4-f5-f4-CHLOROPHENYLl-2-f2-CYCLOPROPYLACETYLl-1.4-DIMETHYL-lHPYRROL-
3-YL1BENZENESULFONAMIDE AS ALPHA 7 NACHR MODULATOR
FIELD OF THE INVENTION
[1] The present invention relates to 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)- 1,4- dimethyl- lH-pyrrol-3-yl)benzenesulfonamide (Compound
1), its tautomeric formats pharmaceutically acceptable salts, its pharmaceutical
compositions, its combination with one or more of suitable other medicaments,
and its use a s nicotinic acetylcholine receptor 7 subunit ( 7 nAChR)
modulator.
CROSS-REFERENCE TO A RELATED APPLICATION
[2] The present application claims the benefit of Indian Provisional Patent
Application No. 1937/MUM/2013 filed on 3 dJune 2013,the disclosure of which
is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[3] 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 all of 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 the brain, forming a significant
component of receptors carrying out its mnemonic and other vital physiological
functions.
[4] Neural nicotinic ACh receptors (NNRs) belong to the class of ligandgated
ion channels (LGIC) comprising five subunits ( 2- 10, 2-4) arranged in
heteropentameric ( 4 2) or homopentameric ( 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 centres 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 Ca2+ 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).
[5] 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 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 7 nAChR impairs memory and its activation enhances the same in
preclinical rodent models, thereby implicating 7 nAChR as a target for
cognitive enhancement (Kenji Hashimoto et al., Biol. Psychiatry, 2008, 63, 92-
97).
[6] 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 Behaviour, 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 pre- attention 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
Behaviour, 70 (2001), 561-570; Suemaru K. Folia et al., Folia Pharmacol. Jpn.,
119, 295-300 (2002)).
[7] Perturbations in the cholinergic and glutamatergic homeostasis have
long been implicated as causative factors for a host of neurological diseases,
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 with -42, is implicated a s
an up-stream pathogenic event in Alzheimer's disease, which is 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).
[8] Disease modification potential of the nAChRs, particularly the 7
receptor, has been recognized. For example, disease-modification of Alzheimer's
disease (AD) and Parkinson's disease (PD) has been proposed 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, it has been proposed that 7 nAChR induced
activation of anti-apoptotic (BCL-2) and anti-inflammatory pathways in the
brain could have neuroprotective effects in neurodegenerative diseases (Mario B.
Marrero et al., Brain Research, 2009, 1256, 1-7). Dopamine-containing neurons
of the ventral tegmental area (VTA) and laterodorsal tegmental nucleus (LDT)
are known to express nicotinic ACh receptors, particularly the 4 , 3 , 2 , 3,
and 4 subunits (Alexander Kuzmin et al., Psychopharmacology, (2009), 203,
99-108). Nicotinic ACh receptors 4 2 and 3 4 have been identified by the
candidate-gene approach to have a 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 of 4 2 , has demonstrated better efficacy in
reducing smoking addiction and relapse prevention than buproprion (Jon O.
Ebbert et al., Patient Preference and Adherence, 2010, 4 , 355-362).
[9] The presence of a high-affinity nicotine binding site a t 4 2 nAChR in
the descending inhibitory pathways from the 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 the use of nicotinic
modulators in pain therapy (Michael C. Rowbotham et al., PAIN, 146, (2009),
245-252).
[10] Another key role of the 7 nAChR is its 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, anti-inflammatory and antinociceptive effects
have been demonstrated in pain disorders (M. Imad Damaj et al.,
Neuropharmacology, 39 (2000), 2785-2791). Additionally, 'cholinergic an ti
inflammatory pathway' has been proposed to b e a regulator 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 the oc7type, 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).
[1 1] Angiogenesis is a critical physiological process for cell survival and is
pathologically important for cancer proliferation; several non-neural nicotinic
ACh receptors, particularly 7 , 5 , 3 , 2 , and 4 , are involved in such
processes (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). The role of nicotinic ACh
receptors in the development of cervical cancer, lung carcinogenesis and
pediatric lung disorders in smoking-exposed population has 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 and partial agonists have been characterized for
their efficacy in clinical and preclinical studies. EVP-6124, an agonist at 7
nAChR, has reportedly demonstrated a 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-
2 1 (DMXB-Anabaseine), an 7 nAChR agonist, in the P II clinical trials, has
reportedly shown efficacy in improving cognitive deficits in schizophrenia and
the inhibition of endotoxin-induced TNF- 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, an 7 nAChR agonist, reportedly exhibits
protection against scopolamine-induced dementia and inhibition of
amphetamine-induced auditory evoked potentials in preclinical studies
(Christopher J . O'Donnell et al., J . Med. Chem., 2010, 53, 1222-1237). SSR18071
1A, also an 7 nAChR agonist, reportedly enhances learning and memory,
and protects against MK-801 /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 reportedly protects
against scopolamine-induced amnesia in a 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 of the 7 nAChR,
reportedly exhibits an improvement in the social recognition task performed in
rats (Marja Van Kampen et al., Psych opharmacology, 2004, 172, 375-383).
ABBF, an agonist of the 7 nAChR, reportedly improves social recognition
memory and working memory in the 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 reportedly 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).
[12] 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 only in preclinical
stages of discovery. A-86774, an 7 nAChR PAM, reportedly 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 a 7 nAChR PAM, reportedly normalizes the
sensorimotor gating deficits in the DBA/2 mice and memory acquisition in the
8-arm radial maze test without altering the receptor desensitization kinetics
(Herman J . Hg et al., PNAS, 2007, 104 (19), 8059-8064). Yet another PAM, PNU-
120596, reportedly alters a 7 nAChR desensitization kinetics while
simultaneously protecting against the disruption of prepulse inhibition by MK-
801. NS-1738, another PAM, reportedly exhibits 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 201 1/036167, US 2010/0190819, WO 2012/104782, WO
2012/1 14285, WO 2012/131576, WO 2013/005153, and WO 2013/132380,
which reportedly disclose efficacy of allosteric modulators of nicotinic ACh
receptors, underscoring their therapeutic potential.
[13] Despite the foregoing proposals in the art, there exists a need for
novel modulators of the nicotinic acetylcholine receptors, particularly the 7
nAChR, pharmaceutical compositions comprising such modulators, and
methods of treating diseases, disorders, or conditions that are treatable or
preventable by the use of such modulators.
BRIEF SUMMARY OF THE INVENTION
[14] The present invention provides 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)- 1,4- dimethyl- lH-pyrrol-3-yl)benzenesulfonamide, its
tautomeric form, its pharmaceutically acceptable salts, its pharmaceutical
compositions, its combinations with one or more of suitable other medicaments,
and its use a s nicotinic acetylcholine receptor 7 subunit ( 7 nAChR)
modulator.
[15] Thus the present invention further provides a pharmaceutical
composition containing 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-
dimethyl-lH-pyrrol-3-yl)benzenesulfonamide, its tautomeric form, and/or its
pharmaceutically acceptable salts in combination with pharmaceutically
acceptable carriers, diluents, and the like, which is useful for the treatment
and/or prophylaxis of diseases, disorders, or conditions 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.
[16] The present invention also provides a pharmaceutical composition
containing 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-
3-yl)benzenesulfonamide, its tautomeric form, its pharmaceutically acceptable
salts, in combination with pharmaceutically acceptable carriers, diluents, and
the like, which is useful for the treatment and/or prophylaxis of diseases,
disorders, or conditions classified or diagnosed as major or minor
neurocognitive disorders, or disorders arising due to neurodegeneration.
[17] The present invention also provides a method of treatment wherein 4-
(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-
yl)benzenesulfonamide, its tautomeric form, or its pharmaceutically acceptable
salt is administered 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, or traumatic brain
injury.
[18] The present invention also provides a method of treatment wherein 4-
(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-
yljbenzenesulfonamide, its tautomeric form, or its pharmaceutically acceptable
salt is administered 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.
[19] The present invention also provides the use of 4-(5-(4-chlorophenyl)-
2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide,its
tautomeric form, or its pharmaceutically acceptable salt, in the preparation of a
medicament for treating a disease, disorder, or condition selected from the
group of disorders classified or diagnosed as major or minor neurocognitive
disorders and disorders arising due to neurodegeneration.
[20] The present invention also provides the use of 4-(5-(4-chlorophenyl)-
2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide,its
tautomeric form, or its pharmaceutically acceptable salt, in the preparation of a
medicament for treating a disease, 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.
[21] The present invention also provides the use of 4-(5-(4-chlorophenyl)-
2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide,its
tautomeric form, or its pharmaceutically acceptable salt, 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.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
Fig. 1 depicts the results of Novel Object Recognition Task subchronic
study. Fig. 1A depicts the result obtained using Compound 1 in 24 h time
delay-induced amnesia. Subchronic (7 day) treatment with compound 1 (0.05
mg/Kg, p.o.) significantly increased the discrimination index as compared to
vehicle-treated group. Fig. IB depicts the result obtained using Compound 1 in
Scopolamine-induced amnesia. Subchronic (7 day) treatment with compound 1
(0.05 mg/Kg, p.o.) significantly increased the discrimination index as compared
to scopolamine treated group.
Fig. 2 depicts the results of Social Recognition Task subchronic study.
Fig. 2A depicts the result obtained using Compound 1 in 24 h time delayinduced
amnesia. Subchronic (7 day) treatment with compound 1 (0.05 mg/Kg,
p.o.) significantly decreased the recognition index (RI) as compared to vehicletreated
group. Fig. 2B depicts the result obtained using Compound 1 in
Scopolamine-induced amnesia. Subchronic (7 day) treatment with compound 1
(0.05 mg/Kg, p.o.) significantly decreased the recognition index (RI) as
compared to scopolamine treated group.
DETAILED DESCRIPTION OF THE INVENTION
[22] The present invention provides 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide, its
tautomeric form, its pharmaceutically acceptable salts, its combinations with
suitable other medicaments, and its pharmaceutical compositions.
[23] According to another aspect of the present invention, 4-(5-(4-
chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-
yl)benzenesulfonamide was prepared by methods outlined in Scheme - 1 below.
However, the synthetic methods should not be construed limiting the
invention; compound 1 may also be prepared by any method known to those
skilled in the art.
(Compound 1)
Scheme - 1
[24] Scheme - shows a method of preparation of 4-(5-(4-chloropheriyl)-2-
(2-cyclopropylacetylj- 1,4-dimethyl- H-pyrrol-3-yl)benzenesulfonamide (1) from
2-(4-chlorophenyl)- l ,3-dimethyl- lH-pyrrole (2) in accordance with an
embodiment of the invention.
[25] Kazuhiko Taguchi et al. , Tetrahedron Letters, 2005, 46, 4539-4542
teacha method for the preparation of (2) .
[26] Reaction of (2) with 2-cyclopropyl-N,N -dimethylacetamide, in the
presence of POCb under Vilsmeier-Haackreaction conditions as described in
Jeffrey A. Pfefferkorn et al. , Tetrahedron, 2007, 63, 8 124-8 134, yields l -(5-(4-
chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-cyclopropylethanone (3) .
[27] Alternatively, reaction of (2) with 2-cyclopropylacetyl chloride, in the
presence of acid or zinc under Friedel-Crafts reaction conditions as described in
J.S. Yadav et al. , Tetrahedron Letters, 2002, 43, 8 133-81 35,yields (3).
Preferably, the reaction is carried out in toluene in the presence of zinc.
[28] Bromination of (3) usinga brominating reagent such as bromine, Nbromosuccinimide,
or phosphorous tribromide (as described in Elena
Dvornikova et al. ,Synlett, 2002, No. 7, 1152- 1154) yields l-(3-bromo-5-(4-
chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-cyclopropylethanone (4).
Preferably, the bromination reaction is carried out in the presence of Nbromosuccinimide
in THF.
[29] Suzuki coupling of (4) with (4-sulfamoylphenyl)boronic acid (5), which
is available commercially, provides 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-
l,4-dimethyl-lH-pyrrol-3-yl)benzenesulfonamide (Compound 1). Suzuki
coupling with boronic acid can be carried out following the procedures well
known in the art (Sambasivarao Kotha et. al., Tetrahedron, 2002, 58, 9633-
9695; Timothy E. Harder et al, J . Am. Chem. Soc, 2005, 127, 4685-4696).
Preferably, the Suzuki coupling is carried out in a mixture of ethanol and
toluene, in the presence of a base such as potassium phosphate, potassium
carbonate or the like, and tetrakis(triphenylphosphine)palladium(0) at a
temperature of about 50°C or higher.
[30] The term 'room temperature' denotes any temperature ranging
between about 20°C to about 40°C, except and otherwise it is specifically
mentioned in the specification.
[31] The intermediates and the compound 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 as pentane, diethyl ether, isopropyl ether, chloroform,
dichloromethane, ethyl acetate, acetone or their combinations or subjecting
them to one of the purification methods, such as column chromatography (e.g.,
flash chromatography) on a suitable support material such as alumina or silica
gel using an eluent such as dichloromethane, ethyl acetate, hexane, methanol,
acetone and their combinations. Preparative LC-MS method is also used for the
purification of the molecules described herein.
[32] Salts of 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-l,4-dimethyllH-
pyrrol-3-yl)benzenesulfonamide can be obtained by dissolving it in a suitable
solvent, for example in a chlorinated hydrocarbon, such as methylene chloride
or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol
or isopropanol, which is 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 the 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 an ammonium salt.
[33] 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, ammonium hydroxide, potassium
hydroxide, and organic bases, such as mono-, di . trialkyi, and aryl amines and
substituted ethanolamines. The conversion to a salt is accomplished by
treatment of the base compound with a 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.
[34] The prodrugs can be prepared in situ during the isolation and
purification of the compound, or by separately reacting the purified compound
with a suitable derivatizing agent. For example, the hydroxy group of a
tautomeric form 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 alkyl 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, di-lower alkyl amides, and hydroxy amides.
[35] The present invention further provides a pharmaceutical composition
comprising a compound as described above and a pharmaceutically acceptable
carrier. The present invention provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and an effective amount, e.g.,
a therapeutically effective amount, including a prophylactically effective amount
of the aforesaid compound, or a salt thereof, of the present invention.
[36] The pharmaceutically acceptable carrier can be any of those
conventionally used and is limited only by chemico-physical considerations,
such as solubility and lack of reactivity with the compound, and by the route of
administration .
[37] The pharmaceutically acceptable carriers described herein, for
example, vehicles, adjuvants, excipients, or diluents, are well known to those
who are skilled in the art and are readily available to the public.
[38] The following formulations for oral, aerosol, parenteral,
subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal,
intrathecal, rectal, and vaginal administration are merely exemplary and are in
no way limiting.
[39] Formulations suitable for oral administration can consist of (a) liquid
solutions, such as an effective amount of the compound dissolved in diluents,
such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges,
and troches, each containing a predetermined amount of the active ingredient,
as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and
(e) suitable emulsions. Liquid formulations may include diluents, such as water
and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene
alcohols, either with or without the addition of a pharmaceutically acceptable
surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the
ordinary hard- or soft-shelled gelatin type containing, for example, surfactants,
lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and
cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol,
corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia,
gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc,
magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other
excipients, colorants, diluents, buffering agents, disintegrating agents,
moistening agents, preservatives, flavoring agents, and pharmacologically
compatible carriers. Lozenge forms can comprise the active ingredient in a
flavour, usually sucrose and acacia or tragacanth, as well as pastilles
comprising the active ingredient in an inert base, such as gelatin and glycerine,
or sucrose and acacia, emulsions, gels, and the like containing, in addition to
the active ingredient, such carriers as are known in the art.
[40] The compound, a salt thereof, or a tautomer thereof, can be
administered in a physiologically acceptable diluent in a pharmaceutical carrier,
such as a sterile liquid or mixture of liquids, including water, saline, aqueous
dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol,
or hexadecyl alcohol, glycols, such as propylene glycol, polyethylene glycol, or
glycerol, ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such
as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or
an acetylated fatty acid glyceride with or without the addition of a
pharmaceutically acceptable surfactant, such as a soap or a detergent,
suspending agent, such as pectin, carbomers, methylcellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents
and other pharmaceutical adjuvants.
[41 Oils, which can be used in parenteral formulations, include
petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include
peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral.
Suitable fatty acids for use in parenteral formulations include oleic acid, stearic
acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of
suitable fatty acid esters. Suitable soaps for use in parenteral formulations
include fatty alkali metal, ammonium, and triethanolamine salts, and suitable
detergents include (a) cationic detergents such as, for example, dimethyl dialkyl
ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such
as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and
monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for
example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene
copolymers, (d) amphoteric detergents such as, for example,
alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium
salts, and (e) mixtures thereof.
[42] The parenteral formulations will typically contain from about 0.5 to
about 25% by weight of the active ingredient in solution. Suitable preservatives
and buffers can be used in such formulations. In order to minimize or eliminate
irritation at the site of injection, such compositions may contain one or more
nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about
12 to about 17. The quantity of surfactant in such formulations ranges from
about 5 to about 15% by weight. Suitable surfactants include polyethylene
sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular
weight adducts of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol. The parenteral
formulations can be presented in unit-dose or multi-dose sealed containers,
such as ampoules and vials, and can be stored in a freeze- dried (lyophilized)
condition requiring only the addition of the sterile liquid carrier, for example,
water, for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions can be prepared from sterile powders, granules, and
tablets of the kind previously described.
[43] The compound of the present invention, salt thereof, or a tautomer
thereof, may be made into injectable formulations. The requirements for
effective pharmaceutical carriers for injectable compositions are well known to
those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J .
B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250
(1982), and ASHP Handbook on Injectable Drugs, Toissel, 4 e d., pages 622-630
(1986).
[44] Additionally, the compound of the present invention may be made
into suppositories by mixing with a variety of bases, such as emulsifying bases
or water-soluble bases. Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas
containing, in addition to the active ingredient, such carriers a s are known in
the art to b e appropriate.
[45] In accordance with the invention, modulation of the nicotinic
cholinergic receptors, particularly 7 , provides for efficacy in a range of
cognitive states, right from pre-attention to attention and subsequently working,
reference and recognition memory. Accordingly, the present invention finds
application in the treatment and prophylaxis of a multitude of diseases or
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). The cholinergic system, particularly
through 7 nAChR, also has implications in traumatic brain injury-induced
psychosis. Accordingly, the present invention also finds application in the
treatment of deficits in cholinergic 7 nAChR following traumatic brain injury.
4 6 Modulation of nicotinic ACh receptors, particularly the 7 subtype,
also helps to supplement the down-regulated cholinergic receptor expression
and transmission a s in dementia(s), and also in slowing disease progression by
reduction of the 7- -42 complexation 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).
[47] The compound of the invention, a salt thereof, or a tautomer thereof,
also finds application in the treatment and prophylaxis of a number of diseases
or conditions including, either one or combinations of, dementia(s) due to
Alzheimer's disease, dementia with Lewy bodies, or dementia due to 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, chronic medication, drug abuse, drug addiction, alcohol abuse,
alcohol addiction, metal poisoning such as aluminium, lead, mercury, heavy
metal etc., 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 Duris
et al., Stroke, 201 1, 42(12), 3530-3536). The compound of the present invention
also finds application in the prophylaxis and preventive measures immediately
after early-stage identification of neurodegenerative diseasessuch a s Alzheimer's
disease and Parkinson's disease.
[48] Modulation of the nicotinic ACh receptors, particularly 4 2, 34
and 7 receptors, also has implications in the development of therapies for
nicotine or cannabis addiction and relapse prevention. Accordingly, the
compound of the invention finds application in the prophylaxis or therapy of
nicotine addiction, cannabis addiction, and relapse prevention of nicotine or
cannabis addiction. Additionally, the invention further provides an alternative
therapy for non-responding addiction patients, patients having intolerable sideeffects
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).
[49J The efficacy of the compound of the invention in treating the above
diseases, disorders, or conditions can be determined by any suitable method.
For example, the Novel Object Recognition Task (NORT) is the preclinical
equivalent of the visual paired comparison task in humans, a sensitive screen
for evaluation of memory dysfunctions related to cognitive impairments
associated with schizophrenia (CIAS), dementia and other amnesic states
(Manns, J . R. et al., Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 12375-12379).
Novelty recognition and discrimination forms the core principle for preclinical
tests mimicking human amnesic conditions, with underpinnings to critical
brain structures including the hippocampus and the cerebral cortex (Clark, R.
E. et al., J . Neurosci., 2000, 20, 8853-8860). NORT is based on the innate
tendency of the rodents to explore novelty in an otherwise familiar environment,
a dependent measure for the formation and retention of memory episodes. It
has successfully been utilized as a rapid, single-trial assay for investigating
effects of pharmacological manipulations on memory and attentional
parameters in rodents (Ennaceur A et al., Behav. Brain. Res., 2010, 215, 244-
254). Both the procognitive effects per s e and the reversal of chemically-induced
disruption of memory can reliably be evaluated on the short-term, intermediate
and long-term formation of episodic memory through NORT. Typically, with this
task, modulation of a single-memory episode is recorded as it is more vulnerable
to loss rather than being reinforced by multiple presentations, and hence
adding more sensitivity to measurement. Retention interval of 1 h is commonly
utilized in combination of amnesic drugs like scopolamine or MK-801 or PCP,
when mimicking memory loss in specific disease conditionssuch as dementias
or schizophrenia. For time-delay induced natural forgetting, intervals of 24 h or
more are preferred.
[50] Social functioning requires intact processing of the emotional
conditioned and un-conditioned stimuli based on the formation of short-term
recognition or working memory, which is hypothesized to be deregulated in
several neuropsychiatric disorders such as Alzheimer's disease, Schizophrenia
and Parkinson's disease (Dickerson F. et al. , Schizophr. Res. , 1996, 2 1, 75-83) .
Particularly, patients with schizophrenia are poor in initiation and maintenance
of social interactions due to deficits in short-term memory and cholinergic
neurotransmission (Hyde T. M. et al. , J . Chem. Neuroanat., 200 1, 22, 53-63).
Recognition cues for these short-term memories are thought to have a strong
'olfactory' component, the neural substrates of which have been traced to the
perirhinal and entorhinal cortices in parahippocampal region. Role played by
hippocampus and basolateral amygdala has also been well documented in
formation of recognition memory (Dantzer R. et al. , Behav. Brain Res. 1990, 40,
53-60) . Short-term working/recognition memory can be rapidly evaluated in the
rat social recognition task for several targets using pharmacological modulation.
Both the procognitive potential per se and the anti-amnesic properties (reversal
of scopolamine and MK-80 1-induced memory deficits) can be reliably tested for
the compound of the invention using this model.
5 1 The compound, a tautomer thereof, or salt thereof of the
inventionalso finds application in the treatment and prophylaxis of a number 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
Anaesthesia, 105(2) , 20 1-207, (20 10); A. Bruchfeld et al. , Journal of Internal
Medicine, 20 10, 268, 94- 10 1) .
52 The compound, tautomer thereof, or salt thereof of the invention also
finds application in the treatment and prophylaxis of a number of inflammation
and pain related states involving TNF- and in 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 diseases, 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).
[53] The present invention further provides a pharmaceutical composition,
containing compound 1, a tautomer thereof, or a pharmaceutically acceptable
salt thereof, in combination with a pharmaceutically acceptable carrier,
excipient, diluents, or the like.
[54J The pharmaceutically acceptable carrier (or excipient) is preferably
one that is chemically inert to the compound of the invention and one that has
no detrimental side effects or toxicity under the conditions of use. Such
pharmaceutically acceptable carriers preferably include saline (e.g., 0.9%
saline), Cremophor EL (which is a derivative of castor oil and ethylene oxide
available from Sigma Chemical Co., St. Louis, MO) (e.g., 5% Cremophor EL/5%
ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor
EL/50% ethanol), propylene glycol (e.g., 40% propylene glycol/ 10%
ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and
alcohol (e.g., 40% ethanol/ 60% water). A preferred pharmaceutical carrier is
polyethylene glycol, such as PEG 400, and particularly a composition
comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be
determined in part by the particular compound chosen, as well as by the
particular method used to administer the composition. Accordingly, there is a
wide variety of suitable formulations of the pharmaceutical composition of the
present invention.
55 The pharmaceutical compositions can be administered parenterally,
e.g., intravenously, intraarterially, subcutaneously, intradermally, intrathecally,
or intramuscularly. Thus, the invention provides compositions for parenteral
administration that comprise a solution of the compound of the invention
dissolved or suspended in an acceptable carrier suitable for parenteral
administration, including aqueous and non-aqueous, isotonic sterile injection
solutions.
56 Such compositions include solutions containing anti-oxidants,
buffers, bacteriostats, and solutes that render the formulation isotonic with the
blood of the intended recipient, and aqueous and non-aqueous sterile
suspensions that can include suspending agents, solubilizers, thickening
agents, stabilizers, and preservatives.
[57J Topical formulations, including those that are useful for transdermal
drug release, are well known to those of skill in the art and are suitable in the
context of the present invention for application to skin.
58 A compound of the present invention, alone or in combination with
other suitable components, can be made into aerosol formulations to be
administered via inhalation. A compound of the invention is preferably supplied
in finely divided form along with a surfactant and propellant. Typical
percentages of the compound of the invention can be about 0.01% to about 20%
by weight, preferably about 1% to about 10% by weight. The surfactant must, of
course, be nontoxic, and preferably soluble in the propellant. Representative of
such surfactants are the esters or partial esters of fatty acids containing from 6
to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic,
linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its
cyclic anhydride. Mixed esters, such as mixed or natural glycerides can be
employed. The surfactant can constitute from about 0. 1% to about 20% by
weight of the composition, preferably from about 0.25% to about 5%. The
balance of the composition is ordinarily propellant. A carrier can also be
included as desired, e.g., lecithin, for intranasal delivery. These aerosol
formulations can be placed into acceptable pressurized propellants, such as
dichlorodifiuoromethane, propane, nitrogen, and the like. They also can be
formulated as pharmaceuticals for non-pressured preparations, such as in a
nebulizer or an atomizer. Such spray formulations can be used to spray
mucosa.
[59] The concentration of the compound in the pharmaceutical
formulations can vary, e.g., from less than about 1% to about 10%, to as much
as 20% to 50% or more by weight, and can be selected primarily by fluid
volumes, and viscosities, in accordance with the particular mode of
administration selected.
[60] For example, a typical pharmaceutical composition for intravenous
infusion could be made up to contain 250 ml of sterile Ringer's solution, and
100 mg of the compound of the invention. Actual methods for preparing
parenterally administrable composition of the invention will be known or
apparent to those skilled in the art and are described in more detail in, for
example, Remington's Pharmaceutical Science (17th ed., Mack Publishing
Company, Easton, PA, 1985).
[61] It will be appreciated by one of ordinary skill in the art that, in
addition to the afore-described pharmaceutical compositions, the compound of
the invention can be formulated as inclusion complexes, such as cyclodextrin
inclusion complexes, or liposomes. Liposomes can serve to target a compound of
the invention to a particular tissue. Liposomes can also be used to increase the
half-life of a compound of the invention. Many methods are available for
preparing liposomes, as described in, for example, Szoka et al., Ann. Rev.
Biophys. Bioeng., 1980,9, 467, and US4235871, US4501728, US4837028, and
US50 19369.
[62] In another embodiment, the pharmaceutical compositions are useful
for the treatment and/ or prophylaxis of diseases, disorders or conditions
classified or diagnosed as major or minor neurocognitive disorders, or disorders
arising due to neurodegeneration.
[63] The present invention also provides a method of administering 4-(5-
(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)
benzenesulfonamide or a pharmaceutically acceptable salt thereof 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, and/or traumatic brain injury.
[64] The present invention also provides a method of administering 4-(5-
(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)
benzenesulfonamide, a tautomer thereof, or a pharmaceutically acceptable salt
thereof in combination with or as an adjunct to acetylcholinesterase inhibitors,
disease modifying drugs or biologies for neurodegenerative disorders,
dopaminergic drugs, antidepressants, and/or typical or an atypical
antipsychotic.
[65S Accordingly, 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-
dimethyl- lH-pyrrol-3-yl) benzenesulfonamide or its pharmaceutically acceptable
salts are useful for preventing or treating a disorder mediated by nicotinic
acetylcholine receptors. The compound, a tautomer, or salt thereof, can be
administered to a subject having such a disorder or susceptible to such
disorders in a therapeutically effective amount. 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)-l,4-dimethyl-lH-pyrrol-3-yl) benzenesulfonamide or its
pharmaceutically acceptable salts are particularly useful for a method of
treating a mammal having a condition where modulation of the nicotinic
acetylcholine receptor activity is of therapeutic benefit, wherein the method is
accomplished by administering a therapeutically effective amount of the
compound of the present invention to a subject having, or susceptible to, such a
disorder.
66 The compounda tautomer, or salt thereof, of the invention can be
administered in a dose sufficient to treat the disease, condition or disorder.
Such doses are known in the art (see, for example, the Physicians' Desk
Reference(2004)) . The compound a tautomer, or salt thereof, can be
administered using techniques such as those described in, for example,
Wasserman et al., Cancer, 1975, 36, 1258-1268, and Physicians' Desk
Reference, 58th ed., Thomson PDR (2004).
[67] Suitable doses and dosage regimens can be determined by
conventional range-finding techniques known to those of ordinary skill in the
art. Generally, treatment is initiated with smaller dosages that are less than the
optimum dose of the compound of the present invention. Thereafter, the dosage
is increased by small increments until the optimum effect under the
circumstances is reached. The present method can involve the administration of
about 0. 1 ug to about 50 mg of the compound of the invention per kg body
weight of the individual. For a 70 kg patient, dosages of from about 10 ug to
about 200 mg of the compound of the invention would be more commonly used,
depending on a patient's physiological response.
68 By way of example and not intending to limit the invention, the dose
of the compound, a tautomer, or salt thereof.described herein for methods of
treating or preventing a disease or condition as described above can be about
0.00 1 to about 1 mg/kg body weight of the subject per day, for example, about
0.00 1 mg, 0.002 mg, 0.005 mg, 0.0 10 mg, 0.0 15 mg, 0.020 mg, 0.025 mg,
0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1
mg/kg body weight per day. The dose of the pharmaceutically active agent(s)
described herein for the described methods can be about 1 to about 1000
mg/kg body weight of the subject being treated per day, for example, about 1
mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150
mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
[69] In accordance with embodiments, the present invention provides
methods of treating, preventing, ameliorating, and/or inhibiting a condition
modulated by the nicotinic acetylcholine receptor comprising administering
compound 1, a tautomer thereof, or a salt thereof.
70 The invention also 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 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-
l ,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide, its tautomeric form, or its
pharmaceutically acceptable salts.
[7 1] 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, 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.
[72] 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.
[73S The invention further provides a method comprising administering 4-
(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-
yljbenzenesulfonamide 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 medications can be administered simultaneously,
sequentially, or cyclically with 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-l,4-
dimethyl-lH-pyrrol-3-yl)benzenesulfonamide.
74 The invention further provides a method comprising administering 4-
(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-
yljbenzenesulfonamide in combination with or as an adjunct to other
medications, for example, acetylcholinesterase inhibitors, disease modifying
drugs or biologies for neurodegenerative disorders, dopaminergic drugs,
antidepressants, or a typical or atypical antipsychotic. The other medications
can be administered simultaneously, sequentially, or cyclically with 4-(5-(4-
chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-
yljbenzenesulfonamide.
[75] The invention also provides for the use of 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide, its
tautomeric form, and its pharmaceutically acceptable salts in the preparation of
a medicament for preventing or treating a disease or its symptoms or a disorder
mediated partially or completely by nicotinic acetylcholine receptors.
[76] In the use described above, 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.
77] The use 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.
[78] The use 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.
[79] It would be useful to list h re some of the known medications that are
used to treat 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 and
acetylcholinesterase inhibitors, disease modifying drugs or biologies for
neurodegenerative disorders, dopaminergic drugs, antidepressants, or a typical
or atypical antipsychotic.
[80] The terms "treat" or "prevent," as well as words stemming therefrom,
as used herein, do not necessarily imply 100% or complete treatment or
prevention. Rather, there are varying degrees of treatment and prevention of
which one of ordinary skill in the art recognizes as having a potential benefit or
therapeutic effect. In this respect, the inventive methods can provide any
amount of any level of treatment or prevention of the disorder in a mammal. For
example, a disorder, including symptoms or conditions thereof, may be reduced
by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.
Furthermore, the treatment or prevention provided by the inventive method can
include treatment or prevention of one or more conditions or symptoms of the
disorder. Also, for purposes herein, "treatment" or "prevention," can encompass
delaying the onset of the disorder, or a symptom or condition thereof.
[81] In accordance with the invention, the term subject includes an
"animal" which in turn includes a mammal such as, without limitation, the
order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. It is
preferred that the mammals are from the order Carnivora, including Felines
(cats) and Canines (dogs). It is more preferred that the mammals are from the
order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order
Perssodactyla, including Equines (horses). It is most preferred that the
mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the
order Anthropoids (humans and apes). An especially preferred mammal is the
human.
[82J In accordance with the invention, 'Minimal/Minimum effective dose' is
the smallest dose that produces a desired therapeutic outcome. In case of
behavioral studies, it is the minimum dose that produced statistically
significant (p<0.05, 95% confidence interval) behavioral outcome in comparison
to the control-treated group. In case of delay-dependent control is vehicletreated
group, and scopolamine group is the comparative control in
scopolamine-induced amnesia experiments.
[83] Following are the abbreviations used and meaning thereof in the
specification:
84 AIDS: Acquired Immunodeficiency Syndrome.
8 5] HBSS: Hanks Balanced Salt Solution.
86] HEPES: 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid.
87] THF: Tetrahydrofuran.
88] TLC: Thin Layer Chromatography.
89] NMR: Nuclear Magnetic Resonance.
90] a 7 nAChR: nicotinic acetylcholine receptor 7 subunit.
9 1] The following examples further illustrate the present invention and
should not be construed in any way to limit the scope of the present invention.
[92] 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) .
[93] Preparative Example: Preparation of 4-(5-(4-chlorophenyl)-l,4-
dimethyl-2-propionyl- lH-pyrrol-3-yl)benzenesulfonamide (Compound A)
[94] Compound A was prepared according to the procedures described in
Examples 10 and 11 ofWO 201 2/ 114285.
[95] Example 1: Preparation of 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide
(Compound 1)
[96] Step l :Preparation of l-(5-(4-chlorophenyl)- l ,4-dimethyl- lH-pyrrol-2-
yl)-2-cyclopropylethanone (3) using 2-cyclopropyl -N,N -dimethylacetamide
POCb (1.36 g, 0.82 ml, 8.88 mmol) was added to 2-cyclopropyl -NNdimethylacetamide
(prepared according to the procedure described in Nils
Schroder et al.,J. Am. Chem. Soc, 2012, 134, 8298-8301), 1.13 g (8.88 mmol)
at 0°C and under stirring and the reaction was continued at 0°C for 15 min. The
reaction mixture was allowed to warm up to room temperature, stirred for 20
min, and diluted with 1,2-dichloroethane (10 ml). 2-(4-chlorophenyl)-l,3-
dimethyl-lH-pyrrole (prepared according to the procedure described in
Kazuhiko Taguchi et. al., Tetrahedron Letters, 2005, 46, 4539-4542) (1.64 g, 8.0
mmol) was dissolved in 1,2- dichloroethane (20 ml) and was added to the
reaction mixture at 0°C. The reaction mixture was heated to reflux temperature
(95°C) for 30 min. The progress of the reaction was monitored by TLC. The
reaction mixture was cooled to room temperature. Sodium acetate (4.01 g, 48.9
mmol) was dissolved in water (15 ml) and added to the reaction mixture. The
reaction mixture was stirred at 100°C fori hr. The progress of the reaction was
monitored by TLC. The reaction mixture was cooled to room temperature,
diluted with DCM (50 ml) and water (20 ml) was added to it. The organic layers
were separated, dried over anhydrous sodium sulfate, filtered and concentrated
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
the title compound 3(0.77 g, 30.5%). MS: m/z 288 (M+l).
9 7 Ή NMR (CDCb, 400 ) :7.47 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz,
2H), 6.84 (s, 1H), 3.79 (s, 3H), 2.68 (d, J=6.8 Hz, 2H), 2.02 (s, 3H), 1. 15-1. 19 (m,
1H), 0.56-0.61 (m, 2H), 0.21-0.24 (m, 2H).
[98] Step 1: Preparation of l-(5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrol-
2-yl)-2-cyclopropylethanone (3) using 2-cyclopropylacetyl chloride
[99] 2-cyclopropylacetyl chloride (1 1.83 g, 100.00 mmol) solution in
chlorobenzene (60 ml) was added to the stirred solution of 2-(4-chlorophenyl)-
1,3-dimethyl-lH- pyrrole (prepared according to the procedure given in Kazuhiko
Taguchi et al., Tetrahedron Letters, 2005, 46, 4539-4542) (17. 10 g, 83.00 mmol)
and Zinc (10.87 g, 166.00 mmol) in toluene (100 ml) at 25°C. The reaction
mixture was stirred at 25°C for 3 h . The progress of the reaction was monitored
by TLC. The mixture was diluted with a saturated solution of sodium
bicarbonate (100 ml) and thelayers were separated. The aqueous layer was
extracted with ethyl acetate (3 100 ml). The combined organic layer was washed
with water (1x50 ml) and dried over anhydrous Na2S04. The solvent was
evaporated under reduced pressure to obtain a crude product. The crude
product was purified by column chromatography using 5-10% ethyl acetate in
hexanes as an eluent to obtain the title compound 3(7.20 g, 30.1%). MS: m/z
288 (M+l).
[100] HNMR (CDC13, 400 MHz): 7.47 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz,
2H), 6.84 (s, 1H), 3.79 (s, 3H), 2.68 (d, J=6.8 Hz, 2H), 2.02 (s, 3H), 1. 15-1. 19 (m,
1H), 0.56-0.61 (m, 2H), 0.21-0.24 (m, 2H).
[101] Step 2 : Preparation of l-(3-bromo-5-(4-chlorophenyl)-l,4-dimethyllH-
pyrrol-2-yl)-2-cyclopropylethanone (4)
[102] To a stirred solution of l-(5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrol-
2-yl)-2-cyclopropylethanone (Stepl)(0.30 g, 1.04 mmol) in THF (10 ml) at -78°C
was added a solution of N-bromosuccinimide (0.18 g, 1.04 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 the reaction was monitored by TLC. The reaction mixture
was quenched by the addition of a saturated sodium bicarbonate solution (5
ml). The solvent was evaporated under reduced pressure and the residue was
dissolved in ethyl acetate (30 ml). The organic layer was washed with a
saturated sodium bicarbonate solution (1x10 ml) followed by water (1x10 ml).
The combined organic layer was dried over anhydrous Na2S04. The solvent was
evaporated under reduced pressure to obtain a crude product which was
purified by column chromatography using 10% ethyl acetate in hexanes to
obtain the title compound 4(0.34 g, 89.0%). MS: m/z 367 (M+l).
[103] HNMR (CDCla, 400 MHz): 7.48 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz,
2H), 3.71 (s, 3H), 3.03 (d, J=6.8 Hz, 2H), 1.98 (s, 3H), 1.17-1.22 (m, 1H), 0.57-
0.62 (m, 2H), 0.21-0.24 (m, 2H).
[104] Step 3 : Preparation of 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-
l,4-dimethyl-lH-pyrrol-3-yl)benzenesulfonamide (Compound 1)
[105] 4-aminosulfonylbenzene boronic acid (5) (0.18 g, 0.88 mmol) and
potassium carbonate (0.31 g, 2.21 mmol) were added to the solution of l-(3-
bromo-5-(4-chlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)-2-cyclopropylethanone
(Step-2)(0.32 g, 0.88 mmol) in a mixture of toluene: ethanol (4: 16 ml) in a tube
at 25°C. Nitrogen gas was bubbled through the resulting mixture for 15
minutes. Tetrakis(triphenylphosphine)palladium(0) (0.051 g, 0.044 mmol) was
added to the reaction mixture under nitrogen atmosphere and the tube was
sealed. The reaction mixture was heated at 90-95°C for 5hr under stirring. The
progress of the reaction was monitored by TLC. The reaction mixture was cooled
to 25°C and filtered through celite. The residue was washed with a mixture of
10% methanol in dichloromethane. The filtrate was concentrated under reduced
pressure to obtain a crude product which was purified by column
chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the
title compound 1 (0.12 g, 31.8 %). MS: m/z 443 (M+l).
[106] HNMR (CDCb, 400 MHz): 8.01 (d, J=8.4 Hz, 2H), 7.44-7.50 (m, 4H),
7.31 (d, J=8.4 Hz, 2H), 4.93 (bs-exchanges with D20 , 2H), 3.72 (s, 3H), 2.09 (d,
J=7.2 Hz, 2H), 1.76 (s, 3H), 0.89-0.93 (m, 1H), 0.41-0.44 (m, 2H), -0.13t to -0. 11
(m, 2H).
[107] Example 2 : in vitro activity
[108] Compound 1 and compound Awere tested in a cell-based real-time
kinetic assay in human IMR-32 cells with native expression of a7nAChR. The
increase in intracellular Ca + levels was measured in a Fluorometric Imaging
Plate Reader (FLIPR). Test compounds and their agonist solutions were made in
an assay buffer (HBSS, pH 7.4, 20 mM HEPES, and 10 mM CaC ). 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 the 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 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. The baseline fluorescence was
monitored for the first 10 to 30 secondfoUowed by the addition of 25 ul of the
test compound solutions and subsequent monitoring of fluorescence changes
for up to 10 min. This was followed by the addition of 25 ul of agonist solution
(PNU-282987, 10 uM) and measurement of fluorescence for 4 min. (Faghih R. et
al., J . Med. Chem., 2009,52, 3377-84.)
[109] The compound induced fold increase in agonist response (fold PAM
activity) was computed by dividing the maximum effect (Max-Min fluorescence)
obtained with the test compound in the presence of agonist with the agonistalone
effect. EC50 of compound 1 and compound A were calculated using
GraphPad Prism software version 5.0, by plotting compound concentrations
against fold PAM activity.
[1 10] Compounds 1 and Aexhibited more than 15 fold PAM activity at 1 uM
concentration.
[ ] Example 3 : in vivo activity
[ 12] (i) Novel Object Recognition Task
[1 13] Briefly, Wistar rats were acclimatized to the CNS-Laboratory- animal
holding room for at least 7 days prior to the randomization, under standard
housing conditions. Animals were handled and familiarized with the injection
procedures during this period. Two days before the experimentation (acquisition
trial, Tl), rats were randomized in different treatment- groups based on their
body weights namely, vehicle (Tween 80 (1%, v/v), Vitamin E TPGS (Speziol®,
10%, v/v) q.s. 100% v/v in milli-Q water, 2 ml/kg, p.o.), scopolamine (1 mg/kg,
i.p.) and test compounds (Compound 1: ranging from 0.005 to0.05 mg/kg, p.o.
and compound A:ranging from 0.05 to 0.5 mg/kg, p.o.)
[1 14] Vehicle or test compounds (Compounds 1 and A) were administered in
a single-dose, subchronically for 7 days, and 1 h before the acquisition trial on
day-8 in respective treatment-groups. In order to induce cognitive deficits,
scopolamine (1 mg/kg) was injected 25 min before the acquisition trial (Tl).
Acquisition (Tl) and Retention (T2) trials were separated by an intertrial interval
of 30 min. In the first trial (acquisition trial, Tl), the rats were subjected to
arena with two identical objects for a period of 5 min and exploration time
towards individual object was measured. In retention trial, one of the identical
object was replaced with novel object.
[1 15] In the time-delay induced amnesia paradigm, vehicle or test
compounds (Compounds 1 and A) were administered once-daily for 7 days, and
1 h before the acquisition trial (Tl) on day-8 in the respective treatment-groups.
After this, a second, retention (T2) trial, was conducted on day-9. A 24 h inter
trial interval served to induce spontaneous decay of memory and resultant
amnesia in this paradigm.
[1 16] In the second trial (retention trial, T2), one of the objects presented in
Tl was replaced by a novel object, and the rats were left to explore in the arena
for 5 min. The time spent exploring the familiar (F) and the novel object (N) was
recorded separately. All the animals underwent habituation session of 10 min
duration 24 h prior to acquisition trial to get them acclimatized to the test
arena. Both the trials (acquisition and retention) were of 5 min duration. The
NOR task was performed in the square-open-field boxes (40 cm long x 40 cm
wide x 40 cm high) made up of non-reflective PVC sheets with black
surrounding walls and light gray floor. Colored plastic and glass bottles of
different size, shapes and texture, served as object of exploration.
[1 17] Object exploration was measured as the 'time spent by the animal'
directing its nose at a distance 2 cm to the object or touching and exploring it.
Time spent climbing on the object was not accounted as object exploration. In
order to avoid the presence of olfactory trails, the test boxes and objects were
always thoroughly cleaned between trials of individual animals.
1 18] Mean and standard error of the mean (S.E.M.) was calculated for the
exploration time of each identical objects in Tl, novel and familiar objects in T2
and discrimination index across the treatment groups. Exploration time within
groups was compared with Student's paired t-test. Discrimination index was
compared between groups by One-way ANOVAwith Dunnett's post hoc test in
comparison to the scopolamine-treated group or vehicle-treated group as per
the paradigm. Discrimination index was compared between groups by unpaired
t-test in comparison to the vehicle-treated group. p<0. 05 was considered as
significant. All statistical comparisons were performed using GraphPad Prism
version 5.00 for Windows, GraphPad Software, San Diego California USA.
[1 19] The discrimination index (DI) was calculated based on explorations in
T2 trial, using the formula.
[120] Discrimination Index equals (time spent investigating novel objecttime
spent investigating familiar object) / (time spent investigating novel object
+ time spent investigating familiar object). Any subjects that failed to explore
either of the objects during Tl and T2 were excluded from the analysis. All the
experimental recordings were carried out by manual observation of animals by
trained scientists. Observers were kept blind to the treatment groups.
[121] Results are provided in Figures 1.
[122] Table 1 below shows test results of Novel Object Recognition Task
(Subchronic studies) of compounds 1 and A.
Table 1:
1. Scopolamine induced amnesia 0.0 15 > 0.5
2 Time -delay induced amnesia 0.0 15 0.15
[123] (ii) Social Recognition Task
[124] Briefly, Sprague Dawley rats were acclimatized to the CNSLaboratory-
animal holding room for at least 7 days prior to the randomization,
under standard housing conditions. The animals were handled and familiarized
with the injection procedures during this period. Two days before the
experimentation (social interaction trial, SITl) , the rats were randomized in
different treatment-groups based on their body weights namely, vehicle (Tween
80 (1%, v/v) , Vitamin E TPGS (Speziol®, 10%, v/v) q.s. 100% v/v in milli-Q
water; 2 ml/kg, p.o.) , scopolamine (0. 5 mg/kg, i.p.) and test compound
(Compound l :ranging from 0.05 to 0.50 mg/kg, p.o.).
125] Seven days before experiment, the vehicle or the test compound was
administered to the adult rats once-daily and 1 h before the SITl on day-8 in
respective treatment- groups. Scopolamine or vehicle was administered 20 min
prior to the first social interaction (acquisition, SITl) trial; scopolamine
administration served to induced amnesia. After this treatment, the animals
were subjected to the first social interaction (acquisition, SITl) trial, which was
followed by a second (retention, SIT2) trial, 30 min later.
[126] In the case of time-delay induced amnesia paradigm, the vehicle or
the test compounds (Compound 1) were administered to the adult rats oncedaily
for 7 days and 1 h before the SITl on day-8, in respective treatmentgroups.
After this treatment, the animals were subjected to a second (retention,
SIT2) trial on day-9.The 24 h inter- trial interval served to induce spontaneous
decay of memory and resultant amnesia.
[127] Both the trials (acquisition and retention) were of 5 min duration. The
social recognition task was performed in the home-cages made up of
transparent polycarbonate. Juvenile rats of 3-4 weeks of age served as subjects
for exploration to the adult rats. Adult rats were habituated to the home-cage
(without juvenile) for 5 min just before SITl .
[128] Subject exploration (towards juvenile) was measured as the 'time
spent by the adult animal' exploring the juvenile rat socially viz. sniffing,
following, climbing over or going under or aggression. In order to avoid the
confounding olfactory trails, the home-cage was individualized for each adult
rat. During the second trial (retention trial, SIT2), adult rats were re-exposed to
the same juvenile rat previously introduced earlier in the SITl. The time of
exploration in seconds was recorded for both sessions (SITl and SIT2).
[129] Mean and standard error of mean (S.E.M) were determined for the
exploration time of each social recognition trial (SITl, SIT2) and recognition
index across the treatment- groups. Recognition index was compared between
groups by One-way ANOVAwith Dunnett's post hoc test in comparison to the
scopolamine-treated group or vehicle-treated group as per paradigm.
Exploration time within treatment groups was compared with unpaired
student's t-test. Recognition index was compared between groups by unpaired ttest
in comparison to the vehicle-treated group. p<0.05 was considered as
significant. All statistical comparisons were performed using GraphPad Prism
version 5.00 for Windows, GraphPad Software, San Diego California USA.
[130] The recognition index (RI) was calculated using the formula:
Recognition index equals (time spent investigating juvenile rat in SIT2/time
spent investigating juvenile rat in SITl).
[131] Any subjects that failed to explore either of the objects during SITl
and SIT2 were excluded from the analysis. All the experimental recordings were
carried out by manual observation of animals by trained scientists. Observers
were kept blind to the treatment groups.
[132] The results obtained are provided in Figure 2.
[133] Table 2 below shows the test results of Social Recognition Task
(Subchronic study) of compound 1.
Table 2 :
3 r Parameter Minimum effective dose
No. (mg/kg)
of Compound 1
1. Scopolamine induced amnesia 0.015
2. Time- delay induced amnesia 0.05
[134] All references, including publications, patent applications, and
patents, cited herein are hereby incorporated by reference to the same extent as
if each reference were individually and specifically indicated to be incorporated
by reference and were set forth in its entirety herein.
[135] The use of the terms "a" and "an" and "the" and "at least one" and
similar referents in the context of describing the invention (especially in the
context of the following claims) are to b e construed to cover both the singular
and the plural, unless otherwise indicated herein or clearly contradicted by
context. The use of the term "at least one" followed by a list of one or more items
(for example, "at least one of A and B") is to be construed to mean one item
selected from the listed items (A or B) or any combination of two or more of the
listed items (A and B), unless otherwise indicated herein or clearly contradicted
by context. The terms "comprising," "having," "including," and "containing" are
to be construed as open-ended terms (i.e., meaning "including, but not limited
to,") unless otherwise noted. Recitation of ranges of values herein are merely
intended to serve as a shorthand method of referring individually to each
separate value falling within the range, unless otherwise indicated herein, and
each separate value is incorporated into the specification as if it were
individually recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise clearly
contradicted by context. The use of any and all examples, or exemplary
language (e.g., "such as") provided herein, is intended merely to better
illuminate the invention and does not pose a limitation on the scope of the
invention unless otherwise claimed. No language in the specification should be
construed as indicating any non-claimed element as essential to the practice of
the invention.
[136] Preferred embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the invention.
Variations of those preferred embodiments may become apparent to those of
ordinary skill in the art upon reading the foregoing description. The inventors
expect skilled artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended hereto as
permitted by applicable law. Moreover, any combination of the above-described
elements in all possible variations thereof is encompassed by the invention
unless otherwise indicated herein or otherwise clearly contradicted by context.
CLAIMS
4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)
benzenesulfonamide, a tautomer thereof, or a pharmaceutically
acceptable salt thereof.
A pharmaceutical composition comprising 4-(5-(4-chlorophenyl)-2-(2-
cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide, a
tautomer thereof, or a pharmaceutically acceptable saltthereof and a
pharmaceutically acceptable carrier.
A method of preventing or treating a disease or its symptoms, condition,
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 a therapeutically
effective amount of 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-l,4-
dimethyl-lH-pyrrol-3-yl)benzenesulfonamide, a tautomer thereof, or a
pharmaceutically acceptable salt thereof.
The method of claim 3, wherein the disorder, condition or disease is
selected from the group consisting of Alzheimer's disease, mild cognitive
impairment, senile dementia, vascular dementia, dementia of Parkinson's
disease, attention deficit disorder, attention deficit hyperactivity disorder,
dementia associated with Lewy bodies, AIDS dementia complex, Pick's
disease, dementia associated with Down's syndrome, Huntington's
disease, cognitive deficits associated with traumatic brain injury,
cognitive 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 method of claim 3, 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 method of claim 3, comprising administering 4-(5-(4-chlorophenyl)-2-
(2-cyclopropylacetyl)- 1,4-dimethyl- lH-pyrrol-3-yl)benzenesulfonamide, a
tautomer thereof, or a pharmaceutically acceptable salt thereof 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 of claim 3, further comprising administering an
acetylcholinesterase inhibitor, a disease modifying drug or biologic
fortreating a neurodegenerative disorder, a dopaminergic drug, an
antidepressant, or a typical or an atypical antipsychotic.
Use of 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)- 1,4-dimethyl- 1Hpyrrol-
3-yl) benzenesulfonamide, a tautomer thereof, or its
pharmaceutically acceptable salts inthe 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 claimed in claim 8, 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.
10. The use as claimed in claim 8, 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.
11. The use as claimed in claim 8, which is in combination with or as an
adjunct to an acetylcholinesterase inhibitor, a disease modifying drug or
biologic for a neurodegenerative disorder, a dopaminergic drug, an
antidepressant, or a typical or atypical antipsychotic.
12. The compound or pharmaceutically acceptable salt of claim 1, or the
pharmaceutical composition of claim 2, for use in treating a disorder,
condition or disease selected from the group consisting of Alzheimer's
disease, mild cognitive impairment, senile dementia, vascular dementia,
dementia of Parkinson's disease, attention deficit disorder, attention
deficit hyperactivity disorder, dementia associated with Lewy bodies,
AIDS dementia complex, Pick's disease, dementia associated with Down's
syndrome, Huntington's disease, cognitive deficits associated with
traumatic brain injury, cognitive 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;
for use in treating a major or minor neurocognitive disorder, or a disorder
arising due to neurodegeneration; or
for use 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.