BIARYL DERIVATIVES AS NACHR MODULATORS
Field of the Invention:
The present invention is related to novel compounds of the general formula (I),
their tautomeric forms, their stereoisomers, their analogues, their prodrugs, their
isotopically labeled analogues, their N-oxides, their metabolites, their
pharmaceutically acceptable salts, their polymorphs, their solvates, their optical
isomers, their clathrates, their co-crystals, their combinations with suitable
medicament, pharmaceutical compositions containing them, methods of making
the above compounds, and their use as nicotinic acetylcholine receptor 7 subunit
( 7 nAChR) modulator.
Background of the invention:
Cholinergic neurotransmission, mediated primarily through the neurotransmitter
acetylcholine (ACh), is a predominant regulator of the physiological functions of the
body via the central and autonomic nervous system. ACh acts on the synapses of
the neurons present in of all the autonomic ganglia, neuromuscular junctions and
the central nervous system. Two distinct classes of ACh target receptors viz.
muscarinic (mAChRs) and the nicotinic (nAChRs) have been identified in brain,
forming a significant component of receptors carrying its mnemonic and other vital
physiological functions.
Neural nicotinic ACh receptors (NNRs) belong to the class of ligand-gated ion
channels (LGIC) comprising of five subunits ( 2- 10, 2-4) arranged in
heteropentameric ( 4 2) or homopertameric ( 7 ) configuration (Paterson D et al.,
Prog. Neurobiol., 2000, 61, 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 centers of brain, hippocampus and the cerebral cortex (Rubboli F et
al., Neurochem. Int., 1994, 25, 69-71). Particularly, 7 nAChR is characterized by
a high Ca2+ ion permeability, which is responsible for neurotransmitter release and
consequent modulation of excitatory and inhibitory neurotransmission (Alkondon
M et al., Eur. J . Pharmacol., 2000, 393, 59-67; Dajas-Bailador F et al., Trends
Pharmacol. Sci., 2004, 25, 317-324). Furthermore, high Ca + ion influx also has
implications on the long-term potentiation of memory via alterations in gene
expression (Bitner RS et al., J . Neurosci., 2007, 27, 10578-10587; McKay BE et al.,
Biochem. Pharmacol., 2007, 74, 1120-1 133).
Several recent studies have confirmed the role of 7 nAChR in neural processes
like attention, memory and cognition (Mansvelder HD et al., Psychopharmacology
(Berl), 2006, 184, 292-305; Chan WK et al., Neuropharmacology, 2007, 52, 1641-
1649; Young JW et al., Eur. Neuropsychopharmacol., 2007, 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 (Freedman R et al., Biol.
Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J . Med. Genet., 2001, 105,
662-668). Also, preclinical studies in a 7 nAChR knock-out and anti-sense
oligonucleotide treated mice have demonstrated impaired attention and defective
cognition underscoring the prominent role of 7 nAChR in cognition (Curzon P et
al., Neurosci. Lett., 2006, 410, 15-19; Young JW et al., Neuropsychopharmacology,
2004, 29, 891-900). Additionally, pharmacological blockade of a 7 nAChR impairs
memory and its activation enhances same in preclinical rodent models implicating
7 nAChR as target for cognitive enhancement (Hashimoto K et al., Biol.
Psychiatry, 2008, 63, 92-97).
Pathological brain function in sensory-deficit disorders has been associated with
nicotinic cholinergic transmission particularly through 7 receptors (Freedman R
et al., Biol. Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J . Med. Genet.,
2001, 105, 662-668; Carson R et al., Neuromolecular, 2008, Med. 10, 377-384;
Leonard S et al., Pharmacol. Biochem. Behav., 2001, 70, 561-570; Freedman R et
al., Curr. Psychiatry Rep., 2003, 5, 155-161; Cannon TD et al., Curr. Opin.
Psychiatry, 2005, 18, 135-140). A defective pre-attention processing of sensory
information is understood to be the basis of cognitive fragmentation in
schizophrenia and related neuropsychiatric disorders (Leiser SC et al., Pharmacol.
Ther., 2009, 122, 302-31 1). Genetic linkage studies have traced sharing of the 7
gene locus for several affective, attention, anxiety and psychotic disorders (Leonard
S et al., Pharmacol. Biochem. Behav., 2001, 70, 561-570; Suemaru K et al., Nippon
Yakurigaku Zasshi, 2002, 119, 295-300).
Perturbations in the cholinergic and glutamatergic homeostasis, has long been
implicated as causative factors for host of neurological disease, including
dementia(s) (Nizri E et al., Drug News Perspect, 2007, 20, 421-429). Dementia is a
severe, progressive, multi-factorial cognitive disorder affecting memory, attention,
language and problem solving. Nicotinic ACh receptor, particularly the interaction
of 7 receptor to -42 is implicated as an up-stream pathogenic event in
Alzheimer's disease, a major causative factor for dementia (Wang HY et al., J .
Neurosci., 2009, 29, 10961-10973). Moreover, gene polymorphisms in CHRNA7
have been implicated in dementia with lewy bodies (DLB) and Pick's disease (Feher
A et al., Dement. Geriatr. Cogn. Disord., 2009, 28, 56-62).
Disease modification potential of nAChRs particularly the 7 receptor has
application for disease-modification of Alzheimer's disease (AD) and Parkinson's
disease (PD) by enhancing neuron survival and preventing neurodegeneration
(Wang et al. 2009; Nagele RG et al., Neuroscience, 2002, 110, 199-21 1;
Jeyarasasingam G et al., Neuroscience, 2002, 109, 275-285). Additionally, 7
nAChR induced activation of anti-apoptotic (BCL-2) and anti-inflammatory
pathways in brain could have neuroprotective effects in neurodegenerative diseases
(Marrero MB et al., Brain. Res., 2009, 1256, 1-7). Dopamine containing neurons of
ventral tegmental area (VTA) and laterodorsal tegmental nucleus (LDT) are known
to express nicotinic ACh receptors, particularly 4 , 3 , 2 , 3 , 4 subunits
(Kuzmin A et al., Psychopharmacology (Berl), 2009, 203, 99-108). Nicotinic ACh
receptors, 42 and 34 have been identified with candidate-gene approach to
have strong mechanistic link for nicotine addiction (Weiss RB et al., PLoS Genet.,
2008, 4, el000125). 7 nAChR has particularly been studied for a putative role in
cannabis addiction (Solinas M et al., J . Neurosci., 2007, 27, 5615-5620).
Varenicline, a partial agonist at 42, has demonstrated better efficacy in reducing
the smoking addiction and relapse prevention in comparison to buproprion (Ebbert
J O et al., Patient. Prefer. Adherence, 2010, 4, 355-362).
Presence of a high-affinity nicotine binding site at 42 nAChR, in the descending
inhibitory pathways from brainstem has sparked interest in the antinociceptive
properties of nicotinic ACh receptor agonists like epibatidine (Decker MW et al.,
Expert. Opin. Investig. Drugs, 2001, 10, 1819-1830). Several new developments
have opened the area for use of nicotinic modulators for therapy of pain
(Rowbotham MC et al., Pain, 2009, 146, 245-252). Appropriate modulation of the
nicotinic ACh receptors could provide for remedial approach to pain related states.
Another key role of the 7 nAChR is the ability to modulate the production of pro
inflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha (TNF-a),
and high mobility group box (HMGB-1) in the central nervous system.
Consequently, an anti-inflammatory and antinociceptive effect in pain disorders
have been demonstrated (Damaj MI et al., Neuropharmacology, 2000, 39, 2785-
2791). Additionally, 'cholinergic anti- inflammatory pathway' is proposed to be a
regulatory of local and systemic inflammation and neuro-immune interactions
through neural and humoral pathways (Gallowitsch-Puerta Met al., Life Sci., 2007,
80, 2325-2329; Gallowitsch-Puerta and Pavlov, 2007; Rosas-Ballina M et al., Mol.
Med., 2009, 15, 195-202; Rosas-Ballina M et al., J . Intern. Med., 2009, 265, 663-
679). Selective modulators of nicotinic ACh receptors, particularly 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
(Westman M et al., Scand. J . Immunol., 2009, 70, 136-140). A putative role for 7
nAChR has also been implicated in severe sepsis, endotoxemic shock and systemic
inflammation (Jin Y et al. (2010) Int. J . Immunogenet. , Liu C et al., Crit. Care.
Med., 2009, 37, 634-641).
Angiogenesis, is a critical physiological process for the cell survival and
pathologically important for cancer proliferation; several non-neural nicotinic ACh
receptors, particularly 7 , 5 , 3 , 2 , 4 , are involved (Arias HR et al., Int. J .
Biochem. Cell. Biol., 2009, 41, 1441-1451; Heeschen C et al., J . Clin. Invest.,
2002, 110, 527-536). A role of nicotinic ACh receptors in the development of
cervical cancer, lung carcinogenesis and paediatric lung disorders in smokingexposed
population has also been studied (Calleja-Macias IE et al., Int. J . Cancer,
2009, 124, 1090-1096; Schuller HM et al., Eur. J . Pharmacol., 2000, 393, 265-
277). Several 7 nAChR agonists, partial agonists, have been characterized for
their efficacy in clinical and preclinical studies. EVP-6124, an agonist at 7
nAChR, has demonstrated significant improvement in sensory processing and
cognition biomarkers in Phase lb study with patients suffering from schizophrenia
(EnVivo Pharmaceuticals press release 2009, Jan 12). GTS-21 (DMXB-Anabaseine),
an 7 nAChR agonist, in the P II clinical trials, has shown efficacy in improving
cognitive deficits in schizophrenia and inhibition of endotoxin-induced TNF-a
release (Olincy A et al., Biol. Psychiatry, 2005, 57(8, Suppl.), Abst 44; Olincy A et
al., Arch. Gen. Psychiatry, 2006, 63, 630-638; Goldstein R et al., Acad. Emerg.
Med., 2007, 14 (15, Suppl. 1), Abst 474). CP-810123, a 7 nAChR agonist, exhibits
protection against the scopolamine-induced dementia and inhibition of
amphetamine-induced auditory evoked potentials in preclinical studies (O'Donnell
CJ et al., J . Med. Chem., 2010, 53, 1222-1237). SSR-18071 1A, also an 7 nAChR
agonist, enhances learning and memory, and protects against MK-
801 /Scopolamine-induced memory loss and prepulse inhibition in preclinical
studies (Redrobe J P et al., Eur. J . Pharmacol., 2009, 602, 58-65; Dunlop J et al.,
J . Pharmacol. Exp. Ther., 2009, 328, 766-776; Pichat P et al.,
Neuropsychopharmacology, 2007, 32, 17-34). SEN- 12333, protected against
scopolamine-induced amnesia in passive avoidance test in preclinical studies
(Roncarati R et al., J . Pharmacol. Exp. Ther., 2009, 329, 459-468). AR-R-17779, an
agonist at 7 nAChR, exhibits improvement in the social recognition task
performed in rats (Van KM et al., Psychopharmacology (Berl), 2004, 172, 375-383).
ABBF, an agonist at 7 nAChR, improves social recognition memory and working
memory in Morris maze task in rats (Boess FG et al., J . Pharmacol. Exp. Ther.,
2007, 321, 716-725). TC-5619, a selective 7 nAChR agonist has demonstrated
efficacy in animal models of positive and negative symptoms and cognitive
dysfunction in schizophrenia (Hauser TA et al., Biochem. Pharmacol., 2009, 78,
803-812).
An alternative strategy to reinforce or potentiate the endogenous cholinergic
neurotransmission of ACh without directly stimulating the target receptor is the
positive allosteric modulation (PAM) of a 7 nAChR (Albuquerque EX et al., Alzheimer
Dis. Assoc. Disord., 2001, 15 Suppl 1, S19-S25). Several PAMs have been
characterized, albeit in the preclinical stages of discovery. A-86774, a 7 nAChR
PAM, improves sensory gating in DBA/2 mice by significantly reducing the T:C
ratio in a preclinical model of schizophrenia (Faghih R et al., J . Med. Chem., 2009,
52, 3377-3384). XY-4083, an a 7 nAChR PAM, normalizes the sensorimotor gating
deficits in the DBA/2 mice and memory acquisition in 8-arm radial maze without
altering the receptor desensitization kinetics (Ng HJ et al., Proc. Natl. Acad. Sci., U.
S. A., 2007, 104, 8059-8064). Yet another PAM, PNU- 120596, profoundly alters a7
nAChR desensitization kinetics and simultaneously protecting against the
disruption of prepulse inhibition by MK-801. NS-1738, another PAM, has exhibited
efficacy in-vlvo in the animal models of social recognition and spatial memory
acquisition in the Morris maze task (Timmermann DB et al., J . Pharmacol. Exp.
Ther., 2007, 323, 294-307). In addition, several patents/applications published are
listed below 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 7,683,084, US 7,741,364,
WO 2009/145996, US 2010/0240707, WO 201 1/064288, US 2010/0222398, US
2010/0227869, EP 1 866 314, WO 2010/130768, WO 201 1/036167, US
2010/0190819 disclose efficacy of allosteric modulators of nicotinic ACh receptors
and underscoring their therapeutic potential.
Summary of the Invention
Acccording to one aspect of the present invention there is provided compounds
represented by the general formula (I), their tautomeric forms, their stereoisomers,
their analogues, their prodrugs, their isotopically substituted analogues, their
metabolites, their pharmaceutically acceptable salts, their polymorphs, their
solvates, their optical isomers, their clathrates, their co-crystals, their
combinations with suitable medicament and pharmaceutical compositions
containing them
wherein, R1, R2, R3, R4, D, E, m and n are as described hereinbelow.
Thus the present invention further provides a pharmaceutical composition,
containing the compound of the general formula (I) as defined herein, its
tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically
substituted analogues, its metabolites, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates and its co-crystals in
combination with the usual pharmaceutically employed carriers, diluents and the
like are useful for the treatment and/or prophylaxis of diseases or disorder or
condition such as Alzheimer's disease (AD), mild cognitive impairment (MCI), senile
dementia, vascular dementia, dementia of Parkinson's disease, attention deficit
disorder, attention deficit hyperactivity disorder (ADHD), dementia associated with
Lewy bodies, AIDS dementia complex (ADC), Pick's disease, dementia associated
with Down's syndrome, Huntington's disease, cognitive deficits associated with
traumatic brain injury (TBI), cognitive decline associated with stroke, poststroke
neuroprotection, cognitive and sensorimotor gating deficits associated with
schizophrenia, cognitive deficits associated with bipolar disorder, cognitive
impairments associated with depression, acute pain, post-surgical or post
operative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain,
smoking cessation, need for new blood vessel growth associated with wound
healing, need for new blood vessel growth associated with vascularization of skin
grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's
disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease,
periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune
disease associated with organ transplantation, chronic immune disease associated
with organ transplantation, septic shock, toxic shock syndrome, sepsis syndrome,
depression, and rheumatoid spondylitis.
The present invention also provides a pharmaceutical composition, containing the
compounds of the general formula (I) as defined herein, its tautomeric forms, its
stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues,
its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates,
its optical isomers, its clathrates and its co-crystals in combination with the usual
pharmaceutically employed carriers, diluents and the like are useful for the
treatment and/or prophylaxis of diseases or disorder or condition classified or
diagnosed as major or minor neurocognitive disorders, or disorders arising due to
neurodegeneration.
The present invention also provides method of administering a compound of
formula (I), as defined herein in combination with or as adjunct to medications
used in the treatment of attention deficit hyperactivity disorders, schizophrenia,
and other cognitive disorders such as Alzheimer's disease, Parkinson's dementia,
vascular dementia or dementia associated with Lewy bodies, traumatic brain
injury.
The present invention also provides method of administering a compound of
formula (I), as defined herein in combination with or as an adjunct to
acetylcholinesterase inhibitors, disease modifying drugs or biologies for
neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an
atypical antipsychotic.
The present invention also provides use of a compound of formula (I) as defined
herein in the preparation of a medicament for treating a disease or disorder or
condition selected from the group classified or diagnosed as major or minor
neurocognitive disorders, or disorders arising due to neurodegeneration.
The present invention also provides use of a compound of formula (I) as defined
herein in the preparation of a medicament for treating a disease or disorder or
condition selected from the group consisting of attention deficit hyperactivity
disorders, schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's
dementia, vascular dementia or dementia associated with Lewy bodies, and
traumatic brain injury.
The present invention also provides use of a compound of formula (I) as defined
herein in combination with or as an adjunct to acetylcholinesterase inhibitors,
disease modifying drugs or biologies for neurodegenerative disorders, dopaminergic
drugs, antidepressants, or a typical or atypical antipsychotic.
Detailed Description of the invention:
The present invention relates to novel compounds of the general formula (I), their
tautomeric forms, their stereoisomers, their analogues, their prodrugs, their
isotopically substituted analogues, their metabolites, their sulfoxides, their Noxides,
their pharmaceutically acceptable salts, their polymorphs, their solvates,
their optical isomers, their clathrates, their co-crystals, their combinations with
suitable medicament and pharmaceutical compositions containing them,
wherein,
'D' is selected from N and CR5;
Έ ' is selected from S and NR6 ;
with a proviso that when 'E' is NR6 , 'D' is not selected as N;
R 1 is selected from hydrogen or substituted- or unsubstituted- alkyl, substitutedor
unsubstituted- alkenyl, halogen, perhaloalkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, cyano, nitro, (R7)(R )N-,
(R7a)(R8)NC(=0)-, and R7bS (0 p- , wherein 'p' is an integer ranging from 1 to 2 ;
R2 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- hererocyclyl, (R7)(R8)N-, (R )N(OR¾)-, and R7A - ;
R3 is selected independently at each occurrence from halogen, cyano, substitutedor
unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- heterocyclyl, (R7a)(R8a)NC(=0)-, R7aA 1- , (R7b)C (=0)N(R a)-, (R7a (R a
(R7a)(R8a)NC(=A )N(R )-, (R7a)(R8a)NC(=0)0-, R7 OC (=0 (R a - , R7 S (0)p-, wherein 'p'
is an integer ranging from 1 to 2, and two R3s and the carbon atoms to which they
are attached can combine to form an substituted- or unsubstituted- 5 to 8 member
cyclic system which may contain 1 to 3 heteroatoms/groups selected from -NH-, -
S-, -0-, -C(=0)-, and -C(=S)-;
'n' is selected from 0, 1, 2 and 3 ;
R4 is selected independently at each occurrence from halogen, cyano, substitutedor
unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- heterocyclyl, (R7a)(R8a)NC(=0)-, R7aA 1- , (R7b)C (=0)N(R a)-, (R7a (R a
and two R4s and the carbon atoms to which they are attached can combine to form
a substituted- or unsubstituted- 5 to 8 membered cyclic system which may contain
1 to 3 heteroatoms/groups such as -NH-, -S-, -0-, -C (=0)-, and -C(=S)-;
'm' is selected from 0, 1, 2 and 3 ;
R5 is selected from hydrogen, halogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedheterocyclyl,
(R7)(R )N-, and R7 C(=0)-;
R6 is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, and R C(=0)-;
R7 and R8 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and
substituted- or unsubstituted- heterocyclyl;
R a, R a, and R9 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R b is selected from substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;
the substituents on 'alkyl' and 'alkenyl' are selected from the group consisting of
oxo, halogen, nitro, cyano, perhaloalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,
Riob i - , Ri aSC -, R10aOC(=O)-, R 0aC(=O)O-, R 0N(H)C(=O)-, R °N(a]_kyl)C(=0)- ,
R
ioaC(=0)N(H)-, R oN(H)-, R °N(alkyl)-, R °N(H)C(=A )N(H)-, and
R oN(alkyl)C(=A )N(H)-;
the substituents on 'cycloalkyl' and 'cycloalkenyl' are selected from the group
consisting of oxo, halogen, nitro, cyano, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, perhaloalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
heterocyclyl, R A i - , R S C - , R 10aC(=O)-, R 0aOC(=O)-, R 0 C(=O)O-, R 0 (H)NC(=O)-,
R N(alkyl)C(=O)-, R ° C (=0)N(H)-, R o(H)N-, R 0 (alkyl)N-, R °(H)NC(=A )N(H)-, and
R (alkyl)NC(=A )N(H)-;
the substituents on 'aryl' are selected from the group consisting of halogen, nitro,
cyano, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, perhaloalkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted- or unsubstituted- heterocycle, alkyl-O-,
perhaloalkyl-O-, alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- ,
alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-,
H2NC(=0)-, alkyl(alkyl)NS02- , alkyl(H)NS02- , and H2NS02- ;
the substituents on 'heteroaryl' are selected from the group consisting of halogen,
nitro, cyano, hydroxy, substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, perhaloalkyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstitutedheterocycle,
alkyl-O-, perhaloalkyl-O-, alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-S0 2- ,
perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl(alkyl)NC(=0)-,
alkyl(H)NC(=0)-, H2NC(=0)-, alkyl(alkyl)NS02- , alkyl(H)NS02- , and H2NS0 2- ;
the substituents on ring carbon of 'heterocycle' is selected from the group
consisting of halogen, nitro, cyano, oxo, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- heterocyclyl, substituted- or unsubstituted- alkyl,
R
i ob i - , - R i aOC (=0)-, R 0aC(=O)O-, R 0(H)NC(=O)-, R N(alkyl)C(=O)-,
R
i oaC (=0)N(H)-, R o(H)N-, R (alkyl)N-, R o(H)NC(=A )N(H)-, and
R (alkyl)NC(=Ai)N(H)-;
the substituents on ring nitrogen of 'heterocycle' is selected from the group
consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstitutedalkenyl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedcycloalkenyl,
substituted- or unsubstituted- aryl, substituted- or unsubstitutedheteroaryl,
R S0 2- , R10aC(=O)-, R 0aOC(=O)-, R 0(H)NC(=O)-, and R °N(a]_kyl)C(=0)-;
the "5 to 8 membered cyclic system" is substituted with 1 to 3 substituents
selected from the group consisting of halogen, nitro, cyano, aryl, hereroaryl, alkyl,
alkenyl, alkynyl, R 0aC(=O)-, R10aSO2- , R10bA - , R 0aOC(=O)-, R10aC(=O)O-,
(R o)(H)NC(=0)-, (R ) (alkyl)NC(=0)-, R C(=O)N(H)-, (R o)(H)N-, (R ) (alkyl)N-,
(R 0)(H)NC(=A )N(H)-, and (R 0)(alkyl)NC(=A )N(H)-;
R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
R oa
S selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
R10b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
A1 is selected from S and O.
Whenever a range of the number of atoms in a structure is indicated (e.g. , a C 12 ,
C , C , or C alkyl, alkylamino, etc.) , it is specifically contemplated that any
sub-range or individual number of carbon atoms falling within the indicated range
also can b e used. Thus, for instance, the recitation of a range of 1-8 carbon atoms
(e.g. , C -Ce), 1-6 carbon atoms (e.g. , C -Ce), 1-4 carbon atoms (e.g. , C1-C4), 1-3
carbon atoms (e.g. , C1-C3) , or 2-8 carbon atoms (e.g. , C2-C8) as used with respect to
any chemical group (e.g. , alkyl, alkylamino, etc.) referenced herein encompasses
and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12 carbon atoms,
as appropriate, as well as any sub-range thereof (e.g. , 1-2 carbon atoms, 1-3
carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon
atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-1 1 carbon
atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon
atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms,
2-10 carbon atoms, 2-1 1 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5
carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon
atoms, 3-10 carbon atoms, 3-1 1 carbon atoms, 3-12 carbon atoms, 4-5 carbon
atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms,
4-10 carbon atoms, 4-1 1 carbon atoms, and/or 4-12 carbon atoms, etc., as
appropriate) .
In any of the embodiments of the invention described above, D is selected from the
group consisting of CH, C(alkyl), and N.
In any of the embodiments of the invention described above, E is selected from -Sand
-N(alkyl)-.
In any of the embodiments of the invention described above, R1 is preferably
selected as substituted- or unsubstituted- alkyl.
In any of the embodiments of the invention described above, R2 is preferably
selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- heterocyclyl.
In any of the embodiments described above, R3 is preferably selected from halogen,
R7aA - , and (R7a)(R a)N-; and n is preferably selected from 0 and 1.
In any of the embodiments described above, m is preferably selected as 0.
In any of the embodiments described above D is selected from CH, C(alkyl), and N;
E is selected from -S- and -N(alkyl)-; R1 is preferably selected as substituted- or
unsubstituted- alkyl; R2 is preferably selected from substituted- or unsubstitutedalkyl
and substituted- or unsubstituted- heterocyclyl; R3 is preferably selected from
halogen, R^A1- , and (R a)(R a)N-; n is preferably selected from 0 and 1; and m is
preferably selected as 0.
General terms used in formula can be defined as follows; however, the meaning
stated should not be interpreted as limiting the scope of the term per se.
The term "alkyl", as used herein, means a straight chain or branched hydrocarbon
containing from 1 to 20 carbon atoms. Preferably the alkyl chain may contain 1 to
10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms.
Representative examples of alkyl include, but are not limited to, methyl, ethyl, npropyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,
neopentyl, and n-hexyl.
The term "alkenyl" as used herein, means an 'alkyl' group as defined hereinabove
containing 2 to 20 carbon atoms and containing at least one double bond.
Representative examples of alkenyl include, but are not limited to, pent-2-enyl,
hex-3-enyl, allyl, venyl, etc.
The term "alkynyl" as used herein, means an 'alkyl' group as defined hereinabove
containing 2 to 20 carbon atoms and containing at least one triple bond.
Representative examples of alkynyl include, but are not limited to, pent-2-ynyl,
hex-3-ynyl, acetylene, etc.
'Alkyl', 'alkenyl' or 'alkynyl' as defined hereinabove may be substituted with one or
more substituents selected independently from the group comprising of oxo,
halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aSO2- , R^A1- , R10aOC(=O)-,
R 0 C(=O)O-, (R10)(H)NC(=O)-, (R10)(alkyl)NC(=O)-, R 0aC(=O)N(H)-, (R 0)(H)N-,
(R )(alkyl)N-, (R io)(H)NC(=A )N(H)-, and (R °)(alkyl)NC(=A )N H)-; wherein R is
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocyclyl; A1 is selected from S and O; and R10a is selected from alkyl, alkenyl,
alkynyl perhaloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl.
The term "perhaloalkyl" used herein means an alkyl group as defined hereinabove
wherein all the hydrogen atoms of the said alkyl group are substituted with
halogen. The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl
and the like.
The term "cycloalkyl" as used herein, means a monocyclic, bicyclic, or tricyclic
non-aromatic ring system containing from 3 to 14 carbon atoms, preferably
monocyclic cycloalkyl ring containing 3 to 6 carbon atoms. Examples of monocyclic
ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
and cyclooctyl. Bicyclic ring systems are also exemplified by a bridged monocyclic
ring system in which two non-adjacent carbon atoms of the monocyclic ring are
linked by an alkylene bridge. Representative examples of bicyclic ring systems
include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2. l]heptane,
bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and
bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane,
bicyclo[410]heptane, bicyclo[3. 2.0]heptanes, octahydro-lH-indene. Tricyclic ring
systems are also exemplified by a bicyclic ring system in which two non-adjacent
carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge.
Representative examples of tricyclic-ring systems include, but are not limited to,
tricyclo[3.3.1.0 3 7]nonane and tricyclo[3.3.1.1 3 7]decane (adamantane) . The term
cycloalkyl also include spiro systems wherein one of the ring is annulated on a
single carbon atom such ring systems are exemplified by spiro[2.5]octane,
spiro[4.5]decane, spiro [bicyclo[4. 1.0]heptane-2, l'-cyclopentane], hexahydro-2'Hspiro
[cyclopropane- 1,1'-pentalene] .
'Cycloalkyl' as defined hereinabove may be substituted with one or more
substituents selected independently from the group comprising of oxo, halogen,
nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R10aC(=O)-, R10aSO2- , R A ,
RioaOC (=0 )-,
(Rio)(H)N-, (R )(alkyl)N-, wherein
R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocyclyl; A1 is selected from S and O; and R10a is selected from alkyl,
alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl
The term "aryl" refers to a monovalent 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 include
partially saturated bicyclic and tricyclic aromatic hydrocarbons such as
tetrahydro-naphthalene. The said aryl group also includes aryl rings fused with
heteroaryl or heterocyclic rings such as 2,3-dihydro-benzo[l,4]dioxin-6-yl, 2,3-
dihydro-benzo[ 1,4]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.
'Aryl' as defined hereinabove may be substituted with one or more substituents
selected independently from the group comprising of halogen, nitro, cyano,
hydroxy, Ci to Ce alkyl, C2 to Ce alkenyl, C2 to Ce alkynyl, C 3 to Ce cycloalkyl, 3- to
6- membered heterocycle, Ci to Ce perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-,
perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SOa-, perhaloalkyl-S0 2- ,
alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-N(H)C(=0)-,
H2NC(=0)-, alkyl-N(alkyl)S02- , alkyl-N(H)S02- , and H2NS02- .
The term het eroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic
ring system having 1-4 ring heteroatoms selected from O, N, or S, and the
remainder ring atoms being carbon (with appropriate hydrogen atoms unless
otherwise indicated), wherein at. least one ring in the ring system is aromatic.
Heteroaryl groups may be substituted or unsubstituted with one or more
substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl
group may be substituted by a substituent. Examples of heteroaryl groups include
pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl,
thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidmyl,
pyrazinyl, triazinyl. triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl,
indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolvl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl,
p ny . pyrro o[2.3]py 1d y . pyrazoIo[3,4jpyrimidinyl, and benzo(b)thienyl, 2,3-
thiadiazolyl, lH-pyrazolo[5, 1-cj- 1,2,4-triazolyl, pyiTolo[3,4-d]-l ,2,3-triazolyl,
cyclopentatriazolyl, 3H-pyrrolo[3,4-c] isoxazolyl and the like.
'Heteroaryl' as defined hereinabove may be substituted with one or more
substituents selected independently from the group comprising of halogen, nitro,
cyano, hydroxy, C to Ce alkyl, C2 to Ce alkenyl, C2 to Ce alkynyl, C 3 to Ce
cycloalkyl, 3- to 6- membered heterocycle, C to Ce perhaloalkyl, alkyl-O-, alkenyl-
0-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-S0 2- ,
perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-,
alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S02- , alkyl-N(H)S02- , and H2NS02- .
The term "heterocycle" or "heterocyclic" as used herein, means a 'cycloalkyl' group
wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 2)-, -S(O)-, -
N(Rm)-, -Si(Rm)R - , wherein, Rm and R are independently selected from hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. The
heterocycle may be connected to the parent molecular moiety through any carbon
atom or any nitrogen atom contained within the heterocycle. Representative
examples of monocyclic heterocycle include, but are not limited to, azetidinyl,
azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-
dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,
thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone),
thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle include,
but are not limited to 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-l,4-
benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 2,3-
dihydro-1 H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also
include bridged heterocyclic systems such as azabicyclo[3.2.1]octane,
azabicyclo[3.3.1]nonane and the like.
'Heterocyclyl' group may be substituted on ring carbons with one or more
substituents selected independently from the group comprising of oxo, halogen,
nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^A 1- , R10aOC(=O)-,
Rioac(=0)0-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(O)-, R o C(=0)N(H)-, R °)(H)N-,
(R o)(alkyl)N-, (R °)(H)NC(=A )N(H)-, and (R o)(alkyl)NC(=A )N(H)-; wherein R is
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocyclyl; A1 is selected from S and O; and R10a is selected from alkyl, alkenyl,
alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl.
'Heterocyclyl' group may further be substituted on ring nitrogen(s) with
substituents selected from the group comprising of aryl, hereroaryl, alkyl, alkenyl,
alkynyl, R 0 C(=O)-, R10aSO2- , R10aOC(=O)-, (R 0)(H)NC(=O)-, (R 0)(alkyl)NC(=O)-;
wherein R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl and heterocyclyl; R10a is selected from alkyl, alkenyl, alkynyl,
perhaloalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl.
The term Ό ' means a divalent oxygen (=0) attached to the parent group. For
example oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane
forms a cyclohexanone, and the like.
The term 'annulated' means the ring system under consideration is either
annulated with another ring at a carbon atom of the cyclic system or across a bond
of the cyclic system as in the case of fused or spiro ring systems.
The term 'bridged' means the ring system under consideration contain an alkylene
bridge having 1 to 4 methylene units joining two non adjuscent ring atoms.
A compound, its stereoisomers, racemates, and pharmaceutically acceptable salt
thereof as described hereinabove wherein the compound of general formula (I) is
selected from:
2'-Methoxy-5'-(3-methyl-5-propionylthiophen-2-yl)-[ 1,l'-biphenyl]-4-sulfonamide
(Compound 1);
2'-chloro-5'-(3-methyl-5-propionylthiophen-2-yl)-[l, l'-biphenyl]-4-sulfonamide
(Compound 2);
3'-(3-methyl-5-propionylthiophen-2-yl)-[l,l'-biphenyl]-4-sulfonamide (Compound
3);
2'-(dimethylamino)-5'-(3-methyl-5-propionylthiophen-2-yl)-[ 1,1'-biphenyl] -4-
sulfonamide (Compound 4);
2'-methoxy-5'- (4-methyl-2- (piperidine- 1-carbonyl)thiazol-5-yl)- [1,1'-biphenyl] -4-
sulfonamide (Compound 5);
2'-methoxy-5'-(4-methyl-2-(pyrrolidine- l-carbonyl)thiazol-5-yl)-[l ,l'-biphenyl]-4-
sulfonamide (Compound 6);
2'-chloro-5'-(4-methyl-2-(pyrrolidine- l-carbonyl)thiazol-5-yl)-[l ,l'-biphenyl]-4-
sulfonamide (Compound 7);
2'-methoxy-5'-(4-methyl-2-propionylthiazol-5-yl)-[l, l'-biphenyl]-4-sulfonamide
(Compound 8);
5'-(3 ,4-dimethyl-5-propionylthiophen-2 -yl)-2'-methoxy-[1,1'-biphenyl]-4-
sulfonamide (Compound 9);
5'-(l ,3-dimethyl-5-propionyl- lH-pyrrol-2-yl)-2'-methoxy-[l ,l'-biphenyl]-4-
sulfonamide (Compound 10).
According to another aspect of the present invention, the compounds of general
formula (I) where all the symbols are as defined earlier were prepared by methods
described below. However, the invention is not limited to these methods; the
compounds may also be prepared by using procedures described for structurally
related compounds in the literature.
compounds III to VII, E = S or NR , where R is not hydrogen J
SCHEME - 1
Scheme 1 provides a route for preparation of the compound of the formula (I),
where R1, R2, R3, R4, m, n, D and E are same as deflned earlier, from compound of
formula (II), where R1, R3, n, E and D are same as deflned under generic formula
(I).
Compound of formula (II) can be prepared by the procedures described n the
literature such as US 5,608,082, WO 2007/092751, Organic Letters, 9, 25, 2007,
5191-5194; WO 2006/89076, WO 2005/42540, WO 2008/036541, or methods
well known to the person skilled n the art.
The compound of formula (II), where E is selected from S and NR6, where R6 is
substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, or
R7 C(=0)-, D is selected from CR5 and N, and R1, R3 and n are as defined under
general formula (I), on bromination gives compound of formula IV, where all the
symbols are the same as defined earlier for compound of formula II.
The compound of formula (II), where E is NR6, where R6 hydrogen, and R3, n and D
are same as defined under generic formula (I), reacted with a suitable amino
protecting reagent as described in Greene and Wuts (protective groups in Organic
Synthesis, Wiley and sons, 1999) to obtain compound of formula (III), where E is NP,
where P is a protecting group, and R3, n and D are same as defined under
generic formula (I). Protecting groups 'P', may be selected form but not limited to
tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl(Bn), acetyl and
trifluoroacetyl.
The compound of the formula (III), where E is P, where P is a protecting group, and
R1, R3, n and D are same as defined under generic formula (I), on bromination gives
compound of formula (IV), where E is P, where P is a protecting group, and R1, R3,
n and D are same as defined under generic formula (I). Bromination can be carried
out under a condition generally used in the synthetic organic chemistry using
brominating agents such as N-bromosuccinimide, bromine, phosphorous
tribromide and aluminium tribromide. The inventors have carried out bromination
using bromine in acetic acid.
Alternatively, the bromo compound of formula (IV), where all the symbols are the
same as defined earlier can be prepared by reduction of nitro group of
corresponding nitro-derivative of compound of formula (II) or (III) to amino group
using procedure provided in Tetrahedron, 2008, 64, 6406-6414. The said amino
group can then be converted to diazonium compound using a condition usually
applied for diazotization, i.e. by treating corresponding amino compound with
nitrite e.g. tert-butyl nitrite. The diazo-compound can then subsequently was
treated with copper halide preferably copper(II)bromide or bromoform to obtain
compound of formula (IV) under standard Sandmeyer condition as provided in WO
2007/125934.
The compound of formula (IV), where R1, R3 and n are same as defined under
general formula (I), and D is CR5, and E is S or NR6, where R6 is P, substituted- or
unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, or R7 C(=0)-, was
subjected to Suzuki coupling with compound of formula (VIII), where R4 and m as
defined under generic formula (I), to obtain compound of formula (V), where R1, R3,
R4, m and n are same as defined under general formula (I), and D is CR5, and E is
S or NR6, where R6 is P, substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- cycloalkyl, or R7 C(=0)-. Suzuki coupling can be carried out under
different coupling conditions with boronic acids and boronic esters well known in
the art. Preferably, the Suzuki coupling is carried out in a mixture of water,
ethanol, methanol and toluene in presence of base such as potassium phosphate,
potassium carbonate or the like, and a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0) at an temperature of about 50°C or
higher temperature. Boronic acid used in this reaction can be prepared by the
methods well known in the art by hydrolysing 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, 2547).
Hydrolysis of compound of formula (V) gave compound of formula (VI), where R1,
R3, R4, m, n , D and E are same as defined earlier for compound of formula (V).
Ester hydrolysis may be carried out using standard procedure generally used in
synthetic organic chemistry or well known in the art with reagents such as sodium
hydroxide, potassium hydroxide, lithium hydroxide or the like in solvents such as
water, alcohol, THF or the like or mixtures thereof. Preferably aqueous solution of
sodium hydroxide and ethanol were used for the reaction.
Compound of formula (IV), where R1, R3 and n are same as defined under general
formula (I), and E is S, and D is N as obtained in the previous step, on Suzuki
condition with compound of formula (VIII) gives compound of formula (VI) directly.
The compounds of formula (VI) where R1, R3, R4, m and n are same as defined
earlier for compound of formula (V), D is CR5, and E is S, can be converted to acid
chloride using oxalyl chloride in dichloromethane and DMF followed by reaction
with iV,0-dimethylhydroxylamine hydrochloride in presence of triethylamine in
dichloromethane to provide compounds of formula (VII), where R1, R3, R4, m and n
are same as defined earlier for compound of formula (V), and D is CR5, and E is S.
The compounds of formula (VI), where R1, R3, R4, m and n are same as defined
under compound of formula (V), D is N when E is S, and D is CR5 when E is NR6,
were converted to compounds of formula (VII) by coupling reaction followed by
sulfonamide protection. The coupling reaction can be carried out following the
conditions generally used for converting carboxylic acids to amides. The reaction
can be carried out preferably with iV,0-dimethylhydroxylamine hydrochloride and
triethylamine in DMF using reagents such as l-(3-dimethylaminopropyl)-3-
ethylcarbodimide hydrochloride (EDCI), benzotriazole hydrate (HOBT) or the like.
Sulfonamide protection can be carried out under a condition known to a person
skilled in the art or by utilizing the teaching provided in Organic Preparations and
Procedures International, 2002, 37(5), 545-549. Inventors have protected
sulfonamide using N,N -dimethylformamide dimethyl acetal in presence of DMF to
provide compound of formula (VII).
The compound of the formula (VII) is reacted with Grignard reagent R MgX where
R2 is substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedhererocyclyl,
and X1 is a halogen, to obtain the compounds of formula I , where R2
is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl, substituted- or
unsubstituted- hererocyclyl. The reaction of compound of formula (VII) with
R2MgX can be carried out according to the procedure given in literature such as J .
Med. Chem., 2009, 52, 3377.
Compounds of formula (I), where R6 is selected as hydrogen, can be prepared by
deprotecting the protective group used, by following an appropriate procedure as
provided in Greene and Wuts (protective groups in Organic Synthesis, Wiley and
sons, 1999).
Compound of formula (VI) is alternatively reacted with (R7)(R )NH, (R7)(OR7b)NH, or
R OH, where R7 and R8 are as defined under definition of R2 in general formula (I),
to obtain compound of formula (I) , where R2 is selected from the group consisting of
(R7)(R )N-, (R7)(OR b)N-, and R70-, wherein R7 and R8 are as defined under
definition of R2 in general formula (I) . The reaction was carried out according to the
conditions known in converting carboxylic acids to amides and esters as known to
one skilled in the art. The reaction may be carried out in the presence of solvents,
for example, DMF, THF, a halogenated hydrocarbon such as chloroform and
dichlorome thane, an aromatic hydrocarbon such as xylene, benzene, toluene, or
mixtures thereof or the like, in the presence of suitable base such as triethylamine,
diisopropylethylamine, pyridine or the like at a temperature between 0-50°C using
reagents such as l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
(EDCI), 1,3-dicyclohexylcarbodiimide (DCC), and auxiliary reagents such as 1-
hydroxy-7-azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT) or the
like.
Groups covered under R1 can be introduced in any of the steps of scheme 1 using
general group transformation method.
[for compounds IX, X, I, D =N, E = S, R2 = (R )(R )N-, heterocyclyl (Point of attachment through Nitrogen)]
SCHEME - 2
Scheme 2 provides a route for preparation of compound of formula (I), where R2 is
(R7)(R )N-, heterocycle wherein point of attachment is through Nitrogen, D = N, E =
S, R1, R3, R4, m and n are same as described under compound of formula (I), from
compound of formula (II) where D = N and E = S, R1, R3 and n are same as defined
under compound of formula (I) .
Compound of formula (II), where D = N and E = S, R1, R3 and n are same as defined
under compound of formula (I), can be prepared by the procedure described in the
literature such as WO 2006/89076, or methods well known to the person skilled in
the art.
Compound of the formula (II) was reacted with (R7)(R )NH or heterocycle containing
atleast one nitrogen in an organic solvent such as ethanol at a temperature ranging
between about 20°C and about 100°C to obtain a compounds of formula (IX),
where R2 is (R7)(R )N-, D = N, E = S, and R , R3 and n are same as defined under
compound of formula (I) .
The compound of formula (IX), as obtained in the previous step was further
brominated by using procedures described hereinabove to obtain compounds of
formula (X). The compound of formula (X) so obtained was further subjected to
Suzuki coupling with compound of formula (VIII) using the procedures described
hereinabove to obtain compound of formula (I) .
The term 'room temperature' denotes any temperature ranging between about 20°C
to about 40°C, except and otherwise it is specifically mentioned in the specification.
The intermediates and the compounds of the present invention may obtained in
pure form in a manner known per se, for example, by distilling off the solvent in
vacuum and re- crystallizing the residue obtained from a suitable solvent, such as
pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate,
acetone or their combinations or subjecting it to one of the purification methods,
such as column chromatography (e.g., flash chromatography) on a suitable support
material such as alumina or silica gel using eluent such as dichloromethane, ethyl
acetate, hexane, methanol, acetone and their combinations. Preparative LC-MS
method is also used for the purification of molecules described herein.
Salts of compound of formula (I) can be obtained by dissolving the compound in a
suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride
or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or
isopropanol, which was then treated with the desired acid or base as described in
Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of
Pharmaceutical sciences volume 66, page 1-19 (1977)" and in handbook of
pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland
Camille G.wermuth, Wiley- VCH (2002). Lists of suitable salts can also be found in
Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton,
PA, 1990, p . 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For
example, they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline
earth metal (e.g., calcium), or ammonium of salt.
The compound of the invention or a composition thereof can potentially be
administered as a pharmaceutically acceptable acid-addition, base neutralized or
addition salt, formed by reaction with inorganic acids, such as hydrochloric acid,
hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and
phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid,
glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid,
maleic acid, and fumaric acid, or by reaction with an inorganic base, such as
sodium hydroxide, potassium hydroxide. The conversion to a salt is accomplished
by treatment of the base compound with at least a stoichiometric amount of an
appropriate acid. Typically, the free base is dissolved in an inert organic solvent
such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like,
and the acid is added in a similar solvent. The mixture is maintained at a suitable
temperature (e.g., between 0 °C and 50 °C). The resulting salt precipitates
spontaneously or can be brought out of solution with a less polar solvent.
The stereoisomers of the compounds of formula (I) of the present invention may be
prepared by stereospecific syntheses or resolution of the achiral compound using
an optically active amine, acid or complex forming agent, and separating the
diastereomeric salt/complex by fractional crystallization or by column
chromatography.
The term "prodrug" denotes a derivative of a compound, which derivative, when
administered to warm-blooded animals, e.g. humans, is converted into the
compound (drug). The enzymatic and/or chemical hydrolytic cleavage of the
compounds of the present invention occurs in such a manner that the proven drug
form (parent carboxylic acid drug) is released, and the moiety or moieties split off
remain nontoxic or are metabolized so that nontoxic metabolic products are
produced. For example, a carboxylic acid group can be esterified, e.g., with a
methyl group or ethyl group to yield an ester. When an ester is administered to a
subject, the ester is cleaved, enzymatically or non-enzymatically, reductively,
oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be
esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an
intermediate compound which subsequently decomposes to yield the active
compound.
The prodrugs can be prepared in situ during the isolation and purification of the
compounds, or by separately reacting the purified compound with a suitable
derivatizing agent. For example, hydroxy groups can be converted into esters via
treatment with a carboxylic acid in the presence of a catalyst. Examples of
cleavable alcohol prodrug moieties include substituted or unsubstituted, branched
or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, dilower
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, substituted or
unsubstituted, e.g., with methyl, halo, or methoxy substituents aryl and aryl-lower
alkyl esters, amides, lower-alkyl amides, di-lwer alkyl amides, and hydroxy amides.
Modulation of the nicotinic cholinergic receptors, particularly 7 may provide for
efficacy in a range of cognitive states, right from pre-attention to attention and
subsequently working, reference and recognition memory. Accordingly, this
invention may find application in the treatment and prophylaxis of multitude of
disease conditions including, either one or combinations of, schizophrenia,
schizophreniform disorder, cognitive deficits in schizophrenia, brief psychotic
disorder, delusional disorder, schizoaffective disorder, shared psychotic disorder,
paranoid personality disorder, schizoid personality disorder, schizotypal
personality disorder, attention deficit disorder, attention deficit hyperactivity
disorder, depression, maniac depression, major depressive disorder, posttraumatic
stress disorder, generalized anxiety disorder, tourette's syndrome, cyclothymic
disorder, dysthymic disorder, agoraphobia, panic disorder (with or without
agoraphobia) , phobias (including social phobia) and bipolar disorders (Thomsen MS
et al., Curr. Pharm. Des., 2010, 16, 323-343; Peng ZZ et al., Zhonghua Yi Xue Yi
Chuan Xue Za Zhi, 2008, 25, 154-158; Young JW et al., Eur.
Neuropsychopharmacol., 2007, 17, 145-155; Martin LF et al., Am. J . Med. Genet.,
B Neuropsychiatr. Genet., 2007, 144B, 6 11-614; Martin LF et al.,
Psychopharmacology (Berl), 2004, 174, 54-64; Feher A et al., Dement. Geriatr.
Cogn. Disord., 2009, 28, 56-62; Wilens TE et al., Biochem. Pharmacol., 2007, 74,
1212-1223; Verbois SL et al., Neuropharmacology, 2003, 44, 224-233; Sanberg PR
et al., Pharmacol. Ther., 1997, 74, 21-25). Cholinergic system, particularly through
7 nAChR seems to have implications in traumatic brain injury-induced psychosis.
Chronic nicotine treatment has shown to attenuate same. Thus, this invention may
also find application in the treatment of deficits in cholinergic 7 nAChR following
traumatic brain injury (Bennouna M et al., Encephale, 2007, 33, 616-620; Verbois
SL et al., Neuropharmacology, 2003, 44, 224-233).
Modulation of nicotinic ACh receptors, particularly the 7 subtype could also help
supplement the down-regulated cholinergic receptor expression and transmission
as in dementia(s), and also slowing disease progression by reduction of 7- -42
complexation and internalization in AD and Down's syndrome (Nordberg A et al.,
Neurotox. Res., 2000, 2, 157-165; Haydar SN et al., Bioorg. Med. Chem., 2009, 17,
5247-5258; Deutsch SI et al., Clin. Neuropharmacol. , 2003, 26, 277-283).
Appropriately, this invention may find application in the treatment and prophylaxis
of multitude of disease conditions including, either one or combinations of,
dementia(s) due to Alzheimer's disease, dementia with Lewy bodies, Down's
syndrome, head trauma, Stroke, hypoperfusion, Parkinson's disease, Huntington's
disease, Prion diseases, progressive supranuclear palsy, radiation therapy, brain
tumors, normal-pressure hydrocephalus, subdural hematoma, human
immunodeficiency virus (HIV) infection, vitamin deficiency, hypothyroidism, drugs,
alcohol, lead, mercury, aluminium, heavy metals, syphilis, Lyme disease, viral
encephalitis, fungal infection and cryptococcosis (Zhao X et al., Ann. N. Y. Acad.
Sci., 2001, 939, 179-186; Perry E et al., Eur. J . Pharmacol., 2000, 393, 215-222;
Harrington CR et al., Dementia, 1994, 5, 215-228; Wang J et al., J . Neurosci. Res.,
2010, 88, 807-815; Duris K et al., Stroke 201 1, 42(12), 3530-6). Thus, this
invention may also find application in the prophylaxis and preventive measures
immediately after early-stage identification of neurodegenerative disease like
Alzheimer's disease and Parkinson's disease.
Modulation of nicotinic ACh receptors particularly 42, 34 and 7 may have
implications in the development of therapies for nicotine, cannabis addiction and
relapse prevention. Accordingly, this invention may find application in the
prophylaxis or therapy of nicotine addiction, cannabis addiction, and relapseprevention
of nicotine or cannabis addiction. Additionally, this invention may also
provide for an alternative therapy for non-responding addiction patients, patients
having intolerable side-effects with de-addiction therapies or those requiring longterm
maintenance therapies. (Kuzmin A et al., Psychopharmacology (Berl), 2009,
203, 99-108; Weiss RB et al., PLoS Genet., 2008, 4, el000125; Solinas M et al., J .
Neurosci., 2007, 27, 5615-5620; Ebbert J O et al., Patient. Prefer. Adherence, 2010,
4, 355-362).
This invention may also find application in the treatment and prophylaxis of
multitude of pain conditions including, either one or combinations of, pain arising
from, peripheral nervous system (PNS), post-diabetic neuralgia (PDN), post- herpetic
neuralgia (PHN), multiple sclerosis, Parkinson's disease, low-back pain,
fibromyalgia, post-operative pain, acute pain, chronic pain, mononeuropathy,
primary lateral sclerosis, pseudobulbar palsy, progressive muscular palsy,
progressive bulbar palsy, postpolio syndrome, diabetes induced polyneuropathy,
acute demyelinating polyneuropathy (Guillain-Barre syndrome), acute spinal
muscular atrophy (Werdnig-Hoffman disease) and secondary neurodegeneration
(Donnelly-Roberts DL et al., J . Pharmacol. Exp. Ther., 1998, 285, 777-786; Rowley
TJ et al., Br. J . Anaesth., 2010, 105, 201-207; Bruchfeld A et al., J . Intern. Med.,
2010, 268, 94-101).
This invention may find application in the treatment and prophylaxis of plethora of
inflammation and pain related states involving TNF-a and thus providing
symptomatic relief in either any one or combination of, rheumatoid arthritis, bone
resorption diseases, atherosclerosis, inflammatory bowel disease, Crohn's disease,
inflammation, cancer pain, muscle degeneration, osteoarthritis, osteoporosis,
ulcerative colitis, rhinitis, pancreatitis, spondylitis, acute respiratory distress
syndrome (ARDS), joint inflammation, anaphylaxis, ischemia reperfusion injury,
multiple sclerosis, cerebral malaria, septic shock, tissue rejection of graft, brain
trauma, toxic shock syndrome, herpes virus infection (HSV-1 & HSV-2), herpes
zoster infection, sepsis, fever, myalgias, asthma, uveititis, contact dermatitis,
obesity-related disease and endotoxemia (Giebelen IA T et al., Shock, 2007, 27,
443-447; pen a G et al., Eur. J . Immunol., 2010, 40, 2580-2589).
Thus the present invention further provides a pharmaceutical composition,
containing the compounds of the general formula (I) as defined above, its
tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically
substituted analogues, its metabolites, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates and its co-crystals in
combination with the usual pharmaceutically acceptable carriers, diluents and the
like.
The pharmaceutically acceptable carrier (or excipient) is preferably one that is
chemically inert to the compound of the invention and one that has no detrimental
side effects or toxicity under the conditions of use. Such pharmaceutically
acceptable carriers preferably include saline (e.g., 0.9% saline), Cremophor EL
(which is a derivative of castor oil and ethylene oxide available from Sigma
Chemical Co., St. Louis, MO) (e.g., 5% Cremophor EL/5% ethanol/90% saline, 10%
Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol), propylene glycol
(e.g., 40% propylene glycol/ 10% ethanol/50% water), polyethylene glycol (e.g., 40%
PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60% water). A preferred
pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a
composition comprising 40% PEG 400 and 60% water or saline. The choice of
carrier will be determined in part by the particular compound chosen, as well as by
the particular method used to administer the composition. Accordingly, there is a
wide variety of suitable formulations of the pharmaceutical composition of the
present invention.
The following formulations for oral, aerosol, parenteral, subcutaneous,
intravenous, intraarterial, intramuscular, interperitoneal, rectal, and vaginal
administration are merely exemplary and are in no way limiting.
The pharmaceutical compositions can be administered parenterally, e.g.,
intravenously, intra-arterially, subcutaneously, intradermally, intrathecally, or
intramuscularly. Thus, the invention provides compositions for parenteral
administration that comprise a solution of the compound of the invention dissolved
or suspended in an acceptable carrier suitable for parenteral administration,
including aqueous and non-aqueous, isotonic sterile injection solutions.
Overall, the requirements for effective pharmaceutical carriers for parenteral
compositions are well known to those of ordinary skill in the art. See Pharmaceutics
and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and
Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs,
Toissel, 4th ed., pages 622-630 (1986). Such compositions include solutions
containing anti-oxidants, buffers, bacteriostats, and solutes that render the
formulation isotonic with the blood of the intended recipient, and aqueous and
non-aqueous sterile suspensions that can include suspending agents, solubilizers,
thickening agents, stabilizers, and preservatives. 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 (for
example in topical applications), or hexadecyl alcohol, glycols, such as propylene
glycol or polyethylene glycol, dimethylsulf oxide, glycerol ketals, such as 2,2-
dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an
oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride
with or without the addition of a pharmaceutically acceptable surfactant, such as a
soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents
and other pharmaceutical adjuvants.
Oils useful in parenteral formulations include petroleum, animal, vegetable, and
synthetic oils. Specific examples of oils useful in such formulations include peanut,
soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. 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^-aminopropionates, and 2-
alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically will contain from about 0.5% or less to about
25% or more by weight of a compound of the invention in solution. Preservatives
and buffers can be used. In order to minimize or eliminate irritation at the site of
injection, such compositions can 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 will typically range from about 5% to about 15%
by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters,
such as sorbitan monooleate and the high molecular weight adducts of ethylene
oxide with a hydrophobic base, formed by the condensation of propylene oxide with
propylene glycol. The parenteral formulations can be presented in unit-dose or
multi-dose sealed containers, such as ampoules and vials, and can be stored in a
freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid
excipient, for example, water, for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions can be prepared from sterile
powders, granules, and tablets.
Topical formulations, including those that are useful for transdermal drug release,
are well known to those of skill in the art and are suitable in the context of the
present invention for application to skin.
Formulations suitable for oral administration can consist of (a) liquid solutions,
such as an effective amount of a compound of the invention dissolved in diluents,
such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and
troches, each containing a pre-determined amount of the compound of the
invention, as solids or granules; (c) powders; (d) suspensions in an appropriate
liquid; and (e) suitable emulsions. Liquid formulations can include diluents, such
as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene
alcohols, either with or without the addition of a pharmaceutically acceptable
surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the
ordinary hard- or soft-shelled gelatin type containing, for example, surfactants,
lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and
cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol,
corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin,
guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium
stearate, calcium stearate, zinc stearate, stearic acid, and other excipients,
colorants, diluents, buffering agents, disintegrating agents, moistening agents,
preservatives, flavoring agents, and pharmacologically compatible excipients.
Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose
and acacia or tragacanth, as well as pastilles comprising a compound of the
invention in an inert base, such as gelatin and glycerin, or sucrose and acacia,
emulsions, gels, and the like containing, in addition to the compound of the
invention, such excipients as are known in the art.
A compound of the present invention, alone or in combination with other suitable
components, can be made into aerosol formulations to be administered via
inhalation. A compound or epimer of the invention is preferably supplied in finely
divided form along with a surfactant and propellant. Typical percentages of the
compounds of the invention can be about 0.01% to about 20% by weight,
preferably about 1% to about 10% by weight. The surfactant must, of course, be
nontoxic, and preferably soluble in the propellant. Representative of such
surfactants are the esters or partial esters of fatty acids containing from 6 to 22
carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic,
olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
Mixed esters, such as mixed or natural glycerides can be employed. The surfactant
can constitute from about 0. 1% to about 20% by weight of the composition,
preferably from about 0.25% to about 5%. The balance of the composition is
ordinarily propellant. A carrier can also be included as desired, e.g., lecithin, for
intranasal delivery. These aerosol formulations can be placed into acceptable
pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and
the like. They also can be formulated as pharmaceuticals for non-pressured
preparations, such as in a nebulizer or an atomizer. Such spray formulations can
be used to spray mucosa.
Additionally, the compound of the invention can be made into suppositories by
mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
Formulations suitable for vaginal administration can be presented as pessaries,
tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to
the compound ingredient, such carriers as are known in the art to be appropriate.
The concentration of the compound in the pharmaceutical formulations can vary,
e.g., from less than about 1% to about 10%, to as much as 20% to 50% or more by
weight, and can be selected primarily by fluid volumes, and viscosities, in
accordance with the particular mode of administration selected.
For example, a typical pharmaceutical composition for intravenous infusion could
be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least
one compound of the invention. Actual methods for preparing parenterally
administrable compounds of the invention will be known or apparent to those
skilled in the art and are described in more detail in, for example, Remington's
Pharmaceutical Science (17th ed., Mack Publishing Company, Easton, PA, 1985).
It will be appreciated by one of ordinary skill in the art that, in addition to the
aforedescribed pharmaceutical compositions, the compound of the invention can
be formulated as inclusion complexes, such as cyclodextrin inclusion complexes,
or liposomes. Liposomes can serve to target a compound of the invention to a
particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes
can also be used to increase the half-life of a compound of the invention. Many
methods are available for preparing liposomes, as described in, for example, Szoka
et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871,
4,501,728, 4,837,028, and 5,019,369.
The compounds or pharmaceutical compositions are useful, in an embodiment, for
the treatment and/or prophylaxis of diseases or disorder or condition such as
Alzheimer's disease (AD), mild cognitive impairment (MCI), senile dementia,
vascular dementia, dementia of Parkinson's disease, attention deficit disorder,
attention deficit hyperactivity disorder (ADHD), dementia associated with Lewy
bodies, AIDS dementia complex (ADC), Pick's disease, dementia associated with
Down's syndrome, Huntington's disease, cognitive deficits associated with
traumatic brain injury (TBI), cognitive 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.
In another embodiment, the pharmaceutical compositions are useful for the
treatment and/or prophylaxis of diseases or disorder or condition classified or
diagnosed as major or minor neurocognitive disorders, or disorders arising due to
neurodegeneration.
The present invention also provide method of administering a compound of formula
(I), as defined hereinabove in combination with or as adjunct to medications used
in the treatment of attention deficit hyperactivity disorders, schizophrenia, and
other cognitive disorders such as Alzheimer's disease, Parkinson's dementia,
vascular dementia or dementia associated with Lewy bodies, traumatic brain
injury.
The present invention also provide method of administering a compound of formula
(I), as defined hereinabove in combination with or as an adjunct to
acetylcholinesterase inhibitors, disease modifying drugs or biologies for
neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an
atypical antipsychotic.
Accordingly, compound of formula (I) is useful for preventing or treating a disorder
mediated by nicotinic acetylcholine receptors. Such compounds can be
administered to a subject having such a disorder or susceptible to such disorders
in a therapeutically effective amount. The compounds are particularly useful for a
method of treating a mammal having a condition where modulation of nicotinic
acetylcholine receptor activity is of therapeutic benefit, wherein the method is
accomplished by administering a therapeutically effective amount of a compound of
formula (I) to a subject having, or susceptible to, such a disorder.
The present invention also provides a pharmaceutical composition, containing the
compound of the general formula (I) as defined above, its tautomeric forms, its
stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its
pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers,
its clathrates and its co-crystals in combination with the usual pharmaceutically
employed carriers, diluents and the like, and for use in any of the methods
described herein.
The compounds of the invention can be administered in a dose sufficient to treat
the disease, condition or disorder. Such doses are known in the art (see, for
example, the Physicians' Desk Reference (2004)). The compounds can be
administered using techniques such as those described in, for example,
Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians' Desk
Reference, 58th ed., Thomson PDR (2004).
Suitable doses and dosage regimens can be determined by conventional rangefinding
techniques known to those of ordinary skill in the art. Generally, treatment
is initiated with smaller dosages that are less than the optimum dose of the
compound of the present invention. Thereafter, the dosage is increased by small
increments until the optimum effect under the circumstances is reached. The
present method can involve the administration of about 0.1 g to about 50 mg of at
least one compound of the invention per kg body weight of the individual. For a 70
kg patient, dosages of from about 10 g to about 200 mg of the compound of the
invention would be more commonly used, depending on a patient's physiological
response.
By way of example and not intending to limit the invention, the dose of the
pharmaceutically active agent(s) described herein for methods of treating or
preventing a disease or condition as described above can be about 0.001 to about 1
mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg,
0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg,
0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day. The
dose of the pharmaceutically active agent(s) described herein for the described
methods can be about 1 to about 1000 mg/kg body weight of the subject being
treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25
mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000
mg/kg body weight per day.
In accordance with embodiments, the present invention provides methods of
treating, preventing, ameliorating, and/or inhibiting a condition modulated by the
nicotinic acetylchoine receptor comprising administering a compound of formula (I)
or a salt thereof.
The terms "treat," "prevent," "ameliorate," and "inhibit," as well as words stemming
therefrom, as used herein, do not necessarily imply 100% or complete treatment,
prevention, amelioration, or inhibition. Rather, there are varying degrees of
treatment, prevention, amelioration, and inhibition 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,
prevention, amelioration, or inhibition 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, prevention, amelioration, or inhibition provided by the
inventive method can include treatment, prevention, amelioration, or inhibition of
one or more conditions or symptoms of the disorder, e.g., cancer. Also, for
purposes herein, "treatment," "prevention," "amelioration," or "inhibition" can
encompass delaying the onset of the disorder, or a symptom or condition thereof.
In accordance with the invention, the term subject includes an "animal" which in
turn includes a mammal such as, without limitation, the order Rodentia, such as
mice, and the order Lagomorpha, such as rabbits. It is preferred that the mammals
are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more
preferred that the mammals are from the order Artiodactyla, including Bovlnes
(cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses). It
is most preferred that the mammals are of the order Primates, Ceboids, or Simoids
(monkeys) or of the order Anthropoids (humans and apes) . An especially preferred
mammal is the human.
Following are the abbreviations used and meaning thereof in the specification:
ACh: Acetylcholine.
AD: Alzheimer's disease.
ADC: AIDS dementia complex.
ADHD: attention deficit hyperactivity disorder.
AIDS: Acquired immunodeficiency syndrome.
ARDS: acute respiratory distress syndrome.
DCC: 1,3-dicyclohexylcarbodiimide.
DCM: dichlorome thane.
DIPEA: diisopropyl ethyl amine
DLB: dementia with Lewy bodies.
DMF: N,N-dimethylformamide.
EDCI: l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride.
FLIPR: Fluorometric Imaging Plate Reader.
HATU: 2-(lH-7-Azabenzotriazol-l-yl)-l, l,3,3-tetramethyl uronium
hexafluorophosphate .
HBSS: Hank's balanced salt solution.
HEPES: 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid.
HMGB: high mobility group box.
HOAT: l-hydroxy-7-azabenzotriazole.
HOBT: hydroxybenzotriazole hydrate.
HPLC: High Performance liquid chromatography.
IL: interleukins.
LDT: laterodorsal tegmental nucleus.
LGIC: ligand-gated ion channels.
MCI: mild cognitive impairment.
NBS: N-bromosuccinimide.
NNRs: Neural nicotinic ACh receptors.
PAM: positive allosteric modulation.
PD: Parkinson's disease.
PDN: post-diabetic neuralgia.
PHN: post-herpetic neuralgia.
PNS: peripheral nervous system.
TBI: traumatic brain injury.
THF: Tetrahydrofuran.
TLC: Thin layer chromatography.
TMS: tetramethylsilane.
TNF-a: tumor necrosis factor alpha.
VTA: ventral tegmental area.
a 7 nAChR: nicotinic acetylcholine receptor a7 subunit.
The following examples are provided to further illustrate the present invention and
therefore should not be construed in any way to limit the scope of the present
invention. All H MR spectra were determined in the solvents indicated and
chemical shifts are reported in units downfield from the internal standard
tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz
(Hz).
Example 1: Synthesis of 2'-Methoxy-5'-(3-methyl-5-propionylthiophen-2-yl)-
[l,l'-biphenyl]-4-sulfonamide (Compound 1)
Step 1 : Methyl 5-(3-bromo-4-methoxyphenyl)-4-methylthiophene-2-carboxylate
(la)
Liquid bromine (1.8 g, 0.57 ml, 11.43 mmol) was added drop wise to a stirred
solution of methyl-5-(4-methoxyphenyl)-4-methylthiophene-2-carboxylate
(prepared according to the procedure reported in WO 2007/092751, 2.0 g, 7.62
mmol) in acetic acid (20 ml) at a temperature of about 25°C. The resulting mixture
was stirred at the same temperature for 16 hours. The progress of reaction was
monitored by TLC. The reaction mixture was poured onto ice water (100 ml). The
mixture so obtained was extracted with ethyl acetate (3 x 100 ml). The separated
combined organic layer was washed with 10% aqueous sodium bicarbonate
solution (2 x 50 ml). The organic layer was then dried over anhydrous Na2S04. The
solvent was evaporated form the organic layer under reduced pressure to obtain a
crude product. The crude product was further purified by flash chromatography
using 15-25% ethyl acetate in hexanes as an eluent to obtain the title compound
(2.35 g, 90%).
MS: m/z 341 (M+l).
HNMR (CDCI3, 400 MHz): 7.67(d, J = 2.4 Hz, 1H), 7.61 (s, 1H), 7.39 (dd, J = 2.4
Hz, 8.8 Hz, 1H), 6.96 (d, J = 8.8Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.30 (s, 3H).
The compounds listed below were prepared by procedure similar to the one
described above for compound ' la' with appropriate variations in reactants,
reaction conditions and quantities of reagents.
2a. Methyl 5-(3-bromo-4-chlorophenyl)-4-methylthiophene-2-carboxylate
3a. Methyl 5-(3-bromophenyl)-4-methylthiophene-2-carboxylate
4a. Methyl 5-(3-bromo-4-(dimethylamino)phenyl)-4-methylthiophene-2-
carboxylate
Step 2 : Ethyl 5-(6-methoxy-4'-sulfamoyl-[ l ,l'-biphenyl]-3-yl)-4-methylthiophene-2-
carboxylate (2b)
4-aminosulfonylbenzene boronic acid (prepared according to the procedure given in
EP 1 012 142, 1.16 g, 5.8 mmol) and potassium carbonate (1.45 g, 10.55 mmol)
were added to the solution of methyl 5-(3-bromo-4-methoxyphenyl)-4-
methylthiophene-2-carboxylate (la, 1.8 g, 5.27 mmol) in a mixture of toluene :
ethanol (9 : 27 ml) at a temperature of about 25°C in a tube under nitrogen
atmosphere for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.3 g , 0.26
mmol) was added to the reaction mixture under nitrogen and the tube was sealed.
Reaction mixture was heated at about 90-95°C for 16 hr under stirring. Completion
of the reaction was monitored by TLC. The reaction mixture was then cooled to
25°C and filtered through celite. The celite cake was washed with 10% methanol in
dichlorome thane. The combined filtrate was then concentrated under reduced
pressure to obtain a crude product. The crude product so obtained was purified by
flash chromatography using 4% methanol in dichloromethane as an eluent to
obtain the title compound l b (1.5 g, 68%).
MS: m/z 432 (M+l).
HNMR (DMSO-d6, 400 MHz): 7.86(d, J = 8.4 Hz, 2H), 7.71(d, J = 8.4 Hz, 2H),
7.68 (s, 1H), 7.57 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.45 (d, J = 2.4Hz , 1H), 7.4 (bsexchange
with D20 , 2H), 7.27 (d, J = 8.8Hz , 1H), 4.27 (q, J = 7.2Hz , 2H), 3.84 (s,
3H), 2.31 (s, 3H), 1.28 (t, J = 7.2Hz , 3H).
Note: Due to trans-esterification, it is fully converted into corresponding ethyl
ester. However, mixture of ethyl ester and methyl ester is also obtained during
some experiments due to partial conversion methyl ester into corresponding ethyl
ester.
The compounds given below were prepared by procedure similar to the one
described above for compound 'lb' with appropriate variations in reactants,
reaction conditions and quantities of reagents.
2b. Ethyl 5-(6-chloro -4'- sulfamoyl -[1,1' -biphenyl] -3-yl) -4-methylthiophene -
2-carboxylate
MS: m/z 436 (M+l).
3b. Ethyl 4-methyl-5-(4'-sulfamoyl-[ 1,1'-biphenyl]-3-yl)thiophene-2-carboxylate
MS: m/z 402 (M+l).
4b. Ethyl 5-(6-(dimethylamino)-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-4-
methylthiophene-2-carboxylate
MS: m/z 445 (M+l).
Step 3 : 5-(6-methoxy-4'-sulfamoyl-[l ,1'-biphenyl] -3-yl)-4-methylthiophene-2-
carboxylic acid (lc)
Ethyl 5-(6-methoxy-4'-sulfamoyl-[l ,l'-biphenyl]-3-yl-4-methylthiophene-2-
carboxylate (lb, 1.4 g, 3.24 mmol) was suspended in ethanol (21 ml), to this was
added IN solution of NaOH (16 ml) at 25°C. The reaction mixture was heated at
about 85°C under stirring for 30-40 minutes. The progress of the reaction was
monitored by TLC. Reaction mixture was concentrated at reduced pressure.
Residue was diluted with water (10 ml). To the resulting diluted mixture was added
aqueous 2N HC1 to bring the pH of the mixture to about 1 at 0°C. The solid
obtained was filtered and dried to obtain the title compound (1.3 g, 99.3%).
MS: m/z 404 (M+l).
HNMR (DMSO-de, 400 MHz): 13.01 (bs-exchange with D20 , 1H), 7.86(d, J = 8.4
Hz, 2H), 7.72(d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.56 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.44
(d, J = 2.4 Hz, 1H), 7.4 (bs-exchange with D20 , 2H), 7.25 (d, J = 8.8Hz , 1H), 3.84
(s, 3H), 2.30 (s, 3H).
The compounds given below were prepared by following a procedure similar to the
one described above for compound 'lc' with appropriate variations of reactants,
reaction conditions and quantities of reagents.
2c. 5-(6-chloro-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-4-methylthiophene-2-
carboxylic acid
MS: m/z 408 (M+l).
3c. 4-methyl-5-(4'-sulfamoyl-[l, l'-biphenyl]-3-yl)thiophene-2-carboxylic acid
MS: m/z 374 (M+l).
4c. 5- (6 -(dimethylami.no) -4'- sulfamoyl- [1,1' -biphenyl] -3-yl)- 4-
methylthiophene -2-carboxylic acid
MS: m/z 417 (M+l).
Step 4 : 5-(4'-(N -((dimethylamino)methylene)sulfamoyl)-6-methoxy-[l,l'-biph^
3-yl)-N -methoxy -N ,4-dimethylthiophene-2-carboxamide (Id)
Oxalyl chloride (0.87 g, 0.58 ml, 6.94 mmol) was added drop wise to a solution of
5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-4-methylthiophene-2-carboxylic
acid (lc, 1.4 g, 3.47 mmol) in dichloromethane (28 ml) and DMF (0.53 ml, 6.94 m
mol) at 0°C. The reaction mixture was then allowed to come to room temperature
and stirred for 1.5 hr under nitrogen atmosphere. The progress of the reaction was
monitored by TLC. The reaction mixture was then concentrated under reduced
pressure and used directly for further reaction. Residue obtained after
concentration was dissolved in dry dichloromethane (20 ml) and to this was added
triethylamine (2.1 g, 2.89 ml, 20.8 mmol) followed by the addition of ,-
dimethylhydroxylamine hydrochloride (1.34 g, 13.88 mmol) under stirring. The
reaction mixture was stirred at room temperature for 2 hours. The progress of the
reaction was monitored by TLC. The reaction mixture was then diluted with
dichloromethane (100 ml). The mixture obtained was washed with water (2 x 20
ml), followed by washing with brine (1 x 20 ml). The separated organic layer was
dried over anhydrous sodium sulphate, and concentrated under reduced pressure
to obtain a crude product. The crude product was further purified by column
chromatography over silica gel using 80% ethyl acetate in hexane as an eluent to
obtain the title compound (1.1 g, 63.2%).
MS: m/z 502 (M+l).
HNMR (CDCI3, 400 MHz): 8.17 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.66
(d, J = 8.4 Hz, 2H), 7.48 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.42 (d, J = 2.4Hz , 1H), 7.06
(d, J = 8.8Hz , 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 3. 13 (s, 3H), 3.05 (s,
3H), 2.32 (s, 3H).
The compounds given below were prepared by following a procedure similar to the
one described above for compound 'Id' with appropriate variations of reactants,
reaction conditions and quantities of reagents.
2d. 5-(6-chloro-4'-(N-((dimethylamino)methylene)sulfamoyl)-[ 1,1'-biphenyl]-3-
yl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide
MS: m/z 506 (M+l).
3d. 5-(4'-(N-((dimethylamino)methylene)sulfamoyl)-[ 1,1'-biphenyl]-3-yl)-Nmethoxy-
N,4-dimethylthiophene-2-carboxamide
MS: m/z 472 (M+l).
4d. 5-(6-(dimethylamino)-4'-(N-((dimethylamino)methylene)sulfamoyl)-[ 1,1'-
biphenyl]-3-yl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide
MS: m/z 515 (M+l).
Step 5 : 2'-Methoxy-5'-(3-methyl-5-propionylthiophen-2-yl)-[l,l'-biphenyl]-4-
sulfonamide (Compound 1)
Grignard reagent (ethyl magnesium bromide, 1.32 g , 9.9 ml, 9.97 mmol) was
added drop wise to a stirred solution of 5-(4'-(iV-((dimethylamino)methylene)
sulfamoyl)-6-methoxy-[ 1,1'-biphenyl]-3-yl)-iV-methoxy-iV,4-dimethylthiophene-2-
carboxamide (Id, 1.0 g , 1.99 mmol) in anhydrous THF (20 ml) at 25°C. The
reaction mixture was heated at 80-85°C for 1 hour. The progress of the reaction
was monitored by TLC. The reaction mixture was cooled to 0°C. The cooled reaction
mixture was then quenched by adding a saturated solution of ammonium chloride
(10 ml). The mixture was then extracted with ethyl acetate (3 x 60 ml). The
combined organic layer was dried over anhydrous Na2S04. The solvent was
evaporated from the dried organic layer under reduced pressure to obtain a crude
product. The crude product so obtained was purified by flash chromatography
using 30-40% ethyl acetate in hexane as an eluent to obtain the title compound.
The compound was re-purified by by dissolving 0.68 g of the compound in ethyl
acetate (5 ml) and precipitating it by slow addition of diisopropyl ether. (0.180 g,
21.7 %).
MS: m/z 416 (M+l).
HNMR (DMSO-de, 400 MHz): 7.86 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.71 (d, J =
8.4 Hz, 2H), 7.58 (dd, J = 2.4 Hz, 8.8 Hz, 1H),7.45 (d, J = 2.4Hz , 1H), 7.41 (bs,
exchanges with D20 , 2H), 7.27 (d, J = 8.8Hz , 1H), 3.84 (s, 3H), 2.95 (q, J = 7.2Hz ,
2H), 2.32 (s, 3H), 1.09 (t, J = 7.2Hz , 3H).
The compounds given below were prepared by following a procedure similar to the
one described above for compound '1' with appropriate variations of reactants,
reaction conditions and quantities of reagents.
Compound 2: 2'-chloro-5'-(3-methyl-5-propionylthiophen-2-yl)-[l,l'-biphenyl]-4-
sulfonamide
MS: m/z 420 (M+l).
HNMR (DMSO-de, 400 MHz): 7.92 (d, J = 8.4 Hz, 2H), 7.86 (s, IH), 7.70-7.74 (m,
3H), 7.62 (dd, J = 2.4, 8.4 Hz, IH), 7.56 (d, J = 2.4Hz , IH), 7.47 (bs-exchanges
with D20 , 2H), 2.95 (q, J = 7.6Hz, 2H), 2.34 (s, 3H), 1.09 (t, J = 7.6Hz , 3H).
Compound 3: 3'-(3-methyl-5-propionylthiophen-2-yl)-[l, l'-biphenyl]-4-sulfonamide
MS: m/z 386 (M+l).
iHNMR (CDC13, 400 MHz): 8.01 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.68
(s, IH), 7.48-7.62 (m, 4H), 4.87 (bs-exchanges with D20 , 2H), 2.93 (q, J = 7.2 Hz,
2H), 2.37 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).
Compound 4: 2'-(dimethylamino)-5'-(3-methyl-5-propionylthiophen-2-yl)-[l, -
biphenyl] -4-sulfonamide
MS: m/z 429 (M+l).
iHNMR (CDCI3, 400 MHz): 7.99 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.53
(s, IH), 7.70-7.45 (dd, J = 2.0, 8.4 Hz, IH), 7.32 (d, J = 2.4 Hz , IH), 7.1 1 (d, J =
8.4 Hz , IH), 4.91 (bs-exchanges with D20 , 2H), 2.94 (q, J = 7.2 Hz, 2H), 2.61 (s,
6H), 2.36 (s, 3H), 1.25 (t, J = 7.2 Hz , 3H).
Example 2 : Preparation of 2'-methoxy-5'-(4-methyl-2-(piperidine-lcarbonyl)
thiazol-5-yl)-[l,l'-biphenyl]-4-sulfonamide (Compound 5)
Step 1: (5-(4-methoxyphenyl)-4-methylthiazol-2-yl)(pi^ (5a)
Piperidine (1.84 g, 21.63 mmol) was added to a stirred solution of ethyl 5-(4-
methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the
procedure reported in WO 2006/089076, 0.6 g, 2.16 mmol) in a ethanol (10 ml) in
a tube at 25°C under nitrogen atmosphere. The tube was agitated for about 15
minutes under nitrogen and was sealed. The reaction mixture was heated at 90-
95°C for 15 hr with stirring. The progress of the reaction was monitored by TLC.
The reaction mixture was then cooled to 25°C and was concentrated under reduced
pressure. The residue obtained was dissolved in ethyl acetate (50 ml). The mixture
was washed with saturated sodium bicarbonate solution (20 ml). The separated
organic layer was concentrated under reduced pressure to obtain a crude product,
which was then purified by flash column chromatography using 40% ethyl acetate
in hexanes as an eluent to obtain the title compound (0.50 g, 73.0%).
MS: m/z 317 (M+l).
HNMR (DMSO-de, 400 MHz): 7.47 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.21-
4.24 (m, 2H), 3.79 (s, 3H), 3.59- 3.62 (m, 2H), 2.45 (s, 3H), 1.57- 1.65 (m, 6H).
The compound given below was prepared by following a procedure similar to the
one described above for compound '5a' with appropriate variations of reactants,
reaction conditions and quantities of reagents.
6a. (5- (4-methoxyphenyl)-4-methylthiazol-2-yl) (pyrrolidin- 1-yl)methanone
MS: m/z 303 (M+l).
7a. (5- (4-chlorophenyl)-4-methylthiazol-2-yl) (pyrrolidin- 1-yl)methanone
Step 2 : (5-(3-bromo-4-methoxyphenyl)-4-methylthiazol-2-yl)(piperidin- 1-
yl)methanone (5b)
Liquid bromine (0.30 g, 0.097 ml, 1.89 mmol) was added drop wise to a stirred
solution (5-(4-methoxyphenyl)-4-methylthiazol-2-yl)(piperidin- 1-yfjmethanone (5a,
0.5 g, 1.58 mmol) in acetic acid (6 ml) at 25°C. The resulting mixture was stirred at
25°C for 3 hrs. The progress of the reaction was monitored by TLC. The reaction
mixture was then concentrated under reduced pressure. The residue obtained after
concentration was dissolved in ethyl acetate (50 ml). The mixture was then washed
with saturated sodium bicarbonate solution (20 ml). The separated organic layer
was concentrated under reduced pressure to obtain a crude product, which was
then purified by flash column chromatography using 30% ethyl acetate in hexanes
as an eluent to obtain the title compound 5b (0.54 g, 86.0%).
MS: m/z 396 (M+l).
HNMR (DMSO-de, 400 MHz): 7.74 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.4, 2.0 Hz,
1H), 7.22 (d, J = 8.4 Hz, 1H), 4.20-4.22 (m, 2H), 3.90 (s, 3H), 3.59-3.61 (m, 2H),
2.44 (s, 3H), 1.52-1.65 (m, 6H).
The compounds given below were prepared by following a procedure similar to the
one described above for compound '5b' with appropriate variations of reactants,
reaction conditions and quantities of reagents.
6b. (5-(3-bromo-4-methoxyphenyl)-4-methylthiazol-2-yl)(pyrrolidin-l-yl)methanone
MS: m/z 382 (M+l).
7b. (5-(3-bromo-4-chlorophenyl)-4-methylthiazol-2-yl)(pyrrolidin-l-yl)methanone
MS: m/z 386 (M+l).
Step 3 : 2'-methoxy-5'-(4-methyl-2-(piperidine-l-carbonyl)thiazol-5-yl)-[l, -
biphenyl]-4-sulfonamide (Compound 5)
4-aminosulfonylbenzene boronic acid (0.42 g, 2.12 mmol) and potassium
carbonate (0.73 g, 5.31 mmol) were added to a solution of (5-(3-bromo-4-
methoxyphenyl)-4-methylthiazol-2-yl)(piperidin-l-yl)methanone (5b, 0.70 g, 1.77
mmol) in a mixture of toluene: ethanol (5 ml: 15 ml) in a tube at about 25°C under
nitrogen atmosphere. The reaction mixture was agitated under nitrogen
atmosphere for 15 minutes, to it was then added tetrakis(triphenylphosphine)
palladium(O) (0.10 g, 0.089 mmol) under nitrogen and the tube was sealed. The
reaction mixture was heated at 90-95°C for 18 hr with stirring. The progress of the
reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and
filtered through celite. The celite cake was washed with mixture of 10% methanol
in dichloromethane (2 x 20 ml). The combined filtrate was concentrated under
reduced pressure to obtain a crude product, which was then purified by flash
column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain
the title compound 5 (0.20 g, 23.9%).
MS: m/z 472 (M+l).
HNMR (DMSO-de, 400 MHz): 7.85 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H),
7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.33 (bs-exchanges with
D20 , 2H), 7.27 (d, J = 8.8 Hz, 1H), 4.21- 4.23 (m, 2H), 3.84 (s, 3H), 3.59- 3.61 (m,
2H), 2.47 (s, 3H), 1.57- 1.65 (m, 6H).
The compounds given below were prepared by following a procedure similar to the
one described above for compound '5' with appropriate variations of reactants,
reaction conditions and quantities of reagents.
Compound 6 : 2,-methoxy-5'-(4-methyl-2-(pyrrolidine-l-carbonyl)thiazol-5-yl)-[l, -
biphenyl] -4-sulfonamide
MS: m/z 458 (M+l).
iHNMR (CDC13, 400 MHz): 7.98 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.49
(dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 4.86 (bsexchanges
with D20 , 2H), 4.12 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.69 (t, J = 6.4 Hz,
2H), 2.54 (s, 3H), 2.01 (quintet, J = 6.0 Hz, 2H), 1.97 (quintet, J = 6.0 Hz, 2H).
Compound 7: 2,-chloro-5 ,-(4-methyl-2-(pyrrolidine-l-carbonyl)thiazol-5-yl)-[l,l'-
biphenyl] -4-sulfonamide
MS: m/z 462 (M+l).
iHNMR (CDCI3, 400 MHz): 8.04 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.58
(d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 5.00 (bsexchanges
with D20 , 2H), 4.13 (t, J = 6.8 Hz, 2H), 3.69 (t, J = 6.8 Hz, 2H), 2.54 (s,
3H), 2.01 (quintet, J = 6.4 Hz, 2H), 1.94 (quintet, J = 6.4 Hz, 2H).
Example 3 : Preparation of 2'-methoxy-5'-(4-methyl-2-propionylthiazol-5-yl)-
[l,l'-biphenyl]-4-sulfonamide (Compound 8)
Step 1: Ethyl 5-(3-bromo-4-methoxyphenyl)-4-methylthiazole-2-carboxylate (8a)
Liquid bromine (1.04 g, 0.36 ml, 6.49 mmol) was added to a stirred solution of
ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to
the procedure reported in WO 2006/089076, 1.5 g, 5.41 mmol) in acetic acid (15
ml) at 25°C. The resulting reaction mixture was then stirred at 25°C for 3 hours.
The progress of the reaction was monitored by TLC. The reaction mixture was then
concentrated under reduced pressure. The residue obtained after concentration
was dissolved in ethyl acetate (100 ml). The mixture obtained was washed with
saturated sodium bicarbonate solution (30 ml). The separated organic layer was
concentrated under reduced pressure to obtain a crude product, which was then
purified by flash column chromatography using 30% ethyl acetate in hexanes as an
eluent to obtain the title compound 8a (1.70 g, 88.5%).
MS: m/z 357 (M+l).
HNMR (CDCI3, 400 MHz): 7.66 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz, 1H),
6.98 (d, J = 8.4 Hz, 1H), 4.50 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 2.57 (s, 3H), 1.45 (t,
J = 7.2 Hz, 3H).
Step 2 : 5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-4-methylthiazole-2-
carboxylic acid (8b)
4-aminosulfonylbenzene boronic acid (1.15 g, 5.73 mmol) and potassium
carbonate (1.97 g, 14.31 mmol) were added to a solution of ethyl 5-(3-bromo-4-
methoxyphenyl)-4-methylthiazole-2-carboxylate (Step 1, 1.70 g, 4.77 mmol) in a
mixture of toluene: ethanol (15 ml: 40 ml) in a tube at 25°C. Nitrogen gas was
bubbled through reaction mixture for 15 minutes and to it was added
tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol) under nitrogen and
the tube was sealed. The reaction mixture was heated at 90-95°C for 18 hr with
stirring. The progress of the reaction was monitored by TLC. The reaction mixture
was then cooled to 25°C and filtered through celite. The celite cake was then
washed with 10% methanol in dichloromethane (3 x 30 ml). The filtrate was dried
over sodium sulphate and was concentrated under reduced pressure to obtain the
title compound 8b (1.70 g, 88.08%).
MS: m/z 405 (M+l).
HNMR (DMSO-de, 400 MHz): 11.33 (bs-exchanges with D20 , 1H), 7.86 (d, J = 8.4
Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.51 (dd, J = 8.4, 2.0 Hz, 1H), 7.39-7.41 (m, 3H),
7.24 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 2.43 (s, 3H).
Step 3 : N-methoxy-5-(6-methoxy-4'-sulfamoyl-[l,l ,-biphenyl]-3-yl)-N,4-
dimethylthiazole-2-carboxamide (8c)
HOBT (0.62 g, 4.62 mmol) was added to a solution of 5-(6-methoxy-4'-sulfamoyl-
[l, l'-biphenyl]-3-yl)-4-methylthiazole-2-carboxylic acid (8b, 1.70 g, 4.20 mmol) in
DMF (15 ml) at room temperature under stirring. ,-dimethylhydroxylamine
hydrochloride (0.82 g, 8.40 mmol) was then added to the reaction mixture. The
reaction mixture was cooled to 0°C and to this were added EDC (1.20 g, 6.31
mmol) and triethylamine (1.69 g, 2.34 ml, 16.80 mmol). The reaction mixture was
stirred at room temperature for 15 hours. The progress of the reaction was
monitored by TLC. The reaction mixture was then concentrated under reduced
pressure. The residue so obtained was mixed with ethyl acetate (100 ml). The
mixture obtained was washed with saturated sodium bicarbonate solution (20 ml)
followed by washing with brine (20 ml) . The separated organic layer was dried over
anhydrous sodium sulphate. The dried organic layer was then concentrated under
reduced pressure to obtain a crude product. The crude product was then purified
by column chromatography using 50% ethyl acetate in hexanes as an eluent to
obtain the title compound 8c (0.70 g, 37.23%).
MS: m/z 448 (M+l).
HNMR (DMSO-de, 400 MHz): 7.87 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H),
7.60 (dd, J = 8.4, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.40 (bs-exchanges with
D20 , 2H), 7.29 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.49 (s, 3H), 2.51 (s,
3H).
Step 4 : 5-(4'-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[ 1,1'-biphenyl]-
3-yl)-N-methoxy-N,4-dimethylthiazole-2-carboxamide (8d)
DMF (0.7 ml) and DMF acetal (0.22 g, 0.25 ml, 1.88 mmol) were added
subsequently to a solution of N-methoxy-5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-
3-yl)-N,4-dimethylthiazole-2-carboxamide (8c, 0.70 g, 1.56 mmol) in ethyl acetate
(12 ml) at room temperature. The reaction mixture was then stirred at room
temperature for 15 hr under nitrogen atmosphere. The progress of the reaction was
monitored by TLC. The solid obtained was filtered and washed with ether (10 ml) to
obtain the title compound 8d (0.60 g, 76.33%).
MS: m/z 503 (M+l).
HNMR (DMSO-de, 400 MHz): 8.26 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.67 (d, J =
8.4 Hz, 2H), 7.60 (dd, J = 8.4, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.4
Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.48 (s, 3H), 3. 16 (s, 3H), 2.93 (s, 3H), 2.51 (s,
3H).
Step 5 : 2,-methoxy-5'-(4-methyl-2-propionylthiazol-5-yl)-[l,l'-biphenyl]-
sulfonamide (Compound 8)
Ethyl magnesium bromide (0.4 g , 2.98 ml, 2.98 mmol) was added drop wise to a
solution of 5-(4'-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[l, 1'-
biphenyl]-3-yl)-N-methoxy-N,4-dimethylthiazole-2-carboxamide (8d, 0.3 g, 0.56
mmol) in anhydrous THF (10 ml) under stirring at 25°C. The reaction mixture was
then heated at 70-75°C for 1 hour. The progress of the reaction was monitored by
TLC. The reaction mixture was cooled to 0°C and quenched by adding a saturated
solution of ammonium chloride (10 ml). The mixture was then extracted with ethyl
acetate (3 x 20 ml). The combined organic layer was dried over anhydrous Na2S04.
The solvent was evaporated from the dried organic layer under reduced pressure to
obtain a crude product. The crude product was then purified by column
chromatography using 30-35% ethyl acetate in hexane as an eluent to obtain the
title compound 8 (0.07 g, 28.1 1%).
MS: m/z 417 (M+l).
HNMR (DMSO-de, 400 MHz): 7.86 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H),
7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.40 (bs-exchanges with
D20 , 2H), 7.29 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.1 1 (q, J = 7.2 Hz, 2H), 2.54 (s,
3H), 1.12 (t, J = 7.2 Hz, 3H).
Example 4 : Preparation of 5'-(3,4-dimethyl-5-propionylthiophen-2-yl)-2'-
methoxy-[l,l'-biphenyl]-4-sulfonamide (Compound 9).
Step 1: Methyl 3,4-dimethylthiophene-2-carboxylate (9a)
Methyl boronic acid (0.94 g, 16.02 mmol), potassium phosphate (6.8 g, 32.04
mmol) and BINAP (1.33 g, 2.14 mmol) were added to a solution of methyl 3-bromo-
4-methylthiophene-2-carboxylate (Prepared according to the procedure reported in
Bioorganic Med. Chem. Lett., 2007, 15, 5, 2127-2146, 2.5 g, 10.68 mmol) in a
toluene (60 ml) in a tube at 25°C. Nitrogen gas was bubbled through reaction
mixture for 15 minutes. Palladium acetate (0.24 g, 1.07 mmol) was added to the
reaction mixture under nitrogen and the tube was sealed. The reaction mixture
was heated at 95-100°C for 20 hr under stirring. The progress of the reaction was
monitored by TLC. The reaction mixture was cooled to 25°C and filtered through
celite. The celite cake was washed with ethyl acetate (100 ml). The combined
filtrate was concentrated under reduced pressure to obtain residue, which was
dissolved in ethyl acetate (150 ml) and washed with water (2 x 30 ml). The
separated organic layer was dried over sodium sulphate and concentrated under
reduced pressure to obtain a crude product, which was purified by column
chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title
compound 9a (1.32 g, 73%).
HNMR (CDCI3, 400 MHz): 7.07 (s, 1H), 3.84 (s, 3H), 2.45 (s, 3H), 2. 16 (s, 3H).
Step 2 : Methyl 5-bromo-3,4-dimethylthiophene-2-carboxylate (9b)
Liquid bromine (1.88 g, 0.6 ml, 11.76 mmol) was added to a stirred solution of
methyl 3,4-dimethylthiophene-2-carboxylate (9a, 1.0 g, 5.88 mmol) in DCM (30
ml) at 0°C. The reaction mixture was stirred at 25°C for 3 hrs. The progress of the
reaction was monitored by TLC. The reaction mixture was then concentrated under
reduced pressure. The residue obtained after concentration was dissolved in DCM
(100 ml). The resulting mixture was washed with water (2 x 30 ml). The separated
organic layer was dried over a2S0 and concentrated under reduced pressure to
obtain a crude product. The crude product was then purified by column
chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title
compound 9b (0.81 g, 58.0%).
HNMR (CDC13, 400 MHz): 3.83 (s, 3H), 2.48 (s, 3H), 2.1 1 (s, 3H).
Step 3 : Methyl 5-(4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (9c)
(4-methoxyphenyl)boronic acid (0.56 g, 3.70 mmol) and potassium carbonate (1.40
g, 10.1 1 mmol) were added to a solution of methyl 5-bromo-3,4-
dimethylthiophene-2-carboxylate (9b, 0.8 g, 3.37 mmol) in a mixture of toluene:
ethanol (10:30 ml) in a tube at 25°C. Nitrogen gas was bubbled through reaction
mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0. 19 g, 0. 17
mmol) was added to the reaction mixture under nitrogen and the tube was sealed.
The reaction mixture was heated at 95-100°C for 2 hr under stirring. The progress
of the reaction was monitored by TLC. The reaction mixture was then cooled to
25°C and was filtered through celite. The celite cake was washed with ethyl acetate
(30ml). The combined filtrate was concentrated under reduced pressure to obtain a
crude product. The resulting crude product was further purified by column
chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title
compound 9c (0.84 g, 90%).
MS: / z 277 (M+l).
iHNMR (CDCI3, 400 MHz): 7.36 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 3.86
(s, 3H), 3.84 (s, 3H), 2.50 (s, 3H), 2.15 (s, 3H).
Step 4 : Methyl 5-(3-bromo-4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate
(9d)
Liquid bromine (0.58 g, 0. 19 ml, 3.60 mmol) was added to a solution of methyl 5-
(4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-3, 0.83 g, 3.00
mmol) in acetic acid (20 ml) under stirring at 25°C. The reaction mixture was then
stirred at 25°C for 3 hrs. The progress of the reaction was monitored by TLC. The
reaction mixture was concentrated under reduced pressure. The residue was
dissolved in ethyl acetate (100 ml). The resulting mixture was washed with
saturated sodium bicarbonate solution (30 ml). The separated organic layer was
concentrated under reduced pressure to obtain a crude product. The crude product
obtained was purified by flash column chromatography using 5% ethyl acetate in
hexanes as an eluent to obtain the title compound 9d (0.91 g, 83.0%).
MS: m/z 356 (M+l).
HNMR (CDCI3, 400 MHz): 7.65 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H),
6.96 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.52 (s, 3H), 2.18 (s, 3H).
Step 5 : Methyl 5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-3,4-
dimethylthiophene-2-carboxylate (9e)
4-aminosulfonylbenzene boronic acid (0.54 g, 2.68 mmol) and potassium carbonate
(0.67 g, 4.86 mmol) were added to the solution of methyl 5-(3-bromo-4-
methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-4, 0.9 g, 2.43 mmol) in
a mixture of toluene: ethanol (5:20 ml) in a tube at 25°C. Nitrogen gas was bubbled
through reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)
palladium (0.14 g, 0.12 mmol) was added to the reaction mixture under nitrogen
atmosphere and tube was sealed. The reaction mixture was heated at 95-100°C for
lhr under stirring. The progress of the reaction was monitored by TLC. The
reaction mixture was cooled to 25°C and filtered through celite. The celite cake was
washed with ethyl acetate (30 ml). The combined filtrate was concentrated under
reduced pressure to obtain a crude product. The crude product so obtained was
purified by column chromatography using 40% ethyl acetate in hexanes as an
eluent to obtain the title compound 9e (0.23 g, 21.2%).
MS: m/z 432 (M+l).
Step 6: 5-(6-methoxy-4' -sulfamoyl- [1,1 '-biphenyl] -3-yl)-3,4-dimethylthiophene- 2-
carboxylic acid (9f)
Methyl 5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-3,4-dimethylthiophene-2-
carboxylate (step-5, 0.2 g , 0.45 mmol) was suspended in ethanol (10 ml). Aqueous
solution of NaOH (0.09 g. 2.24 mmol in water 2 ml) was added to the reaction
mixture at 0°C. The reaction mixture was heated at 80°C under stirring for 1.5
hour. The progress of the reaction was monitored by TLC. The reaction mixture
was then concentrated under reduced pressure. Dilute hydrochloric acid was
added to the separated aqueous layer to bring the pH of the solution to between 6
and 7. The resulting mixture was extracted with ethyl acetate (2 x 25 ml). The
combined organic layer was dried over anhydrous Na2S04. The solvent was
evaporated from the dried organic layer under reduced pressure to obtain the title
compound 9f (0.17 g, 86.0%).
MS: m/z 418 (M+l).
HNMR (DMSO-de, 400 MHz): 12.70 (bs-exchanges with D20 , 1H), 7.75 (d, J = 8.0
Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.50-7.62 (m, 4H), 7.26 (d, J = 8.8 Hz, 1H), 3.83
(s, 3H), 2.45 (s, 3H), 2.17 (s, 3H).
Step 7 : 5-(4'-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[ 1,1'-biphenyl]-
3-yl)-N-methoxy-N,3,4-trimethylthiophene-2-carboxamide (9g)
Oxalyl chloride (0.09 g, 0.06 ml, 0.72 mmol) was added drop wise to a solution of
5-(6-methoxy-4 ,-sulfamoyl-[l,l'-biphenyl]-3-yl)-3,4-dimethylthiophene-2-carboxylic
acid (9f, 0.16 g, 0.36 mmol) in dichloromethane (10 ml) and DMF (0.05 g, 0.06 ml,
0.72 mmol) at 0°C. The reaction mixture was allowed to come to room temperature
and stirred for 1.5 hr under nitrogen atmosphere. The progress of the reaction was
monitored by TLC. The reaction mixture was then concentrated under reduced
pressure. The residue so obtained was dissolved in dry dichloromethane (10 ml)
and to this was added triethylamine (0.18 g, 0.25 ml, 1.79 mmol) followed by the
addition of ,-dimethylhydroxylamine hydrochloride (0.07 g, 0.72 mmol) under
stirring. The reaction mixture was then stirred at room temperature for 2 hours.
The progress of the reaction was monitored by TLC. Dichloromethane (10 mL) was
added to the reaction mixture. The resultant mixture was washed with water (2 x
10 ml) . The separated organic layer was dried over anhydrous sodium sulphate and
concentrated at reduced pressure to get a crude product. The crude product so
obtained was purified by column chromatography using 30% ethyl acetate in
hexane as an eluent to obtain the title compound 9g (0. 12 g, 65%).
MS: m/z 516 (M+l).
HNMR (CDCI3, 400 MHz): 8.18 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4
Hz, 2H), 7.44 (dd, J = 8.4, 2.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.4 Hz,
1H), 3.86 (s, 3H), 3.71 (s, 3H), 3.41 (s, 3H), 3.15 (s, 3H), 3.04 (s, 3H), 2.47 (s, 3H),
2.19 (s, 3H).
Step 8 : 5'-(3,4-dimethyl-5-propionylthiophen-2-yl)-2'-methoxy-[l,l'-biphenyl]-4-
sulfonamide (Compound 9)
Ethyl magnesium bromide (0.14 g , 1.1 ml, 1.06 mmol) was added drop wise to a
solution of 5-(4'-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[l, -
biphenyl]-3-yl)-N-methoxy-N,3,4-trimethylthiophene-2-carboxamide (Step 7, 0.11
g, 0.21 mmol) in anhydrous THF (10 ml) at 25°C under stirring. The reaction
mixture was then heated to 70-75°C for 1 hour. The progress of the reaction was
monitored by TLC. The reaction mixture was then cooled to 0°C. The cooled
reaction mixture was then quenched with a saturated solution of ammonium
chloride (10 ml). The resultant mixture was then extracted with ethyl acetate (3 x
20 ml). The combined organic layer was dried over anhydrous a S0 . The solvent
was evaporated from the organic layer under reduced pressure to obtain a crude
product, which was then purified by column chromatography using 35% ethyl
acetate in hexane as an eluent to obtain the title compound 9 (0.03 g, 33.0%).
MS: m/z 430 (M+l).
HNMR (CDCI3, 400 MHz): 7.97 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.39-
7.47 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 4.90 (bs-exchanges with D20 , 2H), 3.87 (s,
3H), 2.86 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.20 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).
Example 5 : Preparation of 5'-(l,3-dimethyl-5-propionyl-lH-pyrrol-2-yl)-2'-
methoxy-[l,l'-biphenyl]-4-sulfonamide (Compound 10)
Step 1: Methyl 5-(3-bromo-4-methoxyphenyl)-l,4-dimethyl-lH-pyrrole
carboxylate (10a)
A solution of methyl 5-(3-bromo-4-methoxyphenyl)-4-methyl-lH-pyrrole-2-
carboxylate (prepared according to the procedure reported in J . Org. Chem., 2009,
74(2), 903-905, Org. Lett, 2007, Vol. 9, 25, 5191-5194, 1.40 g, 4.32 mmol) in DMF
(3 ml) was added to a solution of sodium hydride (0.21 g 60% in paraffin oil , 4.75
mmol) in DMF (2 ml) at 0°C under stirring. Methyl iodide (0.67 g, 0.29 ml, 4.75
mmol) was then added to the reaction mixture. The reaction mixture was stirred at
room temperature for 45 minutes. The progress of the reaction was monitored by
TLC. The reaction mixture was quenched with water (5 ml)and then extracted with
ethyl acetate (2 x 50 ml). The combined organic layer was dried over anhydrous
Na2S04. The solvent was evaporated from the dried organic layer under reduced
pressure to obtain a crude product. The crude product was further purified by
flash column chromatography using 20% ethyl acetate in hexanes as an eluent to
obtain the title compound 10a (1.25 g, 85%).
MS: m/z 338 (M+l).
HNMR (CDCI3, 400 MHz): 7.49 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H),
6.99 (d, J = 2.0 Hz, 1H), 6.85 (s, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 1.94 (s,
3H).
Step 2 : Methyl 5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-l,4-dimethyl-lHpyrrole-
2-carboxylate (10b)
4-aminosulfonylbenzene boronic acid (0.72 g, 3.57 mmol) and potassium carbonate
(0.89 g, 6.50 mmol) were added to a solution of methyl 5-(3-bromo-4-
methoxyphenyl)-l,4-dimethyl-lH-pyrrole-2-carboxylate (10a, 1.1 g, 3.25 mmol) in
a mixture of toluene: ethanol (5:15 ml) in a tube at 25°C. Nitrogen gas was bubbled
through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)
palladium (0.18 g, 0.16 mmol) was then added to the reaction mixture under
nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at
95-100°C for lhr under stirring. The progress of the reaction was monitored by
TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The
celite cake was washed with 10% methanol in DCM (30 ml). The combined filtrate
was concentrated under reduced pressure to obtain a crude product, which was
then purified by column chromatography using 40% ethyl acetate in hexanes as an
eluent to obtain the title compound 10b (0.84 g, 62.6%).
MS: m/z 415 (M+l).
HNMR (CDCI3, 400 MHz): 7.97 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.30
(dd, J = 8.4, 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.87 (s,
1H), 4.89 (bs-exchanges with D20 , 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H), 2.01
(s, 3H).
Step 3 : 5-(6-methoxy-4'-sulfamoyl-[l ,1'-biphenyl]-3-yl)- 1,4-dimethyl- lH-pyrrole-2-
carboxylic acid 10c
Methyl 5-(6-methoxy-4'-sulfamoyl- [1,1 '-biphenyl] -3-yl)- 1,4-dimethyl- 1H-pyrrole-2-
carboxylate (step-2, 0.77 g , 1.85 mmol) was suspended in ethanol (15 ml), to this
was then added aqueous solution of NaOH (0.37 g. 9.29 mmol in 5 ml water) at
0°C. The reaction mixture was stirred at 25°C for 15 hours. The progress of the
reaction was monitored by TLC. The reaction mixture was concentrated under
reduced pressure. The residue obtained after concentration was then dissolved in
water (10 ml) and dilute hydrochloric acid was added to the mixture so obtained to
bring the pH of the mixture to between 6 and 7. The mixture was then extracted
with ethyl acetate (2 x 50 ml). The separated combined organic layer was then
dried over anhydrous sodium sulfate. The solvent was evaporated from the dried
organic layer under reduced pressure to obtain the title compound 10c (0.71 g,
95.9%).
MS: m/z 401 (M+l).
HNMR (DMSO-de, 400 MHz): 12.05 (bs-exchanges with D20 , 1H), 7.85 (d, J = 8.4
Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.38-7.41 (m, 3H), 7.26-7.30 (m, 2H), 6.76 (s,
1H), 3.85 (s, 3H), 3.70 (s, 3H), 1.96 (s, 3H).
Step 4 : N-methoxy-5-(6-methoxy-4'-sulfamoyl-[l,l'-biphenyl]-3-yl)-N,l,4-trimethyllH-
pyrrole-2-carboxamide (lOd).
HOBT (0.29 g, 1.92 mmol) was added to a solution of 5-(6-methoxy-4'-sulfamoyl-
[l, l'-biphenyl]-3-yl)-l,4-dimethyl-lH-pyrrole-2-carboxylic acid (10c, 0.70 g, 1.75
mmol) in DMF (15 ml) under stirring at room temperature. ,-
dimethylhydroxylamine hydrochloride (0.33 g, 3.5 mmol) was then added to the
reaction mixture. The reaction mixture was cooled to 0°C and EDC (0.50 g, 2.60
mmol) and triethylamine (0.70 g, 0.97 ml, 7.00 mmol) were added to it. The
reaction mixture was stirred at room temperature for 15 hours. The progress of the
reaction was monitored by TLC. The reaction mixture was concentrated under
reduced pressure. The residue obtained after concentration was mixed with ethyl
acetate (50 ml) and the resultant mixture was washed with saturated sodium
bicarbonate solution (10 ml) followed by washing with brine (10 ml). The organic
layer separated was dried over anhydrous sodium sulphate and concentrated
under reduced pressure to obtain a crude product. The crude product was further
purified by flash column chromatography using 4% methanol in DCM as an eluent
to obtain the title compound lOd (0.67 g, 87%).
MS: m/z 444 (M+l).
HNMR (CDCI3, 400 MHz): 7.96 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.32
(dd, J = 8.4, 2.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 (s,
1H), 5.13 (bs-exchanges with D20 , 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 3.35
(s, 3H), 2.03 (s, 3H).
Step 5 : 5-(4'-(N-((dimethylamino)methylene)sulfamo
3-yl)-N-methoxy-N,l,4-trimethyl-lH-pyrrole-2-carboxamide (lOe)
DMF (0.65 ml) and DMF acetal (0.19 g, 0.21 ml, 1.61 mmol) were added to a
solution of N-methoxy-5-(6-methoxy-4'-sulfamoyl-[l ,1'-biphenyl]-3-yl)-N, 1,4-
trimethyl-lH-pyrrole-2-carboxamide (lOd, 0.65 g, 1.46 mmol) in ethyl acetate (13
ml) under stirring at room temperature. The mixture was stirred at room
temperature for 15 hr under nitrogen atmosphere. The progress of the reaction was
monitored by TLC. The reaction mixture was diluted with ethyl acetate (50 ml) and
the mixture so obtained was washed with water (2 x 20 ml). The organic layer
separated was dried over a2S0 and concentrated to obtain a crude product. The
crude product was purified by flash column chromatography using 4% methanol in
DCM as an eluent to obtain the title compound lOe (0.62 g, 84.9%).
MS: m/z 499 (M+l).
iHNMR (CDCI3, 400 MHz): 8.16 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4
Hz, 2H), 7.30 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz,
IH), 6.78 (s, IH), 3.87 (s, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 3.34 (s, 3H), 3.14 (s, 3H),
3.04 (s, 3H), 2.03 (s, 3H).
Step 6 : 5'-( 1,3-dimethyl-5-propionyl- lH-pyrrol-2-yl)-2'-methoxy-[ 1,1'-biphenyl]-4-
sulfonamide (Compound 10).
Ethyl magnesium bromide (0.53 g , 3.96 ml, 3.98 mmol) was added drop wise to a
solution of 5-(4'-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[l, 1'-
biphenyl]-3-yl)-N-methoxy-N,l,4-trimethyl-lH-pyrrole-2-carboxamide (Step 5, 0.4 g
, 0.80 mmol) in anhydrous THF (10 ml) under stirring at 25°C. The reaction
mixture was heated at 70-75°C for 1 hour. The progress of the reaction was
monitored by TLC. The reaction mixture was then cooled to 0°C and was quenched
by addition of saturated solution of ammonium chloride (10 ml). The resulting
mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic layer
was dried over anhydrous Na2S04. The solvent was evaporated from the dried
organic layer under reduced pressure to obtain a crude product, which was then
purified by column chromatography using mixture of ethyl acetate and hexane as
an eluent to obtain the title compound 10 (0.04 g, 12.12%).
MS: m/z 413 (M+l).
HNMR (CDC13, 400 MHz): 7.98 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.32
(dd, J = 8.4, 2.4 Hz, IH), 7.25 (d, J = 2.4 Hz, IH), 7.1 1 (d, J = 8.4 Hz, IH), 6.91 (s,
IH), 4.87 (bs-exchanges with D20 , 2H), 3.90 (s, 3H), 3.80 (s, 3H), 2.83 (q, J = 7.2
Hz, 2H), 2.05 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).
Example 19: Pharmacological screening
Compounds were tested in a cell-based real-time kinetic assay in human IMR-32
cells with native expression of a7nAChR. The increase in intracellular Ca2+ levels
was measured in a Fluorometric Imaging Plate Reader (FLIPR). Test compound and
agonist solutions were made in assay buffer (HBSS, pH 7.4, 20 mM HEPES, and 10
mM CaCLJ. Briefly, cells were plated into Poly-D-Lysine coated back- walled clearbottom
96-well microplates at a density of 80,000 to 100,000 cells/well and
incubated at 37°C/5% CO2 for 40-48 h prior to the experiment. For evaluation of
compound mediated potentiation of agonist response, growth media was removed
from the wells and 200 ul of FLIPR calcium 4 dye (Molecular Devices) , reconstituted
in assay buffer, and was added to the wells. After dye loading, microplates were
incubated for 30 min at 37°C and 30 min at room temperature and then directly
transferred to the FLIPR. Baseline fluorescence was monitored for the first 10 to 30
s followed by the addition of 25 ul of test compound solution and subsequent
monitoring of fluorescence changes for up to 10 min. This was followed by addition
of 25 ul of agonist solution (PNU-282987, 10 uM) and measurement of fluorescence
for 4 min. (Faghih R. et al. 2009, J . Med. Chem., 52, 3377 - 84.)
The compound induced fold increase in agonist response (fold PAM activity) was
computed by dividing the maximum effect (Max-Min fluorescence) obtained with
test compound in presence of agonist with the agonist-alone effect. EC50 of the
compound was calculated using GraphPad Prism software version 5.0, by plotting
compound concentrations against fold PAM activity.
Fold activity at luM concentration: Compounds of invention showed increase in the
activity upto 30 folds compared to control.
CLAIMS
1. A compound of formula (I), its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
wherein,
'D' is selected from N and CR5;
Έ ' is selected from S and NR6;
with a proviso that when Έ ' is NR6, 'D' is not selected as N;
R1 is selected from hydrogen or substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, halogen, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocyclyl, cyano,
nitro, (R7)(R )N-, R7 C(=0)N(R )-, (R7 )(R8)NC(=A )N(R )-, R7 OC(=0 R a- ,
R7 S0 2N(R )-, R7A - , (R7 )(R8)NC(=0)-, and R7 S (0 p- , wherein 'p' is an integer
ranging from 1 to 2 ;
R2 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- hererocyclyl, (R7)(R8)N-, (R )N(OR¾)-, and R7A - ;
R3 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, (R7 )(R )NC(=0)-,
R7 A - , (R7 )C(=0)N(R )-, (R7a)(R8 )N-, (R7a)(R8 )NC(=A )N(R9)-,
(R7a)(R a)NC(=0)0-, R7 OC(=0)N(R a)-, R7bS(0)p- , wherein 'p' is an integer
ranging from 1 to 2 , and two R3s and the carbon atoms to which they are
attached can combine to form an substituted- or unsubstituted- 5 to 8
member cyclic system which may contain 1 to 3 heteroatoms/groups selected
from -NH-, -S-, -0-, -C(=0)-, and -C(=S)-;
'n' is selected from 0 , 1, 2 and 3 ;
R4 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, (R a)(R a)NC(=0)-,
R7aA - , (R7 )C(=0)N(R a)-, (R7a)(R a)N-, and two R4s and the carbon atoms to
which they are attached can combine to form a substituted- or unsubstituted-
5 to 8 membered cyclic system which may contain 1 to 3 heteroatoms/groups
such as -NH-, -S-, -0-, -C(=0)-, and -C(=S)-;
'm' is selected from 0 , 1, 2 and 3 ;
R5 is selected from hydrogen, halogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedheterocyclyl,
(R7)(R )N-, and R7cC(=0)-;
R6 is selected from hydrogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- cycloalkyl, and R C(=0)-;
R7 and R8 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and
substituted- or unsubstituted- heterocyclyl;
R a , R a, and R9 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R7b is selected from substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R7 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;
the substituents on 'alkyl' and 'alkenyl' are selected from the group consisting
of oxo, halogen, nitro, cyano, perhaloalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, R °bA - , R °aS0 2- , R10aOC(=O)-, R 0 C(=O)O-,
R 0N(H)C(=O)-, R 0N(alkyl)C(=O)- , R 0aC(=O)N(H)-, R 0N(H)-, R 0N(alkyl)-,
R °N(H)C(=A )N(H)-, and R °N(alkyl)C(=A )N(H)-;
the substituents on 'cycloalkyl' and 'cycloalkenyl' are selected from the group
consisting of oxo, halogen, nitro, cyano, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, perhaloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, R^A - , R 0aSO2- , R10aC(=O)-, R10aOC(=O)-,
R
ioac(=0)0-, R 0(H)NC(=O)-, R N(alkyl)C(=O)-, R C(=O)N(H)-, R o(H)N-,
R 0 (alkyl)N-, R 0(H)NC(=A )N(H)-, and R 0(alkyl)NC(=A )N(H)-;
the substituents on 'aryl' are selected from the group consisting of halogen,
nitro, cyano, hydroxy, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, perhaloalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, substituted- or unsubstitutedheterocycle,
alkyl-O-, perhaloalkyl-O-, alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-
SO2-, perhaloalkyl-SCb-, alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-,
alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-, H2NC(=0)-, alkyl(alkyl)NS02- ,
alkyl(H)NS02- , and H2NS0 2- ;
the substituents on 'heteroaryl' are selected from the group consisting of
halogen, nitro, cyano, hydroxy, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- heterocycle, alkyl-O-, perhaloalkyl-O-,
alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-
C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-,
H2NC(=0)-, alkyl(alkyl)NS02- , alkyl(H)NS02- , and H2NS02- ;
the substituents on ring carbon of 'heterocycle' is selected from the group
consisting of halogen, nitro, cyano, oxo, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- heterocyclyl, substituted- or unsubstitutedalkyl,
R^A - , - R 10aOC(=O)-, R 0aC(=O)O-, R 0(H)NC(=O)-, R N(alkyl)C(=O)-,
and
R (alkyl)NC(=A )N(H)-;
the substituents on ring nitrogen of 'heterocycle' is selected from the group
consisting of substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl, R 10aSO2- , R 10aC(=O)-,
R
ioaoc(=0)-, R 0(H)NC(=O)-, and R N(alkyl)C(=O)-;
the "5 to 8 membered cyclic system" is substituted with 1 to 3 substituents
selected from the group consisting of halogen, nitro, cyano, aryl, hereroaryl,
alkyl, alkenyl, alkynyl, R °aC (=0)-, R 10aSO2- , R °bA - , R °aOC (=0)-, R 10aC(=O)O-,
(R 0)(H)NC(=O)-, (R 10)(alkyl)NC(=O)-, R 0aC(=O)N(H)-, (R 0)(H)N-, (R 0)(alkyl)N-,
(R ) (H)NC(=A )N(H)-, and (R )(alkyl)NC(=A )N(H)-;
R 10 is selected from the group consisting of hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
R i oa
S selected from the group consisting of alkyl, alkenyl, perhaloalkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
R i ob s selected from the group consisting of hydrogen, alkyl, alkenyl,
perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
A1 is selected from S and O.
2 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in claim 1, wherein D is selected from the group consisting of -
CH=, -C(alkyl)=, and -N=.
3 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1 or 2, wherein E is selected from -S- and -
N(alkyl)-.
4 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1-3, wherein R1 is selected as substituted- or
unsubstituted- alkyl.
5 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1-4, wherein R2 is selected from substitutedor
unsubstituted- alkyl and substituted- or unsubstituted- heterocyclyl.
6 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1-5, wherein R3 is selected from halogen,
R7aA-, and (R7a)(R a)N-; and p is preferably selected from 0 and 1.
7 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1-6, wherein m is selected as 0.
8 . The compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1-7, wherein D is selected from -CH=, -
C(alkyl)=, and -N=;
E is selected from -S- and -N(alkyl)-;
R1 is selected as substituted- or unsubstituted- alkyl;
R2 is selected from substituted- or unsubstituted- alkyl and substituted- or
unsubstituted- heterocyclyl;
R is selected from halogen, R aA-, and (R7a)(R a)N-;
p is selected from 0 and 1; and m is selected as 0.
9 . The compound of formula (I), its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
as claimed in any one of claims 1-8, wherein the compound is selected from-
2'-Methoxy-5'-(3-methyl-5-propionylthiophen-2-yl)-[l,l'-biphenyl]-4-
sulfonamide;
2'-chloro-5'-(3-methyl-5-propionylthiophen-2-yl)-[ 1,1'-biphenyl]-4-
sulfonamide;
3'-(3-methyl-5-propionylthiophen-2-yl)-[ 1,1'-biphenyl]-4-sulfonamide;
2,-(dimethylamino)-5'-(3-methyl-5-propionylthiophen-2-yl)-[l,l'-biphenyl]-4-
sulfonamide;
2'-methoxy-5'-(4-methyl-2-(piperidine-l-carbonyl)thiazol-5-yl)-[l, l'-biphenyl]-
4-sulfonamide;
2'-methoxy-5'-(4-methyl-2-(pyrrolidine-l-carbonyl)thiazol-5-yl)-[l, l'-biphenyl]-
4-sulfonamide;
2,-chloro-5'-(4-methyl-2-(pyrrolidine-l-carbonyl)thiazol-5-yl)-[l,l'-biphenyl]-4-
sulfonamide;
2'-methoxy-5'-(4-methyl-2-propionylthiazol-5-yl)-[ 1,1'-biphenyl]-4-
sulfonamide;
5'-(3,4-dimethyl-5-propionylthiophen-2-yl)-2'-methoxy-[l,l'-biphenyl]-4-
sulfonamide;
5'-(l ,3-dimethyl-5-propionyl- lH-pyrrol-2-yl)-2'-methoxy-[l ,l'-biphenyl]-4-
sulfonamide (Compound 10).
10. A pharmaceutical composition comprising a compound of any one claims 1-9
and a pharmaceutically acceptable carrier.
11. A method of preventing or treating a disease or its symptoms or a disorder
mediated partially or completely by nicotinic acetylcholine receptors, said
method comprising administering to a subject having or susceptible to said
disease or its symptoms or disorder with a therapeutically effective amount of
a compound of any one of claims 1-9.
12. A method of treating a disease or disorder or condition mediated partially or
completely by nicotinic acetylcholine receptors in a subject in need thereof,
comprising administering to the subject a therapeutically effective amount of
a compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
wherein,
'D' is selected from N and CR5;
Έ ' is selected from S and NR6;
with a proviso that when Έ ' is NR6, 'D' is not selected as N;
R1 is selected from hydrogen or substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, halogen, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocyclyl, cyano,
nitro, (R7)(R )N-, R7 C(=0)N(R )-, (R7a)(R8)NC(=A )N(R )-, R OC(=0 R - ,
R7 S0 2N(R )-, R7A - , (R7 )(R8)NC(=0)-, and R7 S (0 p- , wherein 'p' is an integer
ranging from 1 to 2 ;
R2 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- hererocyclyl, (R7)(R )N-, (R7)N(OR )-, and R7A - ;
R3 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, (R a)(R a)NC(=0)-,
R aA - ,
(R7 )(R )NC(=0)0-, R7bOC(=0)N(R a)-, R7bS(0)P- , wherein 'p' is an integer
ranging from 1 to 2, and two R3s and the carbon atoms to which they are
attached can combine to form an substituted- or unsubstituted- 5 to 8
member cyclic system which may contain 1 to 3 heteroatoms/groups selected
from -NH-, -S-, -0-, -C(=0)-, and -C(=S)-;
'n' is selected from 0, 1, 2 and 3 ;
R4 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, (R a)(R a)NC(=0)-,
R aA - , (R )C(=0)N(R a)-, (R a)(R a)N-, and two R4s and the carbon atoms to
which they are attached can combine to form a substituted- or unsubstituted-
5 to 8 membered cyclic system which may contain 1 to 3 heteroatoms/groups
such as -NH-, -S-, -0-, -C(=0)-, and -C(=S)-;
'm' is selected from 0, 1, 2 and 3 ;
R5 is selected from hydrogen, halogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedheterocyclyl,
(R7)(R )N-, and R7 C(=0)-;
R6 is selected from hydrogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- cycloalkyl, and R C(=0)-;
R7 and R8 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and
substituted- or unsubstituted- heterocyclyl;
R a , R a, and R9 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R7b is selected from substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;
the substituents on 'alkyl' and 'alkenyl' are selected from the group consisting
of oxo, halogen, nitro, cyano, perhaloalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, R^A - , R 0 SO2- , R10aOC(=O)-, R10aC(=O)O-,
R °N(H)C(=0)-, R 0N(alkyl)C(=O)- , R aC(=O)N(H)-, RioN(H)-, R oN(alkyl)-,
R 0N(H)C(=A )N(H)-, and R 0N(alkyl)C(=A )N(H)-;
the substituents on 'cycloalkyl' and 'cycloalkenyl' are selected from the group
consisting of oxo, halogen, nitro, cyano, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, perhaloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, R °bA - , R °aS0 2- , R10aC(=O)-, R10aOC(=O)-,
R
i0a C (=O)O-, R 0(H)NC(=O)-, R N(alkyl)C(=O)-, R C(=O)N(H)-, Rio(H)N-,
Rio(alkyl)N-,
the substituents on 'aryl' are selected from the group consisting of halogen,
nitro, cyano, hydroxy, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, perhaloalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, substituted- or unsubstitutedheterocycle,
alkyl-O-, perhaloalkyl-O-, alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-
SO2-, perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-,
alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-, H2NC(=0)-, alkyl(alkyl)NS0 2- ,
alkyl(H)NS02- , and H2NS0 2- ;
the substituents on 'heteroaryl' are selected from the group consisting of
halogen, nitro, cyano, hydroxy, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- heterocycle, alkyl-O-, perhaloalkyl-O-,
alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-
C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-,
H2NC(=0)-, alkyl(alkyl)NS0 2- , alkyl(H)NS02- , and H2NS0 2- ;
the substituents on ring carbon of 'heterocycle' is selected from the group
consisting of halogen, nitro, cyano, oxo, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- heterocyclyl, substituted- or unsubstitutedalkyl,
R^A - , - R 10aOC(=O)-, R 0aC(=O)O-, R 0(H)NC(=O)-, R N(alkyl)C(=O)-,
R
ioaC (=0)N(H)-, R o(H)N-, R (alkyl)N-, R o(H)NC(=A )N(H)-, and
R (alkyl)NC(=A )N(H)-;
the substituents on ring nitrogen of 'heterocycle' is selected from the group
consisting of substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl, R 10aSO2- , R 10aC(=O)-,
R
ioaoc(=0)-, R 0(H)NC(=O)-, and R N(alkyl)C(=O)-;
the "5 to 8 membered cyclic system" is substituted with 1 to 3 substituents
selected from the group consisting of halogen, nitro, cyano, aryl, hereroaryl,
alkyl, alkenyl, alkynyl, R °aC(=0)-, R10aSO2-, R10bA - , R °aOC(=0)-, R 0 C(=O)O-,
(R )(H)N-, (R )(alkyl)N-,
(R )(H)NC(=A )N(H)-, and (R )(alkyl)NC(=A )N(H)-;
R10 is selected from the group consisting of hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
Rioa
S selected from the group consisting of alkyl, alkenyl, perhaloalkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
R10b is selected from the group consisting of hydrogen, alkyl, alkenyl,
perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
A1 is selected from S and O.
13. The method of claim 12, wherein the disorder or condition or disease is
selected from the group consisting of Alzheimer's disease, mild cognitive
impairment, senile dementia, vascular dementia, dementia of Parkinson's
disease, attention deficit disorder, attention deficit hyperactivity disorder,
dementia associated with Lewy bodies, AIDS dementia complex, Pick's
disease, dementia associated with Down's syndrome, Huntington's disease,
cognitive deficits associated with traumatic brain injury, cognitive decline
associated with stroke, poststroke neuroprotection, cognitive and
sensorimotor gating deficits associated with schizophrenia, cognitive deficits
associated with bipolar disorder, cognitive impairments associated with
depression, acute pain, post-surgical or post-operative pain, chronic pain,
inflammation, inflammatory pain, neuropathic pain, smoking cessation, need
for new blood vessel growth associated with wound healing, need for new
blood vessel growth associated with vascularization of skin grafts, and lack of
circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease,
ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease,
periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute
immune disease associated with organ transplantation, chronic immune
disease associated with organ transplantation, septic shock, toxic shock
syndrome, sepsis syndrome, depression, and rheumatoid spondylitis.
14. The method of claim 12, wherein the disease or disorder or condition is
selected from the group classified or diagnosed as major or minor
neurocognitive disorders, or disorders arising due to neurodegeneration.
15. The method of claim 12, comprising administering a compound of formula I in
combination with or as adjunct to medications utilized in the treatment of
attention deficit hyperactivity disorders, schizophrenia, cognitive disorders
such as Alzheimer's disease, Parkinson's dementia, vascular dementia or
dementia associated with Lewy bodies, or traumatic brain injury.
16. The method of claim 12, further comprising administering a compound of
formula I in combination with or as an adjunct to acetylcholinesterase
inhibitors, disease modifying drugs or biologies for neurodegenerative
disorders, dopaminergic drugs, antidepressants, or a typical or an atypical
antipsychotic.
17. Use of a compound of claim 1 for preventing or treating a disease or its
symptoms or a disorder mediated partially or completely by nicotinic
acetylcholine receptors.
18. Use of a compound of formula I, its tautomeric forms, its stereoisomers, its
analogues, its prodrugs, its isotopically substituted analogues, its metabolites,
its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its
polymorphs, its solvates, its optical isomers, its clathrates or its co-crystals,
for treating a disease or disorder or condition,
wherein,
'D' is selected from N and CR5;
Έ ' is selected from S and NR6 ;
with a proviso that when Έ ' is NR6 , 'D' is not selected as N;
R 1 is selected from hydrogen or substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, halogen, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocyclyl, cyano,
nitro, (R7)(R )N-, R7 C (=0)N(R )-, (R7a)(R8)NC(=A )N(R )-, R7bOC (=0 R a- ,
R7 S 0 2N(R )-, R7A - , (R7 )(R8)NC(=0)-, and R7bS (0 p- , wherein 'p' is an integer
ranging from 1 to 2 ;
R2 is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- hererocyclyl, (R7)(R )N-, (R7)N(OR7 )-, and R7A1- ;
R3 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, (R7 )(R )NC(=0)-,
(R7a)(R8a)NC(=0)0-, R7 OC (=0)N(R a)-, R7bS (0)p-, wherein 'p' is an integer
ranging from 1 to 2, and two R3s and the carbon atoms to which they are
attached can combine to form an substituted- or unsubstituted- 5 to 8
member cyclic system which may contain 1 to 3 heteroatoms/groups selected
from -NH-, -S-, -0-, -C(=0)-, and -C(=S)-;
'n' is selected from 0, 1, 2 and 3 ;
R4 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedcycloalkyl,
substituted- or unsubstituted- heterocyclyl, (R7a)(R a)NC(=0)-,
R7aA - , (R7 )C(=0)N(R a)-, (R7a)(R a)N-, and two R4s and the carbon atoms to
which they are attached can combine to form a substituted- or unsubstituted-
5 to 8 membered cyclic system which may contain 1 to 3 heteroatoms/groups
such as -NH-, -S-, -0-, -C(=0)-, and -C(=S)-;
'm' is selected from 0, 1, 2 and 3 ;
R5 is selected from hydrogen, halogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, substituted- or unsubstitutedheterocyclyl,
(R7)(R )N-, and R7 C(=0)-;
R6 is selected from hydrogen, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- cycloalkyl, and R C(=0)-;
R7 and R8 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or
unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and
substituted- or unsubstituted- heterocyclyl;
R a , R a, and R9 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
R b is selected from substituted- or unsubstituted- alkyl, and substituted- or
unsubstituted- cycloalkyl;
R is selected from substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or
unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;
the substituents on 'alkyl' and 'alkenyl' are selected from the group consisting
of oxo, halogen, nitro, cyano, perhaloalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, R °bA - , R °aS0 2- , R10aOC(=O)-, R 0 C(=O)O-,
R °N(H)C(=0)-, R 0N(alkyl)C(=O)- , R C(=O)N(H)-, R oN(H)-, R 0N(alkyl)-,
R °N(H)C(=A )N(H)-, and R °N(alkyl)C(=A )N(H)-;
the substituents on 'cycloalkyl' and 'cycloalkenyl' are selected from the group
consisting of oxo, halogen, nitro, cyano, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, perhaloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, R^A - , R 0aSO2- , R10aC(=O)-, R10aOC(=O)-,
R
ioac(=0)0-, R 0(H)NC(=O)-, R N(alkyl)C(=O)-, R C(=O)N(H)-, R o(H)N-,
R 0 (alkyl)N-, R 0(H)NC(=A )N(H)-, and R 0(alkyl)NC(=A )N(H)-;
the substituents on 'aryl' are selected from the group consisting of halogen,
nitro, cyano, hydroxy, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, perhaloalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, substituted- or unsubstitutedheterocycle,
alkyl-O-, perhaloalkyl-O-, alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-
SO2-, perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-,
alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-, H2NC(=0)-, alkyl(alkyl)NS0 2- ,
alkyl(H)NS02- , and H2NS0 2- ;
the substituents on 'heteroaryl' are selected from the group consisting of
halogen, nitro, cyano, hydroxy, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- heterocycle, alkyl-O-, perhaloalkyl-O-,
alkyl(alkyl)N-, alkyl(H)N-, H2N-, alkyl-S0 2- , perhaloalkyl-S0 2- , alkyl-
C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl(alkyl)NC(=0)-, alkyl(H)NC(=0)-,
H2NC(=0)-, alkyl(alkyl)NS0 2- , alkyl(H)NS02- , and H2NS0 2- ;
the substituents on ring carbon of 'heterocycle' is selected from the group
consisting of halogen, nitro, cyano, oxo, substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, perhaloalkyl, substituted- or
unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl,
substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- heterocyclyl, substituted- or unsubstitutedalkyl,
R A i - , - R aOC(=O)-, R 10aC(=O)O-, R 0 (H)NC(=O)-, R °N(a]_kyl)C(=0)-,
R
ioaC (=0)N(H)-, R o(H)N-, R (alkyl)N-, R °(H)NC(=A )N(H)-, and
R (alkyl)NC(=A )N(H)-;
the substituents on ring nitrogen of 'heterocycle' is selected from the group
consisting of substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl,
substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl, R 10aSO2-, R 10aC(=O)-,
R
ioaoc(=0)-, R 0 (H)NC(=O)-, and R °N(alkyl)C(=0)-;
the "5 to 8 membered cyclic system" is substituted with 1 to 3 substituents
selected from the group consisting of halogen, nitro, cyano, aryl, hereroaryl,
alkyl, alkenyl, alkynyl, R °aC (=0)-, R 10aSO2- , R 10bA - , R °aOC (=0)-, R 10aC(=O)O-,
(R ) (H)NC (=0)-, (R )(alkyl)NC(=0)-, R aC(=O)N(H)-, (R o)(H)N-, (R 0)(alkyl)N-,
(R ) (H)NC(=A )N(H)-, and R °)(alkyl)NC(=A )N(H)-;
R 10 is selected from the group consisting of hydrogen, alkyl, alkenyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
ioa
S selected from the group consisting of alkyl, alkenyl, perhaloalkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
iob s selected from the group consisting of hydrogen, alkyl, alkenyl,
perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
A 1 is selected from S and O.
19. The use as claimed in claim 18, wherein the disease or disorder or condition is
selected from the group classified or diagnosed as major or minor
neurocognitive disorders, or disorders arising due to neurodegeneration.
20. The use as claimed in claim 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 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.