyl)phenyl) -5-(4,4-
dimethylchroman-6-yl)-iV-methoxy-iV,2-dimethyl-lH-pyrrole-3-carboxamide
Oxalyl chloride (0.98g, 0.65ml, 7.72 mmol) was added dropwlse at 0°C to a
solution of 5-(4,4-dimethylchroman-6-yl)-2-methyl- l-(4-sulfamoylphenyl)- 1 -
pyrrole-3-carboxylic acid (step 3,1.7g, 3.86 mmol) in dichloromethane (100 ml)and
DMF (0.56g, 0.59 ml, 7.72 m mol). Mixture was allowed to come at room
temperature and stirred for 2 hr. under nitrogen atmosphere. The completion of
reaction was monitored by TLC. The mixture was concentrated under reduced
pressure and used directly for further reaction.
To this residue was added ,-dimethy lhydroxylamine hydrochloride (0.75g, 7.72
mmol) in dry dichloromethane (50 ml) at 0°C followed by the addition of
triethylamine (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, filtered
and concentrated at reduced pressure to get a crude product. This crude product
was purified 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+l)
Step 5 : 4-(5-(4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide
To a solution of l-4-(iV-((dimethylamino)methylene)sulfamoyl)phenyl)-5-(4,4-
dimethylchroman-6-yl )-N -methoxy -N ,2-dimethyl-lH-pyrrole-3-carboxamide (Step
4 , 1.67g , 3.10 mmol) in anhydrous THF (25 ml) at 0°C, Grignard reagent [ethyl
magnesium bromide, 2.06g , 15.5 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, reaction mixture was
quenched by addition of solution of saturated ammonium chloride (20 ml) and
extracted with ethyl acetate (2 xlOO ml) . Combined organic layer was dried over
anhydrous Na2S04. 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 finally purified by preparative HPLC (0.1 OOg, 7.1 %)
MS: m/z 453 (M+l)
HNMR (CDC13, 400 MHz): 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), 4.1 1 (t,
J=5.2Hz, 2H), 2.86 (q, J=7.2Hz, 2H), 2.44 (s, 3H), 1.71 (t, J = 5.2 Hz, 2H), 1.21(t,
J=7.2Hz, 3H) , 1.02 (s, 6H).
Example 3 : Following compounds of the present inventions were prepared using a
process analogous to Example 1 and 2 by appropriately changing the reactants
required.
4-(5-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)-2-methyl-3-propionyl- IH-pyrrol- 1-
yl)benzenesulfonamide
MS: m/z 427 (M+l),
HNMR (CDCI3, 400 MHz): 7.96 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4,Hz, 2H), 6.64-
6.66 (m, 2H), 6.58 (d, J=2.0 Hz, IH), 6.40 (dd, J=8.4, 2.0 Hz, IH), 4.87 (bs,
exchanged with D2O 2H), 4. 19-4.22 (m, 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][l ,4]dioxin-6-yl)-3,5-dimethyl-4-propionyl- IH-pyrrol- 1-
yl)benzenesulfonamide
MS: m/z 441 (M+l);
HNMR (CDCI3, 400 MHz): 7.87 (d, J=8.4Hz, 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,
exchanged 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-yl) -2,4- dimethyl- 1-(4-sulfamoylphenyl) -
1H-pyrrole-3-carboxylate
MS: m/z 457 (M+l),
iHNMR (CDCI3, 400 MHz): 7.87 (d, J=8.4Hz, 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-methyl-3-propionyl-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-lH-pyrrol-lyl)
benzenesulfonamide.
MS: m/z 423 (M+l),
HNMR (CDCI3, 400 MHz): 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, J=7.2Hz, 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 4-(5-(2,3-dihydro-lH-inden-4-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide.
Step 1: 2-bromo-l-(2,3-dihydro-lH-inden-4-yl)ethanone
To a stirred solution of l-(2,3-dihydro-lH-inden-4-yl)ethanone (prepared according
to the procedure reported in Monatshefte fur chemie 1996, 127, 275-290, 0.8 gm,
5.00 mmol) in diethyl ether (8 ml) were added AICI3 (0.73 gm, 5.5 mmol) and
bromine (0.96 gm, 0.31 ml, 6.00 mmol) in a drop wise manner at 0°C. 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 product; 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+l),
HNMR (CDCI3, 400 MHz): 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-l-(2,3-dihydro-lH-inden-4-yl)hexane-l,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, 67, 9, , 1510-1512, 0.21 gm, 1.85 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo-l-(2,3-dihydro-lH-inden-4-yl)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 reaction was monitored by TLC. To this reaction mixture
was added cold water (5 ml) and extracted with ethyl acetate (2x30 ml) and the
combined organic layer was dried over anhydrous Na2S04. 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+l),
iHNMR (CDCI3, 400 MHz): 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 (quintet, J=7.2 Hz,
2H), 1.08 (t, J=7.2 Hz, 3H).
Step 3 : 4-(5-(2,3-dihydro- lH-inden-4-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide
To the solution of 3-acetyl-l-(2,3-dihydro-lH-inden-4-yl)hexane-l,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 110° 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). Combined organic layer was dried over anhydrous
Na2S04. The solvent was evaporated under reduced pressure to obtain a crude
product; 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+l),
HNMR (DMSO, 400 MHz): 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, IH), 6.93 (t, J=7.6 Hz, IH), 6.79 (s,
IH), 6.64 (d, J=7.6 Hz, IH), 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 : Preparation of 4-(5-(2,2-dimethylchroman-6-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide.
Step 1: 2-bromo-l-(2,2-dimethylchroman-6-yl)ethanone
To a stirred solution of l-(2,2-dimethylchroman-6-yl)ethanone (prepared according
to the procedure reported in J.Med. Chem,, 1997, 40, 16, 2445-2451, 2.5 gm,
12.25 mmol) in methanol (25 ml) was and bromine (1.96 gm, 0.63ml, 12.25 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 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+l),
HNMR (CDC13, 400 MHz): 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-l-(2,2-dimethylchroman-6-yl)hexane-l,4-dione
To the stirred solution of pulverized sodium (0.37 gm, 16.08 mmol) in toluene (10
ml) was added hexane-2,4-dione (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 1.82 gm, 15.96 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo-l-(2,2-dimethylchroman-6-yl)ethanone (step 1, 3.0 gm, 10.60
mmol) in toluene (10 ml) and reaction mixture was heated at 60°C 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 (2x 100 ml) and the
combined organic layer was dried over anhydrous Na2S04. 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+l),
HNMR (CDC13, 400 MHz): 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, 4H), 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-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide
To the solution of 3-acetyl-l-(2,2-dimethylchroman-6-yl)hexane-l,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 110° 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). Combined organic layer was dried over anhydrous
Na2S04. The solvent was evaporated under reduced pressure to obtain a crude
product; which was purified by column chromatography using 5% methanol in
DCM as an eluent to yield the title compound (0.10 gm, 21.27%).
MS: m/z 453 (M+l),
HNMR (DMSO, 400 MHz): 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, IH), 6.78 (s, IH), 6.57 (dd, J=8.4,
2.0 Hz, IH), 6.47 (d, J=8.4 Hz, IH), 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-dimethylchroman-6-yl)-2-methyl-
3-propionyl- 1H-pyrrol-1-yljbenzenesulfonamide .
Step 1: Methyl 3-(2-iluorophenoxy)propanoate
To a stirred solution of 3-(2-fluorophenoxy)propanoic acid (prepared according to
the procedure reported in WO2010013794, 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 0°C. 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 Ethyl acetate (300 ml). Organic
layer was washed with water (2x 50 ml), dried over anhydrous 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),
H MR (CDCla, 400 MHz): 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)-2-methylbutan-2-ol
To a stirred solution of methyl 3-(2-fluorophenoxy)propanoate (Step-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 0°C
under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 hr. The
completion of reaction was monitored by TLC. Reaction mixture was quenched by
addition of saturated NH4CI 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, filtered and concentrated at reduced pressure to
get a crude product; which was purified by column chromatography 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),
HNMR (CDCI3, 400 MHz): 6.88 - 7.09 (m, 4H), 4.24 (t, J=6.4 Hz, 2H), 2.35 (bs,
exchanges 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 AICI3 (8.67 gm, 65.05 mmol) in nitromethane (50 ml) was
added solution of 4-(2-fluorophenoxy)-2-methylbutan-2-ol (Step-2, 8.5 gm, 43.36
mmol) in nitromethane (20 ml) in a drop wise manner at 0°C. The resulting mixture
was stirred at room temperature for 3 hr. The completion of reaction was
monitored by TLC. Reaction mixture was quenched with 2N HC1 (50 ml) at 0°C.
Aqueous layer was extracted with ethyl acetate (2 x 100 ml). Organic layers
separated were 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 (5.80 gm, 74.35%).
MS: m/z No ionization,
HNMR (CDCla, 400 MHz): 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-l-(8-fluoro-4,4-dimethylchroman-6-yl)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 resulting 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 extracted with ethyl acetate (2 x 100
ml). Organic layers washed with IN HC1 (50 ml), water (50 ml). Organic layer
separated was dried over anhydrous sodium sulphate, filtered and concentrated at
reduced pressure to get a crude product; 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+l),
HNMR (CDCI3, 400 MHz): 7.75 - 7.76 (m, 1H), 7.28 (d, J=1 1.2 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- l-(8-iluoro-4,4-dimethylchroman-6-yl)hexane- 1,4-dione
To the stirred solution of pulverized sodium (0.057 gm, 2.49 mmol) in toluene (5
ml) was added hexane-2,4-dione (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 0.23 gm, 1.99 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 2-bromo-l-(8-fluoro-4,4-dimethylchroman-6-yl)ethanone (step 4, 0.5
gm, 1.66 mmol) in toluene (5 ml) and reaction mixture was heated at 60°C for 2 hr
under stirring. The completion of reaction was monitored by TLC. To this reaction
mixture was added cold water (10 ml) and extracted with ethyl acetate (2x 30 ml)
and the combined organic layer was dried over anhydrous Na2S04. 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),
HNMR (CDC13, 400 MHz): 7.34-7.43 (m, 1H), 7.12-7.21 (m, 1H), 5.12-5.15(m,
1H), 4.12-4.34 (m, 4H), 2.04 (s, 3H), 1.84-1.91 (m, 4H), 1.35 (s, 6H), 1.21 (t, J=7.2
Hz, 3H).
Step 6 : 4-(5-(8-fluoro-4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl- lH-pyrrol-
1-yfjbenzenesulfonamide
To the solution of 3-acetyl-l-(8-fluoro-4,4-dimethylchroman-6-yl)hexane-l,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 110° 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 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). Combined organic layer
was dried over anhydrous a S0 . 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+l),
HNMR (CDC13, 400 MHz): 7.99 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 6.74
(dd, J=1 1.6, 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-tetrahydroisoquinolin-7-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide.
And
4-(5-(2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide.
Step 1: 1-(4 ,4-dimethyl-3,4-dihydroisoquinolin- 2(1H)-yl)ethanone
To a stirred solution of 4,4-dimethyl-l,2,3,4-tetrahydroisoquinoline (prepared
according to the procedure reported in WO20050037214 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 0°C 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 completion of reaction was monitored by TLC. Reaction mixture was diluted
with DCM (100 ml), washed with water (2x 25 ml) followed by brine (25 ml).
Combined organic layer was dried over anhydrous Na2S04. 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 2.5% methanol in
DCM as an eluent to yield the title compound (4.9 g, 97%)
MS: m/z 204 (M+l),
HNMR (DMSO, 400 MHz): 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 l-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-
bromoethanone
And
:tyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-2-bromoethanone
To a stirred solution of A1C13 (1.84 gm, 13.79 mmol) in DCE (30 ml) was added
solution of l-(4,4-dimethyl-3,4-dihydroisoquinolin-2(lH)-yl)ethanone (Step-1, 2.0
gm, 9.85 mmol) in DCE (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, filtered and concentrated at reduced pressure to get 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 l-(2-acetyl-
4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2- bromoethanone and l-(2-
acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)-2-bromoethanone (2. 1 gm,
65.83%)
Step 3 : Mixture of 3-acetyl-l-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-
7-yl)hexane- 1,4-dione
And
3-acetyl-l-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)hexane-
To the stirred solution of pulverized sodium (0.22 gm , 9.42 mmol) in toluene (40
ml) was added hexane-2,4-dione (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 0.98 gm, 8.56 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of mixture of the l-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-
yl)-2-bromoethanone and l-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-6-
yl)-2-bromoethanone (step 2 , 2.5 gm , 7.71 mmol) in toluene (10 ml) and reaction
mixture was heated at 60°C 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 a S0 . 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 2.5% methanol in DCM as an eluent to yield mixture of
3-acetyl- l-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)hexane- 1,4-
dione and 3-acetyl- l-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-6-
yl)hexane- 1,4-dione (1.45 gm, 47.5%).
Step 4 : 4-(5-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide
And
4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide
To the solution of the mixture of 3-acetyl-l-(2-acetyl-4,4-dimethyl-l,2,3,4-
tetrahydroisoquinolin-7-yl)hexane- 1,4-dione and 3-acetyl- l-(2-acetyl-4,4-dimethyll,
2,3,4-tetrahydroisoquinolin-6-yl)hexane-l,4-dione (step 3, 1.4 gm , 3.92 mmol) in
acetic acid (5 ml) was added 4-aminobenzenesulfonamide (0.68 gm, 3.92 mmol) at
room temperature. Reaction mixture was heated at 110° 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 concentrated at reduced
pressure. Ethyl acetate (100 ml) was added to the residue, washed with water (10
ml). Combined organic layer was dried over anhydrous Na2S04. 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-(2-acetyl-4,4-dimethyl-l,2,3,4-
tetrahydroisoquinolin-7-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide and 4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-
tetrahydroisoquinolin-6-yl)-2-methyl-3-propionyl 1H-pyrrol- 1-
yl)benzenesulfonamide. The mixture 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)-2-methyl-3-propionyl- 1H-pyrrol- l-yl)benzenesulfonamide
MS: m/z 494 (M+l),
HNMR (DMSO, 400 MHz): 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, IH), 7.01 (s, IH), 6.92 (d, J=2.4 Hz, IH),
6.72-6.74 (m, IH), 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), 1.1 1 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).
Second title compound : 4-(5-(2-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroisoquinolin-
6-yl)-2-methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide
MS: m/z 494 (M+l),
HNMR (DMSO, 400 MHz): 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, IH), 6.78-6.81 (m, IH), 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).
Example 8 : Preparation of 4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-
yl)-2-methyl-3-propionyl- 1H-pyrrol-1-yl)benzenesulfonamide .
To the solution of the 4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-
yl)-2-methyl-3-propionyl-lH-pyrrol-l-yl)benzenesulfonamide (First title compound
of step 4 in Example-7, 0.2 gm, 0.40 mmol) in acetonitrile (8 ml) was 6M HC1 (10
ml) at room temperature. Reaction mixture was heated at 80° C for 15 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 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 Na2S04. 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+l),
HNMR (DMSO, 400 MHz): 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-methyl-3-propionyl-5-(3Hspiro
[benzo[b][1,4]dioxine-2 ,1'-cyclopropan]-7-yl)-1H-pyrrol-1-
yl)benzenesulfonamide.
And
4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropan]-6-
yl)-1H-pyrrol-1-yl)benzenesulfonamide .
Step 1: Methyl 4-bromo-2-(2-((4-methoxybenzyl)oxy)phenoxy)butanoate
To a stirred solution of 2-((4-methoxybenzyl)oxy)phenol (prepared according to the
procedure reported in JOC, 1994, 59, 22, 6567-6587, 10.0 gm , 43.48 mmol) in
DMF (100 ml) were added K2CO3 (7.81 gm, 56.52 mmol) and methyl 2,4-
dibromobutanoate (14.58 gm, ml, 56.52 mmol) at 25°C. The resulting mixture was
stirred at 150°C 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
Na2S04. 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 10% ethyl acetate in hexanes as an eluent to yield the title compound
(10.0 g, 56.24%)
MS: m/z 410 (M+l),
HNMR (CDC13, 400 MHz): 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 l-(2-((4-methoxybenzyl)oxy)phenoxy)cyclopropanecarboxylate
To a stirred solution of methyl 4-bromo-2-(2-((4-
methoxybenzyl)oxy)phenoxy)butanoate (Step-1, 8.0 gm, 19.60 mmol) in THF (100
ml) was added potassium t-butoxide (2.41 gm, 21.56 mmol) at 0°C under nitrogen
atmosphere. The resulting mixture was stirred at room temperature for 3 hr. The
completion of reaction was monitored by TLC. Excess of reagent was quenched
with saturated NH4CI solution (20 ml) at 0°C. Aqueous layer was extracted with
ethyl acetate (2 x 150 ml). Organic layers separated were dried over anhydrous
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),
HNMR (CDCI3, 400 MHz): 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 : (l-(2-((4-methoxybenzyl)oxy)phenoxy)cyclopropyl)methanol
To a stirred solution of methyl l-(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 0°C under nitrogen
atmosphere. The resulting mixture was stirred at room temperature for 3 hr. The
completion of reaction was monitored by TLC. Excess of reagent was quenched
with saturated NH4CI solution (10 ml) at 0°C. Reaction mixture was filtered
through bed of a2S0 ; 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),
iHNMR (CDCI3, 400 MHz): 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-(l-(hydroxymethyl)cyclopropoxy)phenol
To a stirred solution of 10% palladium on carbon (1.5 gm) in methanol (25 ml), was
added solution of (l-(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 stirred at 60°C 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 filtered. Filtrate was
concentrated under reduced pressure to yield the title compound (0.85 g, 94.4%)
MS: m/z 203 (M+23),
HNMR (CDC13, 400 MHz): 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][l,4]dioxine-2, l'-cyclopropane]
To a stirred solution of 2-(l-(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 followed by addition of diethyl azodicarboxylate (1.39 gm, 1.26 ml, 7.99 mmol)
under nitrogen 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 Na2S04. 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 10% ethyl acetate
in hexanes as an eluent to yield the title compound (0.91 g, 84.2%)
MS: m/z No Ionization,
HNMR (CDCI3, 400 MHz): 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-l-(3H-spiro[benzo[b][l,4]dioxine-2,l ,-cyclopropan]-7-
yl)ethanone
And
2-bromo-l-(3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropan]-6-yl)ethanone
To a stirred solution of AICI3 (0.88 gm, 6.66 mmol) in CS2 (5 ml) was added solution
of 3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropane] (Step-5, 0.9 gm, 5.55 mmol) in
CS2 (5 ml) and 2-bromoacetyl bromide (1.35 gm, 0.58 ml, 6.66 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
quenched by addition of cold water (10 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
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-l-(3Hspiro[
benzo[b][ 1,4]dioxine-2, 1'-cyclopropan]-7-yl)ethanone and 2-bromo- 1-(3Hspiro[
benzo[b][l,4]dioxine-2,l'-cyclopropan]-6-yl)ethanone (0.4 gm, 25.47%)
Step 7 : Mixture 3-acetyl-l-(3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropan]-7-
yl)hexane- 1,4-dione
And
3-acetyl- l-(3H-spiro[benzo[b] [1,4]dioxine-2, l'-cyclopropan]-6-yl)hexane- 1,4-dione
To the stirred solution of pulverized sodium (0.034 gm, 1.47 mmol) in toluene (5
ml) was added hexane-2,4-dione (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 0.15 gm, 1.36 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of mixture of 2-bromo-l-(3H-spiro[benzo[b][l,4]dioxine-2,l'-cyclopropan]-
7-yl)ethanone and 2-bromo-l-(3H-spiro[benzo[b][l,4]dioxine-2,l ,-cyclopropan]-6-
yl)ethanone (step 6, 0.35 gm, 1.23 mmol) in toluene (5 ml) and reaction mixture
was heated at 60°C 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 Na2S04. 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 25% ethyl acetate in hexanes as an eluent to yield
mixture of 3-acetyl- 1-(3H-spiro[benzo[b] [1,4 ]dioxine-2,1'- cyclopropan]-7-yl)hexane-
1,4-dione and 3-acetyl- l-(3H-spiro[benzo[b][ 1,4]dioxine-2, 1'-cyclopropan]-6-
yl)hexane-l,4-dione (0.23 gm, 58.9%).
Step 8 : 4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][l,4]dioxine-2, 1'-
cyclopropan]-7-yl)-lH-pyrrol-l-yl)benzenesulfonamide
And
4-(2-methyl-3-propionyl-5-(3H-spiro [benzo[b] [1,4]dioxine-2, l'-cyclopropan]-6-yl)-
1H-pyrrol- 1-yl)benzenesulfonamide
To the solution of the mixture of 3-acetyl- 1-(3H-spiro [benzo[b] [l,4]dioxine-2, -
cyclopropan]-7-yl)hexane- 1,4-dione and 3-acetyl- l-(3H-spiro [benzo[b] [1 ,4]dioxine2,
l'-cyclopropan]-6-yl)hexane-l,4-dione (step 7, 0.2 gm, 0.63 mmol) in
toluene: acetic acid (5:0.5 ml) was added 4-aminobenzenesulfonamide (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
110° 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 (50 ml) was added to the
residue, washed with water (10 ml). Combined organic layer was dried over
anhydrous Na2S04. 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 40 % ethyl acetate in hexanes as an eluent to yield mixture of the
4-(2-methyl-3-propionyl-5-(3H-spiro[benzo[b][l,4]dioxine-2, l'-cyclopropan]-7-yl)-
lH-pyrrol- l-yl)benzenesulfonamide and 4-(2-methyl-3-propionyl-5-(3Hspiro[
benzo[b][ 1,4]dioxine-2, 1'-cyclopropan]-6-yl)- lH-pyrrol- 1-
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-methyl-3-propionyl-5-(3H-spiro[benzo[b] [1,4]dioxine-2, 1'-
cyclopropan]-7-yl)-lH-pyrrol-l-yl)benzenesulfonamide
MS: m/z 453 (M+l),
HNMR (DMSO, 400 MHz): 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, IH), 6.72 (d, J=8.4 Hz, IH), 6.55 (d, J=2.0 Hz,
IH), 6.47 (dd, J=8.4, 2.0 Hz, IH), 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-methyl-3-propionyl-5-(3H-spiro[benzo[b][l,4]dioxine-
2,l'-cyclopropan]-6-yl)-lH-pyrrol-l-yl)benzenesulfonamide
MS: m/z 453 (M+l),
iHNMR (DMSO, 400 MHz): 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, IH), 6.70 (d, J=2.0 Hz, IH), 6.61 (d, J=8.4 Hz,
IH), 6.42 (dd, J=8.4, 2.0 Hz, IH), 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-(l-acetyl-4,4-dimethyl-l, 2,3,4-
tetrahydroquinolin-6-yl)-2-methyl-3-propionyl-lH-pyrrol-lyl)
benzenesulfonamide.
And
4-(5-( l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide.
Step 1: Mixture of l-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-
bromoethanone
And
l-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-bromoethanone
To a stirred solution of AICI3 (1.31 gm, 6.40 mmol) in DCE (30 ml) was added
solution of l-(4,4-dimethyl-3,4-dihydroquinolin-l(2H)-yl)ethanone (prepared
according to the procedure reported in US 4808597, 1.2 gm, 5.91 mmol) in DCE
(10 ml) and 2-bromoacetyl bromide (0.94 gm, 0.41 ml, 7.00 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 (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 purified by
column chromatography using 30% ethyl acetate in hexanes as an eluent to yield
the mixture of l-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-
bromoethanone and l-( l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)-2-
bromoethanone (0.80 gm, 42.10%).
Step 2 : Mixture of 3-acetyl-l-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-
yl)hexane- 1,4-dione
And
3-acetyl-l-(l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)hexane- 1,4-dione
To the stirred solution 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, 67, 9, , 1510-1512, 0.30 gm, 2.71 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of mixture of l-(l-acetyl-4,4-dimethyl- 1,2,3, 4-tetrahydroquinolin-6-yl)-2-
bromoethanone and l-( l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)-2-
bromoethanone (step 1, 0.80 gm, 2.47 mmol) in toluene (10 ml) and reaction
mixture was heated at 60°C for 2 hr under stirring. 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 a S0 . 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-l-(l-acetyl-4,4-
dimethyl- 1,2,3,4-tetrahydroquinolin-6-yl)hexane- 1,4-dione and 3-acetyl-l-(lacetyl-
4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)hexane- 1,4-dione (0.60 gm,
54.5%).
Step 3 : 4-(5-( l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide
And
4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-propionyl-
1H-pyrrol- 1-yl)benzenesulfonamide
To the solution of the mixture of 3-acetyl-l-(l-acetyl-4,4-dimethyl-l,2,3,4-
tetrahydroquinolin-6-yl)hexane- 1,4-dione and 3-acetyl- 1-(1-acetyl-4,4-dimethyll,
2,3,4-tetrahydroquinolin-7-yl)hexane-l,4-dione (step 2, 0.25 gm , 0.70 mmol) in
acetic acid (5 ml) was added 4-aminobenzenesulfonamide (0.24 gm, 1.40 mmol) at
room temperature. Reaction mixture was heated at 110° 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 (50 ml) was added to the residue, washed with water (10
ml). Combined organic layer was dried over anhydrous Na2S04. 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-(l-acetyl-4,4-dimethyl-l,2,3,4-
tetrahydroquinolin-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-yl)benzenesulfonamide
and 4-(5-(l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide. The mixture was separated 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-(l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-6-yl)-
2-methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide
MS: m/z 494 (M+l),
HNMR (DMSO, 400 MHz): 7.90 (d, J=8.4 Hz, 2H), 7.47-7.53 (m, 5H), 7.05 (d,
J=8.0 Hz, IH), 6.94 (s, IH), 6.75 (s, IH), 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-( l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-
yl)-2-methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide
MS: m/z 494 (M+l),
HNMR (DMSO, 400 MHz): 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).
Example 11: Preparation of 4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-
yl)-2-methyl-3-propionyl-1H-pyrrol-1-yljbenzenesulfonamide.
And
4-(5-(4,4-dimethyl-1,2,3,4-tetrahy droquinolin-7-yl)-2-methyl-3-propionyl-1Hpyrrol-
1-yljbenzenesulfonamide.
To the stirred solution of mixture of the 4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-
tetrahydroquinolin-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-yl)benzenesulfonamide
and 4-(5-(l-acetyl-4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide (step 3 in Example-8, 0.1 gm, 0.20
mmol) in acetonitrile (5 ml) was 6M HCl (10 ml) at room temperature. Reaction
mixture was heated at 100° 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 minutes.
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 Na2S04. The solvent was evaporated under reduced
pressure to obtain a crude product; 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, 27.47%).
First title compound : 4-(5-(4,4-dimethyl- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-
3-propionyl- lH-pyrrol- 1-yl)benzenesulfonamide
MS: m/z 452 (M+l),
HNMR (CDCI3, 400 MHz): 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-dimethyl- 1,2,3, 4-tetrahydroquinolin-7-yl)-2-
methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide
MS: m/z 452 (M+l),
iHNMR (CDCI3, 400 MHz): 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 (bs-exchanges 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 (bs-exchanges with D20 , 1H), 1.22 (s, 6H),
1.20 (t, J=7.2 Hz, 3H).
Example 12: Preparation of 4-(5-(4,4-dimethyl-2-oxo-l, 2,3,4-
tetrahydroquinolin-6-yl)-2-methyl-3-propionyl-lH-pyrrol-lyl)
benzenesulfonamide.
And
4-(5-(4,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide.
Step 1: Mixture of 6-(2-bromoacetyl)-4,4-dlmethyl-3,4-dlhydroqulnolln-2(lH)-one
And
7-(2-bromoacetyl)-4,4-dlmethyl-3,4-dlhydroqulnolln-2(lH)-one
To a stirred solution of AICI3 (7.50 gm, 56.25 mmol) in CS2 (30 ml) was added
solution of 4,4-dimethyl-3,4-dihydroquinolin-2(lH)-one (prepared according to the
procedure reported in US 4808597, 2.5 gm, 14.20 mmol) in CS2 (20 ml) and 2-
bromoacetyl bromide (4.32 gm, 1.88 ml, 21.70 mmol) in a drop wise manner at
0°C. 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 acetate (2 x 100 ml).
Organic layers separated were dried over anhydrous sodium sulphate, filtered 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(lH)-one and
7-(2-bromoacetyl)-4,4-dimethyl-3,4-dihydroquinolin-2(lH)-one (2.00 gm, 47.4%).
Step 2 : Mixture of 3-acetyl-l-(4,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-
yl)hexane- 1,4-dione
And
3-acetyl- l-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-7-yl)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 (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 0.77 gm, 6.70 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of mixture of 6-(2-bromoacetyl)-4,4-dimethyl-3,4-dihydroquinolin-2(lH)-
one and 7-(2-bromoacetyl)-4,4-dimethyl-3,4-dihydroquinolin-2(lH)-one (step 1,
2.00 gm, 6.70 mmol) in toluene (15 ml) and reaction mixture was heated at 60°C
for 2 hr under stirring. 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 a S0 . 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-l-(4,4-dimethyl-2-oxo-l,2,3,4-
tetrahydroquinolin-6-yl)hexane-l,4-dione and 3-acetyl-l-(4,4-dimethyl-2-oxol,
2,3,4-tetrahydroquinolin-7-yl)hexane-l,4-dione (1.30 gm, 58.55%).
Step 3 : 4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide
4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-propionyl- 1Hpyrrol-
1-yl)benzenesulfonamide
To the solution of the mixture of 3-acetyl-l-(4,4-dimethyl-2-oxo-l,2,3,4-
tetrahydroquinolin-6-yl)hexane-l,4-dione and 3-acetyl-l-(4,4-dimethyl-2-oxol,
2,3,4-tetrahydroquinolin-7-yl)hexane-l,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 110° 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 (30
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 (30 ml). Combined organic layer was dried over anhydrous Na2S04. 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-2-
oxo- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide and 4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-7-
yl)-2-methyl-3-propionyl-lH-pyrrol-l-yl)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-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)-2-
methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide
MS: m/z 466 (M+l),
HNMR (DMSO, 400 MHz): 10.46 (bs-exchanges with D20 , IH), 7.99 (d, J=8.4 Hz,
2H), 7.56-7.72 (m, 6H), 6.97 (d, J=8.4 Hz, IH), 6.21 (s, IH), 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-dimethyl-2-oxo- 1,2,3, 4-tetrahydroquinolin-7-yl)-
2-methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide
MS: m/z 466 (M+l),
iHNMR (DMSO, 400 MHz): 10.13 (bs-exchanges with D20 , IH), 7.89 (d, J=8.4 Hz,
2H), 7.46-7.51 (m, 4H), 7.03 (dd, J=8.0, 2.0 Hz, IH), 6.87 (s, IH), 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-methyl-3-propionyl-5-(l,4,4-trimethyl-2-
1,2, 3,4-tetrahy droquinolin-6-yl)- 1H-pyrrol-1-yljbenzenesulfonamide.
Step 1: 6-(2-bromoacetyl)-l,4,4-trimethyl-3,4-dihydroquinolin-2(lH)-one
To a stirred solution of A1C13 (2.36 gm, 17.7 mmol) in CS2 (30 ml) was added
solution of l,4,4-trimethyl-3,4-dihydroquinolin-2(lH)-one, (prepared according to
the procedure reported in European Journal of Medicinal Chemistry, 2008, 43, 8 ,
1730 - 1736, 2.8 gm, 14.80 mmol) in CS2 (20 ml) and 2-bromoacetyl bromide (3.26
gm, 1.42 ml, 16.20 mmol) in a drop wise manner at 0°C. 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). Organic layers separated were
dried over anhydrous sodium sulphate, filtered and concentrated at reduced
pressure to get a crude product; which was purified by column chromatography
using 45% ethyl acetate in hexanes as an eluent to yield the title compound (2.00
gm, 43.57%).
MS: m/z 3 11 (M+l),
Step 2 : 3-acetyl- 1- (1,4,4-trimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)hexane-
1,4-dione
To the stirred solution of pulverized sodium (0.220 gm, 9.56 mmol) in toluene (15
ml) was added hexane-2,4-dione (prepared according to the procedure given in J .
Amer. Chem. Soc, 1945, 67, 9, , 1510-1512, 0.87 gm, 7.60 mmol) at 0°C and
reaction mixture was stirred at room temperature for 2 hr. To this was added
solution of 6-(2-bromoacetyl)-l,4,4-trimethyl-3,4-dihydroquinolin-2(lH)-one (step
1, 2.00 gm, 6.40 mmol) in toluene (15 ml) and reaction mixture was heated at 60°C
for 2 hr under stirring. 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 Na2S04. 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+l),
Step 3 : 4-(2-methyl-3-propionyl-5-(l ,4,4-trimethyl-2-oxo- 1,2,3,4-
tetrahydroquinolin-6-yl)- lH-pyrrol- l-yl)benzenesulfonamide
To the solution of the 3-acetyl-l-(l,4,4-trimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-
6-yl)hexane-l,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 110° 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 (30 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 (30 ml). Combined
organic layer was dried over anhydrous a S0 . 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, 11.2%).
MS: m/z 480 (M+l),
HNMR (CDC13, 400 MHz): 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 screening
Compounds were tested in a cell-based real-time kinetic assay in human IMR-32
cells with native expression of 7nAChR. The increase in intracellular Ca2+ levels
was measured in a Fluoro metric Imaging Plate Reader (FLIPR). Test compound and
agonist solutions were made in assay buffer (HBSS, pH 7.4, 20 mM HEPES, and 10
mM CaCk). Briefly, cells were plated into Poly-D-Lysine coated back- walled clearbottom
96-well microplates at a density of 80,000 to 100,000 cells/well and
incubated at 37°C/5% CO2 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 ul 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 37°C 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 ul of test compound solution and subsequent
monitoring of fluorescence changes for up to 10 min. This was followed by addition
of 25 ul of agonist (PNU-282987, 10 uM) solution and measurement of fluorescence
for 4 min. (Faghih R. et al. 2009, J . Med. Che 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. EC50 of the
compound was calculated using GraphPad Prism software version 5.0, by plotting
compound concentrations against fold PAM activity.
The compounds of the present invention showed 2 to 30 fold activation at 1 
concentration.
CLAIMS
1. A compound of the general formula I, its tautomeric forms, its
stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its
pharmaceutically acceptable salts, its polymorphs, its solvates, its optical
isomers, its clathrates and its co-crystals;
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, optionally substituted
heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted heterocyclyl, or -
NR5(R6), -A R , -N(R5)OR6;
R3 is selected from hydrogen, optionally substituted alkyl, halo, optionally
substituted cycloalkyl, optionally substituted aryl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, cyano, nitro or -NR (R6), -
OR5;
R s
wherein, phenyl ring 'D' is fused with ring Έ ', which is a non-aromatic five
to eight member ring inclusive of group(s);
o
Y ntly selected at each repetition from -0-, -S-, - -, ,
or q = 1 - 4 ; wherein when Yis selected as -NH- or it is
optionally substituted by [R ]n;
wherein, R5 and R6 are independently selected from hydrogen, optionally
substituted alkyl, optionally substituted heteroalkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted heterocyclyl, R aC(=A1)-;
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, -, R C(=A )-;
m = 0 to 2 ;
n = 0 to 3 ;
p = 0 to 4 ;
such that, when p = 0 then n 0 ;
wherein, R9 wherever it appears, is selected from hydrogen, optionally
substituted Ci 6 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;
R a wherever it appears, is selected from optionally substituted Ci-6 alkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl, and optionally
substituted heterocyclyl;
wherein,
"optionally substituted alkyl", includes a alkyl group optionally substituted
with 1 to 6 substituents selected independently from the group comprising
of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO2- , R^A 1- ,
Rioaoc(=0)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-,
RioaC(=0)N(H)-, (R ) (H)N-, (Ri o) (alkyl)N-, (R °)(H)NC(=A )N(H)-,
(R o)(alkyl)NC(=A )N(H)-;
"optionally substituted heteroalkyl" includes a heteroalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl.
"optionally substituted cycloalkyl" includes a cycloalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R10aC(=O)-,
Rioa o 2- , R A - , R o OC(=0)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-,
(R o)(alkyl)NC(=0)-, Ri0a C(=O)N(H)-, (R o)(H)N-, (R o)(alkyl)N-,
(R o)(H)NC(=A )N(H)-, (Rio)(alkyl)NC(=A )N(H)-;
"optionally substituted aryl" includes (i) an aryl group optionally substituted
with 1 to 3 substituents selected independently from the group comprising
of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C 3 to Ce cycloalkyl, Ci to Ce
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-,
alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N (alkyl)-, alkyl-C(=0)N(H)-, alkylN(
alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-
N(H)S02-, H2NSO2-, 3 to 6 membered heterocycle containing 1 to 2
heteroatoms selected from N, O and S optionally substituted with alkyl or
alkyl-C(=0)-, (ii) an aryl ring optionally fused with cycloalkane or heterocycle
across a bond optionally substituted with oxo, alkyl or alkyl-C(=0)-;
"optionally substituted heterocyclyl" includes a (i) heterocyclyl group
optionally substituted on ring carbons with 1 to 6 substituents selected
independently from the group comprising of oxo, halogen, nitro, cyano, aryl,
hereroaryl, alkyl, R A - , Ri aOC(=0)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-,
(R 0)(alkyl)NC(O)-, R 0aC(=O)N(H)-, (R 0)(H)N-, (R 0)(alkyl)N-,
(ii) heterocyclyl group
optionally substituted on ring nitrogen(s) with substituents selected from the
group comprising of aryl, hereroaryl, alkyl, R10aC(=O)-, R10aSO2-,
R
ioa
0 C(=0)-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-;
"optionally substituted heteroaryl" includes
a heteroaryl group optionally substituted with 1 to 3 substituents selected
independently from the group comprising of halogen, nitro, cyano, hydroxy,
Ci to Ce alkyl, C 3 to Ce cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-,
perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-S0 2- , perhaloalkyl-
SO2-, alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-
N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-N(H)S0 2- , H2NSO2-, 3 to 6
membered heterocycle containing 1 to 2 heteroatoms selected from N, O and
S optionally substituted with alkyl or alkyl-C(=0)-;
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.
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.
4 . The compound of formula I as claimed in claim 1, wherein R3 is selected
from hydrogen and methyl.
5 . The compound of formula I as claimed in claim 1, wherein R4 is selected
from
6 . The compound of formula I as claimed in claim 1, wherein R1 is selected
from methyl, R2 is selected from ethyl and ethoxy, R3 is selected from
hydrogen and methyl, and R4 is selected from
7 . The compound of formula I as claimed in claim 1, wherein the compound is
selected from-
4-(5-(4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl-lH-pyrrol-
1-yl)benzenesulfonamide;
4-(5-(2,3-dihydrobenzo[b][l,4]dioxln-6-yl)-2-methyl-3-propionyl-
1H-pyrrol- 1-yl)benzenesulfonamide ;
4-(2-(2,3-dihydrobenzo[b][l,4]dioxln-6-yl)-3,5-dimethyl-4-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
Ethyl 5-(2, 3-dihydrobenzo[b] [1,4] dioxin-6-yl)-2 ,4-dimethyl- 1-(4-
sulfamoylphenyl)-lH-pyrrole-3-carboxylate;
4-(5- (2 ,2-d1methylchroman-6-yl)-2-methyl-3-prop 1onyl- 1H-pyrrol-
1-yl)benzenesulfonamlde;
4-(5-(8-fluoro-4,4-d 1methylchroman-6-yl)-2-methyl-3-prop 1onyl-
1H-pyrrol- 1-yl)benzenesulfonamide ;
4-(5-(2-acetyl-4,4-d 1methyl-l,2,3,4-tetrahydro 1soqu 1nolm-7-yl)-2-
methyl-3-propionyl- 1H-pyrrol- l-yl)benzenesulfonamlde;
4-(5-(2-acetyl-4,4-d 1methyl-l,2,3,4-tetrahydro 1soqu 1nolm-6-yl)-2-
methyl-3-proplonyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-d 1methyl-l,2,3,4-tetrahydro 1soqu 1nolln-7-yl)-2-methyl-
3-proplonyl- 1H-pyrrol- 1-yl)benzenesulfonamide;
4-(2-methyl-3-prop 1onyl-5-(3H-sp 1ro[benzo[b][l,4]d 1ox1ne-2,l'-
cyclopropan] -7-yl) -1H-pyrrol- 1-yl)benzenesulfonamide ;
4-(2-methyl-3-prop 1onyl-5-(3H-sp 1ro[benzo[b][l,4]d 1ox1ne-2,l'-
cyclopropan] -6-yl) -1H-pyrrol- 1-yl)benzenesulfonamide ;
4-(5-(l-acetyl-4,4-d 1methyl-l,2,3,4-tetrahydroqu 1nolm-6-yl)-2-
methyl-3-proplonyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-
methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)-2-
methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-7-yl)-2-
methyl-3-propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl-5-(l, 4,4-trimethyl-2-oxo- 1,2,3,4-
tetrahydroquinolin-6-yl)- lH-pyrrol- l-yl)benzenesulfonamide.
8 . A pharmaceutical composition comprising a compound of claim 1 and a
pharmaceutically acceptable carrier.
9 . A method of preventing or treating a disease or its symptoms or a disorder
mediated partially or completely by nicotinic acetylcholine receptors, said
method comprising administering to a subject having or susceptible to said
disease or its symptoms or disorder with a therapeutically effective amount
of a compound of claim 1.
10. A method of treating a disease or disorder or condition, comprising
administration of a therapeutically effective amount of a compound of
formula I,
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, optionally substituted
heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted heterocyclyl, or -
NR5(R6), -A R , -N(R )OR6;
R3 is selected from hydrogen, optionally substituted alkyl, halo, optionally
substituted cycloalkyl, optionally substituted aryl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, cyano, nitro or -NR5(R6), -
OR5;
R s
wherein, phenyl ring 'D' is fused with ring Έ ', which is a non-aromatic five
to eight member ring inclusive of group(s);
Y ependently selected at each repetition from -0-, -S-, - -,
or where q = 1 - 4 ; wherein when Yis selected as -NH- or , it is
optionally substituted by [R ]n;
wherein, R5 and R6 are independently selected from hydrogen, optionally
substituted alkyl, optionally substituted heteroalkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted heterocyclyl, R aC(=A1)-;
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, -, R C(=A )-;
m = 0 to 2 ;
n = 0 to 3 ;
p = 0 to 4 ;
wherein, R9 wherever it appears, is selected from hydrogen, optionally
substituted Ci 6 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;
R9a wherever it appears, is selected from optionally substituted Ci 6 alkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl, and optionally
substituted heterocyclyl;
wherein,
"optionally substituted alkyl", includes a alkyl group optionally substituted
with 1 to 6 substituents selected independently from the group comprising
of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO - , R^A 1- ,
R i oao c (=0 )-, R 0aC(=O)O-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-,
(R o)(alkyl)NC(=A )N(H)-;
"optionally substituted heteroalkyl" includes a heteroalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl.
"optionally substituted cycloalkyl" includes a cycloalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R10aC(=O)-,
Rioa o 2- , R A - , R o OC(=0)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-,
(R o)(H)N-, (R o) (alkyl)N-,
(R o)(H)NC(=A )N(H)-, (R o)(alkyl)NC(=A )N(H)-;
"optionally substituted aryl" includes (i) an aryl group optionally substituted
with 1 to 3 substituents selected independently from the group comprising
of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C 3 to Ce cycloalkyl, Ci to Ce
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-,
alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N (alkyl)-, alkyl-C(=0)N(H)-, alkyl-
N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-
N(H)S0 2- , H2NS0 2- , 3 to 6 membered heterocycle containing 1 to 2
heteroatoms selected from N, O and S optionally substituted with alkyl or
alkyl-C(=0)-, (ii) an aryl ring optionally fused with cycloalkane or heterocycle
across a bond optionally substituted with oxo, alkyl or alkyl-C(=0)-;
"optionally substituted heterocyclyl" includes a (i) heterocyclyl group
optionally substituted on ring carbons with 1 to 6 substituents selected
independently from the group comprising of oxo, halogen, nitro, cyano, aryl,
hereroaryl, alkyl, R A - , Ri0aQC(=O)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-,
(R o)(alkyl)NC(0)-, R ° C(=0)N(H)-, (R 0)(H)N-, (R °)(alkyl)N-,
(R o)(H)NC(=A )N(H)-, (R °)(alkyl)NC(=A )N(H)-; (ii) heterocyclyl group
optionally substituted on ring nitrogen(s) with substituents selected from the
group comprising of aryl, hereroaryl, alkyl, R10aC(=O)-, R10aSO -,
Rioaoc(=0)-, (R10)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-;
"optionally substituted heteroaryl" includes a heteroaryl group optionally
substituted with 1 to 3 substituents selected independently from the group
comprising of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C 3 to Ce
cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-,
alkyl-N(H)-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-
C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-
N(alkyl)S0 2- , alkyl-N(H)S0 2- , H2NS0 2- , 3 to 6 membered heterocycle
containing 1 to 2 heteroatoms selected from N, O and S optionally
substituted with alkyl or alkyl-C(=0)-;
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.
1. The method of claim 10, wherein the compounds are selected from, 4-(5-
(4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl- 1 -pyrrol- 1-
yl)benzenesulfonamide;
4-(5-(2,3-dihydrobenzo[b] [l ,4]dioxin-6-yl)-2-methyl-3-propionyl- lHpyrrol-
l-yl)benzenesulfonamide;
4-(2-(2,3-dihydrobenzo[b] [l ,4]dioxin-6-yl)-3,5-dimethyl-4-propionyl- lHpyrrol-
l-yl)benzenesulfonamide;
Ethyl 5-(2 ,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-2 ,4-dimethyl- 1-(4-
sulfamoylphenyl)- lH-pyrrole-3-carboxylate;
4-(5-(2,3-dihydro- lH-inden-4-yl)-2-methyl-3-propionyl- IH-pyrrol- 1-
yl)benzenesulfonamide;
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-lHpyrrol-
1-yl)benzenesulfonamide ;
4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-
methyl-3-propionyl- IH-pyrrol- 1-yl)benzenesulfonamide;
4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-2-
methyl-3-propionyl- IH-pyrrol- 1-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl- 5-(3H-spiro [benzo [b] [1,4] dioxine-2 ,1'-
cyclopropan]-7-yl)- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl- 5-(3H-spiro [benzo [b] [1,4] dioxine-2 ,1'-
cyclopropan]-6-yl)- IH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4 ,4-dimethyl- 1,2,3,4-tetrahydro quinolin- 7-yl)-2-methyl- 3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl-5-(l,4,4-trimethyl-2-oxo- 1,2,3,4-
tetrahydroquinolin-6-yl)- lH-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-lHpyrrol-
l-yl)benzenesulfonamide.
12. The method of claim 10, wherein the disorder or condition or disease is
selected from the group comprising of Alzheimer's disease, mild cognitive
impairment, senile dementia, vascular dementia, dementia of Parkinson's
disease, attention deficit disorder, attention deficit hyperactivity disorder,
dementia associated with Lewy bodies, AIDS dementia complex, Pick's
disease, dementia associated with Down's syndrome, Huntington's disease,
cognitive deficits associated with traumatic brain injury, cognitive and
sensorimotor gating deficits associated with schizophrenia, cognitive deficits
associated with bipolar disorder, cognitive impairments associated with
depression, acute pain, post-surgical or post-operative pain, chronic pain,
inflammation, inflammatory pain, neuropathic pain, smoking cessation, 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,
periodontitis, 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,
comprising the step of administering a compound of formula I.
13. The method of claim 10, wherein the disease or disorder or condition is
selected from the group classified or diagnosed as major or minor
neuro cognitive disorders, or disorders arising due to neurodegeneration.
14. The method of claim 10, comprising administering a compound of formula I
in combination with or as adjunct to medications used in the treatment of
attention deficit hyperactivity disorders, schizophrenia, and other cognitive
disorders such as Alzheimer's disease, Parkinson's dementia, vascular
dementia or dementia associated with Lewy bodies, traumatic brain injury.
15. The method of claim 10, further comprising administering a compound of
formula I in combination with or as an adjunct to acetylcholinesterase
inhibitors, disease modifying drugs or biologies for neurodegenerative
disorders, dopaminergic drugs, antidepressants, typical or an atypical
antipsychotic.
16. Use of a therapeutically effective amount of a compound of claim 1 for
preventing or treating a disease or its symptoms or a disorder mediated
partially or completely by nicotinic acetylcholine receptors, comprising
administration of therapeutically effective amount of a compound of claim 1
to a subject having or susceptible to said disease or its symptoms or
disorder.
Use of therapeutically effective amount of a compound of formula I for
treating a disease or disorder or condition, comprising administration of a
therapeutically effective amount of a compound of formula I,
wherein,
R 1 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, optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted heterocyclyl, or -
NR5 (R6), -A R , -N(R5)OR 6 ;
R3 is selected from hydrogen, optionally substituted alkyl, halo, optionally
substituted cycloalkyl, optionally substituted aryl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, cyano, nitro or -NR (R6), -
OR5;
R s
wherein, phenyl ring 'D' is fused with ring Έ ', which is a non-aromatic five
to eight member ring inclusive of group(s);
o
Y ependently selected at each repetition from -0-, -S-, - -, ,
or where q = 1 - 4 ; wherein when Yis selected as -NH- or it is
optionally substituted by [R ]n;
wherein, R5 and R6 are independently selected from hydrogen, optionally
substituted alkyl, optionally substituted heteroalkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted heterocyclyl, R aC(=A1)-;
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, -, R C(=A )-;
m = 0 to 2 ;
n = 0 to 3 ;
p = 0 to 4 ;
wherein, R9 wherever it appears, is selected from hydrogen, optionally
substituted Ci 6 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;
R9 wherever it appears, is selected from optionally substituted Ci 6 alkyl,
optionally substituted heteroalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl, and optionally
substituted heterocyclyl;
wherein,
"optionally substituted alkyl", includes a alkyl group optionally substituted
with 1 to 6 substituents selected independently from the group comprising
of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO2- , R^A 1- ,
Rioao c (=0 )-, R10aC(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-,
R
ioaC(=0)N(H)-, (R o)(H)N-, (R o) (alkyl)N-, (R °) H)NC(=A )N H)-,
(R 0)(alkyl)NC(=A )N(H)-;
"optionally substituted heteroalkyl" includes a heteroalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl.
"optionally substituted cycloalkyl" includes a cycloalkyl group optionally
substituted with 1 to 6 substituents selected independently from the group
comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, R10aC(=O)-,
R
ioa o - R 0A - , R 0aOC(=O)-, R10aC(=O)O-, (R10)(H)NC(=O)-,
(R o)(alkyl)NC(=0)-, Ri0a C(=O)N(H)-, (R o)(H)N-, (R o)(alkyl)N-,
(R 0)(H)NC(=A )N(H)-, (R 0)(alkyl)NC(=A )N(H)-;
"optionally substituted aryl" includes (i) an aryl group optionally substituted
with 1 to 3 substituents selected independently from the group comprising
of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C 3 to Ce cycloalkyl, Ci to Ce
perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-,
alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N (alkyl)-, alkyl-C(=0)N(H)-, alkyl-
N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-
N(H)S02- , H2NS0 2- , 3 to 6 membered heterocycle containing 1 to 2
heteroatoms selected from N, O and S optionally substituted with alkyl or
alkyl-C(=0)-, (ii) an aryl ring optionally fused with cycloalkane or heterocycle
across a bond optionally substituted with oxo, alkyl or alkyl-C(=0)-;
"optionally substituted heterocyclyl" includes a (i) heterocyclyl group
optionally substituted on ring carbons with 1 to 6 substituents selected
independently from the group comprising of oxo, halogen, nitro, cyano, aryl,
hereroaryl, alkyl, R A - , R 0aOC(=O)-, R 0aC(=O)O-, (R 0)(H)NC(=O)-,
(R o)(alkyl)NC(0)-, R C(=O)N(H)-, (R °)(H)N-, (R °)(alkyl)N-,
(R o)(H)NC(=A )N(H)-, (R °)(alkyl)NC(=A )N(H)-; (ii) heterocyclyl group
optionally substituted on ring nitrogen(s) with substituents selected from the
group comprising of aryl, hereroaryl, alkyl, R10aC(=O)-, R10aSO2-,
Rioaoc(=0)-, (R10)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-;
"optionally substituted heteroaryl" includes a heteroaryl group optionally
substituted with 1 to 3 substituents selected independently from the group
comprising of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C 3 to Ce
cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-,
alkyl-N(H)-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-
C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-
N(alkyl)S0 2- , alkyl-N(H)S0 2- , H2NS0 2- , 3 to 6 membered heterocycle
containing 1 to 2 heteroatoms selected from N, O and S optionally
substituted with alkyl or alkyl-C(=0)-;
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 use of claim 10, wherein the compounds are selected from, 4-(5-(4,4-
dimethylchroman-6-yl)-2-methyl-3-propionyl- 1 -pyrrol- 1-
yl)benzenesulfonamide;
4-(5-(2,3-dihydrobenzo[b] [l ,4]dioxin-6-yl)-2-methyl-3-propionyl- lHpyrrol-
l-yl)benzenesulfonamide;
4-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3,5-dimethyl-4-propionyl-lHpyrrol-
1-yl)benzenesulfonamide ;
Ethyl 5-(2 ,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-2 ,4-dimethyl- 1-(4-
sulfamoylphenyl)-lH-pyrrole-3-carboxylate;
4-(5-(2,3-dihydro- lH-inden-4-yl)-2-methyl-3-propionyl- IH-pyrrol- 1-
yl)benzenesulfonamide;
4-(5- (2 ,2-dimethylchroman-6-yl)-2-methyl-3-propionyl- 1H-pyrrol- 1-
yl)benzenesulfonamide;
4-(5-(8-iluoro-4,4-dimethylchroman-6-yl)-2-methyl-3-propionyl-lHpyrrol-
1-yl)benzenesulfonamide ;
4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-
methyl-3-propionyl- IH-pyrrol- 1-yl)benzenesulfonamide;
4-(5-(2-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-2-
methyl-3-propionyl- IH-pyrrol- 1-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyl-3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl- 5-(3H-spiro [benzo [b] [1,4] dioxine-2 ,1'-
cyclopropan]-7-yl)- IH-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl- 5-(3H-spiro [benzo [b] [1,4] dioxine-2 ,1'-
cyclopropan]-6-yl)- IH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(l-acetyl-4,4-dimethyl-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl- lH-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- 1-yl)benzenesulfonamide;
4-(5-(4 ,4-dimethyl- 1,2,3,4-tetrahydro quinolin- 7-yl)-2-methyl- 3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yl)-2-methyl-3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(5-(4,4-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-7-yl)-2-methyl-3-
propionyl- 1H-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl-5-(l,4,4-trimethyl-2-oxo- 1,2,3,4-
tetrahydroquinolin-6-yl)- lH-pyrrol- l-yl)benzenesulfonamide;
4-(2-methyl-3-propionyl-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-lHpyrrol-
l-yl)benzenesulfonamide.
19. The use of claim 10, wherein the disorder or condition or disease is selected
from the group comprising of Alzheimer's disease, mild cognitive
impairment, senile dementia, vascular dementia, dementia of Parkinson's
disease, attention deficit disorder, attention deficit hyperactivity disorder,
dementia associated with Lewy bodies, AIDS dementia complex, Pick's
disease, dementia associated with Down's syndrome, Huntington's disease,
cognitive deficits associated with traumatic brain injury, cognitive and
sensorimotor gating deficits associated with schizophrenia, cognitive deficits
associated with bipolar disorder, cognitive impairments associated with
depression, acute pain, post-surgical or post-operative pain, chronic pain,
inflammation, inflammatory pain, neuropathic pain, smoking cessation,
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, periodontitis, 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,
comprising the step of administering a compound of formula I.
20. The use of claim 10, wherein the disease or disorder or condition is selected
from the group classified or diagnosed as major or minor neurocognitive
disorders, or disorders arising due to neuro degeneration.
21. The use of claim 10, comprising administering a compound of formula I in
combination with or as adjunct to medications used in the treatment of
attention deficit hyperactivity disorders, schizophrenia, and other cognitive
disorders such as Alzheimer's disease, Parkinson's dementia, vascular
dementia or dementia associated with Lewy bodies, traumatic brain injury.
22. The use of claim 10, further comprising administering a compound of
formula I in combination with or as an adjunct to acetylcholinesterase
inhibitors, disease modifying drugs or biologies for neurodegenerative
disorders, dopaminergic drugs, antidepressants, typical or an atypical
antipsychotic.