PYRROLE DERIVATIVES AS NICOTINIC ACETYLCHOLINE RECEPTOR
MODULATORS FOR USE IN THE TREATMENT OF NEURODEGENERATIVE
DISORDERS SUCH AS ALZHEIMER'S AND PARKINSON'S DISEASE
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, polymorphs, solvates, optical isomers,
clathrates, co-crystals, combinations with suitable medicament, pharmaceutical
compositions containing them, methods of making of the above compounds,
and their use as nicotinic acetylcholine receptor o 7 subunit (o 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 (oc2-oclO, 2-4) arranged in
heteropentameric ( 4 2) or homopertameric (o 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. o 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 Met al., Eur. J . Pharmacol., 2000, 393,
59-67; Dajas-Bailador F et al., Trends Pharmacol. Sci., 2004, 25, 317-324).
Furthermore, high Ca2+ 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 o 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 o 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 o 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 o 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 o 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 TO et al.,
Curr. Opin. Psychiatry, 2005, 18, 135-140). A defective pre-attention processing
of sensory information is understood to b e 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 o 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 a s 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 o 7 receptor to - 2 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 o 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 o 4 , o 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 candidategene
approach to have strong mechanistic link for nicotine addiction (Weiss RB
et al., PLoS Genet., 2008, 4 , e l 000 125). 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 o 7 nAChR is the ability to modulate the production of
pro-inflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha
(TNF-oc), and high mobility group box (HMGB-1) in the central nervous system.
Consequently, an anti-inflammatory and antinociceptive effect in pain disorders
have been demonstrated (Damaj MI et al., Neuropharmacology, 2000, 39, 2785-
2791). Additionally, 'cholinergic anti-inflammatory pathway' is proposed to be a
regulatory of local and systemic inflammation and neuro-immune interactions
through neural and humoral pathways (Gallowitsch-Puerta M et al., Life Sci.,
2007, 80, 2325-2329; Gallowitsch-Puerta and Pavlov 2007; Rosas-Ballina M et
al., Mol. Med., 2009, 15, 195-202; Rosas-Ballina M et al., J . Intern. Med., 2009,
265, 663-679). Selective modulators of nicotinic ACh receptors, particularly o 7
type, like GTS-21, attenuate cytokine production and IL- after endotoxin
exposure. Furthermore, o 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 o 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 o 7 , o 5 , o 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 o 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-
2 1 (DMXB-Anabaseine), an o 7 nAChR agonist, in the P II clinical trials, has
shown efficacy in improving cognitive deficits in schizophrenia and inhibition of
endotoxin-induced TNF-oc 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 o 7 nAChR agonist, exhibits protection against the scopolamineinduced
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-180711A, also an 7 nAChR agonist, enhances learning and
memory, and protects against MK-80 1/Scopolamine- induced memory loss and
prepulse inhibition in preclinical studies (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 o 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 a7 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-vivo 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
US20060142349, US20070 142450, US20090253691, WO2007031440,
WO2009115547, WO2009 135944, WO2009 127678, WO2009 127679,
WO2009043780, WO2009043784, US7683084, US7741364, WO2009145996,
US20 100240707, WO20 1 1064288, US20 100222398, US20 100227869,
EP1866314, WO20 10 130768, WO201 1036167, US20100190819 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 , 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, its co-crystals, their combinations with suitable
medicament and pharmaceutical compositions containing them.
Thus the present invention further 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 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), Picks 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 definded
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 definded
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 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 , 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, its co-crystals, their combinations with suitable
medicament and pharmaceutical compositions containing them.
wherein,
R1 is selected from the group consisting of hydrogen, halogen, substituted- or
unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or
unsubstituted- alkynyl, perhaloalkyl, and substituted- or unsubstitutedcycloalkyl;
R2 is selected from the group consisting of substituted- or unsubstituted- alkyl,
(R6 )(R7)N-, (R6 )N(OR7 )-, and O -
R3 is selected from the group consisting of substituted- or unsubstituted- alkyl,
substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl,
substituted- or unsubstituted- cycloalkyl;
R4 is selected from the group consisting of substituted- or unsubstituted- aryl,
substituted- or unsubstituted- heteroaryl;
[R ]a is 'a' times repetition of 'R5' groups, each R5 is independently selected from
the group consisting of halo, substituted- or unsubstituted- alkyl, R 0-; 'a' is an
integer selected from 0, 1, and 2 ;
wherein, R6 and R7 are independently selected from hydrogen, substituted- or
unsubstituted- alkyl, R9C(=0)-, R S0 2- ; such that when R 2 is (R 6)(R7)N-, R6 and
R7 together with the nitrogen atom to which they are attached may form a 3 to
10 member substituted- or unsubstituted- heterocycle containing one to three
hetero atoms/groups selected from the group consisting of S, N, O the said
heterocycle may be saturated or unsaturated, monocyclic or bicyclic or spiro, or
the said heterocycle may contain an alkylene bridge;
R a is selected from hydrogen and substituted- or unsubstituted- alkyl;
R7a is selected as substituted- or unsubstituted- alkyl;
wherein R8 is selected from hydrogen, substituted- or unsubstituted- alkyl, and
perhaloalkyl;
wherein, R9 is independently selected from the group consisting of hydrogen,
substituted- or unsubstituted- alkyl, substituted- or unsubstituted- aryl,
substituted- or unsubstituted- heteroaryl, substituted- or unsubstitutedcycloalkyl,
and substituted- or unsubstituted- heterocyclyl;
wherein,
the "alkyl", "alkenyl", and "alkynyl" are substituted with 1 to 6 substituents
selected independently from the group consisting of oxo, halogen, nitro, cyano,
aryl, hereroaryl, cycloalkyl, R aSO2- , R^A 1- , R aOC(=O)-, R aC(=O)O-,
(R °)(H)NC(=0 )-, (R 0)(alkyl)NC(=O)-, R °aC(= 0)N(H)-, (R °)(H)N-, (R °)(alkyl)N-,
(R °)(H)NC(=A )N(H)-, and (Ri )(alkyl)NC(=A )N(H)-;
the "cycloalkyl" is substituted with 1 to 6 substituents selected independently
from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl,
alkenyl, alkynyl, R °aC(=0 )-, R aSO2- , R °A - , R aOC(=O)-, R aC(=O)O-,
(R 0)(H)NC(=O)-, (R )(alkyl)NC(=O)-, R °aC(= 0)N(H)-, (R °)(H)N-, R 0)(alkyl)N-,
(R 0)(H)NC(=A )N(H)-, and (R °)(alkyl)NC(=A )N(H)-;
the "aryl" is substituted with 1 to 3 substituents selected independently from
the group consisting of halogen, nitro, cyano, hydroxy, Ci to C alkyl, C2 to C
alkenyl, C2 to C alkynyl, C 3 to C cycloalkyl, 3- to 6- membered heterocycle, Ci
to C 6 perhaloalkyl, alkyl-O-, alkenyl-O-, 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)S0 2- , alkyl-N(H)S02- , H2NS0 2- ;
the "heterocyclyl" is substituted on ring carbons with 1 to 6 substituents
selected independently from the group consisting of oxo, halogen, nitro, cyano,
aryl, hereroaryl, alkyl, alkenyl, alkynyl, R °A - , R °aOC(=0)-, R aC(=O)O-,
(R 0)(H)NC(=O)-, (R )(alkyl)NC(O)-, R °aC(=0)N(H)-, (R °)(H)N-, (R 0)(alkyl)N-,
(R 0)(H)NC(=A )N(H)-, and (R °)(alkyl)NC(=A )N(H)-;
the "heterocyclyl" is substituted on ring nitrogen(s) with one or more
substituents selected from the group consisting of aryl, hereroaryl, alkyl,
alkenyl, alkynyl, R °aC(=0 )-, R °aS0 2- , R °aOC(=0)-, R °)(H)NC (=0 )-,
R °)(alkyl)NC(=0)-;
the "heteroaryi" is substituted with 1 to 3 substituents selected independently
from the group consisting of halogen, nitro, cyano, hydroxy, Ci to alkyl, C2
to C 6 alkenyl, C2 to alkynyl, C 3 to cycloalkyl, 3- to 6- membered
heterocycle, Ci to perhaloalkyl, alkyl-O-, alkenyl-O-, 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)S0 2- , and alkyl-N(H)S0 2- , H2NS0 2- ;
the "3- to 10- membered heterocyclic ring" is substituted with 1 to 3
substituents selected from the group consisting of oxo, halogen, nitro, cyano,
aryl, hereroaryl, alkyl, alkenyl, alkynyl, R C(=O)-, R aSO2- , R A - , R aOC(=O)-
, Ri °aC(=0)0-, R °)(H)NC (=0 )-, (R 0)(alkyl)NC(=O)-, R °aC(=0)N(H)-, (R °)(H)N-,
(R °)(alkyl)N-, (R °)(H)NC(=A )N(H)-, and (R °)(alkyl)NC(=A )N(H)-;
wherein,
A1 is selected from the group consisting of O and S ;
R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
or heterocyclyl; and
i oa S selected from the group consisting of alkyl, alkenyl, alkynyl, perhaloalkyl,
aryl, heteroaryl, cycloalkyl or heterocyclyl.
Whenever a range of the number of atoms in a structure is indicated (e.g., a C i
12, Ci-8, Ci-6, or C i - alkyl, alkylamino, etc.), it is specifically contemplated that
any sub-range or individual number of carbon atoms falling within the indicated
range also can be used. Thus, for instance, the recitation of a range of 1-8
carbon atoms (e.g., Ci-Cs), 1-6 carbon atoms (e.g., - , 1-4 carbon atoms
(e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-Cs) as
used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced
herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g.,
1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6
carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10
carbon atoms, 1-1 1 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4
carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8
carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-1 1 carbon atoms, 2-12
carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7
carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-1 1
carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7
carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-1 1
carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).
In one of the embodiments of the invention described above, R is preferably
selected as substituted- or unsubstituted- alkyl.
In any of the embodiments described above, R2 is preferably selected as
substituted- or unsubstituted- alkyl.
In any of the embodiments described above, R3 is preferably selected as
substituted- or unsubstituted- alkyl.
In any of the embodiments described above, R4 is preferably selected as
substituted- or unsubstituted- aryl.
In any of the embodiments described above, 'a' is preferably selected as 0.
In any of the embodiments described above, R1 is preferably selected as
substituted- or unsubstituted- alkyl; R2 is preferably selected as substituted- or
unsubstituted- alkyl; R3 is preferably selected as substituted- or unsubstitutedalkyl;
R4 is preferably selected as substituted- or unsubstituted- aryl; and 'a' 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, n-propyl, 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.
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.
'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, R1 aSO2-, R^A1- , R1 aOC(=O)-,
Ri0a C(=O)O-, (R )(H)NC(=O)-, (R )(alkyl)NC(=O)-, R ° C(=0)N(H)-, (R °)(H)N-,
(R °)(alkyl)N-, (R °)(H)NC(=A )N(H)-, and (Ri )(alkyl)NC(=A )N(H)-; wherein Ri is
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl; and Ai is selected from S and O; and Ri0a is selected from alkyl,
alkenyl, alkynyl perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
The term "perhaloalkyl" used herein means an alkyl group as defined
hereinabove wherein all the hydrogen atoms of the said alkyl group are
substituted with halogen. The perhaloalkyl group is exemplified by
trifluoromethyl, 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.l]heptane,
bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,
bicyclo[3.3. l]nonane, and bicyclo[4.2. l]nonane, bicyclo[3.3.2]decane,
bicyclo[3. 1.0]hexane, bicyclo [4 10 ]heptane, bicyclo[3.2.0]heptanes, octahydrolH-
indene. Tricyclic ring systems are also exemplified by a bicyclic ring system
in which two non-adjacent carbon atoms of the bicyclic ring are linked by a
bond or an alkylene bridge. Representative examples of tricyclic-ring systems
include, but are not limited to, tricyclo[3.3. 1.03 7]nonane and
tricyclo[3.3. 1.13 7]decane (adamantane) . The term cycloalkyl also include spiro
systems wherein one of the ring is annulated on a single carbon atom such ring
systems are exemplified by spiro[2. 5]octane, spiro[4. 5]decane,
spiro[bicyclo[4. 1.0]heptane-2, 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, R C(=O)-, R10aSO2-, R^A -
, R ° OC(=0)-, R ° C(=0)0-, (R °)(H)NC(=0)-, (R )(alkyl)NC(=O)-, R ° C(=0)N(H)-,
(R 0)(H)N-, (R 0)(alkyl)N-, (R 0)(H)NC(=A )N(H)-, and (R °)(alkyl)NC(=A )N(H)-;
wherein R 0 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl or heterocyclyl; and A1 is selected from S and O; and R10a is selected
from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl
The term "aryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic
hydrocarbon ring system. Examples of aryl groups include 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 C alkyl, C2 to C alkenyl, C2 to C alkynyl, C 3 to C cycloalkyl, 3-
to 6- membered heterocycle, Ci to C perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-
0-, perhaloalkyl-O-, alkyl- (alkyl)-, alkyl-N(H)-, H2N-, alkyl-S0 2- , perhaloalkyl-
SO2-, alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-N(alkyl)C(=0)-, alkyl-
N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S02- , alkyl-N(H)S02- , H2NS02- .
The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or
tricyclic ring system having 1-4 ring heteroatoms selected from O, , 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 b e optionally substituted with one or more
substituents. In one embodiment, 0, 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, pyrazolvl, isothiazolyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazlnyl. triazolyl, thiadlazolyl, isoquinollnyl,
benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl,
benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,
azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl,
pyrazolo[3,4jpyrimidinyl, and benzo(b)thienyl , 2,3-thiadiazolyl, lH-pyrazolo[5, 1-
c]- 1,2,4-triazolyl, pyrrolol3,4-d]- 1,2,3-triazolyl, cyclopentatriazolyi, 3Hpyrrolo[
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, Ci to C alkyl, C2 to C alkenyl, C2 to C alkynyl, C 3 to C
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-
S0 2- , perhaloalkyl-S0 2- , alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-
N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , and alkyl-
N(H)SOa-, H2NS0 2- .
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(R )-, -Si(R )R - , wherein, R 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- 1,4-benzodioxinyl, 2,3-dihydro- 1-benzofuranyl, 2,3-dihydro- 1-
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. l]octane, azabicyclo[3.3. l]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 )(H)NC(=O)-, (R )(alkyl)NC(O)-, R °aC(=0)N(H)-, (R °)(H)N-,
(R o)(alkyl)N-, (R °)(H)NC(=A )N(H)-, and (Rio)(alkyl)NC(=A )N(H)-; wherein Ri is
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or
heterocyclyl; and A1 is selected from S and O; and Ri0a is selected from alkyl,
alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or 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 °aC(=0)-, R °aS0 2- , R °aOC(=0)-, Rio)(H)NC(=0)-,
(R10)(alkyl)NC(=O)-; wherein R10 is selected from hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and R a is selected from
alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
The term 'oxo' 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, pharmaceutically acceptable salt
thereof as described hereinabove wherein the compound of general formula I is
selected from:
4-(2-(4-chlorophenyl)-3, 5-dimethyl-4-propionyl- lH-pyrrol- 1-
yl)benzenesulfonamide; and
4-(2-(4-chlorophenyl)-3-ethyl-5-methyl-4-propionyl-lH-pyrrol-l-yl)
benzenesulfonamide.
Prophetic compounds are listed below:
4-(2-(4-chlorophenyl)-3,5-dimethyl-4-(pyrrolidine- 1-carbonyl)- lH-pyrrol- 1-yl)
benzenesulfonamide.
4-(2-(4-chlorophenyl)-4-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-3,5-
dimethyl- lH-pyrrol- 1-yl)benzenesulfonamide.
4-(3-(3-azabicyclo[3. 1.0]hexane-3-carbonyl)-5-(4-chlorophenyl)-2,4-dimethyllH-
pyrrol-l-yl)benzenesulfonamide.
4-(2-(4-chlorophenyl)-3,5-dimethyl-4-(5-azaspiro[2.5]octane-5-carbonyl)-lHpyrrol-
1-yl)benzenesulfonamide.
4-(3-(8-oxa-3-azabicyclo[3.2. l]octane-3-carbonyl)-5-(4-chlorophenyl)-2,4-
dimethyl- lH-pyrrol- l-yl)benzenesulfonamide.
According to another aspect of the present invention, the compounds of general
formula I where all the symbols are as defined earlier were prepared by 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.
X
Scheme 1 shows route of synthesis of compound of formula I from compound of
formula II.
Compound of formula II is subjected to Friedal-Crafts acylation with acid
chloride of formula III in the presence of an acid as described in the literature
EP 2168959 to obtain compound of formula IV. Friedal Craft reaction can be
carried out under different conditions well known in the art. Besides, a person
skilled in the art would appreciate various other possible methods to arrieve at
compound of formula IV, where R3 and R4 are same as described under
compound of formula I hereinabove.
The compounds of the formula IV where R3 and R4 are same as defined earlier in
compound of general formula I on halogenation gives compound of formula V.
Halogenation can be carried out according to the procedure generally used in
the synthetic organic chemistry using bromine, iodine, NCS, NBS, S, sufuryl
chloride, cupric chloride, cupric bromide or cupric iodide in an organic solvent
such as ethyl acetate, dichloromethane, methanol, THF, 1,4-dioxane, or the
like, or a suitable mixture thereof. Preferably halogenation is carried out using
bromine or cupric chloride in dichloromethane or methanol.
The compound of formula V where symbols R3 and R4 are same as defined for
compound IV, and X1 is halogen, when reacted with compound of formula VI,
where R1 is same as defined in compound of general formula I , in presence of
base such as potassium carbonate, sodium hydride preferably pulverized
sodium under room temperature to heated conditions in a solvent such as but
not limited to THF, acetonitrile, an aromatic hydrocarbon such as benzene and
toluene, preferably toluene provides diketo ester (compound of formula VII).
The compound of the formula VI can be prepared according to the procedure
given in literature such as Chem. Pharm. Bull. 1982, 30, 2590 and Journal of
Med. Chemistry, 1997. , 547.
The compound VII where symbols R1, R3, R4 are same as defined earlier is then
reacted with compound of formula Vila under heating conditions in a solvent
such as acetic acid to obtain compound of the formula VIII.
Compound of formula Vila is generally avalible commercially or the same can be
prepared using procedures provided in literature such as WO200429066 or
Chemistry, A European Journal 201 1, 17(21), 5903 - 5907.
Hydrolysis of compound of the formula VIII gives compound of formula IX. The
hydrolysis may be carried out by standard procedure generally used in
synthetic organic chemistry or well known in the art using reagents such as
sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such
as alcohol, THF, water, or their mixture of suitable proportions. Preferably,
hydrolysis of compound of formula VIII is carried out using an aqueous solution
of sodium hydroxide and ethanol.
The compound of formula IX where R , R3, R4, R5 and 'a' are same as defined
earlier can be converted to its corresponding acid chloride using standard
procedures known in synthetic organic chemistry or preferably by reaction with
oxalyl chloride in dichloromethane along with DMF followed by reaction with
N,O-dimethylhydroxylamine hydrochloride in presence of triethylamine in
dichloromethane to provide compounds of formula X.
The compounds of the formula X can be reacted with Grignard reagents R2MgX1
where R2 is substituted- or unsubstituted- alkyl, and X1 is a halogen, to obtain
compound of formula I , where R2 is substituted- or unsubstituted- alkyl. The
reaction of compound of formula X with R MgX may be carried out according to
the procedure given in literature such as J . Med. Chem. , 2009, 52, 3377.
Compound of formula IX is alternatively reacted with amines of formula
(R6 ) R7)NH, (R6 )(OR7)NH, where R and R7 are as defined under definition of R2 in
general formula I , except R C(=0)- and R S02-, to obtain compound of formula I ,
where R2 is selected from (R )(R7)N- and (R )(OR7)N-, wherein R6 and R7 are as
defined under definition of R2 in general formula I , except R C(=0)- and R S02-.
The reaction was carried out according to the conditions known in converting
carboxylic acids to amides 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 dichloromethane, an aromatic
hydrocarbon such as xylene, benzene, toluene, or mixtures thereof or the like,
in the presence of suitable base such as triethylamine, diisopropylethylamine,
pyridine or the like at a temperature between 0-50°C using reagents such as 1-
(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDCI), 1,3-
dicyclohexylcarbodiimide (DCC) , bis(2-oxo-3-oxazolidinyl)phosphinic chloride
(BOPC1), O-benzo triazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU), 0-(7-aza-benzo triazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), phosphonium based coupling agents such as 1-
benzo-triazolyloxytris-(pyrolidino) phosphonium hexafluorophosphate (PyBOP),
/DMAP, cyclophos, and auxiliary reagents such as l-hydroxy-7-
azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT) or the like.
The compounds of formula I , wherein R2 is selected as (R )(R7)N- and
(R6 )(OR7 )N-, wherein R and R7 are selected from R9C(=0)- and R S0 2- , can be
prepared using the chemistry described in literature such as Tet. Lett. 2007, 48,
5181-5184 and Syn. Lett. 2005, 13, 2089-2091.
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, dichloromethane, ethyl
acetate, acetone or their combinations or subjecting it to one of the purification
methods, such as column chromatography (e.g., flash chromatography) on a
suitable support material such 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, di-lower alkylamino lower-alkyl esters, e.g., dimethylaminoethyl
ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g.,
pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters,
e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy
substituents aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, dilwer
alkyl amides, and hydroxy amides.
Modulation of the nicotinic cholinergic receptors, particularly o 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 o 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 o 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 o 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, normalpressure
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 relapse
prevention of nicotine or cannabis addiction. Additionally, this invention may
also provide for an alternative therapy for non-responding addiction patients,
patients having intolerable side-effects with de-addiction therapies or those
requiring long-term maintenance therapies. (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-oc and thus providing
symptomatic relief in either any one or combination of, rheumatoid arthritis,
bone resorption diseases, atherosclerosis, inflammatory bowel disease, Crohn's
disease, inflammation, cancer pain, muscle degeneration, osteoarthritis,
osteoporosis, ulcerative colitis, rhinitis, pancreatitis, spondylitis, acute
respiratory distress syndrome (ARDS), joint inflammation, anaphylaxis,
ischemia reperfusion injury, multiple sclerosis, cerebral malaria, septic shock,
tissue rejection of graft, brain trauma, toxic shock syndrome, herpes virus
infection (HSV-1 & HSV-2), herpes zoster infection, sepsis, fever, myalgias,
asthma, uveititis, contact dermatitis, obesity- related disease and endotoxemia
(Giebelen IA T et al., Shock, 2007, 27, 443-447; Pena G et al., Eur. J . Immunol.,
2010, 40, 2580-2589).
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, intraarterially, subcutaneously, intradermally, intrathecally, or
intramuscularly. Thus, the invention provides compositions for parenteral
administration that comprise a solution of the compound of the invention
dissolved or suspended in an acceptable carrier suitable for parenteral
administration, including aqueous and non-aqueous, isotonic sterile injection
solutions.
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, dimethylsulfoxide,
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 alkanol amides, 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.
An 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), Picks 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 compounds of the general formula (I) as defined above, its tautomeric forms,
its stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its
pharmaceutically acceptable salts, its polymorphs, its solvates, its optical
isomers, its clathrates and its co-crystals in combination with the usual
pharmaceutically employed carriers, diluents and the like, 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 pg 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 pg 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 Bovines (cows) and Swine (pigs) or of the order
Perssodactyla, including Equines (horses). It is most preferred that the
mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the
order Anthropoids (humans and apes) . An especially preferred mammal is the
human.
Following are the abbreviations used and meaning thereof in the specification:
ACh: Acetylcholine.
AD: Alzheimer 's disease.
ADC: AIDS dementia complex.
ADHD: attention deficit hyperactivity disorder.
AIDS: Acquired immunodeficiency syndrome.
ARDS: acute respiratory distress syndrome.
DCC: 1,3-dicyclohexylcarbodiimide.
DCE: dichloroethane.
DCM: dichloromethane.
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 uranium
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.
NCS: N-chlorosuccinimide.
S: N-iodosuccinamide
NNRs: Neural nicotinic ACh receptors.
PAM: positive allosteric modulation.
PD: Parkinson's disease.
PDN: post-diabetic neuralgia.
PHN: post-herpetic neuralgia.
PMBO: p-methoxy benzyloxy.
PNS: peripheral nervous system.
TBI: traumatic brain injury.
THF: Tetrahydrofuran.
TLC: Thin layer chromatography.
TMS: tetramethylsilane.
TNF-oc: tumor necrosis factor alpha.
VTA: ventral tegmental area.
a 7 nAChR: nicotinic acetylcholine receptor a 7 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 4-(2-(4-chlorophenyl)-3,5-dimethyl-4-propionyl-lHpyrrol-
l-yl) benzenesulfonamide (Compound 1)
Step 1: Ethyl 5-(4-chlorophenyl)-2,4-dimethyl-l-(4-sulfamoylphenyl)-lHpyrrole-
3-carboxylate
A mixture of ethyl [2-acetyl-4-(4-chlorophenyl)-3-methyl-4-oxo]butyrate
(prepared according to the procedure given in Med.Chem. Res. (1994), 5, 54-62,
1.6g, 5.39 mmol) and 4-aminobenzenesulfonamide (0.928g, 5.39 mmol) in acetic
acid (40 ml) was heated at 95° C for 17 hr under stirring. The completion of
reaction was monitored by TLC. Reaction mixture was concentrated at reduced
pressure. Dichloromethane (100 ml) was added to the residue, washed with
water (lx 25 ml). Organic layer was dried over anhydrous a2S04. The solvent
was evaporated under reduced pressure to obtain a crude product; which was
purified by column chromatography over silica gel (100-200 mesh) using 1%
methanol in dichloromethane as an eluent to yield the title compound (1.65 g,
71%)
MS: m/z 433 (M+l)
HNMR (CDCls, 400 MHz): 7.90 (d, J=8.4 Hz, 2H), 7. 16-7.25 (m, 4H), 6.92 (d,
J=8.4 Hz, 2H), 4.93 (bs, exchanged with D20 2H), 4.33 (q, J=7.2Hz, 2H), 2.37 (s,
3H), 2.23 (s, 3H), 1.38 (t, J= 7.2 Hz, 3H).
Step 2 : 5-(4-Chlorophenyl)-2,4-dimethyl- l-(4-sulfamoylphenyl)- lH-pyrrole-3-
carboxylic acid
Ethyl 5-(4-chlorophenyl)-2,4-dimethyl- l-(4-sulfamoylphenyl)- lH-pyrrole-3-
carboxylate
(Step 1, 1.6g, 3.69 mmol) was suspended in ethanol (50 ml) and treated with
aqueous solution of NaOH (2.22g in 20 ml. water) at room temperatue. The
reaction mixture was refluxed for 3 hr. The completion of reaction was
monitored by TLC. Reaction mixture was concentrated at reduced pressure.
Residue was taken in mixture of solvents ethyl acetate and dichloromethane in
1: 1 ratio (75 ml.). Organinc layer was decanted and solid so obtained was taken
in water (25 ml) and neutralized with 5N HC1 upto pH7, Aqueous layer was
extracted with ethyl acetate (2 x 50 ml). Combined organic layer was dried over
anhydrous a2S 0 . The solvent was evaporated under reduced pressure to
obtain a product. (1.47g, 98%)
MS: m/z 405 (M+l)
HNMR (DMSO-D6 , 400 MHz): 12.03 (bs, exchanges with D20 , 1H), 7.80 (d,
J=8.4 Hz, 2H), 7.41 (bs, exchanged with D20 2H), 7.38 (d, J=8.4 Hz, 2H), 7.31
(d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 2.28 (s, 3H), 2. 15 (s, 3H).
Step 3 : 5-(4-Chlorophenyl)- l-(4 -(N-
((dimethylamino)methylene)sulfamoyl)ph N-methoxy -N, 2,4-trimethyl- 1Hpyrrole-
3-carboxamide
Oxalyl chloride (0.908g, 0.60 ml, 7. 16 mmol) was added dropwise at 0°C to a
solution of 5-(4-Chlorophenyl)-2,4-dimethyl- l-(4-sulfamoylphenyl)- lH-pyrrole-
3-carboxylic acid (step 2, 1.45g, 3.58 mmol) in dichloromethane (50 ml)/ DMF
(0.544g, 0.50 ml, 7. 16 m mol). Mixture was allowed to come at room temperature
and stirred for 1 hr. under nitrogen atmosphere. The completion of reaction was
monitored by TLC. The mixture was concentrated under reduced pressure
under nitrogen atmosphere. To this residue was added ,-
dimethylhydroxylamine hydrochloride (0.690g, 7. 16 mmol) in dry
dichloromethane (50 ml) at 0°C followed by the addition of triethylamine (1.44g,
2.0ml, 14.32 mmol,) under stirring. The reaction mixture was stirred at room
temperature for 2 hr. The completion of reaction was monitored by TLC. The
solvent was removed under reduced pressure. The residue so obtained was
taken in dichloromethane (50 ml), washed with water (2x 25 ml.) and organic
layers separated were dried over anhydrous sodium sulphate, filtered and
concentrated at reduced pressure to get a crude product. This crude product
was purified by column chromatography over silica gel (100-200 mesh) using
0.8% methanol in dichloromethane as an eluent to yield the title compound
(0.763g, 42%).
MS: m/z 503 (M+l)
HNMR (CDCla, 400 MHz): 8.13 (s, 1H), 7..82 (d, J=8.4 Hz, 2H), 7. 15 (d, J=8.4
Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 3.67 (s, 3H), 3.37 (s, 3H),
3. 15 (s, 3H), 3.04 (s, 3H), 2. 13 (s, 3H), 2. 10 (s, 3H).
4-(2-(4-chlorophenyl)-3,5-dimethyl-4-propionyl- lH-pyrrol- 1-yl)
To a stirred solution of 5-(4-Chlorophenyl)-l-(4 -(N-((dimethylamino) methylene)
sulfamoyl) phenyl)- N-methoxy -N,2,4-trimethyl-lH-pyrrole-3-carboxamide (step
3, 0.750g, 1.49 mmol) in anhydrous THF (50 ml) at 0°C, ethyl magnesium
bromide (Grignard reagent, 0.994g, 7.4 ml, 7.46 mmol) was added dropwise
and reaction mixture was heated to reflux for 1 h . The completion of reaction
was monitored by TLC. After cooling, reaction mixture was quenched by
addition of solution of saturated ammonium chloride (10 ml) and extracted with
ethyl acetate (1 x50 ml). Combined organic layer was dried over anhydrous
a2S04. The solvent was evaporated under reduced pressure to obtain a crude
product; which was purified by column chromatography over silica gel (100-200
mesh) using 0.4% methanol in dichloromethane as an eluent to yield the title
compound which was finally purified by preparative HPLC (0.062g, 10 %)
MS: m/z 417(M+1)
HNMR (CDCb, 400 MHz): 7.88 (d, J=8.8Hz, 2H), 7. 16-7. 19 (m, 4H), 6.91 (d,
J=8.4Hz, 2H), 4.92 (bs, exchanged with D20 2H), 2.84 (q, J=7.2Hz, 2H), 2.34 (s,
3H), 2.24 (s, 3H), 1.21 (t, J= 7.2 Hz, 3H).
Example 2 : Preparation of 4-(2-(4-chlorophenyl)-3-ethyl-5-methyl-4-
propionyl-lH-pyrrol-l-yl)benzenesulfonamide (Compound 2).
Compound 2 was prepared using appropriate reagents and by following a
procedure analogous to the one provided under example 1.
4-(2-(4-chlorophenyl)-3-ethyl-5-methyl-4-propionyl-lH-pyrrol-l-yl)
benzenesulfonamide (Compound 2)
MS: m/z 431 (M+l),
iHNMR (DMSO-D6, 400 MHz): 7.78 (d, J=8.4Hz, 2H), 7.46 (bs-exchanged with
D20 , 2H), 7.39 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.10 (d, J=8.4Hz, 2H),
2.82 (q, J=7.2Hz, 2H), 2.53 (q, J=7.2Hz, 2H), 2.26 (s, 3H), 1. 10 (t, J=7.2Hz, 3H),
1.02 (t, J=7.2Hz, 3H).
Example 3 : Pharmacological screening
Compounds were tested in a cell-based real-time kinetic assay in human IMR-
32 cells with native expression of oc7nAChR. 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 CaCb). Briefly, cells were plated into Poly-D-Lysine
coated back-walled clear-bottom 96-well microplates at a density of 80,000 to
100,000 cells/well and incubated at 37°C/5% 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 by between about 20 to about 25 folds.
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,
R1 is selected from the group consisting of hydrogen, halogen,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedalkenyl,
substituted- or unsubstituted- alkynyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from the group consisting of substituted- or unsubstitutedalkyl,
(R )(R7)N-, (R )N(OR7a)-, and R O-;
R3 is selected from the group consisting of substituted- or unsubstitutedalkyl,
substituted- or unsubstituted- alkenyl, substituted- or
unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl;
R4 is selected from the group consisting of substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl;
[R ]a is 'a' times repetition of 'R5' groups, each R5 is independently
selected from the group consisting of halo, substituted- or unsubstitutedalkyl,
R 0-; 'a' is an integer selected from 0, 1, and 2 ;
wherein, R6 and R7 are independently selected from hydrogen,
substituted- or unsubstituted- alkyl, R C(=0)-, R9SC>2-; such that when
R2 is (R )(R )N-, R6 and R7 together with the nitrogen atom to which they
are attached may form a 3 to 10 member substituted- or unsubstitutedheterocycle
containing one to three hetero atoms/groups selected from
the group consisting of S, N, O the said heterocycle may be saturated or
unsaturated, monocyclic or bicyclic or spiro, or the said heterocycle may
contain an alkylene bridge;
R a is selected from hydrogen and substituted- or unsubstituted- alkyl;
R a is selected as substituted- or unsubstituted- alkyl;
wherein R8 is selected from hydrogen, substituted- or unsubstitutedalkyl,
and perhaloalkyl;
wherein, R9 is independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, and substituted- or
unsubstituted- heterocyclyl;
wherein,
the "alkyl", "alkenyl", and "alkynyl" are substituted with 1 to 6
substituents selected independently from the group consisting of oxo,
halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R10aS O2 - , R^A 1- ,
Ri oao c (=0 )-, R aC(=O)O-, (R )(H)NC(=O)-, (R )(alkyl)NC(=O)-,
R °aC(=0)N(H)-, (R °)(H)N-, (R 0)(alkyl)N-, (R 0)(H)NC(=A )N(H)-, and
(R °)(alkyl)NC(=A )N(H)-;
the "cycloalkyl" is substituted with 1 to 6 substituents selected
independently from the group consisting of oxo, halogen, nitro, cyano,
aryl, hereroaryl, alkyl, alkenyl, alkynyl, R °aC(=0 )-, R aS O2 - , R A - ,
Rioao c (=0 )-, R aC(=O)O-, (R )(H)NC(=O)-, (R )(alkyl)NC(=O)-,
RioaC (=0)N(H)-, (R )(H)N-, (Ri °)(alkyl)N-, (R 0)(H)NC(=A!)N(H)-, and
the "aryl" is substituted with 1 to 3 substituents selected independently
from the group consisting of halogen, nitro, cyano, hydroxy, C i to C
alkyl, C2 to C e alkenyl, C2 to C e alkynyl, C 3 to C e cycloalkyl, 3- to 6-
membered heterocycle, C i to C perhaloalkyl, alkyl-O-, alkenyl-O-,
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)S0 2- , alkyl-
N(H)SOa-, H2NS0 2- ;
the "heterocyclyl" is substituted on ring carbons with 1 to 6 substituents
selected independently from the group consisting of oxo, halogen, nitro,
cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^A 1- , R 10a OC(=O)-,
RioaC (=0)0-, ( R °)(H)N -
, R i )(alkyl)N-,
the "heterocyclyl" is substituted on ring nitrogen(s) with one or more
substituents selected from the group consisting of aryl, hereroaryl, alkyl,
alkenyl, alkynyl,
the "heteroaryl" is substituted with 1 to 3 substituents selected
independently from the group consisting of halogen, nitro, cyano,
hydroxy, C i to C alkyl, C2 to C alkenyl, C2 to C alkynyl, C 3 to C
cycloalkyl, 3- to 6- membered heterocycle, C i to C perhaloalkyl, alkyl-O-,
alkenyl -O-, 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)S0 2- , and
alkyl-N(H)S02- , H2NS0 2- ;
the "3- to 10- membered heterocyclic ring" is substituted with 1 to 3
substituents selected from the group consisting of oxo, halogen, nitro,
cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R 10a C(=O)-, R 10a S O2 - ,
R °A - , R ° OC(=0 )-, R C(=O)O-, (R )(H)NC(=O)-, (R )(alkyl)NC(=O)-,
Ri oaC(=0)N(H)-, (R )(H)N-, (R °)(alkyl)N-, (R 0)(H)NC(=A )N(H)-, and
(R )(alkyl)NC(=A )N(H)-;
wherein,
A1 is selected from the group consisting of O and S ;
R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl or heterocyclyl; and
ioa
S selected from the group consisting of alkyl, alkenyl, alkynyl,
perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
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 R1 is selected as substitutedor
unsubstituted- alkyl.
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 R2 is selected
as substituted- or unsubstituted- 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 R3 is selected
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 R4 is selected as
substituted- or unsubstituted- aryl.
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 'a' is selected as
0.
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 R1 is selected as
substituted- or unsubstituted- alkyl; R2 is selected as substituted- or
unsubstituted- alkyl; R3 is selected substituted- or unsubstituted- alkyl;
R4 is selected as substituted- or unsubstituted- aryl; and 'a' 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 the compound
is selected from-
4-(2-(4-chlorophenyl)-3,5-dimethyl-4-propionyl-lH-pyrrol-l-yl)
benzenesulfonamide; and
4-(2-(4-chlorophenyl)-3-ethyl-5-methyl-4-propionyl- lH-pyrrol- 1
yl)benzenesulfonamide.
9 . A pharmaceutical composition comprising a compound of any one claims
1-8 and a pharmaceutically acceptable carrier.
10. 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 1-8.
11. 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,
R is selected from the group consisting of hydrogen, halogen,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedalkenyl,
substituted- or unsubstituted- alkynyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from the group consisting of substituted- or unsubstitutedalkyl,
R 6 )(R 7 )N - , (R6 )N(OR7 )-, and OR3
is selected from the group consisting of substituted- or unsubstitutedalkyl,
substituted- or unsubstituted- alkenyl, substituted- or
unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl;
R4 is selected from the group consisting of substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl;
[R ]a is 'a' times repetition of 'R5' groups, each R5 is independently
selected from the group consisting of halo, substituted- or unsubstitutedalkyl,
R 0-; 'a' is an integer selected from 0, 1, and 2 ;
wherein, R6 and R7 are independently selected from hydrogen,
substituted- or unsubstituted- alkyl, R C(=0)-, R SC>2-; such that when
R2 is (R )(R )N-, R6 and R7 together with the nitrogen atom to which they
are attached may form a 3 to 10 member substituted- or unsubstitutedheterocycle
containing one to three hetero atoms/groups selected from
the group consisting of S, N, O the said heterocycle may be saturated or
unsaturated, monocyclic or bicyclic or spiro, or the said heterocycle may
contain an alkylene bridge;
R a is selected from hydrogen and substituted- or unsubstituted- alkyl;
R a is selected as substituted- or unsubstituted- alkyl;
wherein R8 is selected from hydrogen, substituted- or unsubstitutedalkyl,
and perhaloalkyl;
wherein, R9 is independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, and substituted- or
unsubstituted- heterocyclyl;
wherein,
the "alkyl", "alkenyl", and "alkynyl" are substituted with 1 to 6
substituents selected independently from the group consisting of oxo,
halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R aS O2 - , R^A - ,
Rioao c (=0 )-, R aC(=O)O-, (R )(H)NC(=O)-, (R )(alkyl)NC(=O)-,
Ri oaC(=0)N(H)-, (R )(H)N-, (R °)(alkyl)N-, (R °)(H)NC(=A )N(H)-, and
(R °)(alkyl)NC(=A )N(H)-;
the "cycloalkyl" is substituted with 1 to 6 substituents selected
independently from the group consisting of oxo, halogen, nitro, cyano,
aryl, hereroaryl, alkyl, alkenyl, alkynyl, R aC(=O)-, R aS O2 - , R^A - ,
Ri °aOC(=0 )-, R °aC(=0)0-, (R ) (H)NC (=0 )-, (R 0)(alkyl)NC(=O)-,
Ri oaC(=0)N(H)-, (R o)(H)N-, (R °)(alkyl)N-, (Ri o)(H)NC(=A )N(H)-, and
(R 0)(alkyl)NC(=A )N(H)-;
the "aryl" is substituted with 1 to 3 substituents selected independently
from the group consisting of halogen, nitro, cyano, hydroxy, Ci to C
alkyl, C2 to C alkenyl, C2 to C alkynyl, C3 to C cycloalkyl, 3- to 6-
membered heterocycle, Ci to C perhaloalkyl, alkyl-O-, alkenyl-O-,
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)S0 2- , alkyl-
N(H)SOa-, H2NS0 2- ;
the "heterocyclyl" is substituted on ring carbons with 1 to 6 substituents
selected independently from the group consisting of oxo, halogen, nitro,
cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R A - , R aOC(=O)-,
Ri °aC(=0)0-, (R °)(H)NC (=0 )-, (R 0)(alkyl)NC(O)-, R °aC(=0)N(H)-, (R °)(H)N-
, R )(alkyl)N-, (R 0)(H)NC(=A )N(H)-, and (R °)(alkyl)NC(=A )N(H)-;
the "heterocyclyl" is substituted on ring nitrogen(s) with one or more
substituents selected from the group consisting of aryl, hereroaryl, alkyl,
alkenyl, alkynyl, R °aC(=0 )-, R °aS0 2- , R °aOC(=0 )-, (R °)(H)NC (=0 )-,
(R )(alkyl)NC (=0)-;
the "heteroaryl" is substituted with 1 to 3 substituents selected
independently from the group consisting of halogen, nitro, cyano,
hydroxy, C to C alkyl, C2 to C alkenyl, C2 to C alkynyl, C 3 to C
cycloalkyl, 3- to 6- membered heterocycle, C to C perhaloalkyl, alkyl-O-,
alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-,
alkyl -S02- , perhaloalkyl-SCV, 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- , and
alkyl-N(H )S02- , H2NS02- ;
the "3- to 10- membered heterocyclic ring" is substituted with 1 to 3
substituents selected from the group consisting of oxo, halogen, nitro,
cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R aC(=O)-, R10aSO2- ,
R A - , R ° OC(=0)-, Ri aC(=0)0-, (R 0)(H)NC(=O)-, (R 0)(alkyl )NC(=O)-,
RioaC(=0)N(H)-, (R )(H)N-, (R °)(alkyl )N-, (R °)(H)NC(=A )N(H)-, and
(R 0)(alkyl )NC(=A )N(H)-;
wherein,
A1 is selected from the group consisting of O and S ;
R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl or heterocyclyl; and
oa
S selected from the group consisting of alkyl, alkenyl, alkynyl,
perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
12. The method of claim 11, 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.
13. The method of claim 11, 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.
14. The method of claim 11, 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.
15. The method of claim 11, 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.
16. 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.
17. 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,
R is selected from the group consisting of hydrogen, halogen,
substituted- or unsubstituted- alkyl, substituted- or unsubstitutedalkenyl,
substituted- or unsubstituted- alkynyl, perhaloalkyl, and
substituted- or unsubstituted- cycloalkyl;
R2 is selected from the group consisting of substituted- or unsubstitutedalkyl,
(R )(R7)N-, (R )N(OR7a)-, and R O-;
R3 is selected from the group consisting of substituted- or unsubstitutedalkyl,
substituted- or unsubstituted- alkenyl, substituted- or
unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl;
R4 is selected from the group consisting of substituted- or unsubstitutedaryl,
substituted- or unsubstituted- heteroaryl;
[R ]a is 'a' times repetition of 'R5' groups, each R5 is independently
selected from the group consisting of halo, substituted- or unsubstitutedalkyl,
R 0-; 'a' is an integer selected from 0, 1, and 2 ;
wherein, R6 and R7 are independently selected from hydrogen,
substituted- or unsubstituted- alkyl, R C(=0)-, R9S02-; such that when
R2 is (R )(R )N-, R6 and R7 together with the nitrogen atom to which they
are attached may form a 3 to 10 member substituted- or unsubstitutedheterocycle
containing one to three hetero atoms/groups selected from
the group consisting of S, N, O the said heterocycle may be saturated or
unsaturated, monocyclic or bicyclic or spiro, or the said heterocycle may
contain an alkylene bridge;
R a is selected from hydrogen and substituted- or unsubstituted- alkyl;
R a is selected as substituted- or unsubstituted- alkyl;
wherein R8 is selected from hydrogen, substituted- or unsubstitutedalkyl,
and perhaloalkyl;
wherein, R9 is independently selected from the group consisting of
hydrogen, substituted- or unsubstituted- alkyl, substituted- or
unsubstituted- aryl, substituted- or unsubstituted- heteroaryl,
substituted- or unsubstituted- cycloalkyl, and substituted- or
unsubstituted- heterocyclyl;
wherein,
the "alkyl", "alkenyl", and "alkynyl" are substituted with 1 to 6
substituents selected independently from the group consisting of oxo,
halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R aSO2- , R^A - ,
Ri oao c (=0 )-, R aC(=O)O-, (R )(H)NC(=O)-, (R )(alkyl)NC(=O)-,
R °aC(=0)N(H)-, (R °)(H)N-, (R 0)(alkyl)N-, (R 0)(H)NC(=A )N(H)-, and
(R °)(alkyl)NC(=A )N(H)-;
the "cycloalkyl" is substituted with 1 to 6 substituents selected
independently from the group consisting of oxo, halogen, nitro, cyano,
aryl, hereroaryl, alkyl, alkenyl, alkynyl, R °aC(=0 )-, R aSO2- , R A - ,
R °aOC(=0 )-, R aC(=O)O-, (R 0)(H)NC(=O)-, (R )(alkyl)NC(=O)-,
R °aC(=0)N(H)-, (R o)(H)N-, (R 0)(alkyl)N-, (R 0)(H)NC(=A )N(H)-, and
(R )(alkyl)NC(=A )N(H)-;
the "aryl" is substituted with 1 to 3 substituents selected independently
from the group consisting of halogen, nitro, cyano, hydroxy, C i to C e
alkyl, C2 to C alkenyl, C2 to C alkynyl, C 3 to C cycloalkyl, 3- to 6-
membered heterocycle, C i to C perhaloalkyl, alkyl-O-, alkenyl-O-,
alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-S0 2- ,
perhaloalkyl-SCV, alkyl-C(=0)N(alkyl)-, alkyl-C(=0)N(H)-, alkyl-
N(alkyl)C(=0)-, alkyl-N(H)C(=0)-, H2NC(=0)-, alkyl-N(alkyl)S0 2- , alkyl-
N(H)S02- , H2NS0 2- ;
the "heterocyclyl" is substituted on ring carbons with 1 to 6 substituents
selected independently from the group consisting of oxo, halogen, nitro,
cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R A!-, R a OC(=O)-,
(Ri°) (alkyl)NC(O)-, (Rio)(H)N-
, (Ri °)(alkyl)N-,
the "heterocyclyl" is substituted on ring nitrogen(s) with one or more
substituents selected from the group consisting of aryl, hereroaryl, alkyl,
alkenyl, alkynyl,
the "heteroaryl" is substituted with 1 to 3 substituents selected
independently from the group consisting of halogen, nitro, cyano,
hydroxy, Ci to C alkyl, C2 to C alkenyl, C2 to C alkynyl, C3 to 
cycloalkyl, 3- to 6- membered heterocycle, C i to perhaloalkyl, alkyl-O-,
alkenyl-O-, 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)S0 2- , and
alkyl-N(H)S02- , H2NS0 2- ;
the "3- to 10- membered heterocyclic ring" is substituted with 1 to 3
substituents selected from the group consisting of oxo, halogen, nitro,
cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R a C(=O)-, R 10a S O 2 - ,
R A - , ,
RioaC (=0)N(H)-, (Rio)(H)N-, (Ri °)(alkyl)N-, and
(R 0)(alkyl)NC(=A )N (H)-;
wherein,
A1 is selected from the group consisting of O and S ;
R 0 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl or heterocyclyl; and
ioa
S selected from the group consisting of alkyl, alkenyl, alkynyl,
perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
18. The use as claimed in claim 17, 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.
19. The use as claimed in claim 17, 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.
20. The use as claimed in claim 17, 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.