PYRROLE DERIVATIVES AS ALPHA 7 NACHR MODULATORS
FIELD OF THE INVENTION
The present invention relates to pyrrole derivatives, their tautomeric forms, their
stereoisomers, and their pharmaceutically acceptable salts, pharmaceutical
compositions comprising one or more such compounds, and their use a s
nicotinic acetylcholine receptor 7 subunit ( 7 nAChR) modulators.
CROSS-REFERENCE TO A RELATED APPLICATION
The present application claims the benefit of Indian Provisional Patent
Application No. 52/KOL/2013 filed on 16th January 2013 the disclosure of
which is incorporated herein by reference in its entirety.
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 ( 7 ) configuration (David Paterson
et al., Progress in Neurobiology, 6 1 (2000), 75-11 1). 4 2 and 7 nAChR
constitute the predominant subtypes expressed in the mammalian brain. 7
nAChR has attained prominence a s a therapeutic target due to its abundant
expression in the learning and memory centers of brain, hippocampus and the
cerebral cortex (F. Rubboli et al., Neurochem. Int., 1994, 25 (1), 69-71).
Particularly, 7 nAChR is characterized by a high Ca + ion permeability, which
is responsible for neurotransmitter release and consequent modulation of
excitatory and inhibitory neurotransmission (Manickavasagom Alkondon et al.,
European Journal of Pharmacology, 393 (2000), 59-67; Federico Dajas-Bailador
et al., TRENDS in Pharmacological Sciences, 2004, 25 (6), 317-324).
Furthermore, high Ca + ion influx also has implications on the long-term
potentiation of memory via alterations in gene expression (Robert S. Bitner et
al., The Journal of Neuroscience, 2007, 27 (39), 10578-10587; Bruce E. McKay
et al., Biochemical Pharmacology, 74 (2007), 1120-1 133).
Several recent studies have confirmed the role of 7 nAChR in neural processes
like attention, memory and cognition (Huibert D. Mansvelder et al.,
Psychopharmacology, (2006), 184, 292-305; Wai Kit Chan et al.,
Neuropharmacology, 52 (2007), 1641-1649; Jared W. Young et al., European
Neuropsychopharmacology, (2007), 17, 145-155). Gene polymorphisms
associated with the 7 nAChR protein CHRNA7 have been implicated in the
genetic transmission of schizophrenia, related neurophysiological sensory gating
deficits and resultant cognitive impairment (Robert Freedman et al., Biol.
Psychiatry, 1995, 38, 22-33; Debby W. Tsuang et al., American Journal of
Medical Genetics (Neuropsychiatric Genetics, 105, 662-668 (2001)). 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 7 nAChR in cognition (Peter Curzon et al. ,
Neuroscience Letters, 410 (2006), 15-19; Jared W. Young et al.,
Neuropsychopharmacology, (2004), 29, 891-900). Additionally, pharmacological
blockade of a 7 nAChR impairs memory and its activation enhances same in
preclinical rodent models implicating 7 nAChR as target for cognitive
enhancement (Kenji Hashimoto et al., Biol. Psychiatry, 2008, 63, 92-97).
Pathological brain function in sensory-deficit disorders has been associated with
nicotinic cholinergic transmission particularly through 7 receptors (Robert
Freedman et al., Biol. Psychiatry, 1995, 38, 22-33; T Debby W. Tsuang et al.,
American Journal of Medical Genetics (Neuropsychiatric Genetics, 105, 662-668
(2001); Robyn Carson et al., NeuromoL, Med. (2008), 10, 377-384; S. Leonard et
al., Pharmacology Biochemistry and Behavior, 70 (2001), 561-570; Robert
Freedman et al., Current Psychiatry Report, 2003, 5, 155-161; Tyrone D.
Cannon et al., Current Opinion Psychiatry, 2005, 18, 135-140). A defective preattention
processing of sensory information is understood to be the basis of
cognitive fragmentation in schizophrenia and related neuropsychiatric disorders
(Steven C. Leiser et al., Pharmacology &Therapeutics, 122 (3), (2009), 302-31 1).
Genetic linkage studies have traced sharing of the 7 gene locus for several
affective, attention, anxiety and psychotic disorders (S. Leonard et al.,
Pharmacology, Biochemistry and Behavior, 70 (2001), 561-570; Suemaru K.
Folia et al., Folia Pharmacol. Jpn., 119, 295-300 (2002)).
Perturbations in the cholinergic and glutamatergic homeostasis, has long been
implicated a s causative factors for host of neurological disease, including
dementia(s) (Eran Nizri et al., Drug News Perspect, 2007, 20 (7), 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 7 receptor to -42 is implicated a s an u p
stream pathogenic event in Alzheimer's disease, a major causative factor for
dementia (Hoau-Yan Wang et al., The Journal of Neuroscience, 2009, 29 (35),
10961-10973). Moreover, gene polymorphisms in CHRNA7 have been implicated
in dementia with lewy bodies (DLB) and Pick's disease (Agnes Feher et al.,
Dement. Geriatr. Cogn. Disord., 2009, 28, 56-62).
Disease modification potential of nAChRs particularly the 7 receptor has
application for disease-modification of Alzheimer 's disease (AD) and Parkinson's
disease (PD) by enhancing neuron survival and preventing neurodegeneration
(Hoau-Yan Wang et al., The Journal of Neuroscience, 2009, 29 (35), 10961-
10973; R. G. Nagele et al., Neuroscience, 2002, 110 (2), 199-21 1; G.
Jeyarasasingam et al., Neuroscience, 2002, 109, 275-285). Additionally, 7
nAChR induced activation of anti-apoptotic (BCL-2) and anti-inflammatory
pathways in brain could have neuroprotective effects in neurodegenerative
diseases (Mario B. Marrero et al., Brain Research, 2009, 1256, 1-7). Dopamine
containing neurons of ventral tegmental area (VTA) and laterodorsal tegmental
nucleus (LDT) are known to express nicotinic ACh receptors, particularly 4 ,
3 , 2, 3 , 4 subunits (Alexander Kuzmin et al., Psychopharmacology, (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
(Robert B. Weiss et al., PLoS Genetics, 2008, 4 (7), el000125). 7 nAChR has
particularly been studied for a putative role in cannabis addiction (Marcello
Solinas et al., The Journal of Neuroscience, 2007, 27 (21), 5615-5620).
Varenicline, a partial agonist a t 4 2 , has demonstrated better efficacy in
reducing the smoking addiction and relapse prevention in comparison to
buproprion (Jon O. Ebbert et al., Patient Preference and Adherence, 2010, 4 ,
355-362).
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
(Michael Decker et al., Expert Opin. Investig. Drugs, (2001), 10 (10), 1819-
1830). Several new developments have opened the area for use of nicotinic
modulators for therapy of pain (Michael C. Rowbotham et al., PAIN, 146, (2009),
245-252). Appropriate modulation of the nicotinic ACh receptors could provide
for remedial approach to pain related states.
Another key role of the 7 nAChR is the ability to modulate the production of
pro-inflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha
(TNF-oc), and high mobility group box (HMGB-1) in the central nervous system.
Consequently, an anti-inflammatory and antinociceptive effect in pain disorders
have been demonstrated (M. Imad Damaj et al., Neuropharmacology, 39 (2000),
2785-2791). Additionally, 'cholinergic anti-inflammatory pathway' is proposed to
b e a regulatory of local and systemic inflammation and neuro-immune
interactions through neural and humoral pathways (Margot Gallowitsch-Puerta
et al., Life Sci., 2007, 80 (24-25), 2325-2329; Mauricio Rosas-Ballina et al., Mol.
Med., 15 (7-8), 195-202 (2009); M. Rosas-Ballina et al., J . Intern. Med., 2009,
265, 663-679). Selective modulators of nicotinic ACh receptors, particularly 7
type, like GTS-21, attenuate cytokine production and IL- after endotoxin
exposure. Furthermore, 7 nAChR are understood to have a central role in
arthritis pathogenesis and potential therapeutic strategy for treatment of joint
inflammation (M. Westman et al., Scandinavian Journal of Immunology, 2009,
70, 136-140). A putative role for 7 nAChR has also been implicated in severe
sepsis, endotoxemic shock and systemic inflammation (Y. Jin, et al.,
International Journal of Immunogenetics, 37, 361-365; Chong Liu et al., Crit.
Care Med., 2009, 37 (2), 634-641).
Angiogenesis, is a critical physiological process for the cell survival and
pathologically important for cancer proliferation; several non-neural nicotinic
ACh receptors, particularly 7 , 5 , 3 , 2 , 4 , are involved (Hugo R. Arias et al.,
International Journal of Biochemistry and Cell Biology, 4 1 (2009), 1441-1451;
Christopher Heeschen et al., The Journal of Clinical Investigation, 2002, 110
(4), 527-536). A role of nicotinic ACh receptors in the development of cervical
cancer, lung carcinogenesis and pediatric lung disorders in smoking-exposed
population has also been studied (Itzel E. Calleja-Macias et al., Int. J . Cancer.,
124, 1090-1096 (2009); Hildegard M. Schuller et al., European Journal of
Pharmacology, 393 (2000), 265-277). Several 7 nAChR agonists, partial
agonists, have been characterized for their efficacy in clinical and preclinical
studies. EVP-6124, an agonist at 7 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 7 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 (Ann Olincy et
al., Biol. Psychiatry, 2005, 57 (8, Suppl.), Abst 44; Ann Olincy et al., Arch. Gen.
Psychiatry, 2006, 63, 630-638; Richard Goldstein et al., Acad. Emerg. Med.,
2007, 14 (5), sl85-sl86). CP-810123, a 7 nAChR agonist, exhibits protection
against the scopolamine-induced dementia and inhibition of amphetamineinduced
auditory evoked potentials in preclinical studies (Christopher J .
O'Donnell et al., J . Med. Chem., 2010, 53, 1222-1237). SSR-180711A, also an
7 nAChR agonist, enhances learning and memory, and protects against MK-
80 1/Scopolamine-induced memory loss and prepulse inhibition in preclinical
studies (John P. Redrobe et al., European Journal of Pharmacology, 602
(2009), 58-65; John Dunlop et al., Journal of Pharmacology and Experimental
Therapeutics, 2009, 328, 766-776; Philippe Pichat et al.,
Neuropsychopharmacology, 2007, 32, 17-34). SEN- 12333, protected against
scopolamine-induced amnesia in passive avoidance test in preclinical studies
(Renza Roncarati et al., The Journal of Pharmacology and Experimental
Therapeutics, 2009, 329, 459-468). AR-R- 17779, an agonist at 7 nAChR,
exhibits improvement in the social recognition task performed in rats (Marja
Van Kampen et al., Psychopharmacology, 2004, 172, 375-383). ABBF, an
agonist at 7 nAChR, improves social recognition memory and working memory
in Morris maze task in rats (Frank G. Boess et al., The Journal of Pharmacology
and Experimental Therapeutics, 2007, 321, 716-725). TC-5619, a selective 7
nAChR agonist has demonstrated efficacy in animal models of positive and
negative symptoms and cognitive dysfunction in schizophrenia (T. A. Hauser et
al., Biochemical Pharmacology, 78 (2009), 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 7 nAChR (E. X. Albuquerque et al.,
Alzheimer Diseases and Associated Disorder, Vol. 15, Suppl 1, S19-S25).
Several PAMs have been characterized, albeit in the preclinical stages of
discovery. A-86774, 7 nAChR PAM, improves sensory gating in DBA/2 mice by
significantly reducing the T: C ratio in a preclinical model of schizophrenia
(Ramin Faghih et al., Journal of Medicinal Chemistry, 2009, 52, 3377-3384).
XY-4083, an 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 (Herman J . Hg et al., PNAS, 2007, 104 (19),
8059-8064). Yet another PAM, PNU- 120596, profoundly alters 7 nAChR
desensitization kinetics and simultaneously protecting against the disruption of
prepulse inhibition by MK-801. NS-1738, another PAM, has exhibited efficacy
in-vivo in the animal models of social recognition and spatial memory
acquisition in the Morris maze task (Daniel B. Timmermann et al., Journal of
Pharmacology and Experimental Therapeutics, 2007, 323, 294-307). In
addition, several patents/applications published are listed below - US
2006/0142349, US 2007/0142450, US 2009/0253691, WO 2007/031440, WO
2009/1 15547, WO 2009/135944, WO 2009/127678, WO 2009/127679, WO
2009/043780, WO 2009/043784, US 7683084, US 7741364, WO
2009/145996, US 2010/0240707, WO 201 1/064288, US 2010/0222398, US
2010/0227869, EP 1866314, WO 2010/130768, WO 2011/036167, US
2010/0190819, WO 2012/104782, WO 2012/1 14285, WO 2012/131576, WO
2013/005153 disclose efficacy of allosteric modulators of nicotinic ACh
receptors and underscoring their therapeutic potential.
BRIEF SUMMARY OF THE INVENTION
The present invention provides compound of the general formula (I), its
tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, its
combinations with suitable medicament, its pharmaceutical compositions and
its use a s nicotinic acetylcholine receptor 7 subunit ( 7 nAChR) modulator.
According to one aspect of the present invention there is provided compound
represented by the general formula (I), its tautomeric forms, its stereoisomers,
its pharmaceutically acceptable salts, its combinations with suitable
medicament and its pharmaceutical compositions, wherein R1 to R7 and m are
described in details below.
Thus the present invention further provides a pharmaceutical composition,
containing the compound of the general formula (I) a s defined herein, its
tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts
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 a s 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
decline associated with stroke, poststroke neuroprotection, 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 compound of the general formula (I) as defined herein, its tautomeric forms,
its stereoisomers, its pharmaceutically acceptable salts, its polymorphs, its
solvates, and its optical isomers 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 provides method of administering a compound of
formula (I), as defined herein 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 provides method of administering a compound of
formula (I), as defined herein 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.
The present invention also provides use of a compound of formula (I) as defined
herein in the preparation of a medicament for treating a disease or disorder or
condition selected from the group classified or diagnosed as major or minor
neurocognitive disorders, or disorders arising due to neurodegeneration.
The present invention also provides use of a compound of formula (I) as defined
herein in the preparation of a medicament for treating a disease or disorder or
condition selected from attention deficit hyperactivity disorders, schizophrenia,
cognitive disorders, Alzheimer's disease, Parkinson's dementia, vascular
dementia or dementia associated with Lewy bodies, and traumatic brain injury.
The present invention also provides use of compound of formula (I) as defined
herein in combination with or as an adjunct to acetylcholinesterase inhibitors,
disease modifying drugs or biologies for neurodegenerative disorders,
dopaminergic drugs, antidepressants, or a typical or atypical antipsychotic.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel compound of the general formula (I), its
tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, its
combinations with suitable medicament, and its pharmaceutical compositions,
wherein,
R1 is selected from hydrogen, substituted- or unsubstituted- alkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substitutedor
unsubstituted- heterocyclyl;
R3 is selected from hydrogen and substituted- or unsubstituted- alkyl;
R4 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- heterocyclyl, and -
NR R9; wherein, R8 and R9 are each independently selected from hydrogen,
substituted- or unsubstituted- alkyl, and substituted- or unsubstitutedcycloalkyl;
R5 is selected independently at each occurrence from halogen, substituted- or
unsubstituted- alkyl, perhaloalkyl, substituted- or unsubstituted- cycloalkyl, -
OR b, and -C(=0)R ; or
R6 and R7 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R a is selected from substituted- or unsubstituted- alkyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R b is selected from hydrogen, substituted- or unsubstituted- alkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
m is an integer selected from 0, 1 and 2 ;
wherein,
when the alkyl group is a substituted alkyl group, the alkyl group is substituted
with 1 to 3 substituents selected independently from oxo, halogen, nitro, cyano,
perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b , -SO2R10 , -
C(=O)OR1 , -OC(=O)R1 a , -C(=0)N(H)R1 , -C(=0)N(alkyl)R1 , -N(H)C(=O)R1 a ,
N(H)R1 , -N(alkyl)R1 , -N(H)C(=0)N(H)R1 , and -N(H)C(=0)N(alkyl)R1 ;
when the cycloalkyl and the carbocycle groups are substituted, each of them is
substituted with 1 to 3 substituents selected independently from oxo, halogen,
nitro, cyano, alkyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO 2R10 ,
-C(=O)R1 , -C(=O)OR1 , -OC(=O)R1 , -C(=O)N(H)R d, -C(=O)N(alkyl)R d, -
and
when the aryl group is substituted, it is substituted with 1 to 3 substituents
selected independently from halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl,
cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -
NH2, -S0 2-alkyl, -S0 2-perhaloalkyl, -N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -
C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl,
and -S0 2NH2;
when the heteroaryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy, alkyl,
perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -
N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl, -N(alkyl)C(=0)alkyl, -
N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -C(=0)NH2,
S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heterocyclyl group is substituted, it can be substituted either on a
ring carbon atom(s) or on a ring hetero atom, when it substituted on a ring
carbon atom(s), it is substituted with 1 to 3 substituents selected independently
from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -OR ,
C(=O)N(alkyl)R d , -N(H)C(=O)R1 c , -N(H)R d, -N(alkyl)R d, -N(H)C(=O)N(H)R d,
and -N(H)C(=O)N(alkyl)R10d ; when the 'heterocyclyl' group is substituted on a
ring nitrogen, it is substituted with a substituent selected from alkyl, cycloalkyl,
aryl, heteroaryl, -SO2R c ,
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
io S selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
iob
S selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
and heterocyclyl;
R10 is selected from alkyl, perhaloalkyl, and cycloalkyl;
iod s selected from hydrogen, alkyl, and cycloalkyl.
R1 is particularly selected from substituetd- or unsubstituted- alkyl and
substituted- or unsubstituted- cycloalkyl.
R1 is more particularly selected from methyl, ethyl, cyclopropylmethyl and
cyclopropyl.
R2 is particularly selected as phenyl substituted with halogen.
R2 is more particularly selected as 4-chlorophenyl.
R3 is particularly selected as alkyl.
R3 is more particularly selected as methyl.
R4 is particularly selected from substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedheterocyclyl
and -NR R9; wherein, R8 and R9 are each independently selected
from hydrogen, alkyl, or cycloalkyl.
R4 is more particularly selected from
Whenever a range of the number of atoms in a structure is indicated (e.g., a Cii2,
Ci-8, Ci-6, or Ci-4 alkyl, alkylamino, etc.), it is specifically contemplated that
any sub-range or individual number of carbon atoms falling within the indicated
range also can be used. Thus, for instance, the recitation of a range of 1-8
carbon atoms (e.g., Ci-Cs), 1-6 carbon atoms (e.g., Ci-Ce) , 1-4 carbon atoms
(e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as
used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced
herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g.,
1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6
carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10
carbon atoms, 1-1 1 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4
carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8
carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-1 1 carbon atoms, 2-12
carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7
carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-1 1
carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7
carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-1 1
carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).
General terms used in formula can be defined as follows; however, the meaning
stated should not be interpreted as limiting the scope of the term per se.
The term "alkyl", as used herein, means a straight or branched hydrocarbyl
chain containing from 1 to 20 carbon atoms. Preferably, the alkyl group
contains 1 to 10 carbon atoms. More preferably, alkyl group contains up to 6
carbon atoms. Examples of alkyl groups include, but are not limited to, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, and n-hexyl.
In a substituted alkyl group, the alkyl group is substituted with 1 to 4
substituents selected independently from oxo, halogen, nitro, cyano,
perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b , -SO2R 10 , -
C(=O)OR1 a , -OC(=O)R1 a , -C(=0)N(H)R , -C(=0)N(alkyl)R1 , -N(H)C(=O)R1 a , -
N(H)R1 , -N(alkyl)R1 , -N(H)C(=0)N(H)R1 , and -N(H)C(=0)N(alkyl)R1 ; wherein R10
is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
R10 is selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl; R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and 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
trifiuoromethyl, pentafiuoroethyl, and the like.
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. Examples of
monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Bicyclic ring systems include monocyclic ring
system fused across a bond with another cyclic system which may be an
alicyclic ring or an aromatic ring. Bicyclic rings also include spirocyclic systems
wherein the second ring gets annulated on a single carbon atom. 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. Examples of bicyclic ring systems include, but are not limited to,
bicyclo[3.1. l]heptane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, and bicyclo[4.2. l]nonane,
bicyclo[3.3.2]decane, bicyclo[3. 1.0]hexane, bicyclo[410]heptane,
bicyclo[3.2.0]heptanes, octahydro- IH-indene, spiro[2.5]octane, spiro[4.5]decane,
spiro[bicyclo[4. 1.0]heptane- 2,l'-cyclopentane], hexahydro-2'Hspiro[
cyclopropane-l, l'-pentalene]. Tricyclic ring systems are the systems
wherein the bicyclic systems as described about are further annulated with
third ring, which may be alicyclic ring or aromatic ring. 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. Examples
of tricyclic-ring systems include, but are not limited to,
tricyclo[3.3. 1.03 7]nonane and tricyclo[3.3. 1. 13 ]decane (adamantane).
The term "carbocycle" as used herein, means a cyclic system made up of carbon
atoms, which includes cycloalkyl, and aryl.
When the cycloalkyl or the carbocycle groups are substituted, they are
substituted with 1 to 3 substituents selected independently from oxo, halogen,
nitro, cyano, alkyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO 2R10 ,
-C(=O)R1 , -C(=O)OR1 , -OC(=O)R1 , -C(=O)N(H)R d, -C(=O)N(alkyl)R d, -
and
N(H)C(=O)N(alkyl)R1 d ; wherein R1 is selected from hydrogen, alkyl,
perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R10 is selected from
alkyl, perhaloalkyl, and cycloalkyl; R10d is selected from hydrogen, alkyl, and
cycloalkyl.
The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon
ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl,
fiuorenyl, indenyl, azulenyl, and the like. Aryl group also includes partially
saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydronaphthalene.
When the aryl group is substituted, it is substituted with 1 to 3 substituents
selected independently from halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl,
cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -
NH2, -S0 2-alkyl, -S0 2-perhaloalkyl, -N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -
C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl,
and -S0 2NH2.
The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or
tricyclic ring system having 1 to 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, furanyi, 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,
pyrro1o . |pyri idiny1. pyrazolo |3.4 1pyriniidinyl . and benzo(b)thienyl, 2,3-
thiadiazolyl, lH-pyrazolo[5, l cj-1,2,4-triazolyl, pyrrolo[3,4-d]- 1,2,3-triazolyl,
cyclopentatriazolyl, 3H-pyrrolo[3,4-c] isoxazolyl, 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-dihydrobenzofuran-
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[l,3]dioxol-5-yl,
1,2,3,4-tetrahydroquinolinyl , 1,2,3,4-tetrahydroisoquinolinyl , 2,3-
dihydrobenzothien-4-yl, 2-oxoindolin-5-yl and the like.
When the heteroaryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy, alkyl,
perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -
N(H)alkyl, -NH2, -SCValkyl, -S0 2-perhaloalkyl, -N(alkyl)C(=0)alkyl, -
N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -C(=0)NH2,
S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2.
The term "heterocyclyl" 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. 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. 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- 1-benzofuranyl, 2,3-dihydro- 1-benzothienyl, 2,3-dihydro- 1 Hindolyl
and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also include
bridged heterocyclyl systems such as azabicyclo[3.2. l]octane,
azabicyclo[3.3. l]nonane and the like.
The heterocyclyl group, when it is substituted, it may be substituted on ring
carbon atom or ring nitrogen atom. For example, it is substituted on ring
carbons with 1 to 3 substituents selected independently from halogen, nitro,
cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 10b,
-C(=O)OR , -OC(=O)R , -C(=0)N(H)R , -C(=0)N(alkyl)R ° -N(H)C(=O)R c , -
N(H)Riod, -N(alkyl)Riod, wherein
Riob
S selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
and heterocyclyl; R10 is selected from alkyl, perhaloalkyl, and cycloalkyl; R10d is
selected from hydrogen, alkyl, and cycloalkyl.
When the heterocyclyl group is substituted on ring nitrogen(s), it is substituted
with a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, -SO 2R10 , -
C(=O)R 1 , -C(=O)N(H)R d , and -C(=O)N(alkyl)R d ; wherein R c is selected from
alkyl, perhaloalkyl, and cycloalkyl; R10d is selected from hydrogen, alkyl, and
cycloalkyl.
When a parent group is substituted with an "oxo" group, it means a divalent
oxygen (=0) becomes attached to a carbon atom of the parent group. For
example, when a CH2 group is substituted with an oxo substituent, the parent
CH2 group becomes a carbonyl (C=0) group; thus, oxo substituted on
cyclohexane forms a cyclohexanone, for example.
The term "annulated" means the ring system under consideration is either
annulated with another ring at a carbon atom of the cyclic system or across a
bond of the cyclic system as in the case of fused or spiro ring systems.
The term "bridged" means the ring system under consideration contain an
alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring
atoms.
A compound, its stereoisomers, racemates, and pharmaceutically acceptable
salt thereof as described hereinabove, wherein, the compound of general
formula (I) is selected from:
1. 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1,4-dimethyl- lH-pyrrol-
2-yl)benzenesulfonamide (compound 1) ;
2. 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1,4-dimethyl- lH-pyrrol-
2-yl)-2-fluorobenzenesulfonamide (compound 2);
3. 4-(5-(4-chlorophenyl)-3-(2-cyclobutylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (compound 3);
4. 4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(3-methylbutanoyl)- lH-pyrrol-2-
yl)benzenesulfonamide (compound 4);
5. 4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-propionyl- lH-pyrrol-2-
yl)benzenesulfonamide (compound 5);
6. 4-(3-acetyl-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (compound 6);
7. 4-(3-acetyl-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (compound 7);
8. 4-(5-(4-chlorophenyl)-3-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (compound 8);
9. 4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(3-methylbutanoyl)- lH-pyrrol-2-yl)-
2-fluorobenzenesulfonamide (compound 9);
10. 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- l-cyclopropyl-4-methyllH-
pyrrol-2-yl)benzenesulfonamide (compound 10) ;
11. 4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-propionyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (compound 11) ;
12. 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- l-ethyl-4-methyl- IHpyrrol-
2-yl)benzenesulfonamide (compound 12) ;
13. 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- l-(cyclopropylmethyl)-4-
methyl- lH-pyrrol-2-yl)benzenesulfonamide (compound 13) ;
14. 4-(5-(4-chlorophenyl)-3-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)-2-fiuorobenzenesulfonamide (compound 14);
15. 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- l-cyclopropyl-4-methyllH-
pyrrol-2-yl)-2-fiuorobenzenesulfonamide (compound 15);
16. 4-(5-(4-chlorophenyl)-3-(3,3-dimethylbutanoyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (compound 16) ;
17. 4-(5-(4-chlorophenyl)-3-(3,3-dimethylbutanoyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)-2-fiuorobenzenesulfonamide (compound 17);
18. 4-(5-(4-chlorophenyl)-3-(2-cyclobutylacetyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-
2-fiuorobenzenesulfonamide (compound 18) ;
19. 5-(4-chlorophenyl)-N -cyclopropyl-N, 1,4-trimethyl-2-(4-sulfamoylphenyl)-
lH-pyrrole-3-carboxamide (compound 19);
20. 4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(pyrrolidine- 1-carbonyl)- lH-pyrrol-
2-yl)benzenesulfonamide (compound 20) ;
21. 4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chlorophenyl)- 1,4-
dimethyl- lH-pyrrol-2-yl)benzenesulfonamide (compound 2 1) ;
22. 4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chlorophenyl)- 1,4-
dimethyl- lH-pyrrol-2-yl)-2-fiuorobenzenesulfonamide (compound 22) ;
23. 5-(4-chlorophenyl)-N -cyclopropyl- l ,4-dimethyl-2-(4-sulfamoylphenyl)- l -
pyrrole-3-carboxamide (compound 23);
24. 5-(4-chlorophenyl)-N, 1,4-trimethyl-2-(4-sulfamoylphenyl)- lH-pyrrole-3-
carboxamide (compound 24) ; and
25. 5-(4-chlorophenyl)-N,N, l ,4-tetramethyl-2-(4-sulfamoylphenyl)- l -
pyrrole-3-carboxamide (compound 25).
According to another aspect of the present invention, the compound of general
formula (I) where all the symbols are as defined earlier was prepared by
methods described below. However, the synthetic methods should not be
construed limiting the invention, which lies in the whole genus described by
compound of formula (I) above.
Scheme 1 below shows a method of preparation of the compound of the formula
(I), where R4 is substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- heterocyclyl, R1, R2,
R3, R5, R6, R7 and m are as described under compound of generic formula (I),
from compound represented by general formula (II), where R1, R2 and R3 are
same as defined under general formula (I).
Scheme-1
The compound of formula (II) was prepared according to the procedure
described by Kazuhiko Taguchi et al., in Tetrahedron Letters, 46 (2005), 4539-
4542.
The compound of the formula (II) is reacted with R4COX, where X is a halogen
and R4 is as defined earlier, in the presence of acid or Zinc under Friedel-Crafts
reaction conditions as described by J . S. Yadav et al., in Tetrahedron Letters, 43
(2002), 8133-8135, to obtain the compounds of the formula (III) and (IV), where
R4 is substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstitutedheteroaryl,
substituted- or unsubstituted- heterocyclyl, R1, R2- and R3 are same
a s defined in general formula (I). The compounds of the formula (III) and (IV)
were separated by column chromatography and characterized by spectral data.
Preferably, the reaction is carried out in toluene in presence of Zinc.
The compound of the formula (III) so obtained is reacted with halogenating
reagent such as bromine, N-bromosuccinimide, N-chlorosuccinimide,
phosphorous tribromide (as provided by Elena Dvornikova et al., in Synlett.,
2002, 7, 1152-1 153) to obtain compound of formula (V), where R* is
substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, X
is halogen, R1, R2-and R3 are same as defined in general formula (I). Preferably,
the halogenation reaction is carried out in presence of N- bromosuccinimide in
THF.
The compound of formula (V) a s obtained in the previous step was subjected to
Suzuki coupling with boronic acids or esters represented by formula (VI) , where
R5, R6, R7 and m are a s defined earlier to obtain compound of formula (I), where
R4 is substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstitutedheteroaryl,
R1, R2, R3, R5, R6, R7 and m are as defined earlier. Suzuki coupling
with boronic acids and esters can be carried out following the procedures well
known in the art. Preferably, the Suzuki coupling is carried out in a mixture of
ethanol and toluene, in presence of base such a s potassium phosphate,
potassium carbonate or the like, and tetrakis(triphenylphosphine)palladium(0)
at a temperature of about 50°C or higher. Boronic acid used in this reaction can
be prepared by the methods well known in the art by hydrolyzing the
corresponding boronate. Boronates are generally commercially available.
Besides, such boronates can also be prepared by reacting an appropriate iodoor
bromo compound with an alkyl lithium such as butyl lithium and then
reacting with a borate ester or by methods well known in the art (EP 1012142;
Review article by Norio Miyaura et al., in Chem. Rev., 1995, 95, 2457-2483).
Scheme 2 below shows a method of preparation of the compound of the formula
(I), where R1 is substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl, R4 is substituted- or unsubstituted- heterocyclyl, or -
NR R9, R2, R3, R5, R6, R7 and m are a s described under compound of generic
formula (I), from compound represented by general formula (II), where R2 and R3
are same as defined under general formula (I) .
Scheme-2
The compound of formula (VII) was prepared according to the procedure
described by Christopher D. Gabbutt et al., in Chem. Comm., 1999, 289-290.
The compound of the formula (VII) is de-acetylated to obtain the compound of
the formula (VIII), where R2 and R3 are same a s defined under general formula
(I). The acetylation reaction was carried out in presence of base like NaOH,
LiOH, KOH in solvents like ethanol, methanol, THF, water. Preferably, the deacetylation
reaction is carried out in ethanol in presence of NaOH at room
temperature.
The compound of formula (VIII) is further reacted with alkyl/cycloalkyl halides
in presence of base like sodium ethoxide, sodium hydride, Potassium t-butoxide
to obtain the compound of formula (IX), where R1 is substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl, R2- and R3
are same a s defined in general formula (I). Preferably, the alkylation reaction is
carried out in THF in presence of sodium hydride.
The compound of the formula (IX) so obtained is hydrolyzed (Ester Hydrolysis) to
obtain the compound of the formula (X) , where R1 is substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl, R2- and R3
are same as defined in general formula (I) . The hydrolysis was carried out in
presence of base like NaOH, LiOH, KOH in solvents like ethanol, methanol, THF,
water at room temperature or above. Preferably, the hydrolysis is carried out in
ethanol in presence of NaOH at 90°C.
The compound of formula (X) is further reacted with R R NH or nitrogen
containing heterocycle to obtain the compound of the formula (XI) , where R1 is
substituted- or unsubstituted- alkyl, and substituted- or unsubstitutedcycloalkyl,
R4 is substituted- or unsubstituted- heterocyclyl, or -NR R9, R2-and
R3 are same as defined in general formula (I). The said coupling reaction can be
carried out according to the conditions known for converting carboxylic acids to
amides to a person skilled in the art. The reaction can be carried out in the
presence of an organic solvent, for example, DMF, THF, a halogenated
hydrocarbon such as chloroform and dichloromethane, an aromatic
hydrocarbon such as xylene, benzene, toluene, or mixtures thereof or the like in
the presence of suitable base such as triethylamine, diisopropylethylamine,
pyridine or the like at a temperature between 0-50°C using reagents such a s 1-
(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDCI), 1,3-
dicyclohexylcarbodiimide (DCC) , and auxiliary reagents such as 1-hydroxy- 7-
azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT) or the like.
Preferably, the reaction is carried out in DMF using EDC, HOBT and
triethylamine as base.
The compound of the formula (XI) so obtained is reacted with halogenating
reagent such as bromine, N-bromosuccinimide, N-chlorosuccinimide,
phosphorous tribromide (as provided by Elena Dvornikova et al. , in Synlett. ,
2002, 7, 1152- 1153) to obtain compound of formula (XII) , where R is
substituted- or unsubstituted- alkyl, and substituted- or unsubstitutedcycloalkyl,
R4 is substituted- or unsubstituted- heterocyclyl, or -NR R9, X is
halogen, R2- and R3 are same a s defined in general formula (I). Preferably, the
halogenation reaction is carried out in presence of N- bromosuccinimide in THF.
The compound of formula (XII) a s obtained in the previous step is subjected to
Suzuki coupling with boronic acids or esters represented by formula (VI) , where
R5, R6, R7 and m are a s defined earlier to obtain compound of formula (I), where
R1 is substituted- or unsubstituted- alkyl, and substituted- or unsubstitutedcycloalkyl,
R4 is substituted- or unsubstituted- heterocyclyl, or -NR R9, R2-R3-
R5, e 7 and m are a s defined earlier. Suzuki coupling with boronic acids and
esters can be carried out following the procedures well known in the art.
Preferably, the Suzuki coupling is carried out in a mixture of ethanol and
toluene, in presence of base such as potassium phosphate, potassium
carbonate or the like, and tetrakis(triphenylphosphine)palladium(0) at a
temperature of about 50°C or higher.
The intermediates and the compounds of the present invention may 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
a s 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 (e.g., flash chromatography) on a
suitable support material such a s alumina or silica gel using eluent such as
dichloromethane, 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) can be 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 by Stephen M. Berge, et al. "Pharmaceutical Salts, a review article in
Journal of Pharmaceutical sciences, 1977, 66 (1), 1-19" and in Handbook of
Pharmaceutical Salts, properties, selection, and use by P. Heinrich Stahl and
Camille G. Wermuth, Wiley-VCH (2002). Lists of suitable salts can also be found
in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company,
Easton, PA, 1990, p. 1445, and Stephen M. Berge et al., Journal of
Pharmaceutical Science, 1977, 66 (1), 1-19. For example, they can be a salt of
an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium),
or ammonium of salt.
The compound of the invention or a composition thereof can potentially be
administered as a pharmaceutically acceptable acid-addition, base neutralized
or addition salt, formed by reaction with inorganic acids, such as hydrochloric
acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric
acid, and phosphoric acid, and organic acids such as formic acid, acetic acid,
propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid,
succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic
base, such as sodium hydroxide, potassium hydroxide. The conversion to a salt
is accomplished by treatment of the base compound with at least a
stoichiometric amount of an appropriate acid. Typically, the free base is
dissolved in an inert organic solvent such as diethyl ether, ethyl acetate,
chloroform, ethanol, methanol, and the like, and the acid is added in a similar
solvent. The mixture is maintained at a suitable temperature (e.g., between 0°C
and 50°C). The resulting salt precipitates spontaneously or can be brought out
of solution with a less polar solvent.
The stereoisomers of the compound 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 prodrugs can be prepared in situ during the isolation and purification of the
compounds, or by separately reacting the purified compound with a suitable
derivatizing agent. For example, hydroxy groups can be converted into esters via
treatment with a carboxylic acid in the presence of a catalyst. Examples of
cleavable alcohol prodrug moieties include substituted- or unsubstituted-,
branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower
alkenyl esters, di-lower alkylamino lower-alkyl esters, e.g., dimethylaminoethyl
ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g.,
pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alk l esters,
e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy
substituents aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, dilower
alkyl amides, and hydroxy amides.
Modulation of the nicotinic cholinergic receptors, particularly 7 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, 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 (Morten S. Thomsen, et al., Current Pharmaceutical Design,
2010, 16, 323-343; Peng Zhi-Zhen et al., Zhonghua Yi Xue Yi Chuan Xue Za
Zhi, 2008, 25, 154-158; Jared W. Young, et al., European
Neuropsychopharmacology, (2007), 17, 145-155; Laura F. Martin, et al.,
American Journal of Medical Genetics, Part B (Neuropsychiatry Genetics),
2007, 144B, 6 11-614; Laura F. Martin, et al., Psychopharmacology, (2004), 174,
54-64; Agnes Feher, et al., Dement. Geriatr. Cogn. Disord., 2009, 28, 56-62;
Timothy E. Wilens, et al., Biochem. Pharmacol., 2007, 74 (8), 1212-1223; S. L.
Verbois, et al., Neuropharmacology, 44 (2003), 224-233; Paul R. Sanberg, et al.,
Pharmacol. Ther., 1997, 74 (1), 21-25). Cholinergic system, particularly through
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 7
nAChR following traumatic brain injury (M. Bennouna, et al., L'Encephale,
2007, 33, 616-620; S. L. Verbois, et al., Neuropharmacology, 44 (2003), 224-
233).
Modulation of nicotinic ACh receptors, particularly the 7 subtype could also
help supplement the down-regulated cholinergic receptor expression and
transmission as in dementia(s), and also slowing disease progression by
reduction of 7- - 2Comple ation and internalization in AD and Down's
syndrome (Agneta Nordberg, et al., Neurotoxicity Research, 2000, 2, 157-165;
Simon N. Haydar et al., Bioorganic & Medicinal Chemistry, 17 (2009), 5247-
5258; Stephen I . Deutsch et al., Clinical Neuropharmacology, 2003, 26 (5), 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
(Xilong Zhao et al., Annals New York Academic Science, 2001, 939, 179-186;
Elaine Perry et al., European Journal of Pharmacology, 393 (2000), 215-222; C.
R. Harrington et al., Dementia, 1994, 5, 215-228; Juan Wang et al., Journal of
Neuroscience Research, 88, 807-815 (2010); Kamil Duns et al., Stroke, 201 1,
42 (12), 3530-3536). Thus, this invention may also find application in the
prophylaxis and preventive measures immediately after early-stage
identification of neurodegenerative disease like Alzheimer's disease and
Parkinson's disease.
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, and 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 long-term maintenance therapies. (Alexander Kuzmin et al.,
Psychopharmacology, (2009), 203, 99-108; Robert B. Weiss et al., PLoS
Genetics, 2008, 4 (7), el000125; Marcello Solinas et al., The Journal of
Neuroscience, 2007, 27 (21), 5615-5620; Jon O Ebbert et al., Patient Preference
and Adherence, 2010, 4, 355-362).
This invention may also 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 (Diana L. Donnelly-Roberts et al., Journal of
Pharmacology and Experimental Therapeutics, 1998, 285, 777-786; T. J .
Rowley et al., British Journal of Anesthesia, 105 (2), 201-207, (2010); A.
Bruchfeld et al., Journal of Internal Medicine, 2010, 268, 94-101).
This invention may find application in the treatment and prophylaxis of plethora
of inflammation and pain related states involving TNF- 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
(Ida A. J . Giebelen et al., Shock, 2007, 27 (4), 443-447; Pena Geber et al., Eur.
J . Immunol., 2010, 40, 2580-2589).
The invention provides 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 formula (I), its tautomeric
forms, its stereoisomers, or its pharmaceutically acceptable salts.
The disorder, condition, and disease as described above are selected from
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 decline associated with stroke, poststroke neuroprotection, 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 disease, disorder and condition as described above are particularly selected
from the group classified or diagnosed as major or minor neurocognitive
disorders, or disorders arising due to neurodegeneration.
The invention further provides a method comprising administering a compound
of formula (I) in combination with or as adjunct to medications utilized in the
treatment of attention deficit hyperactivity disorders, schizophrenia, cognitive
disorders such as Alzheimer's disease, Parkinson's dementia, vascular dementia
or dementia associated with Lewy bodies, or traumatic brain injury.
The method as described above 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, or a typical or an atypical antipsychotic.
The invention also provides use of a compound of formula (I), its tautomeric
forms, its stereoisomers, and its pharmaceutically acceptable salts in
preparation of a medicament for preventing or treating a disease or its
symptoms or a disorder mediated partially or completely by nicotinic
acetylcholine receptors.
The use as described above, 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 neurodegeneration.
The use as described above is in combination with or as adjunct to medications
utilized in the treatment of attention deficit hyperactivity disorders,
schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's dementia,
vascular dementia or dementia associated with Lewy bodies, and traumatic
brain injury.
The use as described above is in combination with or as an adjunct to
acetylcholinesterase inhibitors, disease modifying drugs or biologies for
neurodegenerative disorders, dopaminergic drugs, antidepressants, or a typical
or atypical antipsychotic.
Following are the abbreviations used and meaning thereof in the specification:
ACh: Acetylcholine.
AD: Alzheimer 's disease.
AIDS: Acquired immunodeficiency syndrome.
FLIPR: Fluorometric Imaging Plate Reader.
HBSS: Hank's balanced salt solution.
HEPES: 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid.
HOBT: hydroxybenzotriazole hydrate.
PAM: positive allosteric modulation.
THF: Tetrahydrofuran.
TLC: Thin layer chromatography.
TNF- : tumor necrosis factor alpha.
a 7 nAChR: nicotinic acetylcholine receptor a 7 subunit.
Following examples are provided to further illustrate the present invention and
therefore should not be construed in any way to limit the scope of the present
invention. All Ή NMR spectra were determined in the solvents indicated and
chemical shifts are reported in units downfield from the internal standard
tetramethylsilane (TMS) and interproton coupling constants are reported in
Hertz (Hz).
Example 1: Preparation of 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)-
1,4-dimethyl- 1H-pyrrol-2-yl)benzenesulfonamide (Compound 1)
Step 1: (5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrol-3-yl)(cyclopropyl)methanone
(Compound la)
and (5-(4-chlorophenyl) -1,4- dimethyl- 1H-pyrrol- 2-yl) (cyclopropyl)methanone
(Compound la')
Cyclopropanecarbonyl chloride (0.38 g, 0.33 ml, 3.65 mmol) was added to the
stirred solution of 2-(4-chlorophenyl)-l,3-dimethyl-lH-pyrrole (prepared
according to the procedure given by Kazuhiko Taguchi et al., in Tetrahedron
Letters, 46 (2005), 4539-4542) (0.5 g, 2.43 mmol) and Zinc (0.32 g, 4.86 mmol)
in toluene (10 ml) at 25°C. The reaction mixture is stirred at 25°C for 3 h . The
progress of the reaction was monitored by TLC. The mixture was diluted with
saturated solution of sodium bicarbonate (10 ml), phases were separated.
Aqueous layer was extracted with ethyl acetate (3x25 ml). The combined organic
layer was washed with water (1x20 ml) and dried over anhydrous Na2SC»4. The
solvent was evaporated under reduced pressure to obtain a crude product. This
crude product was purified by column chromatography using 5-10% ethyl
acetate in hexanes as an eluent to obtain (5-(4-chlorophenyl)-l,4-dimethyl-lHpyrrol-
3-yl)(cyclopropyl)methanone (0. 18 g, 27.0%) and positional isomer [(5-(4-
chlorophenyl)-l,4-dimethyl-lH-pyrrol-2-yl)(cyclopropyl)methanone] (0.36 g,
54.0%). The isomers were characterized by spectral data.
(5-(4-chlorophenyl) -1,4- dimethyl- 1H-pyrrol- 3-yl) (cyclopropyl)methanone
(Compound la). [MS: m/z 274 (M+l)].
Ή NMR (CDCla, 400 MHz): 7.45 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 7.23 (d, J =
8.4 Hz, 2H), 3.54 (s, 3H), 2.32-2.37 (m, 1H), 2.21 (s, 3H), 1. 14-1. 17 (m, 2H),
0.85-0.89 (m, 2H).
(5-(4-chlorophenyl) -1,4- dimethyl- 1H-pyrrol- 2-yl) (cyclopropyl)methanone
(Compound la'). [MS: m/z 274 (M+l)].
Ή NMR (CDCI3, 400 MHz): 7.45 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H),
7.05 (s, 1H), 3.76 (s, 3H), 2.46-2.53 (m, 1H), 2.04 (s, 3H), 1. 12-1.16 (m, 2H),
0.88-0.93 (m, 2H).
Step 2 : (2-bromo-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-3-yl) (cyclopropyl)
methanone (Compound lb)
To a stirred solution of (5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrol-3-
yl)(cyclopropyl)methanone (Compound la, 0. 18 g, 0.66 mmol) in THF (10 ml) at
-78°C was added a solution of N-bromosuccinimide (0. 13 g, 0.72 mmol) in THF
(10.0 ml) in a drop wise manner. The resulting mixture was stirred at -78°C for
10 min. The progress of reaction was monitored by TLC. Reaction mixture was
quenched by addition of saturated sodium bicarbonate solution (5 ml). Solvent
was evaporated under reduced pressure and residue was dissolved in ethyl
acetate (30 ml). Organic layer was washed with saturated sodium bicarbonate
solution (1 10 ml) followed by water (1 10 ml). Combined organic layer was
dried over anhydrous a 2SC . The solvent was evaporated under reduced
pressure to obtain a crude product; which was purified by flash column
chromatography using 10% ethyl acetate in hexanes to obtain the title
compound (0. 18 g, 80%). MS: m/z 353 (M+l).
Ή NMR (CDCla, 400 MHz): 7.45 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H),
3.48 (s, 3H), 2.62-2.67 (m, 1H), 2. 14 (s, 3H), 1.22-1.26 (m, 2H), 0.87-0.99 (m,
2H).
Step 3 : 4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1,4-dimethyl- lH-pyrrol-
2-yl)benzenesulfonamide (Compound 1)
4-aminosulfonylbenzene boronic acid (0.12 g, 0.59 mmol) and potassium
carbonate (0.23 g, 1.70 mmol) were added to the solution of (2-bromo-5-(4-
chlorophenyl)- 1,4-dimethyl- lH-pyrrol-3-yl)(cyclopropyl)methanone (Compound
lb, 0.2 g, 0.56 mmol) in a mixture of toluene: ethanol (2.5:7.5 ml) in a tube at
25°C. The nitrogen gas was bubbled through resulting mixture for 15 minutes.
Tetrakis(triphenylphosphine)palladium(0) (0.033 g, 0.028 mmol) was added to
the reaction mixture under nitrogen atmosphere and tube was sealed. Reaction
mixture was heated at 90-95°C for 5hr under stirring. The progress of reaction
was monitored by TLC. The reaction mixture was cooled to 25°C and filtered
through celite. Residue was washed with mixture of 10% methanol in
dichloromethane. The filtrate was concentrated under reduced pressure to
obtain a crude product; which was purified by flash column chromatography
using 30% ethyl acetate in hexanes as an eluent to obtain the title compound
(0.045 g, 18.5%). MS: m/z 429 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.93 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz,
2H), 7.58 (d, J = 8.4 Hz, 2H), 7.41-7.47 (m, 4H), 3.25 (s, 3H), 2.09 (s, 3H), 1.55-
1.59 (m, 1H), 0.84-0.87 (m, 2H), 0.52-0.57 (m, 2H).
The following compounds were prepared according to the procedure described
above for compound 1, with appropriate changes to the reactants.
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fiuorobenzenesulfonamide (Compound 2). [MS: m/z 447(M+1)].
Ή NMR (CDCb, 400 MHz): 8.00 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H),
7.29-7.37 (m, 4H), 4.93 (bs-exchanges with D20 , 2H), 3.29 (s, 3H), 2.20 (s, 3H),
1.76-1.79 (m, 1H), 1. 10-1. 13 (m, 2H), 0.69-0.73 (m, 2H).
4-(5-(4-chlorophenyl)-3-(2-cyclobutylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (Compound 3). [MS: m/z 457 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.94 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz,
2H), 7.58 (d, J = 8.0 Hz, 2H), 7.52 (bs-exchanges with D2O, 2H), 7.44 (d, J = 8.0
Hz, 2H), 3. 17 (s, 3H), 2.29 (d, J = 7.2 Hz, 2H), 2.09 (s, 3H), 1.60-1.76 (m, 5H),
1.36-1.41 (m, 2H).
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(3-methylbutanoyl)- lH-pyrrol-2-
yl)benzenesulfonamide(Compound 4). [MS: m/z 445 (M+1)].
Ή NMR (CDCla, 400 MHz): 8.04 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.93 (bs-exchanges with D20 ,
2H), 3.20 (s, 3H), 2. 18 (s, 3H), 2.04-2.09 (m, 2H), 1.23-1.26 (m, IH), 0.77 (d,
J=6.0 Hz, 6H).
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-propionyl- lH-pyrrol-2-
yl)benzenesulfonamide (Compound 5). [MS: m/z 417 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.95 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz,
2H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (bs-exchanges with D20 , 2H), 7.44 (d, J = 8.0
Hz, 2H), 3. 16 (s, 3H), 2. 16 (q, J = 7.2 Hz, 2H), 2.09 (s, 3H), 0.83 (t, J = 7.2 Hz,
3H).
4-(3-acetyl-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)benzenesulfonamide
(Compound 6). [MS: m/z 403 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.96 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz,
2H), 7.58 (d, J = 8.0 Hz, 2H), 7.51 (bs-exchanges with D20 , 2H), 7.42 (d, J = 8.0
Hz, 2H), 3. 16 (s, 3H), 2. 12 (s, 3H), 1.87 (s, 3H).
4-(3-acetyl-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (Compound 7). [MS: m/z 421 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.91 (t, J = 8.4 Hz, IH), 7.81 (bs-exchanges
with D20 , 2H), 7.56-7.64 (m, 3H), 7.41-7.45 (m, 3H), 3. 16 (s, 3H), 2. 12 (s, 3H),
1.95 (s, 3H).
4-(5-(4-chlorophenyl)-3-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (Compound 8). [MS: m/z 443 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.92 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz,
2H), 7.56 (d, J = 8.4 Hz, 2H), 7.51 (bs-exchanges with D2O, 2H), 7.43 (d, J = 8.4
Hz, 2H), 3.16 (s, 3H), 2.08-2. 10 (m, 5H), 0.83-0.85 (m, IH), 0.31-0.34 (m, 2H), -
0. 18- -0. 15 (m, 2H).
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(3-methylbutanoyl)- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (Compound 9). [MS: m/z 463 (M+1)].
Ή NMR (CDCla, 400 MHz): 8.01 (t, J = 8.4 Hz, IH), 7.47 (d, J = 8.4 Hz, 2H),
7.25-7.30 (m, 4H), 5.22 (bs-exchanges with D20 , 2H), 3.21 (s, 3H), 2.25 (d,
J=7.2 Hz, 2H), 2. 18 (s, 3H), 2.08-2. 10 (m, IH), 0.88 (d, J = 7.2 Hz, 6H).
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)-l-cyclopropyl-4-methyl-lHpyrrol-
2-yl)benzenesulfonamide (Compound 10). [MS: m/z 455 (M+1)].
Ή NMR (CDCI3, 400 MHz): 8.01 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H),
7.46 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 4.95 (bs-exchanges with D20 ,
2H), 3.25-3.29 (m, IH), 2. 18 (s, 3H), 1.61-1.63 (m, IH), 1. 11-1. 13 (m, 2H), 0.65-
0.67 (m, 2H), 0.51-0.52 (m, 2H), 0. 15-0. 17 (m, 2H).
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-propionyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (Compound 11). [MS: m/z 436 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.89 (t, J = 8.0 Hz, IH), 7.80 (bs-exchanges
with D20 , 2H), 7.57-7.61 (m, 3H), 7.40-7.43 (m, 3H), 3. 19 (s, 3H), 2.27 (q, J =
7.2 Hz, 2H), 2.1 1 (s, 3H), 0.84 (t, J = 7.2 Hz, 3H).
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- l-ethyl-4-methyl- lH-pyrrol-2-
yl)benzenesulfonamide (Compound 12). [MS: m/z 443 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.93 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz,
2H), 7.58 (d, J = 8.0 Hz, 2H), 7.44-7.49 (m, 4H), 3.72 (q, J = 6.8 Hz, 2H), 2.04 (s,
3H), 1.51-1.53 (m, IH), 0.80-0.82 (m, 2H), 0.68 (t, J = 6.8 Hz, 3H), 0.49-0.51 (m,
2H).
4-(5- (4-chlorophenyl) -3-(cyclopropanecarbonyl) - 1-(cyclopropylmethyl) -4-methyllH-
pyrrol-2-yl)benzenesulfonamide (Compound 13). [MS: m/z 469 (M+1)].
Ή NMR (CDC13, 400 MHz): 8.03 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H),
7.46 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.93 (bs-exchanges with D2O,
2H), 3.61 (d, J = 6.4 Hz, 2H), 2. 18 (m, 4H), 1.24-1.26 (m, IH), 1.08-1. 10 (m,
2H), 0.59-0.61 (m, 2H), 0. 12-0.16 (m, 2H), -0.47 - -0.43 (m, 2H).
4-(5-(4-chlorophenyl)-3-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (Compound 14). [MS: m/z 461(M+1)].
Ή NMR (CDCla, 400 MHz): 8.02 (t, J = 8.0 Hz, IH), 7.48 (d, J = 8.0 Hz, 2H),
7.27-7.30 (m, 4H), 5.12 (bs-exchanges with D20 , 2H), 3.21 (s, 3H), 2.35 (d, J =
6.8 Hz, 2H), 2.18 (S, 3H), 0.98-0.99 (m, IH), 0.49-0.51 (m, 2H), 0.01-0.04 (m,
2H).
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- l-cyclopropyl-4-methyl- IHpyrrol-
2-yl)-2-fluorobenzenesulfonamide (Compound 15). [MS: m/z 473 (M+l)].
Ή NMR (CDCI3, 400 MHz): 7.99 (t, J = 8.0 Hz, IH), 7.35-7.47 (m, 6H), 5. 17
(bs-exchanges with D20 , 2H), 3.25-3.27 (m, IH), 2. 17 (s, 3H), 1.72-1.74 (m, IH),
1. 14-1. 16 (m, 2H), 0.71-0.73 (m, 2H), 0.56-0.58 (m, 2H), 0.18-0.21 (m, 2H).
4-(5-(4-chlorophenyl)-3-(3,3-dimethylbutanoyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide (Compound 16). [MS: m/z 460 (M+l)].
Ή NMR (CDC13, 400 MHz): 8.04 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 5.13 (bs-exchanges with D20 ,
2H), 3.22 (s, 3H), 2.20 (s, 2H), 2. 18 (s, 3H), 0.86 (s, 9H).
4-(5-(4-chlorophenyl)-3-(3,3-dimethylbutanoyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (Compound 17). [MS: m/z 478 (M+l)].
Ή NMR (CDCI3, 400 MHz): 8.02 (t, J = 8.0 Hz, IH), 7.47 (d, J = 8.0 Hz, 2H),
7.24-7.29 (m, 4H), 5.25 (bs-exchanges with D20 , 2H), 3.23 (s, 3H), 2.28 (s, 2H),
2. 16 (s, 3H), 0.93 (s, 9H).
4-(5-(4-chlorophenyl)-3-(2-cyclobutylacetyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide (Compound 18). [MS: m/z 476 (M+l)];
Ή NMR (DMSO-de, 400 MHz): 7.89 (t, J = 8.0 Hz, IH), 7.82 (bs-exchanges
with D20 , 2H), 7.56-7.58 (m, 3H), 7.40-7.43 (m, 3H), 3. 19 (s, 3H), 2.36 (d, J =
7.2 Hz, 2H), 2.08 (s, 3H), 1.65-1.88 (m, 5H), 1.41-1.43 (m, 2H).
Example 2 : Preparation of 4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-
chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)benzenesulfonamide (Compound
21)
Step 1: Ethyl 5-(4-chlorophenyl)-4-methyl-lH-pyrrole-3-carboxylate (Compound
21a)
Ethyl 5-(4-chlorophenyl)-4-methyl-lH-pyrrole-3-carboxylate (Prepared according
to the procedure reported in the literature by Christopher D. Gabbutt et al., in
Chem. Comm., 1999, 289-290) (15.00 g, 49.10 mmol) was suspended in ethanol
(200 ml) and treated with IN solution of NaOH (5.89 g, 147.00 mmol) at 25°C.
The reaction mixture was stirred at 25°C for 2 hrs. The progress of the reaction
was monitored by TLC. The reaction mixture was diluted with water (100 ml).
The aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined
organic layer was dried over anhydrous Na2SC . 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 15-20% ethyl
acetate in hexanes as an eluent to obtain the title compound (1 1.5 g, 89.0%).
Ή NMR (CDCb, 400 MHz): 8.60 (bs-exchanges with D20 , 1H), 7.46 (d, J = 3.2
Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.32 (q, J = 6.8 Hz,
2H), 2.40 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H).
Step 2 : Ethyl 5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrole-3-carboxylate
(Compound 21b)
To a stirred solution of sodium hydride (60% suspension in mineral oil) (1.91g,
48.00 mmol) in THF (50 ml) at 0°C was added solution of ethyl 5-(4-
chlorophenyl)-4-methyl-lH-pyrrole-3-carboxylate (Compound 21a, 11.50 g,
43.60 mmol) in THF (20 ml) followed by the addition of methyl iodide (12.38 g,
5.45 ml, 87.00 mmol). The resulting mixture was stirred at room temperature
for 4 hrs. The progress of reaction was monitored by TLC. The reaction mixture
was quenched with saturated ammonium chloride (20 ml). Organic 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 crude product; which was purified by column chromatography over
silica gel (100-200 mesh) using 15-20% ethyl acetate in hexanes as an eluent to
obtain the title compound (8.0 g, 66. 10%). MS: m/z 279 (M+l).
Ή NMR (CDCb, 400 MHz): 7.44 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.21 (d, J =
8.4 Hz, 2H), 4.30 (q, J = 6.8 Hz, 2H), 3.49 (s, 3H), 2.20 (s, 3H), 1.34 (t, J = 6.8
Hz, 3H).
5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrole-3-carboxylic
Ethyl 5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrole-3-carboxylate (compound
21b, 8.00 g, 28.80 mmol) was suspended in ethanol (100 ml) and treated with
IN solution of NaOH (5.76 g, 144 mmol) at 25°C. The reaction mixture was
heated at 90°C under stirring for 4 hrs. The progress of the reaction was
monitored by TLC. The reaction mixture was concentrated at reduced pressure.
The residue obtained was diluted with water (50 ml). To the resulting diluted
mixture was added aqueous 10% HCl to bring the pH of the mixture to between
5 and 6. The aqueous layer was extracted with ethyl acetate (2 x 100 ml). The
combined organic layer was dried over anhydrous Na2S04. The solvent in the
organic layer was evaporated under reduced pressure to obtain the title
compound (4.90g, 68.0%). MS: m/z 250 (M+l).
Ή NMR (DMSO-de, 400 MHz): 11.60 (bs-exchanges with D20 , IH), 7.51 (d, J =
8.4 Hz, 2H), 7.44 (s, IH), 7.36 (d, J = 8.4 Hz, 2H), 3.48 (s, 3H), 2. 10 (s, 3H).
Step 4 : 3-azabicyclo[3. 1.0]hexan-3-yl(5-(4-chlorophenyl)-l,4-dimethyl-lHpyrrol-
3-yl)methanone (Compound 2 Id)
HOBT (1. 10 g, 7.21 mmol) and EDC (1.72 g, 9.01 mmol) were added to a
solution of 5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrole-3-carboxylic acid
(Compound 21c, 1.50 g, 6.01 mmol) in DMF (20 ml) at 0°C. 3-
azabicyclo[3. 1.0]hexane hydrochloride (0.86 g, 7.21 mmol) and triethylamine
(3.65 g, 5.02 ml, 36.0 mmol) were added and the reaction mixture was stirred at
room temperature for 18 hr. The progress of the reaction was monitored by TLC.
The reaction mixture was diluted with cold water (20 ml). The aqueous layer
was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was
dried over anhydrous Na2S04. The solvent in the organic layer was evaporated
under reduced pressure to obtain a crude product; which was purified by
column chromatography over silica gel (100-200 mesh) using 35-40% ethyl
acetate in hexanes as an eluent to obtain the title compound (1.40 g, 74.00%).
MS: m/z 3 15 (M+l).
Ή NMR (CDCb, 400 MHz): 7.42 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H),
6.80 (s, IH), 4. 12-4. 14 (m, 2H), 3.54-3.56 (m, 2H), 3.49 (s, 3H), 2. 10 (s, 3H),
1.52-1.54 (m, 2H), 0.67-0.69 (m, IH), 0.18-0.20 (m, IH).
Step 5 : 3-azabicyclo[3. 1.0]hexan-3-yl(2-bromo-5-(4-chlorophenyl)-l,4-dimethyllH-
pyrrol-3-yl)methanone (Compound 21e)
To a stirred solution of 3-azabicyclo[3. 1.0]hexan-3-yl(5-(4-chlorophenyl)-l,4-
dimethyl-lH-pyrrol-3-yl)methanone (Compound Id, 1.40 g, 4.45 mmol) in THF
(30 ml) at -78°C was added a solution of N-bromosuccinimide (0.87 g, 4.89
mmol) in THF (10.0 ml) in a drop wise manner. The resulting mixture was
stirred at -78°C for 10 min. The progress of reaction was monitored by TLC.
Reaction mixture was quenched by addition of saturated sodium bicarbonate
solution (20 ml). Solvent was evaporated under reduced pressure and residue
was dissolved in ethyl acetate (50 ml) . Organic layer was washed with saturated
sodium bicarbonate solution (1x10 ml) followed by water (1x10 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 flash
column chromatography using 30% ethyl acetate in hexanes to obtain the title
compound (1.40 g, 80.0%). MS: m/z 394 (M+l).
Ή NMR (CDCla, 400 MHz): 7.41 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),
4. 10-4. 14 (m, 2H), 3.48-3.51 (m, 2H), 3.39 (s, 3H), 1.97 (s, 3H), 1.94-1.96 (m,
1H), 1.50-1.56 (m, 2H), 0.70-0.73 (m, 1H).
Step 6 : 4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chloroph
dimethyl- lH-pyrrol-2-yl)benzenesulfonamide (Compound 21)
4-aminosulfonylbenzene boronic acid (0.24 g, 1.22 mmol) and potassium
carbonate (0.42 g, 3.05 mmol) were added to the solution of 3-
azabicyclo[3. 1.0]hexan-3-yl(2-bromo-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-
3-yl)methanone (Compound 21e, 0.40 g, 1.01 mmol) in a mixture of toluene:
ethanol (3:9 ml) in a tube at 25°C. The nitrogen gas was bubbled through
resulting mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(0)
(0.059 g, 0.051 mmol) was added to the reaction mixture under nitrogen
atmosphere and tube was sealed. Reaction mixture was heated at 90-95°C for
5hr under stirring. The progress of reaction was monitored by TLC. The reaction
mixture was cooled to 25°C and filtered through celite. Residue was washed
with mixture of 10% methanol in dichloromethane (20 ml). The filtrate was
concentrated under reduced pressure to obtain a crude product; which was
purified by flash column chromatography using 40% ethyl acetate in hexanes as
an eluent to obtain the title compound (0.070 g, 14.70%). MS: m/z 470 (M+1)].
iHNMR (DMSO-de, 400 MHz): 7.88 (d, J = 8.4 Hz, 2H), 7.51-7.57 (m, 4H),
7.43-7.48 (m, 4H), 3. 16-3.37 (m, 7H), 1.92 (s, 3H), 1.33-1.44 (m, 3H), 0.51-0.53
(m, 1H).
The following compounds were prepared according to the procedure described
above for compound 21, with appropriate changes to the reactants.
5-(4-chlorophenyl)-N-cyclopropyl-N, 1,4-trimethyl-2-(4-sulfamoylphenyl)- IHpyrrole-
3-carboxamide (Compound 19). [MS: m/z 458 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.87 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz,
2H), 7.52 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 (bs-exchanges with
D20 , 2H), 3.33 (s, 3H), 2.70 (s, 3H), 1.92-1.94 (m, 4H), 0.30-0.44 (m, 4H).
4-(5-(4-chlorophenyl)- 1,4-dimethyl- 3-(pyrrolidine- 1-carbonyl)- lH-pyrrol-2-
yfjbenzenesulfonamide (Compound 20). [MS: m/z 458 (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.86 (d, J = 8.4 Hz, 2H), 7.42-7.57 (m, 8H),
3.34-3.36 (m, 5H), 2.93-2.95 (m, 2H), 1.95 (s, 3H), 1.60-1.70 (m, 4H).
4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chlorophenyl)-l,4-dimethyllH-
pyrrol-2-yl)-2-fiuorobenzenesulfonamide (Compound 22). [MS: m/z 488
(M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.84 (t, J = 8.0 Hz, 1H), 7.62 (bs-exchanges
with D20 , 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0
Hz, 1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 3.14-3.34 (m, 7H), 1.91 (s, 3H), 1.37-
1.47 (m, 3H), 0.51-0.53 (m, 1H).
5-(4-chlorophenyl)-N-cyclopropyl- 1,4-dimethyl-2-(4-sulfamoylphenyl)- 1 -
pyrrole-3-carboxamide (Compound 23). [MS: m/z AAA (M+1)].
Ή NMR (DMSO-de, 400 MHz): 7.86 (d, J = 8.0 Hz, 2H), 7.44-7.65 (m, 9H), 3.29
(s, 3H), 1.97-1.99 (m, 4H), 0.54-0.56 (m, 2H), 0.23-0.25 (m, 2H).
5-(4-chlorophenyl)-N, 1,4-trimethyl-2-(4-sulfamoylphenyl)- lH-pyrrole-3-
carboxamide (Compound 24). [MS: m/z 418 (M+l)].
Ή NMR (DMSO-de, 400 MHz): 7.85 (d, J = 8.0 Hz, 2H), 7.55-7.62 (m, 4H),
7.38-7.49 (m, 5H), 3.30 (s, 3H), 2.59 (d, J = 4.4 Hz, 3H), 2.01 (s, 3H).
5-(4-chlorophenyl)-N,N, 1,4-tetramethyl-2-(4-sulfamoylphenyl)- lH-pyrrole-3-
carboxamide (Compound 25). [MS: m/z 432 (M+l)].
Ή NMR (DMSO-de, 400 MHz): 7.86 (d, J = 8.4 Hz, 2H), 7.55-7.58 (m, 4H), 7.48
(d, J = 8.4 Hz, 2H), 7.42 (bs-exchanges with D20 , 2H), 3.38 (s, 3H), 2.85 (s, 3H),
2.71 (s, 3H), 1.93 (s, 3H).
Example 3 : Pharmacological screening
Compounds were tested in a cell-based real-time kinetic assay in human IMR-
32 cells with native expression of 7 nAChR. The increase in intracellular Ca2+
levels was measured in a Fluorometric Imaging Plate Reader (FLIPR). Test
compound and agonist solutions were made in assay buffer (HBSS, pH 7.4, 20
mM HEPES, and 10 mM CaCl2). Briefly, cells were plated into Poly-D-Lysine
coated back- walled clear-bottom 96-well microplates at a density of 80,000 to
100,000 cells/well and incubated at 37°C/5% C0 2 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 solution (PNU-282987, 10 uM) and measurement of fluorescence for 4
min. (Ramin Faghih et al. Journal of Medicinal Chemistry, 2009, 52, 3377-
3384).
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.
Fold activity at luM concentration: compounds with activity between 1 to 5
folds are grouped as A, the compounds with activity between 5. 1 folds and 15
folds are grouped as B and the compounds with activity above 15 folds are
grouped as C.
Following table 1 provides fold activity of the compounds of the present
invention
Table 1
Sr.No. Fold activation at Compound No.
cone. (Group)
1 A 10, 12, 13, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25
2 B 4, 5, 6
3 C 1, 2, 3, 7, 8, 9, 11, 14, 18
CLAIMS:
1. A compound of formula (I), its tautomeric forms, its stereoisomers and its
pharmaceutically acceptable salts,
wherein,
R1 is selected from hydrogen, substituted- or unsubstituted- alkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- cycloalkyl, substitutedor
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and
substituted- or unsubstituted- heterocyclyl;
R3 is selected from hydrogen and substituted- or unsubstituted- alkyl;
R4 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substitutedor
unsubstituted- heteroaryl, substituted- or unsubstituted- heterocyclyl,
and NR R9; wherein, R8 and R9 are each independently selected from
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R5 is selected independently at each occurrence from halogen, substitutedor
unsubstituted- alkyl, perhaloalkyl, substituted- or unsubstitutedcycloalkyl,
-OR b , and -C(=0)R a ; or
R6 and R7 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R a is selected from substituted- or unsubstituted- alkyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R b is selected from hydrogen, substituted- or unsubstituted- alkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
m is an integer selected from 0, 1 and 2 ;
wherein,
when the alkyl group is a substituted alkyl group, the alkyl group is
substituted with 1 to 3 substituents selected independently from oxo,
halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -OR1 b , -SO2R10a, -C(=O)OR1 a , -OC(=O)R1 a , -C(=0)N(H)R1 , -
C(=0)N(alkyl)R °, -N(H)C(=O)R a , -N(H)R °, -N(alkyl)R ° , -N(H)C(=0)N(H)R °,
and -N(H)C(=0)N(alkyl)R1 ;
when the cycloalkyl and the carbocycle groups are substituted, each of
them is substituted with 1 to 3 substituents selected independently from
oxo, halogen, nitro, cyano, alkyl, perhaloalkyl, aryl, heteroaryl,
heterocyclyl, -OR1 , -SO2R10 , -C(=O)R1 c , -C(=O)OR1 c, -OC(=O)R1 c , -
C(=O)N(H)R d, -C(=O)N(alkyl)R d, -N(H)C(=O)R1 c , -N(H)R d , -N(alkyl)R d, -
N(H)C(=O)N(H)R d, and -N(H)C(=O)N(alkyl)R d ;
when the aryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy,
alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -
N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heteroaryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy,
alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl,
N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heterocyclyl group is substituted, it can be substituted either on
a ring carbon atom(s) or on a ring hetero atom, when it substituted on a
ring carbon atom(s), it is substituted with 1 to 3 substituents selected
independently from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR1 , -C(=O)OR1 c , -OC(=O)R1 c , -
C(=O)N(H)R d, -C(=O)N(alkyl)R d, -N(H)C(=O)R1 c , -N(H)R d , -N(alkyl)R d, -
N(H)C(=O)N(H)R d, and -N(H)C(=O)N(alkyl)R d ; when the 'heterocyclyl'
group is substituted on a ring nitrogen, it is substituted with a substituent
selected from alkyl, cycloalkyl, aryl, heteroaryl, -SO2R10 , -C(=O)R10c ,-
C(=O)N(H)R d, and -C(=O)N(alkyl)R d ;
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
i o S selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
i ob
S selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclyl;
R10 is selected from alkyl, perhaloalkyl, and cycloalkyl;
iod s selected from hydrogen, alkyl, and cycloalkyl.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in claim 1, wherein R1 is
selected from substituetd- or unsubstituted- alkyl and substituted- or
unsubstituted- cycloalkyl.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in claim 1 or 2 , wherein
R1 is selected from methyl, ethyl, cyclopropylmethyl and cyclopropyl.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
3, wherein R2 is selected as phenyl substituted with halogen.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
4, wherein R2 is selected as 4-chlorophenyl.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
5, wherein R3 is selected as alkyl.
7 . The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
6, wherein R3 is selected as methyl.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
7, wherein R4 is selected from substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedheterocyclyl
and -NR R9; wherein, R8 and R9 are each independently
selected from hydrogen, alkyl, or cycloalkyl.
9 . The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
8, wherein R4 is selected from
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of claims 1 to
9, wherein m is selected from 0, 1, and 2.
The compound of formula (I), its tautomeric forms, its stereoisomers, and
its pharmaceutically acceptable salts, as claimed in any one of the claims 1
to 10, wherein the compound is selected from:
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)-2-fluorobenzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(2-cyclobutylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(3-methylbutanoyl)- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-propionyl- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(3-acetyl-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(3-acetyl-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-(3-methylbutanoyl)- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1-cyclopropyl-4-methyl- IHpyrrol-
2-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)- 1,4-dimethyl-3-propionyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(cyclopropanecarbonyl)- 1-ethyl-4-methyl- IHpyrrol-
2-yl)benzenesulfonamide;
4-(5- (4-chlorophenyl)-3-(cyclopropanecarbonyl)-1-(cyclopropylmethyl)-4-
methyl- lH-pyrrol-2-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-
2-fluorobenzenesulfonamide;
4-(5- (4-chlorophenyl) -3-(cyclopropanecarbonyl) -1-cyclopropyl-4-methyl- 1H -
pyrrol-2-yl)-2-fluorobenzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(3,3-dimethylbutanoyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(3,3-dimethylbutanoyl)- 1,4-dimethyl- lH-pyrrol-2-
yl)-2-fluorobenzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(2-cyclobutylacetyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-
fluorobenzenesulfonamide;
5-(4-chlorophenyl) -N- cyclopropyl-N,1,4-trimethyl- 2-(4-sulfamoylphenyl) -
1H - pyrrole- 3-carboxamide ;
4-(5- (4-chlorophenyl)- 1,4-dimethyl- 3-(pyrrolidine- 1-carbonyl)- lH-pyrrol-2-
yl)benzenesulfonamide;
4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chlorophenyl)- l ,4-
dimethyl- lH-pyrrol-2-yl)benzenesulfonamide (compound 2 1) ;
4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chlorophenyl)- l ,4-
dimethyl- 1H - pyrrol- 2-yl)-2-fluorobenzenesulfonamide ;
5-(4-chlorophenyl )-N -cyclopropyl- 1,4-dimethyl-2-(4-sulfamoylphenyl)- IHpyrrole-
3-carboxamide;
5-(4-chlorophenyl )-N, 1,4-trimethyl-2-(4-sulfamoylphenyl)- lH-pyrrole-3-
carboxamide; and
5-(4-chlorophenyl )-N,N, 1,4-tetramethyl-2-(4-sulfamoylphenyl)- lH-pyrrole-
3-carboxamide.
12. A pharmaceutical composition comprising a compound of any one claims 1
to 11 and a pharmaceutically acceptable carrier.
13. 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 any one of claims 1 to 11.
14. A method of treating a disease or disorder or condition mediated partially
or completely by nicotinic acetylcholine receptors in a subject in need
thereof, comprising administering to the subject a therapeutically effective
amount of a compound of formula (I), its tautomeric forms, its
stereoisomers, or its pharmaceutically acceptable salts,
wherein,
R1 is selected from hydrogen, substituted- or unsubstituted- alkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- cycloalkyl, substitutedor
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and
substituted- or unsubstituted- heterocyclyl;
R3 is selected from hydrogen and substituted- or unsubstituted- alkyl;
R4 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substitutedor
unsubstituted- heteroaryl, substituted- or unsubstituted- heterocyclyl,
and NR R9; wherein, R8 and R9 are each independently selected from
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R5 is selected independently at each occurrence from halogen, substitutedor
unsubstituted- alkyl, perhaloalkyl, substituted- or unsubstitutedcycloalkyl,
-OR , and -C(=0)R a ; or
R6 and R7 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R a is selected from substituted- or unsubstituted- alkyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R b is selected from hydrogen, substituted- or unsubstituted- alkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
m is an integer selected from 0, 1 and 2 ;
wherein,
when the alkyl group is a substituted alkyl group, the alkyl group is
substituted with 1 to 3 substituents selected independently from oxo,
halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -OR1 , -SO2R10a, -C(=O)OR1 a , -OC(=O)R1 a , -C(=0)N(H)R1 , -
C(=0)N(alkyl)R1 , -N(H)C(=O)R1 a , -N(H)R10 , -N(alkyl)R1 , -N(H)C(=0)N(H)R1 ,
when the cycloalkyl and the carbocycle groups are substituted, each of
them is substituted with 1 to 3 substituents selected independently from
oxo, halogen, nitro, cyano, alkyl, perhaloalkyl, aryl, heteroaryl,
heterocyclyl, -OR , -SO2R10 , -C(=O)R c , -C(=O)OR c, -OC(=O)R c , -
-N(H)Riod, -N(alkyl)Riod, -
when the aryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy,
alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -
N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heteroaryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy,
alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl,
N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heterocyclyl group is substituted, it can be substituted either on
a ring carbon atom(s) or on a ring hetero atom, when it substituted on a
ring carbon atom(s), it is substituted with 1 to 3 substituents selected
independently from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 1 , -C(=O)OR 1 c , -OC(=O)R 1 c , -
-N(H)Riod, -N(alkyl)R d, -
N(H)C(=O)N(H)R d, and -N(H)C(=O)N(alkyl)R d; when the 'heterocyclyl'
group is substituted on a ring nitrogen, it is substituted with a substituent
selected from alkyl, cycloalkyl, aryl, heteroaryl, -SO 2R10c , -C(=O)R 10c ,-
C(=O)N(H)R d, and -C(=O )N(alkyl)R d;
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
io S selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
iob
S selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclyl;
R1 is selected from alkyl, perhaloalkyl, and cycloalkyl;
iod s selected from hydrogen, alkyl, and cycloalkyl.
The method of claim 13 or 14, wherein the disorder or condition or disease
is selected from 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 decline
associated with stroke, poststroke neuroprotection, 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.
16. The method of claim 13 or 14, 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 neurodegeneration.
17. The method of claim 13 or 14, comprising administering a compound of
formula (I) in combination with or as adjunct to medications utilized in the
treatment of attention deficit hyperactivity disorders, schizophrenia,
cognitive disorders such as Alzheimer's disease, Parkinson's dementia,
vascular dementia or dementia associated with Lewy bodies, or traumatic
brain injury.
18. The method of claim 13 or 14, 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, or a
typical or an atypical antipsychotic.
19. Use of a compound of any one of claims 1 to 11 in preparation of a
medicament for preventing or treating a disease or its symptoms or a
disorder mediated partially or completely by nicotinic acetylcholine
receptors.
Use of a compound of formula (I), its tautomeric forms, its stereoisomers,
and its pharmaceutically acceptable salts, in the preparation of a
medicament for treating a disease or disorder or condition,
wherein,
R1 is selected from hydrogen, substituted- or unsubstituted- alkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- cycloalkyl, substitutedor
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and
substituted- or unsubstituted- heterocyclyl;
R3 is selected from hydrogen and substituted- or unsubstituted- alkyl;
R4 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substitutedor
unsubstituted- heteroaryl, substituted- or unsubstituted- heterocyclyl,
and NR R9; wherein, R8 and R9 are each independently selected from
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R5 is selected independently at each occurrence from halogen, substitutedor
unsubstituted- alkyl, perhaloalkyl, substituted- or unsubstitutedcycloalkyl,
-OR b , and -C(=0)R a ; or
R6 and R7 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R a is selected from substituted- or unsubstituted- alkyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R b is selected from hydrogen, substituted- or unsubstituted- alkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
m is an integer selected from 0, 1 and 2 ;
wherein,
when the alkyl group is a substituted alkyl group, the alkyl group is
substituted with 1 to 3 substituents selected independently from oxo,
halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -OR1 b , -SO2R10a, -C(=O)OR1 a , -OC(=O)R1 a , -C(=0)N(H)R1 , -
C(=0)N(alkyl)R °, -N(H)C(=O)R a , -N(H)R °, -N(alkyl)R ° , -N(H)C(=0)N(H)R °,
and -N(H)C(=0)N(alkyl)R1 ;
when the cycloalkyl and the carbocycle groups are substituted, each of
them is substituted with 1 to 3 substituents selected independently from
oxo, halogen, nitro, cyano, alkyl, perhaloalkyl, aryl, heteroaryl,
heterocyclyl, -OR1 , -SO2R10 , -C(=O)R1 c , -C(=O)OR1 c, -OC(=O)R1 c , -
C(=O)N(H)R d, -C(=O)N(alkyl)R d, -N(H)C(=O)R1 c , -N(H)R d , -N(alkyl)R d, -
N(H)C(=O)N(H)R d, and -N(H)C(=O)N(alkyl)R d ;
when the aryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy,
alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -
N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heteroaryl group is substituted, it is substituted with 1 to 3
substituents selected independently from halogen, nitro, cyano, hydroxy,
alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl,
N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, and -S0 2NH2;
when the heterocyclyl group is substituted, it can be substituted either on
a ring carbon atom(s) or on a ring hetero atom, when it substituted on a
ring carbon atom(s), it is substituted with 1 to 3 substituents selected
independently from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR1 , -C(=O)OR1 c , -OC(=O)R1 c , -
C(=O)N(H)R d, -C(=O)N(alkyl)R d, -N(H)C(=O)R1 c , -N(H)R d , -N(alkyl)R d, -
N(H)C(=O)N(H)R d, and -N(H)C(=O)N(alkyl)R d ; when the 'heterocyclyl'
group is substituted on a ring nitrogen, it is substituted with a substituent
selected from alkyl, cycloalkyl, aryl, heteroaryl, -SO2R10 , -C(=O)R10c ,-
C(=O)N(H)R d, and -C(=O)N(alkyl)R d ;
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
io S selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
iob
S selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclyl;
R10 is selected from alkyl, perhaloalkyl, and cycloalkyl;
iod s selected from hydrogen, alkyl, and cycloalkyl.
The use as claimed in claim 19 or 20 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
neurodegeneration.
The use as claimed in claim 19 or 20, which is in combination with or as
adjunct to medications utilized in the treatment of attention deficit
hyperactivity disorders, schizophrenia, cognitive disorders, Alzheimer's
disease, Parkinson's dementia, vascular dementia or dementia associated
with Lewy bodies, and traumatic brain injury.
The use as claimed in claim 19 or 20, which is in combination with or as
an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or
biologies for neurodegenerative disorders, dopaminergic
antidepressants, or a typical or atypical antipsychotic.
International application No
PCT/IB2014/05823O
A. CLASSIFICATION OF SUBJECT MATTER
INV. C07D403/06 C07D207/33 C07D207/416 A61K31/40 A61K31/4025
A61P25/00
ADD.
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
C07D
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
EPO-Internal , WPI Data, CHEM ABS Data
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
WO 2013/005153 Al (LUPIN LTD [IN] ; SINHA 1-23
NEELIMA [IN] ; KARCHE NAVNATH POPAT [IN] ;
HATNAPU) 1 January 2013 (2013-01-10)
c l aim 1
W0 2012/131576 Al (LUPIN LTD [IN] ; SINHA 1-23
NEELIMA [IN] ; JANA G0URHARI [IN] ; TI LEKAR
AJAY R) 4 October 2012 (2012-10-04)
c l aim 1
W0 2012/114285 Al (LUPIN LTD [IN] ; SINHA 1-23
NEELIMA [IN] ; JANA G0URHARI [IN] ;
SACHCHIDANAND) 30 August 2012 (2012-08-30)
c l aim 1
/ -
X Further documents are listed in the continuation of Box C. See patent family annex.
* Special categories of cited documents :
"T" later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
"A" document defining the general state of the art which is not considered the principle or theory underlying the invention
to be of particular relevance
"E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be
filing date considered novel or cannot be considered to involve an inventive
"L" document which may throw doubts on priority claim(s) orwhich is step when the document is taken alone
cited to establish the publication date of another citation or other " document of particular relevance; the claimed invention cannot be
special reason (as specified) considered to involve an inventive step when the document is
"O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination
means being obvious to a person skilled in the art
"P" document published prior to the international filing date but later than
the priority date claimed "&" document member of the same patent family