PYRROLE DERIVATIVES AS ALPHA 7 NACHR MODULATORS
FIELD OF THE INVENTION
[1] The present invention relates to pyrrole derivatives, their tautomeric
forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical
compositions comprising one or more such compounds, and their use as nicotinic
acetylcholine receptor 7 subunit ( 7 nAChR) modulators.
CROSS-REFERENCE TO A RELATED APPLICATION
[2] The present application claims the benefit of Indian Provisional Patent
Application No. 2049/MUM/2013 filed on 17th June 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 ligand-gated
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, 61(2000), 75-1 11). 4 2 and 7 nAChR constitute
the predominant subtypes expressed in the mammalian brain. 7 nAChR has
attained prominence as 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 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 Ca2+ 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-
1133).
[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 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 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 as an u p
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), 1096 1- 10973; R. G. Nagele et al. , Neuroscience, 2002,
110(2) , 199-2 11; G. Jeyarasasingam et al. , Neuroscience, 2002, 109, 275-285) .
Additionally, it has been proposed that 7 nAChR induced activation of antiapoptotic
(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), e l000 125) . 7 nAChR has particularly been studied for a
putative role in cannabis addiction (Marcello Solinas et al. , The Journal of
Neuroscience, 2007, 27(2 1) , 56 15-5620). 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, 20 10, 4 ,
355-362).
[9] The presence of a high-affinity nicotine binding site at 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, (200 1) , 10( 10), 18 19- 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-a) , 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 anti- inflammatory pathway' has been
proposed to be 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 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).
[11] 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 smokingexposed
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-21 (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-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, 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). SSR-18071 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., Psychopharmacology, 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 a 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 a7 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 a7 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
a7 nAChR desensitization kinetics while simultaneously protecting against the
disruption of prepulse inhibition by MK-801. NS-1738, another PAM, reportedly
exhibits efficacy in-vlvo 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 a7 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 a compound of the general formula (I), its
tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, its
combinations with one or more of suitable other medicaments, its pharmaceutical
compositions, and its use as nicotinic acetylcholine receptor 7 subunit ( 7
nAChR) modulator.
[15] According to one aspect of the present invention, there is provided a
compound represented by the general formula (I), its tautomeric forms, its
stereoisomers, its pharmaceutically acceptable salts, its combinations with one or
more of suitable other medicaments, and its pharmaceutical compositions, wherein
R1 to R7 and m are described in details below.
[16] Thus the present invention further provides a pharmaceutical
composition containing the compound of the general formula (I), its tautomeric
forms, its stereoisomers, 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 as Alzheimer's disease (AD), mild cognitive impairment (MCI),
senile dementia, vascular dementia, dementia of Parkinson's disease, attention
deficit disorder, attention deficit hyperactivity disorder (ADHD), dementia
associated with Lewy bodies, AIDS dementia complex (ADC), Pick's disease,
dementia associated with Down's syndrome, Huntington's disease, cognitive
deficits associated with traumatic brain injury (TBI), cognitive 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.
[17] The present invention also provides a pharmaceutical composition
containing a compound of the general formula (I), its tautomeric forms, its
stereoisomers, its pharmaceutically acceptable salts, its polymorphs, its solvates,
and/or its optical isomers 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.
[18] The present invention also provides a method of treatment wherein a
compound of formula (I), its tautomeric forms, its stereoisomers, or its
pharmaceutically acceptable salts is administered in combination with or as an
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.
[19] The present invention also provides a method of treatment wherein a
compound of formula (I), its tautomeric forms, its stereoisomers, or its
pharmaceutically acceptable salts 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.
[20] The present invention also provides the use of a compound of formula (I) ,
its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable salts, 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.
[21] The present invention also provides the use of a compound of formula (I),
its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable salts, 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.
[22] The present invention also provides the use of compound of formula (I),
its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable salts, 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
[23] The present invention provides a compound of the general formula (I), its
tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, its
combinations with suitable other medicaments, and its pharmaceutical
compositions,
wherein,
R1 is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- cycloalkyl;
R3 is selected from the group consisting of substituted- or unsubstituted- aryl
and substituted- or unsubstituted- heteroaryl;
R4 is selected from the group consisting of substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl,
substituted- or unsubstituted- heteroaryl, substituted- or unsubstitutedheterocyclyl,
and -NR8R9;
R5 is selected independently at each occurrence from the group consisting of
halogen, substituted- or unsubstituted- alkyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, -OR b , -NR8R9, and -C(=0)R ; or
R6 and R7 are independently selected from the group consisting of hydrogen and
substituted- or unsubstituted- alkyl;
R8 and R9 are each independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstitutedcycloalkyl;
R8a is selected from the group consisting of substituted- or unsubstituted- alkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
R8b is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
m is an integer selected from 0, 1, and 2 ;
when the alkyl group is substituted, it is substituted with 1 to 3 substituents
independently selected from oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl,
aryl, heteroaryl, heterocyclyl, -OR 1 b , -SO 2R10a , -C(=O)OR 1 a, -OC(=O)R 1 , -
C(=0)N(H)R1 , -C(=0)N(alkyl)R1 , -N(H)C(=O)R 1 a , -N(H)R 10 , -N(alkyl)R1 , -
N(H)C (=0)N(H)R , and -N(H)C(=0)N(alkyl)R ° ;
when the cycloalkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano, alkyl,
perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR 1 , -SO 2R10c , -C(=O)R 1 , -
N(H)Riod, -N(alkyl)R d,
when the aryl group is substituted, it is substituted with 1 to 3 substituents
independently selected 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;
when the heteroaryl group is substituted, it is substituted with 1 to 3
substituents independently selected 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 independently selected from
halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -OR b , -C(=O)OR c, -OC(=O)R c, -C(=0)N(H)R -C(=0)N (alkyl)R °d, -
and
N(H)C(=O)N(alkyl)R10d; and when the heterocyclyl group is substituted on a ring
nitrogen, it is substituted with a substituent selected from alkyl, cycloalkyl, aryl,
heteroaryl, -SO 2R10c,
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10a is selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
and heterocyclyl;
R1 is selected from alkyl, perhaloalkyl, and cycloalkyl;
R10d is selected from hydrogen, alkyl, and cycloalkyl.
[24] In accordance with an embodiment of the invention, R1 is selected from
substituted- or unsubstituted- alkyl and substituted- or unsubstituted- cycloalkyl.
[25] In certain embodiments, R1 is selected from methyl and ethyl.
[26] In certain embodiments, R2 is selected from methyl, ethyl, and propyl.
[27] In certain embodiments, R3 is phenyl substituted with 1 to 2
substituents selected from chloro, fluoro, and methyl.
[28] In certain embodiments, R4 is selected from ethyl and pyridyl.
[29] In any of the above embodiments, R5 is halogen.
[30] In any of the above embodiments, m is selected from 0 and 1.
[31] In any of the above embodiments, R6 and R7 are hydrogens.
[32] Whenever a range of the number of atoms in a structure is indicated
(e.g., a Ci-12, Ci-8, C i e , 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.,
Ci-C 4) , 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-Cs) 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) .
[33] 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.
[34] 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.
[35] In a substituted alkyl group, the alkyl group is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano, perhaloalkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR1 b , -SO2R10a, -C(=O)OR1 a , -
-N(H)R °, -N(alkyl)R °,
is selected from
hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R10a is selected from
alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; R10b is selected
from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.
[36] The term "perhaloalkyl" used herein means an alkyl group as defined
hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted
with halogen. The perhaloalkyl group is exemplified by trifluoromethyl,
pentafluoroethyl, and the like.
[37] 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. 1]heptane,
bicyclo[2.2.1 ]heptane , bicyclo [2 .2.2] octane , bicyclo[3 .2.2 ]nonane,
bicyclo[3.3. l]nonane, bicyclo [4.2. 1]nonane, bicyclo[3.3.2]decane,
bicyclo[3.1.0]hexane, bicyclo [4. 1.0]heptane, bicyclo[3.2.0]heptanes, octahydro-lHindene,
spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2, -
cyclopentane], and hexahydro-2'H-spiro[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[3.3.1.0 3 7]nonane and tricyclo[3.3.1.1 3 7]decane (adamantane) .
[38] When the cycloalkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano, alkyl,
perhaloalkyl, aryl, heteroaiyl, heterocyclyl, -OR 1 b , -SO 2R10c , -C(=O)R 1 , -
N(H)Riod, -N(alkyl)Riod, wherein
R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaiyl, and
heterocyclyl; R1 is selected from alkyl, perhaloalkyl, and cycloalkyl; R10d is
selected from hydrogen, alkyl, and cycloalkyl.
[39] The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic
hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl,
anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also includes
partially saturated bicyclic and tricyclic aromatic hydrocarbons such as
tetrahydro-naphthalene.
[40] When the aryl group is substituted, it is substituted with 1 to 3
substituents independently selected 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.
[41] The term "heteroaiyl" 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.
Heteroaiyl 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 heteroaiyl group may be
substituted by a substituent. Examples of heteroaiyl groups include, but not
limited to pyridyl, 1-oxo-pyridyl, furanyl, thienyl. pyrrolyl, oxazolyl, oxadiazolyl,
imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,
pvrimidinvl, pyraziiivl, triazinyl, triazolyL thiadiazolyl, isoquinolinyl, benzoxazolyl,
benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzo thiazolyl,
benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl,
purinyl, pyrrolo[2,3jpyrimidinyl, pyrazolo[3 ,4jpyrimidinyl, benzo (b)thienyl, 2,3-
thiadiazolyl , H-pyrazolo [5 ,1-c ]-1,2,4-triazolyl, pyrrolo [3,4-d] -1,2 ,3-triazolyl ,
cyclopentatriazolyl, 3H-pyrrolo[3, -c|isoxazoly1, 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.
[42] When the heteroaryl group is substituted, it is substituted with 1 to 3
substituents independently selected 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.
[43] 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(R )-, and -Si(R )R - , wherein, R 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-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 2,3-dihydro-lH-indolyl, and
1,2,3,4-tetrahydroquinolinyl. The term heterocycle also include bridged
heterocyclyl systems such as azabicyclo[3.2.1]octane, azabicyclo[3.3. l]nonane, and
the like.
[44] The heterocyclyl group, when it is substituted, it may be substituted on
ring carbon atom(s) and/or ring nitrogen atom. For example, it is substituted on
ring carbons with 1 to 3 substituents independently selected from halogen, nitro,
cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 10b , -
C(=O)OR , -OC(=O)R , -C(=0)N(H)R d , -C(=0)N(alkyl)R °d, -N(H)C(=O)R 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 ; wherein
R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl; R1 is selected from alkyl, perhaloalkyl, and cycloalkyl; R10d is
selected from hydrogen, alkyl, and cycloalkyl.
[453 When the heterocyclyl group is substituted on ring nitrogen, it is
substituted with a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl, -
S O2R10c , -C(=O)R 1 , -C(=0)N(H)R °d, and -C(=0)N(alkyl)R °d ; wherein R is selected
from alkyl, perhaloalkyl, and cycloalkyl; R10d is selected from hydrogen, alkyl, and
cycloalkyl.
[48] 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 C group is substituted with an oxo substituent, the parent C
group becomes a carbonyl (C=0) group; thus, oxo substituted on cyclohexane
forms a cyclohexanone, for example.
[47] 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.
[48] 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.
[49] compound, its stereoisomers, its racemates, and its pharmaceutically
acceptable salt thereof as described hereinabove, wherein, the compound of general
formula (I) is selected from:
[503 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 1);
[51] 4-(4-(4-fluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 2);
[52j 4-(4-(4-chloro-3-methylphenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 3);
[533 4-(4-(4-chlorophenyl)-5-ethyl- 1-methyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 4);
[54] 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-yl)-2-
fluorobenzenesulfonamide (Compound 5);
[55] 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-yl)-3-
fluorobenzenesulfonamide (Compound 6);
[563 4-(4-(4-chlorophenyl)- l-ethyl-5-methyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 7);
[57] 4-(4-(3,4-difluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 8);
[58] 4-(4-(2,4-difluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 9);
[59] 4-(4-(3-fluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 10);
[60j 4-(4-(4-fluoro-3-methylphenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 11);
[61] 4-(l ,5-dimethyl-2-propionyl-4-(p-tolyl)- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 12);
[623 4-(4-(4-chloro-2-fluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 13);
[633 4-(4-(4-chloro-3-fluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 14);
[643 4-(4-(4-chlorophenyl)- l-methyl-2-propionyl-5-propyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 15); and
[653 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-nicotinoyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 16);
[663 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.
[673 Scheme 1 below shows a method of preparation of the compound of the
formula (I) (where R1, R2, R3, R4, 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)). The
compound of formula (II) was prepared according to the procedure described in
Tetrahedron Letters, 46 (2005), 4539-4542.
Scheme-1
[68] 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 in Tetrahedron Letters, 43 (2002), 8133-
8135, to obtain the compound of formula (III). Preferably, the reaction is carried
out in toluene in presence of zinc.
[69] The compound of the formula (III) so obtained is reacted with
halogenating reagents such as bromine, N-bromosuccinimide, Nchlorosuccinimide,
and phosphorous tribromide (as provided in Synlett., 2002, No.
7, 1152-1 154) to obtain compound of formula (IV). Preferably, the halogenation
reaction is carried out in presence of N-bromosuccinimide in THF.
[70] The compound of formula (IV) as obtained in the previous step was
subjected to Suzuki coupling with boronic acids or esters represented by formula
(V) (where R5, R6, R7, and m are as defined earlier) to obtain compound of formula
(I) (where R1, R2, R3, R4, R5, R6, R7, and m are as defined earlier). Suzuki coupling
with boronic acid 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 or dioxane and water, 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.
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 iodo- or 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 1 012 142; Review article by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95,
2457-2483).
[71] Scheme 2 below shows a method of preparation of the compound of the
formula (I) (where R2 is methyl, R1, R3, R4, R5, R6, R7, and m are as described under
compound of generic formula (I)) from compound represented by general formula
(VI) (where R2 is methyl and R1 is same as defined under general formula (I)). The
compound of formula (VI) was prepared according to the procedure described in US
6,884,801.
Scheme-2
[72] The compound of the formula (VI) is reacted with R4CON(CH3)2, (where R4
is as defined earlier) in the presence of POCI3 under Vilsmeier-Haack reaction
conditions as described in Tetrahedron, 2007, 63, 8124-8134, to obtain the
compound of the formula (VII) (where R is methyl, R1 and R4 are as defined earlier).
[73] The compound of the formula (VII) so obtained is reacted with
halogenating reagent such as bromine, N-bromosuccinimide, N-chlorosuccinimide,
and phosphorous tribromide (as provided in Synlett., 2002, No. 7, 1152-1 154) to
obtain compound of formula (VIII) . Preferably, the halogenation reaction is carried
out in presence of N-bromosuccinimide in THF.
[74] The compound of formula (VIII) as obtained in the previous step was
subjected to Suzuki coupling with boronic acid represented by formula R3B(OH)2,
(where R3 is as defined earlier) to obtain compound of formula (IX) (where R2 is
methyl, R1,R3, and R4 are as defined earlier).
[75] The compound of the formula (IX) so obtained is reacted with
halogenating reagent such as bromine, N-bromosuccinimide, N-chlorosuccinimide,
and phosphorous tribromide (as provided in Synlett., 2002, No. 7, 1152-1 154) to
obtain compound of formula (X) (where X is halogen, R2 is methyl, R1, R3, and R4
are as defined earlier). Preferably, the halogenation reaction is carried out in
presence of N-bromosuccinimide in THF.
[76] The compound of formula (X) as obtained in the previous step was
subjected to Suzuki coupling with boronic acid or ester represented by formula (V)
(where R5, R6, R7, and m are as defined earlier) to obtain compound of formula (I)
(where R2 is methyl, R1, R3, R4, R5, R6, R7, and m are as defined earlier). Suzuki
coupling with boronic acid and ester can be carried out by following the procedures
described in Scheme 1.
Scheme 3 below shows a method of preparation of the compound of the formula (I)
(where R4 is -NR8R9, R1, R2, R3, R5, R6, R7, and m are as described under compound
of generic formula (I)) from compound represented by general formula (XI) (R1, R2
and R3, are same as defined under general formula (I)). The compound of formula
(XI) can be prepared according to the procedure described in WO 2007/029364.
Where R4 is -NR R9
(XI) II)
Scheme-
[77] The compound of formula (XI) can be reacted with R7R8NH to obtain the
compound of the formula (XII) (where R4 is -NR8R9, R1, R2 and R3 are as described
under compound of generic 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 trie thy lamine, diisopropylethylamine, pyridine or the like at a temperature
between 0-50°C using reagents such as l-(3-dimethylaminopropyl)-3-
ethylcarbodimide hydrochloride (EDCI) and 1,3-dicyclohexylcarbodiimide (DCC),
and auxiliary reagents such as l-hydroxy-7-azabenzotriazole (HOAT),
hydroxybenzotriazole hydrate (HOBT) or the like.
[78] The compound of the formula (XII) so obtained can be reacted with
halogenating reagent such as bromine, N-bromosuccinimide, N-chlorosuccinimide,
and phosphorous tribromide (as provided in Synlett., 2002, No. 7, 1152-1 154) to
obtain compound of formula (XIII).
[79] The compound of formula (XIII) as obtained in the previous step can be
subjected to Suzuki coupling with boronic acid or ester represented by formula (V)
(where R5, R6, R7, and m are as defined earlier) to obtain compound of formula (I)
(where R4 is -NR8R9, R1, R2, R3, R5, R6, R7 and m are as described under compound
of generic formula (I)) . Suzuki coupling with boronic acid and ester can be carried
out by following the procedures described in Scheme 1.
[80] The intermediates and the compounds of the present invention may be
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.
[813 Salts of the compound of formula (I) can be obtained by dissolving the
compounds 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.
[82] 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 and 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.
[83] 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.
[84] The prodrugs can be prepared in situ during the isolation and
purification of the compounds, or by separately reacting purified compound with a
suitable derivatizing agent. For example, the 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 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.
[85] 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 one or more of
the aforesaid compounds, or salts thereof, of the present invention.
[86] 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. It will be appreciated by one of skill in the art that, in addition to
the following described pharmaceutical compositions; the compounds of the
present invention can be formulated as inclusion complexes, such as cyclodextrin
inclusion complexes, or liposomes.
[87] 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. It is preferred that the
pharmaceutically acceptable carrier be one which is chemically inert to the active
compounds and one which has no detrimental side effects or toxicity under the
conditions of use.
[88] The choice of carrier will be determined in part by the particular active
agent, 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. 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.
[89] 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 softshelled
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.
[90] The compounds of the present invention, alone or in combination with
other suitable components, can be made into aerosol formulations to be
administered via inhalation. These aerosol formulations can be placed into
pressurized acceptable propellants, such as dichlorodifluoromethane, propane,
nitrogen, and the like. They also may be formulated as pharmaceuticals for nonpressured
preparations, such as in a nebulizer or an atomizer.
[ Formulations suitable for parenteral administration include aqueous and
non-aqueous, isotonic sterile injection solutions, which can contain 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. The compound 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, or polyethylene glycol, or glycerol, ketals, such as 2,2-dimethyll,
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.
[92] 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 polyoxyethylene-polypropylene copolymers, (d)
amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-
alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
[93] 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 b e presented in unitdose
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.
[94] The compounds of the present invention 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, 4th ed., pages 622-630 (1986).
[95] Additionally, the compounds of the present invention may b e 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 as are known in the
art to be appropriate.
[98] 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,
20 10, 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 (Neuropsychiatric Genetics), 2007, 144B, 6 11-6 14; 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), 12 12- 1223; S. L. Verbois, et al. , Neuropharmacology, 44 (2003), 224-
233; Paul R. Sanberg, et al. , Pharmacol. Ther. , 1997, 74( 1), 2 1-25). 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.
[97] Modulation of nicotinic ACh receptors, particularly the 7 subtype also
helps to supplement the down-regulated cholinergic receptor expression and
transmission as in dementia(s), and also in slowing disease progression by
reduction of the 7- 2 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) .
[98] The compounds of the invention 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, drugs abuse,
drug addiction, alcohol abuse, alcohol addiction, metal poisoning such as
aluminium, lead, mercury, and 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 Duris et al., Stroke, 201 1, 42(12), 3530-3536). The compounds of the
present invention also find application in the prophylaxis and preventive measures
immediately after early-stage identification of neurodegenerative diseases such as
Alzheimer's disease and Parkinson's disease.
[99] Modulation of the nicotinic ACh receptors, particularly the 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 compounds of the
invention find 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 nonresponding
addiction patients, patients having intolerable side-effects with deaddiction
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).
[1 | The compounds of the invention also find application in the treatment
and prophylaxis of a 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 Anaesthesia, 105(2), 20 1-207, (20 10) ; A. Bruchfeld et al. , Journal of
Internal Medicine, 20 10, 268, 94- 10 1).
[1 ] The compounds of the invention also find application in the treatment
and prophylaxis of a number of inflammation and pain related states involving
TNF-a and 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. , 20 10, 40,
2580-2589) .
[102] 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 a compound of formula (I), its tautomeric forms, its
stereoisomers, or its pharmaceutically acceptable salts.
[103] 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.
[104] 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.
[105] 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, dementia associated with Lewy bodies, or traumatic brain injury. The
medications can be administered simultaneously, sequentially, or cyclically with a
compound of formula (I) .
[106] The invention further provides a method comprising administering a
compound of formula (I) 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 a compound of formula (I).
[107] The invention also provides for the use of a compound of formula (I), its
tautomeric forms, its stereoisomers, and it's 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.
[108] 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.
[109] 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.
[110] 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.
[Ill] It would be useful to list here 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.
[ 12] 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.
[1 13] Following are the abbreviations used and meaning thereof in the
specification:
[1 14] AIDS: Acquired Immunodeficiency Syndrome.
[1 15] HBSS: Hank's Balanced Salt Solution.
[1 16] HEPES: 4-(2-hydroxyethyl)piperazine- l -ethanesulfonic acid.
[1 17] THF: Tetrahydrofuran.
[1 18] TLC: Thin Layer Chromatography.
[1 19] NMR: Nuclear Magnetic Resonance.
[120] a 7 nAChR: nicotinic acetylcholine receptor a7 subunit.
[12 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.
[122] All JH 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).
[123] Example 1: Preparation of 4-(4-(4-chlorophenyl)-l,5-dimethyl-2-
propionyl-lH-pyrrol-3-yl)benzenesulfonamide (Compound 1)
[124] Step 1: l-(4-(4-chlorophenyl)-l,5-dimethyl-lH-pyrrol-2-yl)propan-l-one
(Compound la)
I
[125] Propionyl chloride (0.64 g, 6.95 mmol) was added to the stirred solution
of 3-(4-chlorophenyl)-l,2-dimethyl-lH-pyrrole (prepared according to the procedure
given in Tetrahedron Letters, 2005, 46, 4539-4542) (0.65 g, 3.16 mmol) and Zinc
(0.62 g, 9.48 mmol) in toluene (20 ml) at 25°C. The reaction mixture is stirred at
25°C for 1 h and at 60°C for 3 h . The progress of the reaction was monitored by
TLC. The reaction mixture was diluted with saturated solution of sodium
bicarbonate (20 ml) and layers 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 a2S . The solvent was evaporated from organic
layer 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 title compound l a (0.26 g, 31.0%). MS: m/z 262 (M+l).
[126] Ή NMR (CDCls, 400 MHz): 7.35 - 7.39 (m, 2H), 7.29 - 7.30 (m, 2H),
7.02 (s, 1H), 3.95 (s, 3H), 2.83 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.21 (t, J = 7.2 Hz,
3H).
[127] Step 2 : l-(3-bromo-4-(4-chlorophenyl)-l,5-dimethyl-lH-pyrrol-2-
yl)propan- 1-one (Compound lb)
[128] To a stirred solution of l-(4-(4-chlorophenyl)-l,5-dimethyl-lH-pyrrol-2-
yl)propan-l-one (Compound la, 0.25 g, 0.95 mmol) in THF (10 ml) at -78°C was
added a solution of N-bromosuccinimide (0.20 g, 1.15 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. The reaction mixture was quenched by
addition of saturated sodium bicarbonate solution (5 ml) and evaporated under
reduced pressure to obtain a residue which was dissolved in ethyl acetate (30 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 from the organic layer 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 lb (0.085 g,
25.8%). MS: m/z 341 (M+l).
[129] Ή NMR (CDC13, 400 MHz): 7.38 - 7.42 (m, 2H), 7.21 - 7.24 (m, 2H),
3.86 (s, 3H), 2.78 (q, J = 7.2 Hz, 2H), 2.20 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).
[130] Step 3 : 4-(4-(4-chlorophenyl)-l,5-dimethyl-2-propionyl-lH-pyrrol-3-
yDbenzene sulfonamide (Compound 1)
[131] 4-aminosulfonylbenzene boronic acid (0.07 g, 0.35 mmol) and potassium
carbonate (0.067 g, 0.48 mmol) were added to the solution of (l-(3-bromo-4-(4-
chlorophenyl)-l,5-dimethyl-lH-pyrrol-2-yl)propan-l-one (Compound lb, 0.1 1 g,
0.32 mmol) in a mixture of toluene: ethanol (1:3 ml) in a tube at 25°C. The nitrogen
gas was bubbled through resulting mixture for 15 minutes.
Tetrakis(triphenylphosphine) palladium(O) (0.019 g, 0.016 mmol) was added to the
reaction mixture under nitrogen atmosphere and tube was sealed. The reaction
mixture was heated at 90-95°C for 5 hr under stirring. The progress of reaction
was monitored by TLC. The reaction mixture was cooled to 25°C and filtered
through celite. The residue thus obtained was washed with mixture of 10%
methanol in dichloromethane. The resulting 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 1 (0.037 g, 27.5%). MS: m/z 417 (M+l).
[132] H NMR (CDC13, 400 MHz): 7.81 (d, J = 8.4 Hz, 2H), 7.25 - 7.27 (m, 2H),
7.16 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.82 (bs-exchanges with D20 , 2H),
3.86 (s, 3H), 2.22 (s, 3H), 2.01 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H).
[133] The following compounds were prepared according to the procedure
described above for compound 1, with appropriate changes to the reactants.
[134] 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-yl)-2-
fluorobenzenesulfonamide (Compound 5) [MS: m/z 435 (M+l)],
[135] Ή NMR (CDCI3, 400 MHz) 7.82 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz,
2H), 7.04 - 7.08 (m, 1H), 6.96 - 7.02 (m, 1H), 6.88 (d, J = 8.0 Hz, 2H), 5.1 1 (bsexchanges
with D20 , 2H), 3.88 (s, 3H), 2.23 (s, 3H), 2.16 (q, J = 7.2 Hz, 2H), 0.97
(t, J = 7.2 Hz, 3H).
[136] 4-(4-(4-chlorophenyl)- l-ethyl-5-methyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 7) [MS: m/z 432 (M+l)],
[137] H NMR (CDC13, 400 MHz): 7.85 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 7.18 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.85 (bs-exchanges with D20 ,
2H), 4.37 (q, J = 6.8 Hz, 2H), 2.26 (s, 3H), 2.1 1 (q, J = 6.8 Hz, 2H), 1.43 (t, J = 6.8
Hz, 3H), 0.93 (t, J = 6.8 Hz, 3H).
[138] 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-yl)-3-
iluorobenzenesulfonamide (Compound 6) [MS: m/z 435 (M+l)],
[139] Ή NMR (DMSO-de, 400 MHz) 6 7.56 - 7.60 (m, 2H), 7.54 (bs-exchanges
with D20 , 2H), 7.38 - 7.47 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz,
2H), 3.82 (s, 3H), 2.21 (s, 3H), 2.10 (q, J = 7.2 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H).
[140] 4-(4-(4-iluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 2) [MS: m/z 401 (M+l)],
[141] H NMR (CDCI3, 400 MHz): 7.81-7.86 (m, 2H), 7.28 - 7.30 (m, 2H),
6.88-6.92 (m, 4H), 4.82 (bs-exchanges with D2O, 2H), 3.89 (s, 3H), 2.24 (s, 3H),
2.13 (q, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H).
[142] 4-(4-(4-chloro-3-methylphenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 3) [MS: m/z 431 (M+l)],
[143] Ή NMR (CDCI3, 400 MHz): 7.85 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz,
2H), 7.15 (d, J = 8.4 Hz, IH), 6.84 (d, J = 2.0 Hz, IH), 6.67 (dd, J = 8.4, 2.0 Hz, IH),
4.84 (bs-exchanges with D20 , 2H), 3.89 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.13 (q, J
= 6.8 Hz, 2H), 0.93 (t, J = 6.8 Hz, 3H).
[144] 4-(4-(4-chlorophenyl)-5-ethyl- l-methyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 4) [MS: m/z 431 (M+l)],
[145] Ή NMR (CDCls, 400 MHz): 7.84 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz,
2H), 7.17 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.85 (bs-exchanges with D20 ,
2H), 3.91 (s, 3H), 2.62 (q, J = 6.8 Hz, 2H), 2.15 (q, J = 6.8 Hz, 2H), 1.18 (t, J = 6.8
Hz, 3H), 0.93 (t, J = 6.8 Hz, 3H).
[146] 4-(4-(4-chlorophenyl)- l-methyl-2-propionyl-5-propyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 15) [MS: m/z 445 (M+l)],
[147] H NMR (CDC13, 400 MHz): 7.83 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz,
2H), 7.18 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.89 (bs-exchanges with D20 ,
2H), 3.89 (s, 3H), 2.55-2.57 (m, 2H), 2.12 (q, J = 6.8 Hz, 2H), 1.54-1.56 (m, 2H),
0.90-0.92 (m, 6H).
[148] 4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-nicotinoyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 16) [MS: m/z 466 (M+l)],
[149] Ή NMR (CDCls, 400 MHz) 8.47 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 7.80 -
7.88 (m, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.1 1 (dd, J = 8.0,
4.8 Hz, 1H), 6.84 - 6.96 (m, 4H), 5.1 1 (bs-exchanges with D20 , 2H), 3.98 (s, 3H),
2.36 (s, 3H).
[150] Example 2 : Preparation of 4-(l,5-dimethyl-2-propionyl-4-(p-tolyl)-lHpyrrol-
3-yl)benzenesulfonamide (Compound 12)
[151] Step 1: l-(l,5-dimethyl-lH-pyrrol-2-yl)propan-l-one (Compound 12a)
[152] POCls (15.07 g, 9.16 ml, 98.00 mmol) was added to N,Ndimethylpropionamide
(9.94 g, 10.8 ml, 98.00 mmol) at 0°C and under stirring.
The reaction was continued at 0°C for 15 min. The reaction mixture was allowed to
come at room temperature, stirred for 20 min and diluted with 1,2-dichloroethane
(25 ml). 1,2-dimethyl-lH-pyrrole (prepared according to the procedure described in
US 6,884,801) (8.50 g, 89.0 mmol) was dissolved in 1,2 dichloroethane (25 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 reaction was monitored by
TLC. The reaction mixture was cooled to room temperature. Sodium acetate (66.90
g, 491.00 mmol) was dissolved in water (150 ml) and added to the reaction
mixture. The reaction mixture was stirred at 100°C for 1 hr. The progress of
reaction was monitored by TLC. Reaction mixture was cooled to room temperature,
diluted with DCM (150 ml) and water (50 ml) was added to it. The resulting organic
layer was separated, dried over anhydrous sodium sulfate and concentrated to get
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
12a (8.60 g, 63.7%). MS: m/z 152 (M+l).
[153] Ή NMR (CDCls, 400 MHz): 6.93 (d, J = 4.0 Hz, 1H), 5.94 (d, J = 4.0 Hz,
1H), 3.87 (s, 3H), 2.79 (q, J = 7.2 Hz, 2H), 2.26 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H).
[154] Step 2 : l-(4-bromo-l,5-dimethyl-lH-pyrrol-2-yl)propan-l-one
(Compound 12b)
[155] To a stirred solution of l-(l,5-dimethyl-lH-pyrrol-2-yl)propan-l-one
(Compound 12a, 4.00 g, 26.50 mmol) in THF (30 ml) at -78°C was added a solution
of N-bromosuccinimide (5.18 g, 29.10 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. The reaction mixture was quenched by addition of
saturated sodium bicarbonate solution (5 ml) and then evaporated under reduced
pressure to obtain a residue which was dissolved in ethyl acetate (75 ml). The
resulting organic layer was washed with saturated sodium bicarbonate solution
(1x20 ml) followed by water (1x20 ml). The combined organic layer was dried over
anhydrous a2S and 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 12b (4.02 g, 66.0%). MS: m/z 231
(M+l).
[156] Ή NMR (CDCls, 400 MHz): 6.94 (s, 1H), 3.89 (s, 3H), 2.75 (q, J = 7.2
Hz, 2H), 2.24 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).
[157] Step 3 : l-(l,5-dimethyl-4-(p-tolyl)-lH-pyrrol-2-yl)propan-l-one
(Compound 12c)
[158] p-tolylboronic acid (0.84 g, 6.21 mmol) and potassium carbonate (1.95 g,
14.12 mmol) were added to the solution of l-(4-bromo-l,5-dimethyl-lH-pyrrol-2-
yl)propan- 1-one (Compound 12b, 1.30 g, 5.65 mmol) in a mixture of toluene:
ethanol (4:12 ml) in a tube at 25°C. The nitrogen gas was bubbled through
resulting mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.32 g,
0.28 mmol) was added to the reaction mixture under nitrogen atmosphere and
tube was sealed. The reaction mixture was heated at 90-95°C for 5 hr under
stirring. The progress of reaction was monitored by TLC. The reaction mixture was
cooled to 25°C and filtered through celite. The residue thus obtained was washed
with mixture of 10% methanol in dichloromethane. The resulting 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 12c (1.20 g, 88.0%). MS: m/z 242 (M+l).
[159] Ή NMR (CDCls, 400 MHz): 7.21-7.29 (m, 4H), 7.05 (s, 1H), 3.96 (s, 3H),
2.84 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).
[160] Step 4 : l-(3-bromo-l,5-dimethyl-4-(p-tolyl)-lH-pyrrol-2-yl)propan-l-one
(Compound 12d)
[161] To a stirred solution of l-(l,5-dimethyl-4-(p-tolyl)-lH-pyrrol-2-yl)propan-
1-one (Compound 12c, 1.18 g, 4.89 mmol) in THF (10 ml) at -78°C was added a
solution of N-bromosuccinimide (0.95 g, 5.38 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. The reaction mixture was then quenched by
addition of saturated sodium bicarbonate solution (10 ml) evaporated under
reduced pressure to obtain a residue which was dissolved in ethyl acetate (50 ml).
The resulting organic layer was washed with saturated sodium bicarbonate
solution (1x10 ml) followed by water (1x10 ml). The combined organic layer was
dried over anhydrous a2S and 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 12d (0.51 g, 32.6%). MS: m/z
321 (M+l).
[162] H NMR (CDC13, 400 MHz): 7.24-7.32 (m, 4H), 3.87 (s, 3H), 3.12 (q, J =
7.2 Hz, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).
[163] Step 5 : 4-(l,5-dimethyl-2-propionyl-4-(p-tolyl)-lH-pyrrol-3-
yl)benzenesulfonamide (Compound 12)
[164] 4-aminosulfonylbenzene boronic acid (0.34 g, 1.72 mmol) and potassium
carbonate (0.54 g, 3.90 mmol) were added to the solution of l-(3-bromo-l,5-
dimethyl-4-(p-tolyl)-lH-pyrrol-2-yl)propan-l-one (Compound 12d, 0.50 g, 1.56
mmol) in a mixture of 1,4-dioxane: water (4:1 ml) in a tube at 25°C. The nitrogen
gas was bubbled through resulting mixture for 15 minutes.
Tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.078 mmol) was added to the
reaction mixture under nitrogen atmosphere and tube was sealed. The reaction
mixture was heated at 90-95°C for 5 hr under stirring. The progress of reaction
was monitored by TLC. The reaction mixture was cooled to 25°C and filtered
through celite. The residue thus obtained was washed with mixture of 10%
methanol in dichloromethane. The resulting 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 12 (0. 10 g, 17. 1%). MS: m/z 397 (M+l).
[165] Ή NMR (DMSO-d6, 400 MHz): 7.71 (d, J = 8.0 Hz, 2H), 7.39 (bsexchanges
with D20 , 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.87 (d,
J = 8.0 Hz, 2H), 3.79 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H), 2.03 (q, J = 7.2 Hz, 2H),
0.80 (t, J = 7.2 Hz, 3H).
[166] The following compounds were prepared according to the procedure
described above for compound 12, with appropriate changes to the reactants.
[167] 4-(4-(3,4-difluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 8) [MS: m/z 419 (M+l)],
[168] Ή NMR (CDCls, 400 MHz): 7.85 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz,
2H), 7.00-7.02 (m, IH), 6.75-6.78 (m, IH), 6.64-6.67 (m, IH), 4.83 (bs-exchanges
with D20 , 2H), 3.89 (s, 3H), 2.24 (s, 3H), 2.12 (q, J = 6.8 Hz, 2H), 0.94 (t, J = 6.8
Hz, 3H).
[169] 4-(4-(2,4-difluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 9) [MS: m/z 419 (M+l)],
[170] Ή NMR (CDCls, 400 MHz): 7.83 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz,
2H), 6.84-6.86 (m, IH), 6.74-6.76 (m, 2H), 4.80 (bs-exchanges with D20 , 2H), 3.90
(s, 3H), 2.13-2.16 (m, 5H), 0.94 (t, J = 6.8 Hz, 3H).
[171] 4-(4-(3-iluorophenyl)-l,5-dimethyl-2-propionyl-lH-pyrrol-3-
yl)benzenesulfonamide (Compound 10) [MS: m/z 401 (M+l)],
[172] H NMR (CDC13, 400 MHz): 7.84 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 7.15-7.18 (m, IH), 6.86-6.88 (m, IH), 6.67-6.69 (m, 2H), 4.83 (bs-exchanges
with D20 , 2H), 3.89 (s, 3H), 2.26 (s, 3H), 2.13 (q, J = 6.8 Hz, 2H), 0.94 (t, J = 6.8
Hz, 3H).
[173] 4-(4-(4-iluoro-3-methylphenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 11) [MS: m/z 415 (M+l)],
[174] H NMR (DMSO-d6, 400 MHz): 7.72 (d, J = 8.4 Hz, 2H), 7.38 (bsexchanges
with D20 , 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.92-6.96 (m, 2H), 6.75-6.77 (m,
IH), 3.79 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 2.04 (q, J = 6.8 Hz, 2H), 0.80 (t, J = 6.8
Hz, 3H).
[175] 4-(4-(4-chloro-2-iluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 13) [MS: m/z 435 (M+l)],
[176] Ή NMR (CDCls, 400 MHz): 7.84 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 6.98-7.00 (m, 2H), 6.82 (t, J = 8.0 Hz, IH), 4.85 (bs-exchanges with D2O, 2H),
3.89 (s, 3H), 2.13-2.16 (m, 5H), 0.94 (t, J = 6.8 Hz, 3H).
[177] 4-(4-(4-chloro-3-iluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide (Compound 14) [MS: m/z 435 (M+l)],
[178] Ή NMR (CDCls, 400 MHz): 7.86 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 7.23 (t, J = 8.0 Hz, IH), 6.75 (dd, J = 8.0, 2.0 Hz, IH), 6.66 (dd, J = 8.0, 2.0
Hz, IH), 4.81 (bs-exchanges with D20 , 2H), 3.89 (s, 3H), 2.26 (s, 3H), 2. 12 (q, J =
6.8 Hz, 2H), 0.94 (t, J = 6.8 Hz, 3H).
[179] Example 3 : Pharmacological screening
[ISO] The 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 solutions 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 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, and added to the wells. After
dye loading, the 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 the test
compound solution and subsequent monitoring of fluorescence changes for u p 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).
[181] 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 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.
[1S2] Fold activity at luM concentration: the compounds with activity between
2 to 15 folds are grouped as A, and the compounds with activity above 15 folds are
grouped as B.
[1S3] Table 1 provides the fold activity of the compounds of the present
invention.
Table 1
[184] 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.
[1S5] 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 be 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 openended
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.
[1S6] 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
1. A compound of formula (I), a tautomer thereof, a stereoisomer thereof, or
a pharmaceutically acceptable salt thereof,
wherein,
R1 is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- cycloalkyl;
R3 is selected from the group consisting of substituted- or unsubstitutedaryl
and substituted- or unsubstituted- heteroaryl;
R4 is selected from the group consisting of substituted- or unsubstitutedalkyl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl, substituted- or unsubstitutedheterocyclyl,
and -NR8R9;
R5 is selected independently at each occurrence from the group consisting of
halogen, substituted- or unsubstituted- alkyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, -OR b , -NR8R9, and -C(=0)R a ; or
R6 and R7 are independently selected from the group consisting of hydrogen
and substituted- or unsubstituted- alkyl;
R8 and R9 are each independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R8a is selected from the group consisting of substituted- or unsubstitutedalkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
R8b is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, perhaloalkyl, and substituted- or unsubstitutedcycloalkyl;
m is an integer selected from 0, 1, and 2 ;
when the alkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano,
perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 10b , -SO2R10a, -
C(=O)OR , -OC(=O)R a, -C(=0)N(H)R , -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)R ° ;
when the cycloalkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano, alkyl,
perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR 1 , -SO 2R10c , -C(=O)R 1 , -
N(H)Riod, -N(alkyl)R d,
when the aryl group is substituted, it is substituted with 1 to 3 substituents
independently selected 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;
when the heteroaryl group is substituted, it is substituted with 1 to 3
substituents independently selected 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 independently selected
from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -OR1 b , -C(=O)OR1 , -OC(=O)R1 , -C(=O)N(H)R d ,
-N(H)Ri°d, -N(alkyl)Ri°d,
and -N(H)C(=O)N(alkyl)R10d; and when the heterocyclyl group is substituted on a
ring nitrogen, it is substituted with a substituent selected from alkyl, cycloalkyl,
aryl, heteroaryl, -SO2R1 , -C(=O)R1 , -C(=O)N(H)R d, and -C(=O)N(alkyl)R d ;
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10a is selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclyl;
R1 is selected from alkyl, perhaloalkyl, and cycloalkyl;
R10d is selected from hydrogen, alkyl, and cycloalkyl.
The compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R1 is
selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- cycloalkyl.
The compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein R1
is selected from methyl and ethyl.
4 . The compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof, as claimed in any one of claim 1 to 3,
wherein R2 is selected from methyl, ethyl, and propyl.
5 . The compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof, as claimed in any one of claim 1 to 4,
wherein R3 is phenyl substituted with 1 to 2 substituents selected from chloro,
fluoro, and methyl.
6 . The compound of formula (I), a tautomer thereof, a stereoisomer thereof,
or a pharmaceutically acceptable salt thereof, as claimed in any one of claim 1
to 5, wherein R4 is selected from ethyl and pyridyl.
7 . The compound of formula (I), a tautomer thereof, a stereoisomer thereof,
or a pharmaceutically acceptable salt thereof, as claimed in any one of claim 1
to 6, wherein R5 is halogen.
8 . The compound of formula (I), a tautomer thereof, a stereoisomer thereof,
or a pharmaceutically acceptable salt thereof, as claimed in any one of claim 1
to 7, wherein m is selected from 0 and 1.
9 . The compound of formula (I), a tautomer thereof, a stereoisomer thereof,
or a pharmaceutically acceptable salt thereof, as claimed in any one of claim 1
to 8, wherein the compounds is selected from:
4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-fluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-chloro-3-methylphenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-chlorophenyl)-5-ethyl- 1-methyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-yl)-2-
iluorobenzenesulfonamide ;
4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-yl)-3-
iluorobenzenesulfonamide ;
4-(4-(4-chlorophenyl)- 1-ethyl-5-methyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(3,4-difluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(2,4-difluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(3-iluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-iluoro-3-methylphenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(l,5-dimethyl-2-propionyl-4-(p-tolyl)-lH-pyrrol-3-yl)benzenesulfonamide;
4-(4-(4-chloro-2-iluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-chloro-3-iluorophenyl)- 1,5-dimethyl-2-propionyl- lH-pyrrol-3-
yl)benzenesulfonamide;
4-(4-(4-chlorophenyl)-l-methyl-2-propionyl-5-propyl-lH-pyrrol-3-
yl)benzenesulfonamide; and
4-(4-(4-chlorophenyl)- 1,5-dimethyl-2-nicotinoyl- lH-pyrrol-3-
yl)benzenesulfonamide;
10. A pharmaceutical composition comprising a compound of any one of claims 1
to 9, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A method of preventing or treating a disease, a symptom, or a disorder
mediated partially or completely by nicotinic acetylcholine receptors, said
method comprising administering to a subject having or susceptible to said
disease, symptom, or disorder a therapeutically effective amount of a
compound of any one of claims 1 to 9, a tautomer thereof, a stereoisomer
thereof, or a pharmaceutically acceptable salt thereof.
12. A method of treating a disease, 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), a tautomer thereof, a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof,
wherein,
R1 is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- cycloalkyl;
R3 is selected from the group consisting of substituted- or unsubstitutedaryl
and substituted- or unsubstituted- heteroaryl;
R4 is selected from the group consisting of substituted- or unsubstitutedalkyl,
substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- heterocyclyl, and -NR8R9;
R5 is selected independently at each occurrence from the group consisting
of halogen, substituted- or unsubstituted- alkyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, -OR b, -NR8R9, and -C(=0)R a; or
R6 and R7 are independently selected from the group consisting of
hydrogen and substituted- or unsubstituted- alkyl;
R8 and R9 are each independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R8a is selected from the group consisting of substituted- or unsubstitutedalkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
R8b is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, perhaloalkyl, and substituted- or unsubstitutedcycloalkyl;
m is an integer selected from 0, 1, and 2 ;
when the alkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano,
perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR10 , -SO2R10a, -
C(=O)OR a , -OC(=O)R a , -C(=0)N(H)R , -C(=0)N(alkyl)R °, -N(H)C(=O)R a , -
N(H)Rio, -N(alkyl)Rio,
when the cycloalkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano, alkyl,
perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR 1 , -SO2R10c, -C(=O)R1 , -
C(=O)OR , -OC(=O)R , -C(=0)N(H)R d , -C(=0)N(alkyl)R °d , -N(H)C(=O)R , -
N(H)Riod, -N(alkyl)Riod,
when the aryl group is substituted, it is substituted with 1 to 3
substituents independently selected 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 independently selected 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 independently
selected from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, -OR 1 b , -C(=O)OR 1 , -OC(=O)R 1 , -C(=O)N(H)R d , -
-N(H)Ri°d, -N(alkyl)Ri°d,
and -N(H)C(=O)N(alkyl)R10d ; and when the heterocyclyl group is substituted on
a ring nitrogen, it is substituted with a substituent selected from alkyl,
cycloalkyl, aryl, heteroaryl, -SO 2R 1 , -C(=O)R 1 , -C(=O)N(H)R d , and -
R 10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R 10a is selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclyl;
R1 is selected from alkyl, perhaloalkyl, and cycloalkyl;
R10d is selected from hydrogen, alkyl, and cycloalkyl.
13. The method of claim 11 or 12, wherein the disorder, 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, posts troke
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 or 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.
14. The method of claim 11 or 12, wherein the disease, disorder, or condition is
selected from the group classified or diagnosed as major or minor
neurocognitive disorders, and disorders arising due to neuro degeneration.
15. The method of claim 11 or 12, further comprising administering another
medication effective to treat attention deficit hyperactivity disorders,
schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's
dementia, vascular dementia or dementia associated with Lewy bodies, or
traumatic brain injury.
16. The method of claim 11 or 12, further comprising administering an
acetylcholinesterase inhibitor, a disease modifying drug or biologic for
neurodegenerative disorders, a dopaminergic drug, an antidepressant, or a
typical or atypical antipsychotic.
17. Use of a compound of any one of claims 1 to 9, a tautomer thereof, a
stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the
preparation of a medicament for preventing or treating a disease, symptom, or
disorder mediated partially or completely by nicotinic acetylcholine receptors.
18. Use of a compound of formula (I), a tautomer thereof, a stereoisomer thereof,
or a pharmaceutically acceptable salt thereof, in the preparation of a
medicament for treating a disease, disorder, or condition,
wherein,
R1 is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R2 is selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- cycloalkyl;
R3 is selected from the group consisting of substituted- or unsubstitutedaryl
and substituted- or unsubstituted- heteroaryl;
R4 is selected from the group consisting of substituted- or unsubstitutedalkyl,
substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- heterocyclyl, and -NR8R9;
R5 is selected independently at each occurrence from the group consisting
of halogen, substituted- or unsubstituted- alkyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, -OR b, -NR8R9, and -C(=0)R a; or
R6 and R7 are independently selected from the group consisting of
hydrogen and substituted- or unsubstituted- alkyl;
R8 and R9 are each independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R8a is selected from the group consisting of substituted- or unsubstitutedalkyl,
perhaloalkyl, and substituted- or unsubstituted- cycloalkyl;
R8b is selected from the group consisting of hydrogen, substituted- or
unsubstituted- alkyl, perhaloalkyl, and substituted- or unsubstitutedcycloalkyl;
m is an integer selected from 0, 1, and 2 ;
when the alkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano,
perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR10 , -SO2R10a, -
C(=O)OR a , -OC(=O)R a , -C(=0)N(H)R , -C(=0)N(alkyl)R °, -N(H)C(=O)R a , -
N(H)Rio, -N(alkyl)Rio,
when the cycloalkyl group is substituted, it is substituted with 1 to 3
substituents independently selected from oxo, halogen, nitro, cyano, alkyl,
perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR 1 , -SO2R10c, -C(=O)R1 , -
C(=O)OR , -OC(=O)R , -C(=0)N(H)R d, -C(=0)N(alkyl)R °d, -N(H)C(=O)R , -
N(H)Riod, -N(alkyl)R d,
when the aryl group is substituted, it is substituted with 1 to 3
substituents independently selected 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 independently selected 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 independently
selected from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, -OR 1 b, -C(=O)OR 1 , -OC(=O)R 1 , -C(=O)N(H)R d, -
-N(H)Ri°d, -N(alkyl)Ri°d,
and -N(H)C(=O)N(alkyl)R10d ; and when the heterocyclyl group is substituted on
a ring nitrogen, it is substituted with a substituent selected from alkyl,
cycloalkyl, aryl, heteroaryl, -SO 2R1 , -C(=O)R 1 , -C(=O)N(H)R d, and -
R10 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10a is selected from alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and
heterocyclyl;
R10b is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl,
heteroaryl, and heterocyclyl;
R1 is selected from alkyl, perhaloalkyl, and cycloalkyl;
R10d is selected from hydrogen, alkyl, and cycloalkyl.
19. The use as claimed in claim 17 or 18, wherein the disease, disorder, or
condition is selected from the group classified or diagnosed as major or minor
neurocognitive disorders and disorders arising due to neuro degeneration.
20. The use as claimed in claim 17 or 18, 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.
21. The use as claimed in claim 17 or 18, which 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.
22. A compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to
9 or a pharmaceutical composition as claimed in claim 10, for use in treating
or preventing a disease, disorder, or condition 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 or 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.