NOVEL HEAT SHOCK PROTEIN INDUCERS
FIELD OF THE INVENTION:
The present invention relates to novel compounds, their pharmaceutically
acceptable salts and their hydrates, solvates, stereoisomers, conformers,
tautomers, polymorphs and prodrugs and also pharmaceutically acceptable
compositions containing them. The compounds of the present invention are HSP
inducers and by virtue of this effect, useful for the treatment of various diseases
accompanying pathological stress selected from ischemic stroke, myocardial
infarction, inflammatory disorder, diseases of viral origin, tumourous diseases,
brain haemorrhage, endothelial dysfunctions, diabetic complications,
hepatotoxicity, acute renal failure, glaucoma, sepsis, gastric mucosal damage,
allograft rejection, neurodegenerative diseases, epilepsy, post-traumatic
neuronal damage and aging-related skin degeneration. The present invention
also relates to a process for the preparation of the said novel compounds. The
invention also relates to the use of the above-mentioned compounds for the
preparation of medicament for use as Pharmaceuticals.
PRIOR ART AND BACKGROUND OF THE INVENTION:
Heat shock proteins (HSPs) have been well documented to play a cytoprotective
role in almost all living cells under various pathological stresses through a
mechanism known as thermotolerance or cross tolerance. Heat shock proteins
function as molecular chaperones or proteases that, under physiological
conditions, have a number of intracellular functions. Chaperones are involved in
the assembly and folding of misfolded or denatured oligomeric proteins, whereas
proteases mediate the degradation of damaged proteins.
Heat shock proteins are categorized into several families that are named on the
basis of their approximate molecular mass (e.g. the 70 kDa HSP-70, ubiquitin,
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HSP-10, HSP-27, HSP-32, HSP-60, HSP-90 etc). HSP-70 is the most abundant
HSP found in normal cells. HSP-70, and its inducible form, called HSP-72, is
found in all living cells. Following heat shock, its synthesis increases to a point to
where it becomes the most abundant single protein in the cell.
Although some proteins refold spontaneously, in vitro, when diluted at low
concentrations from denaturants, larger, multidomain proteins often have a
propensity to misfold and aggregate. Consequently, the challenge within the
densely packed cellular environment is to ensure that non-native intermediates
are efficiently captured, maintained in intermediate folded states, and
subsequently either refolded or degraded. Molecular chaperones such as HSP-
90, HSP-70 and HSP-60 accomplish this by capturing non-native intermediates
and, together with co-chaperones and ATP.
The HSP-70 chaperones, for example, recognize stretches of hydrophobic
residues in polypeptide chains that are transiently exposed in early folding
intermediates and typically confined to the hydrophobic core in the native state.
The consequence of chaperone interactions, therefore, is to shift the equilibrium
of protein folding and refolding reactions toward productive on-pathway events
and to minimize the appearance of non-productive intermediates that have a
propensity to aggregate as misfolded species.
Over the past years, a number of studies have shown that the major heat-
inducible protein, HSP-72, is critical for protection of cells and tissues from heat
shock and other stresses. HSP-72 functions as molecular chaperone in refolding
and degradation of damaged proteins. This has led to the common assumption
that chaperoning activities of HSP-72 determine its role in ability of a cell to
protect itself against stresses. Upon exposure to stresses that lead to a massive
protein damage and necrotic death, the anti-aggregating and protein refolding
activities of HSP-72 may indeed become critical for cell protection. On the other
hand, upon exposure to stresses that lead to apoptosis, the protective function of
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HSP-72 could be fully accounted for by its distinct role in cell signaling. Under
these conditions, protein damage on its own is not sufficient for cell death
because suppression of the apoptotic signaling pathway restores cell viability.
The term heat shock protein is somewhat of a misnomer, as they are not induced
solely by heat shock. Indeed, in addition to being constitutively expressed
(making up 5-10 % of the total protein content under normal growth conditions),
these proteins can be markedly induced (up to 15% of the total cellular protein
content) by a range of stimuli including various pathological stresses.
Pathological stresses inducing heat shock protein expression include a wide
variety of conditions associated with many diseases. The synthesis of heat shock
proteins in cells exposed to such stresses indicates the first line of defense of the
cell against the pathological stresses.
Stroke
One such pathological condition wherein protective role of HSP-70 has been
implicated is cerebral ischemic injury (stroke). Cerebral ischaemia causes severe
depletion of blood supply to the brain tissues, as a result of which the cells
gradually proceed to death due to lack of oxygen. In such a situation, there is
increased expression of heat shock protein in the brain tissue.Transient ischemia
induces HSPs in the brain and the ability of neuronal population to survive an
ischemic trauma is correlated with increased expression of HSP-70. HSP-70
mRNA was induced in neurons at the periphery of ischemia. It is proposed that
the peripheral zone of ischemia, penumbra can be rescued by pharmacological
agents. It was in this zone that HSP-70 protein was found to be localized
primarily in neurons.[Dienel G.A. et al., J. Cereb. Blood Flow Metab., 1986, Vol.
6, pp. 505-510; Kinouchi H. et al., Brain Research, 1993, Vol. 619, pp. 334-338].
The direct assessment of the protective role of HSP-70 is shown by using
transgenic mice overexpressing the rat HSP (HSP-70tg mice). In contrast to wild-
type littermates, high levels of HSP messenger RNA and protein were detected
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in brains of HSP-70tg mice under normal conditions, immunohistochemical
analysis revealed primarily neuronal expression of HSP-70. Heterozygous HSP-
70tg mice and their wild type littermates were subjected to permanent focal
cerebral ischemia by intraluminal blockade of middle cerebral artery. Cerebral
infarction after 6 hours of ischemia, as evaluated by nissl staining, was
significantly less in HSP-70tg mice compared with wild type littermate mice. The
HSP-70tg mice were still protected against cerebral infarction 24 hours after
permanent focal ischemia. The data suggest that HSP-70 can markedly protect
the brain against ischemic damage. [Rajdev S., Hara K, et al., Ann. Neurol., 2000
Jun, Vol. 47 (6), pp. 782-791] The 72-kD inducible heat shock protein (HSP-72)
plays a very important role in attenuating cerebral ischemic injury. Striatal
neuronal survival was significantly improved when HSP-72 vectors was delivered
after ischemia onset into each striatum. [Hoehn B. et al., J. Cereb. Blood Flow
Metab., 2001 Nov, Vol. 21(11), pp. 1303-1309].
Experiments have proved that neurological deficits induced by ischemia were
found to be reduced on treatment with HSP-inducers like lithium. These
neuroprotective effects were associated with an up-regulation of cytoprotective
heat shock protein -70 in the ischemic hemisphere [Ren M. et al., Proc. Natl.
Acad. Sci. USA., 2003 May 13; Vol. 100(10), pp. 6210-6215]. Thus induction of
HSP-70 would confer a protective effect in cerebral ischaemic injury (stroke).
Myocardial Infarction
Another pathological condition analogous to cerebral ischaemia is myocardial
infarction, in which case, severe ischemia even for relatively short periods of
time, lead to extensive death of cardiomyocytes. Induction of HSP-70 has been
shown to confer protection against subsequent ischemia as is evident by a direct
correlation to post-ischemic myocardial preservation, reduction in infarct size and
improved metabolic and functional recovery.. Overexpression of inducible HSP-
70 in adult cardiomyocytes were associated with a 34% decrease in lactate
dehydrogenase in response to ischemic injury. [Hutter M.M. et al., Circulation,
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1994, Vol. 89, pp. 355-360; Liu X. et al., Circulation, 1992, Vol. 86, pp. II358-
II363; Martin J.L., Circulation, 1997, Vol. 96, pp. 4343-4348].
Experiments have shown that oral pretreatment of rats with an HSP inducer
Bimoclomol elevated myocardial HSP-70 and reduced infarct size in a rat model
of ischemia [Lubbers N.L. et al., Eur. J. Pharmacol., 2002 Jan 18, Vol. 435(1),
pp. 79-83]. There was a significant correlation between HSP-70 induction and
infarct size reduction after oral administration of Bimoclomol. Further, Bimoclomol
also improved cell survival in rat neonatal cardiomyocytes by increasing the
levels of HSP-70 [Polakowski J.S. et al., Eur. J. Pharmacol., 2002 Jan 18, Vol.
435(1), pp. 73-77].
In further experiments, transgenic mice were engineered to express high levels
of the rat-inducible HSP-70 [Marber M.S. et al., J. Clin. Invest, 1995 April, Vol.
95, pp. 1446-1456]. It was observed that there was a significant reduction in
infarct size by about 40% after 20 minutes of global ischemia in the heart of the
transgenic mice, and contractile function doubled during reperfusion period
compared to wild type.
Moreover, evidence indicate that myocardial stress protein HSP-70 is directly
protective is provided by the observation that transfected myocyte lines
overexpressing HSP-70 have enhanced resistance to hypoxic stress [Mestril R.
et al., J. Clin. Invest., 1994 February, Vol. 93, pp. 759-767].
Further investigations into the role of HSP-70 overexpression through gene
therapy on mitochondrial function and ventricular recovery has shown that, HSP-
70 upregulation protects mitochondrial function after ischemia-reperfusion injury
and was associated with improved preservation of myocardial function.
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Post ischemic mitochondrial respiratory control indices linked to NAD and FAD
were better preserved and recovery of mechanical function was greater in HSP
transfected than control hearts. [Jayakumar J. et al., Circulation, 2001 Sep 18,
Vol. 104 (12 Suppl 1), pp. 1303-1307]. Thus, the foregoing evidence indicates
that induction of HSP-70 would be useful for treating myocardial infarction.
Inflammatory disorders
Yet another example of pathological stress on tissues and organs causing HSP-
70 induction is provided by inflammatory diseases.
Inflammation is caused by activation of phagocytic cells like leucocytes, primarily
by monocytes-macrophages, which generate high levels of reactive oxygen
species (ROS) as well as cytokines. Both ROS and cytokines upregulate the
expression of heat shock proteins (HSP), while HSPs in turn protect cells and
tissues from the deleterious effects of inflammation. In an in vivo model for adult
respiratory distress syndrome, an acute pulmonary inflammatory condition which
caused HSP induction, HSP completely prevented mortality. [Jacquier-Salin M.R.
et al., Experientia, 1994 Nov 30, Vol. 50 (11-12), pp. 1031-1038].
HSP exert multiple protective effects in inflammation, including self/non-self
discrimination, enhancement of immune responses, immune protection,
thermotolerance and protection against the cytotoxicity of inflammatory mediators
[Polla B.S. et al., EXS., 1996, Vol. 77, pp. 375-91].
Heat shock proteins (HSPs) have been repeatedly implicated in the control of the
progression of rheumatoid arthritis. An up-regulation of HSP-70 expression in
synovial tissue is consistently observed in patients with rheumatoid arthritis.
Recent investigations have shown that, pro-inflammatory cytokines induced
activation of HSF 1-DNA binding and HSP-70 expression in cultivated synovial
fibroblast-like cells [Georg Schett et. al., J. Clin. Invest., 1998 July, Vol. 102 (2),
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pp. 302-311]. Since HSP-70 is critically involved in protein folding and may
prevent apoptotic cell death, facilitating synovial growth and pannus formation,
their elevated levels would play a crucial role in controlling the progression of the
disease state.
Anti-inflammatory agents such as NSAIDS activate HSF-1 DNA binding and
glucocortcoids at high dose activate HSF-1 as well as induce HSP expression
[Georg Schett et. al., J. Clin. Invest., 1998 July, Vol. 102 (2), pp. 302-311].
HSP-70 has a role in controlling inflammation. The induction of HSP-70 before
the onset of inflammation can reduce organ damage [Hayashi Y. et al,
Circulation, 2002 Nov 12, Vol. 106(20), pp. 2601-2607]. Preoperative
administration of HSP-70 inducers seem to be useful in attenuating
cardiopulmonary bypass (CPB)-induced inflammatory response.
Investigations into the anti-inflammatory property of 2-cyclopentene-1-one
demonstrated that the heat shock factor 1(HSF1)activation , subsequent
induction of HSP-72 expression occurs in inflamed tissue and this effect is
associated with the remission of the inflammatory reaction, [lanaro A. et al., Mol.
Pharmacol., 2003 Jul, Vol. 64(1), pp. 85-93]. The anti-inflammatory properties of
2-cyclopenten-1-one were associated with HSF-1 induced HSP-72 expression in
vivo.
The HSP co-inducer BRX-220 has been examined for effects on the
Cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats
[Rakonczay Z. Jr. et al., Free Radic. Biol. Med., 2002 Jun 15, Vol. 32 (12), pp.
1283-1292]. The pancreatic levels of HSP-60 and HSP-72 were significantly
increased in the animals treated with BRX-220. Further, pancreatic total protein
content, amylase and trypsinogen activities were higher with increased
glutathione peroxidase activity. A decrease in plasma trypsinogen activation
peptide concentration, pancreatic lipid peroxidation, protein oxidation, and the
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activity of Cu/Zn-Superoxide dismutase were also observed. The protective
action of BRX-220 on pancreatitis was ascribed directly to its HSP-70 inducing
action.
Whole body hyperthermia in rats leading to induction of HSP-70 has been shown
to protect against subsequent caerulein-induced acute pancreatitis. More
specifically the degradation and disorganization of the actin cytoskeleton, an
important early component of pancreatitis was prevented [Tashiro M. et al.,
Digestion, 2002, Vol. 65 (2), pp. 118-126], hence, reducing damage in
pancreatitis secondary to inflammation. Thus induction of HSP-70 would be
beneficial in treating inflammatory disorders.
Hepatotoxicity
Another example of a pathological stress wherein protective role of HSP-70 has
been implicated is hepatotoxicity. Overproduction of heat shock protein 70 (HSP-
70) in the liver protects hepatocytes under various pathologic conditions. Studies
aimed at examining the effects of HSP-70 inducers, on acute hepatic failure after
95% hepatectomy have shown significantly suppressed release of aspartate or
alanine aminotransferase and elevation of the serum interleukin-6 level [Oda H.
et al, J. Gastrointest. Surg., 2002 May-Jun, Vol. 6(3), pp. 464-472].
The effect of HSP Inducer gadolinium chloride was studied in relation to its effect
on metallothionein and heat shock protein expression in an in-vivo model of liver
necrosis induced by thioacetamide [Andres D. et al., Biochem. Pharmacol., 2003
Sep 15, Vol. 66 (6), pp. 917-926]. Gadolinium significantly reduced serum
myeloperoxidase activity and serum concentration of TNF-alpha and IL-6,
increased by thioacetamide. The extent of necrosis, the degree of oxidative
stress and lipoperoxidation and microsomal FAD monoxygenase activity were
significantly diminished. These beneficial effects are attributed to enhanced
expression of HSP-70 following Gadolinium administration.
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Thus induction of HSP-70 would exert a protective effect in case of
hepatotoxicity.
Sepsis
Yet another pathological condition wherein induction of HSP-70 has been found
to be beneficial is sepsis. Sepsis is a severe illness caused by overwhelming
infection of the bloodstream by toxin-producing bacteria. Induction of HSPs by
heat shock treatment significantly decreased the mortality rate of late sepsis. The
involvement of HSPs during the progression of sepsis could add to a first line of
host defense against invasive pathogens.
Expression of HSP-72 and their protective role has been studied using a rat
model of cecal ligation and puncture [Yang R.C. et al., Kaohsiung J. Med. Sci.,
1998 Nov, Vol. 14 (11), pp. 664-672]. Induction of HSP-70 expression by
Geranylgeranyl acetone has shown to protect against cecal ligation and
perforation induced diaphragmatic dysfunction. It showed a time dependant
induction of HSP-70 in the diaphragm, which attenuated septic diaphragm
impairment. [Masuda Y. et al., Crit. Care Med., 2003 Nov, Vol. 31(11), pp. 2585-
2591]. GGA has found to induce HSP-70 expression in the diaphragm, which
was attributed to be the underlying mechanism for the protective action of GGA
Further experiments indicate that induction of HSP-70 by the administration of
sodium arsenite conferred significant protection against cecal ligation and
perforation-induced mortality [Ribeiro S.P. et al., Crit. Care Med., 1994 Jun, Vol.
22(6), pp. 922-929]. In-vivo Sodium arsenite injection in the absence of an
increase in body temperature induced expression of HSP-72 in the lungs and
protected against experimental sepsis. Protection conferred resulting in reduced
mortality correlated directly with the expression of heat shock protein 72 in the
lungs at 18 and 24 hours after perforation.
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It was observed that induction of heat shock proteins by thermal stress reduced
organ injury and death in a rat model of intra-abdominal sepsis and sepsis-
induced acute lung injury [Villar J. et al., Crit. Care Med., 1994 Jun, Vol. 22 (6),
pp. 914-921].
Acute respiratory distress syndrome (ARDS) provokes three pathologic
processes: unchecked inflammation, interstitial/alveolar protein accumulation and
destruction of pulmonary epithelial cells. Heat shock protein HSP-70 can limit all
three responses, only if expressed adequately. Restoring expression of HSP-70
using adenovirus-mediated gene therapy has shown to be beneficial [Yoram
G.W. et al., J. Clin. Invest. 2002, Vol. 110, pp. 801-806]. HSP-70 administration
significantly attenuated interstitial and alveolar edema along with protein
exudation and dramatically decreased neutrophil accumulation. Approximately 2-
fold higher expression of HSP-70 conferred 68% survival at 48 hours as opposed
to only 25% in untreated animals. Modulation of HSP-70 production reduced the
pathological changes and improved outcome in experimental acute respiratory
distress syndrome. Thus, inducers of HSP-70 would confer protective effect in
sepsis.
Viral diseases
Another pathological condition in which induction of HSP-70 occurs is in case of
viral diseases. Heat shock proteins (HSPs) and molecular chaperones have been
known for several years to protect cells against virus infection [Lindquist S. et al.,
Annu. Rev. Genet., 1988, Vol. 22, pp. 631-637]. It has been demonstrated that
induction of HSP-70 is associated with inhibition of infectious virus production
and viral protein synthesis in monkey kidney epithelial cells infected with
vesicular stomatitis virus (VSV) [Antonio R. et al., J. of Biol. Chem., 1996 Issue of
December 13, Vol. 271 (50), pp. 32196-32196]. The pathogenic activity of Viral
protein R (Vpr) of human immunodeficiency virus type 1 (HIV-1) is related in part
to its capacity to induce cell cycle G2 arrest and apoptosis of target T cells.
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Overexpression of HSP-70 reduced the Vpr-dependent G2 arrest and apoptosis
and also reduced replication of the Vpr-positive, but not Vpr-deficient, HIV-1.
[lordanskiy S. et al., J. Virol., 2004 Sep, Vol. 78 (18), pp. 9697-9704]. Induction of
HSP-70 by prostaglandin A1 (PGA1) caused the suppression of influenza virus
production. [Hirayama E., Yakugaku Zasshi, 2004 Jul, Vol. 124 (7), pp. 437-442].
The antiviral activity of Cyclopentenone prostaglandins is mediated by induction
of HSP-70. It has been shown that increased synthesis of HSP-70 exerts potent
antiviral activity in several DNA and RNA virus models - vesicular stomatitis
virus, sindbis virus, sendai virus, polio virus etc. [Santoro M.G., Experientia,
1994 Nov 30, Vol. 50 (11-12), pp. 1039-1047; Amici C. et al., J. Gen. Virol., 1991
Aug, Vol. 72, pp. 1877-1885; Amici C. et al., J. Virol., 1994 Nov, Vol. 68(11), pp.
6890-6899; Conti C. et al., Antimicrob. Agents Chemother., 1996 Feb, Vol. 40(2),
pp. 367-372; Conti C. et al., Antimicrob. Agents Chemother., 1999 Apr, Vol. 43
(4), pp. 822-829]-. Therefore, induction of HSP-70 would exert antiviral effect.
Allograft rejection
Allograft (transplant of an organ or tissue from one individual to another of the
same species with a different genotype) rejection is a pathological condition
causing induction of HSP-70. HSP-70 induction has a protective effect, which
preserves organ function after transplantation. Kidneys can be preserved only for
a limited time without jeopardizing graft function and survival. Induction of heat
shock proteins (HSPs) has been found to improve the outcome following
isotransplantation after an extended period of cold storage. Heat precondition
induced the expression of HSP-70 and the grafts were protected against
structural ischemia-reperfusion injuries when assessed histologically. [Wagner M.
et al., Kidney Int., 2003 Apr, Vol. 63 (4), pp. 1564-1573]. There was inhibition of
apoptosis and activation of caspase-3 was found to be inhibited.
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Geranylgeranyl acetone, a non-toxic heat shock protein inducer has been studied
in a rat orthotopic liver transplantation model to study the beneficial effects in
warm ischemia-reperfusion injury [Fudaba Y. et al., Transplantation, 2001 Jul 27,
Vol. 72(2), pp. 184-189]. GGA administration accumulated mRNA for both HSP-
72 and HSP 90 in the livers even before warm ischemia and facilitated the
syntheses of HSP-72 and HSP 90 after warm ischemia. Further, GGA
pretreatment also significantly reduced the serum levels of tumor necrosis factor-
alpha after reperfusion. The findings indicate that both the enhanced induction of
HSPs and the downstream events would be involved in the beneficial effects of
GGA on ischemia-reperfusion injury. Besides, compared to donors treated with
vehicle were all recipients died of primary non-function, when donors were
treated with Geranylgeranyl acetone (GGA) the 7-day survival of the recipients
was closed to 90%.
Investigations revealed an inverse relationship between HSP expression and
rejection with the possibility that elevated levels of HSP in the myocardium
results in low rejection of heart transplants. [Baba H.A. et al., Transplantation,
1998 Mar 27, Vol. 65 (6), pp. 799-804]. Significant improvement of post-ischemic
recovery of mechanical function in HSP-70 gene transfected hearts compared to
controls were observed following a protocol mimicking conditions of preservation
for heart transplantation. These results confirmed the findings observed
previously in cell culture models and extended then to show the role of HSP-70 in
protecting against ischemia-reperfusion injury in a whole-heart model, which
parallels more closely the clinical situation. [Jayakumar J. et al., Circulation,
2000, Vol. 102 [suppl III], pp. III-302 to III-306].
The heat shock response also exerts a protective effect on skin flap ischemia.
Heat shock protein (HSP) expression is augmented in-vivo with the
administration of high dose aspirin before heat treatment [Ghavami A. et al., Ann.
Plast. Surg., 2002 Jan, Vol. 48(1), pp. 60-67]. Immunohistochemistry confirmed
HSP expression, and skin flap survival was improved significantly. Thus, HSP-
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70 induction would be beneficial in preserving organ function after
transplantation.
Tumorous diseases
Induction of HSP-70 has also been shown to be advantageous in treating
neoplasms. Enhanced expression of HSP-70 has been found to help in causing
tumor regression in various animal models. Heat shock proteins (HSPs) are
involved in the development of resistance (thermotolerance) to subsequent
hyperthermic stresses as well as enhancement of the clinical response of certain
chemotherapeutic agents in cancers such as the prostate. Colony formation
assays revealed sensitizing effect of hyperthermia when simultaneously
combined with each chemotherapeutic agent, resulting in a potentiated localized
cytotoxicity [Roigas J. et al., Prostate, 1998 Feb 15, Vol. 34 (3), pp. 195-202].
Synchronous application of chemotherapeutic agents and hyperthermia has been
shown to have synergistic cytotoxic effect on Dunning rat adenocarcinoma of the
prostate. Furthermore it is demonstrated that the induction of HSPs in
thermotolerant cells, as measured by HSP-70 induction, results in a modulation
of the chemotherapeutic-mediated cytotoxicity.
Direct induction of heat shock proteins are recognized to contribute significantly
in cancer immunity. Anti-tumor immunity is induced by hyperthermia and further
enhanced by administration of recombinant HSP-70 protein into the tumor in-situ.
[Ito A. et al., Cancer Immunol. Immunother., 2004 Jan, Vol 53(1), pp. 26-32]. The
induction of hyperthermia using a 500 KHz alternating magnetic field combined
with magnetite cationic liposomes, which have a positive charge and generate
heat in an alternating magnetic field along with administration of recombinant
HSP-70 protein into the subcutaneous murine melanoma inhibited tumor growth
over a 30-day period and complete regression of tumors was observed in 20% of
mice. It was also found that systemic anti-tumor immunity was induced in cured
mice. In another study carried out to determine whether anti-tumor immunity
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induced by hyperthermia is enhanced by HSP-70 gene transfer [Ito A. et al.,
Cancer Gene Ther., 2003 Dec, Vol. 10(12), pp. 918-925] showed that the
combined treatment strongly arrested tumor growth over a 30-day period and
complete regression of tumors was observed in 30% mice. Thus, induction of
HSP-70 would be useful for the treatment of tumorous diseases.
Gastric mucosal damage
Gastric mucosal damage caused by insults derived from ingested foods and
Helicobacter pylori infection constitute another pathological condition causing
induction of HSP-70. Gastric surface mucous cells are the first line of defense
against such insults. Primary cultures of gastric surface mucous cells from
guinea-pig fundic glands exhibited a typical heat shock response after exposure
to elevated temperature or metabolic insults, such as ethanol and hydrogen
peroxide, and they were able to acquire resistance to these stressors. HSP-70
mRNA protein has been induced in rat gastric mucosa following stress and the
extent of induction inversely correlated with the severity of mucosal lesions
suggesting protective role of HSP-70 in gastric mucosal defense. [Rokutan K., J.
Gastroenterol. Hepatol., 2000 Mar, Vol. 15 Suppl, pp. D12-9].
Brain haemorrhage
Another pathological condition causing induction of HSP-70 is in case of brain
haemorrhage. Studies with Bimoclomol showed an ability to reduce the
pathological increase in the permeability of blood brain barrier during
cerebrovascular injury, particularly if the vascular insult is evoked by sub-
arachnoidal autologous blood [Erdo F. et al., Brain Research Bulletin, 1998, Vol.
45(2), pp.163-166]. Bimoclomol strongly reduced the size of cerebral tissue
stained with Evans blue leakage by 39 %. Bimoclomol confers beneficial
influences in experimental sub-arachnoid haemorrhage through its co-inducer
effect on HSP-72 expression.
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Endothelial dysfunctions
Various endothelial dysfunctions constitute pathological conditions which results
in induction of HSP-70 in the body cells. The effect of a co-inducer of heat shock
proteins, Bimoclomol treatment on endothelial function and expression of 72 Kd
heat shock protein was investigated in spontaneously hypertensive rats
[Jednakovits A. et. al., Life Sci., 2000 Aug 25, Vol. 67(14), pp. 1791-1797].
Significant age- dependant decline in relaxation to acetylcholine and vascular
HSP-72 mRNA levels were observed in SHR animals. These changes were
found to be prevented by application of Bimoclomol suggesting the relationship
between preservation of endothelial function with sustained levels of HSP-72.
Diabetic Complications
Complications arising in diabetic patients such as neuropathy, nephropathy and
delayed wound healing constitute pathological conditions wherein protective role
of HSP-70 has been implicated.
(a) Diabetic Neuropathy
Endoneurial microangiopathy causing nerve infarctions is considered to be
involved in the pathogenesis of diabetic neuropathy [Malik R.A. et al., Diabetic
Neuropathy: New Concepts and Insights, 1995, pp 131-135]. Experimental
evidence is suggestive of a protective effect of HSP-72 induction on diabetic
neuropathy [Biro K. et. al., Brain Research Bulletin, 1997, Vol. 44(3), pp. 259-263
]. Treatment with Bimoclomol, by virtue of its HSP-70 inducing property
significantly reduced nerve conduction slowing, motor by 38 % and sensory by
42%, which show a dose dependant response. It also retarded the typical
elevated ischemic resistance due to streptozotocin-induced neuropathy by 71%.
These effects were observed at doses known to induce transcription of HSP-72
in other tissues like heart and kidney in response to ischemia.
(b) Diabetic Retinopathy
16

Diabetic retinopathy is associated with the breakdown of the blood-retinal barrier
(BRB) and results in macular edema, the leading cause of visual loss in diabetes.
The HSP co-inducer Bimoclomol (BRLP-42) has shown efficacy in diabetes-
induced retinopathy [Hegedius S. et al., Diabetologia, 1994, Vol. 37, p. 138]. The
protection reflected in lower degree of edema in and beneath the photoreceptor
zone, almost normal arrangement of retinal pigment epithelial microvilli and a
more compact and even retinal capillary basement membrane. [Biro K. et al,
Neuro Report, 1998 Jun 22, Vol.9(9), pp. 2029-2033]. Improvements are
attributed to the cytoprotective effect of Bimoclomol on retinal glia and /or
neurons against diabetes related ischemic cell damages. Further, overexpression
of HSP-70 has shown protective effect on retinal photic injuries [Kim J.H. et al.,
Korean J. Ophthalmol. 2003 Jun, Vol. 17(1), pp. 7-13].
(c) Chronic wound healing
HSPs are involved in regulation of cell proliferation. Impaired expression of HSP-
70 has been associated with delayed wound healing in diabetic animals
[McMurtry A.L. et al., J. Surg. Res., 1999, Vol. 86, pp. 36-41]. Faster and
stronger healing is achieved by activation of HSP-70 in a wound by laser [Capon
A. et al., Lasers Surg. Med, 2001, Vol. 28, pp. 168-175].
Thus, induction of HSP-70 would be beneficial in treating various diabetic
complications.
Neuro-degenerative diseases
Neurodegenerative diseases such as Alzheimer's disease, Amyotrophic lateral
sclerosis and Parkinson's disease constitute a set of pathological conditions
wherein HSP-70 has been implicated to exert a protective affect and delay the
progression of these diseases.
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(a) Alzheimer' s diseaseis a neurodegenerative disorder characterized by
beta-amyloid and tau protein aggregates (neurofibrillary tangles) Increased levels
of HSP (8-10 fold increase) in various cellular models have shown to promote tau
solubility and tau binding to microtubules, reduce insoluble tau and cause
reduced tau phosphorylation. Hence upregulation of HSP will suppress formation
of neurofibrillary tangles. [Dou F. et al., Proc. Natl. Acad. Sci. USA, 2003 Jan 21,
Vol. 100 (2), pp. 721-726]. Studies have shown that virally mediated HSP-70
overexpression rescued neurons from the toxic effects of intracellular beta-
amyloid accumulation. [Magrane J. et al., J. Neurosci., 2004 Feb 18, Vol. 24 (7),
pp. 1700-1706].
(b) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition
in which motor-neurons of the spinal cord and motor cortex die, resulting in
progressive paralysis. Etiology of ALS involves mutation in the gene encoding
Cu/Zn superoxide dismutase-1 (SOD1). Treatment with arimoclomol, an inducer
of heat shock proteins (HSPs), significantly delays disease progression in
transgenic mice overexpressing human mutant SOD1 that shows a phenotype
and pathology that is very similar to that seen in human ALS patients. [Kieran D.
et al., Nat. Med, 2004 April,Vol 10 (4), pp. 402-405; Susanna C. B. et al., Nat.
Med., 2004, Vol. 10, pp. 345-347].
(c) Parkinson' s disease is a common neurodegenerative disease
characterized by the loss of dopaminergic neurons in the substantia nigra pars
compacta and the accumulation of the misfolded protein alpha-synuclein into
aggregates called Lewy bodies and Lewy neuritis, which are very cytotoxic.
Mitochondrial dysfunction, oxidative stress, protein misfolding, aggregation, and
failure in the proteasomal degradation of specific neuronal proteins have been
implicated in pathogenesis of Parkinson disease (PD). Upregulation of HSP-70
by HSP-70 gene transfer to dopamine neurons by a recombinant adeno-
associated virus significantly protects the mouse dopaminergic system against
MPTP-induced dopamine neuron loss and the associated decline in striatal
18

dopamine levels. [Dong Z. et al., Mol. Ther., 2005 Jan, Vol. 11(1), pp. 80-88].
Recent experimental evidences show that deprenyl and other propargylamines
which are used clinically in treating Parkinson's disease increase neuronal
survivability by increasing synthesis of HSP-70 and other anti-apoptotic proteins.
[Tatton W. et al., J. Neural. Transm., 2003 May, Vol. 110(5), pp. 509-515].
Introducing HSP-70 in alpha-synuclein transgenic mice by breeding with HSP-70
overexpressing mice led to significant reduction in misfolded and aggregated
alpha-synuclein in the progeny. [Klucken J. et al., J. Biol. Chem., 2004 Jun 11,
Vol. 279 (24), pp. 5497-5502]. Recent evidences show that Geldanamycin
protects neurons against alpha-synuclein toxicity by enhancing the HSP-70
mediated chaperonic activity. [Auluck P.K. et al., J. Biol. Chem., 2005 Jan 28,
Vol. 280 (4), pp. 2873-2878].
Thus, HSP-70 inducers would be useful in the treatment and delaying the
progression of the above neurodegenerative disease conditions.
Epilepsy
One of the pathological condition wherein protective role of HSP-70 has been
implicated is seizures (epilepsy). Studies have shown that hsp70 mRNA and
protein are upregulated in response to kainic acid induced seizures in many
areas of the limbic system and cortex in rat brain (Hashimoto K, Minabe Y.; Brain
Res. 1998; 212-23; Akbar et al.; J. Brain Res Mol Brain Res. 2001; 93(2):148-63)
Kainic acid induced seizures in rats represent an established animal model for
human temporal lobe epilepsy, the most common form of adult human epilepsy.
HSP70 expression in the hippocampus positively correlates with the severity of
KA induced limbic seizure (Zhang et al.; Eur J Neurosci. 1997; 9(4):760-9).
Hsp72 over expression (gene therapy) in rats improved survival of hippocampal
neurons (Yenari et al.; Ann Neurol. 1998; 44(4):584-91). Kainic acid shows a
dose dependent severity of seizure which positively correlates with hsp70
induction.
19

Post-traumatic neuronal damage
Pathological stress associated with post-traumatic neuronal damage cause
induction of HSP-70 in the neuronal tissues. The expression of HSP-70 following
traumatic injury to the neuronal tissue has been speculated to be part of a
cellular response, which is involved in the repair of damaged proteins [Dutcher
S.A et al., J. Neurotrauma, 1998, Vol. 15 (6), pp. 411-420]. BRX-220, an inducer
of HSP-70 has been examined for its effect on the survival of injured
motoneurones following rat pup sciatic nerve crush [Kalmar B. et al., Exp.
Neural., 2002 Jul, Vol. 176 (1), pp. 87-97]. It has been found that significantly
more number of neurons survived with BRX-220 treatment and there was no
further loss of motoneurones.14 days after injury, 39 % of motoneurones
survived in BRX220 treated group compared to 21% in vehicle group. Moreover
in BRX 220 treated group no further loss of motoneurones occurred, at 10 weeks
42 % of motoneurons survived compared to 15% in untreated group. There were
also more functional motor units in the hind limb muscles of the treated group
compared to that of the control. These observations were correlated to elevated
levels of HSP-70 and this compound protects motoneurones from axotomy-
induced cell death through a HSP-70 mediated mechanism. Therefore, induction
of HSP-70 would be beneficial in post-traumatic neuronal damage.
Acute Renal Failure
Another pathological condition causing induction of HSP-70 is acute renal failure.
Acute renal failure is the sudden loss of the ability of the kidneys to excrete
wastes, concentrate urine and conserve the electrolytes. Induction of heat shock
proteins (HSPs) plays a protective role in ischaemic acute renal failure.
Administration of Sodium arsenite or Uranyl acetate in cisplatin-induced acute
renal failure resulted in significant increase in HSP-72 expression. Both Sodium
arsenite and Uranyl acetate attenuated the cisplatin-induced increase in serum
creatinine and tubular damage scores [Zhou H. et al., Pflugers Arch., 2003 Apr,
20

Vol. 446 (1), pp. 116-124]. Findings suggest that HSP-72 attenuates CDDP-
induced nephrotoxicity. The protective effects of HSP-72 are associated with an
increased Bcl-2/Bax ratio and reduced apoptosis.
Glaucoma
Still another pathological condition which causes induction of HSP-70 is
glaucoma. Glaucoma is characterized by rising intraocular pressure and
subsequent damage to the optic nerve with selective loss of retinal ganglion cells
(RGCs). It has been postulated that apoptosis, a highly regulated process of cell
death, is the final common pathway for RGC death in glaucoma. Studies suggest
that the induced expression of HSP-72 enhances RGC survival in harmful
conditions and ameliorates glaucomatous damage in a rat model [Ishii Y. et al.,
Invest. Ophthalmol. Vis. Sci., 2003 May, Vol. 44(5), pp. 1982-1992]. The study
revealed that HSP-72 expression was increased in retinal ganglion cells after
administration of HSP inducer geranylgeranyl acetone. The treatment further
reduced the loss of retinal ganglion cells, reduced optic nerve damage and
decreased the number of TUNEL positive cells in retinal ganglion cell layer.
Aging related skin degeneration
There is an attenuation of induction of HSP-70 in human keratocytes with aging
[Verbeke P. et al., Cell Biol. Int., 2001, Vol. 25 (9), pp. 845-857]. Furthermore,
human skin cells have been shown to maintain several characteristics of young
cells until late in life, when exposed to repetitive mild heat shocks [Rattan S.I. et
al., Biochem. Mol. Biol. Int., 1998, Vol. 45(4), pp. 753-759].
Over expression of heat shock protein gene is sufficient to protect against
otherwise lethal exposures to heat, ischemia, cytotoxic drugs, and toxins. The
above examples illustrate the ability of HSP-70 to protect cells against various
pathological stresses contributing towards different diseases.
21

US 5348945 describes methods for enhancing the survivality of cells and tissues
by treating the same with exogenous HSP-70.
A number of compounds have been reported to be useful for increasing levels of
HSPs thereby treating a range of disorders.
US 6096711 discloses methods for inducing HSP-72 production in an aged cell
by contacting the aged cell with a proteasome inhibitor, and treating stress-
induced pathologies associated with apoptosis and inflammation in aged
individuals.
US 6174875 discloses methods for inducing HSP-70 and treating neurological
injuries resulting from cardiac arrest and stroke by inhibiting cell death induced
by oxidative stress, with benzoquinoid ansamycins.
US 6653326 describes methods for increasing expression of molecular
chaperones, including HSP-70 using hydroxylamine derivatives, and thereby
treating stress related diseases like stroke, cerebrovascular ischaemia,
coronarial diseaseas, allergic diseases, immune diseases, autoimmune
diseases, diseases of viral or bacterial origin, tumourous, skin and/or mucous
diseases, epithelial disease of renal tubules, atherosclerosis, pulmonary
hypertonia and traumatic head injury.
In view of the advantages associated with increased expression of HSP-70 in
cells, a method, which increases such expression or increases activity of HSP-70
would be highly advantageous for prevention and treatment of various diseases.
Small molecules that either enhances the expression or function of heat shock
proteins could have promise in chronic or acute treatment of certain human
diseases.
22

Compounds of the present invention have been categorically shown to induce
HSP-70. Therefore, these compounds would be beneficial in the prevention and
treatment of conditions where HSP induction has been shown to protect in
various diseased states, for example in stroke, myocardial infarction,
inflammatory diseases, diseases of viral origin, tumourous diseases, brain
haemorrhage, endothelial dysfunctions, diabetic neuropathy, hepatotoxicity,
acute renal failure, glaucoma, sepsis, gastric mucosal damage, allograft
rejection, chronic wounds in diabetics, neurodegenerative diseases, epilepsy,
post-traumatic neuronal damage and aging-related skin degeneration.
Reference may be made to United States patent US4177241, which describes
hydroxy- and oxo- substituted alpha-benzylidenecycloalkanones having
pharmacological activity on the central nervous system such as antidepressant.
The phenyl ring is essentially a disubstituted ring where in the substitution is
selected from methoxy or methylenedioxy group.
US6288235 describes the 2,4-dioxopipridine compounds as useful intermediates
which can be used for synthesizing libraries on solid supports.
WO 01/40188 US2004009914, US2005069551, US20060089378 describes the
compounds which structurally differs from the compounds of the present
invention.
WO06087194 relates to 4-piperidone compounds useful as a dye composition
comprising an oxonol type methine direct dye for the process of dyeing keratin
fibres.
None of the prior art as mentioned above neither teaches nor suggest use of the
compounds as HSP inducers.
23

DETAILED DESCRIPTION OF THE INVENTION:
One embodiment of the present invention provides for novel compounds of
general formula (I),

their pharmaceutically acceptable salts and their hydrates, solvates,
stereoisomers, conformers , tautomers, polymorphs and prodrugs thereof.
In an alternative embodiment of the present invention there is provided novel
compounds of general formula (II),

their pharmaceutically acceptable salts and their hydrates, solvates,
stereoisomers, conformers, tautomers, polymorphs and prodrugs thereof,
wherein, R1 is selected from unsubstituted or substituted:
24

a.Four to twelve membered monocyclic or bicyclic aryl,
b.Five to twelve membered monocyclic or bicyclic heteroaryl wherein, it contains
one or more heteroatoms selected from nitrogen, oxygen and sulphur, or
c.Four to twelve membered monocyclic or bicyclic heterocyclyl wherein, it
contains one or more heteroatoms selected from nitrogen, oxygen and sulphur.
Examples of such aryl, heteroaryland heterocyclyl systems are phenyl, naphthyl,
pyridinyl, pyrazinyl, pyradiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl,
quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, pyrazolyl, pyrrolyl, triazolyl,
tetrazolyl, thienyl, oxazolinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl,
imidazolidinyl, oxadiazolinyl, thiadiazolinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiomorpholin 1,1-dioxide, piperidinyl, pyrrolidinyl, imidazolidinyl,
pyrazolidinyl, thiazolidinyl, hexahydropyridazinyl, hexahydropyrimidinyl,
hexahydropyrazinyl, azepanyl, diazepanyl, thiazepanyl, azepinyl, benzopyrazolyl,
indolinyl, indolyl, phthalanyl, benzothiophenyl, benzofuryl, benzopyrrolyl,
benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,
benzotriazolyl, benzothiadiazolyl and benzoxadiazolyl;
Said aryl, heteroaryl, heterocyclyl when substituted, it is substituted by one to
eight substituents of R8, wherein R8 is independently selected from the group
consisting of:
halogen,
-OH,
-SH
-Cmalkyl,
nitro,
amino,
cyano,
-N(R9)C(O)(C1-8alkyl),
-N(R9)C(O)(aryl),
-N(R9)C(O)(heteroaryl),
25

-N(R9)C(O)(heterocyclyl),
-N(R9)SO2(C1-8alkyl),
-N(R9)9SO2(aryl),
-N(R9)S02(heteroaryl),
-N(R9)SO2(heterocyclyl),
-N(R9)SO2CF3,
-COOH,
-C(O)N(R9)(R9),
-C(O)N(R9)(aryl),
-C(O)N(R9)(heteroaryl),
-C(0)N(R9)(heterocyclyl),
-SO2N(R9)2,
-SO2N(R9)(aryl),
-S02N(R9)(heteroaryl),
-S02N(R9)(heterocyclyl),
-C(O)O-(C1-8alkyl),
-C(O)O-aryl,
-C(0)0-heteroaryl,
-C(O)O-heterocyclyl,
-N(R9)C(O)O-(C1-8alkyl),
-N(R9)C(O)O-aryl,
-N(R9)C(O)O-heteroaryl,
-N(R9)C(O)O-heterocyclyl,
-CF3,
-C(O)CF3,
-SO2CF3,
-(C1-8alkyl)m-O(C1-8alkyl),
-(C1-8alkyl)m-O(aryl),
-(C1-8alkyl)m -O(heteroaryl),
-(C1-8alkyl)m -O(heterocyclyl),
-(C1-8alky)m-N(R9)(C1-8alkyl),

26

-(C1-8alkyl)m -N (R9)(aryl),
-(C1-8alkyl)m -N (R9)(heteroaryl),
-(C1-8alkyl)m -N (R9)(heterocyclyl),
-(C1-8alkyl)m-C(O)(C1-8alkyl),
-(C1-8alkyl)m-C(O)(aryl),
-(C1-8alkyl)m -C(O)(heteroaryl),
-(C1-8alkyl)m-C(0)(heterocyclyl),
-C(O)(C1-8alkyl)-aryl,
-C(0)(C1-8alkyl)-heteroaryl,
-C(O)(C1-8alkyl)-heterocyclyl,
-(C1-8alkyl)m -S(O)(C1-8 alkyl),
-(C1-8alkyl)m-S(O)(aryl),
-(C1-8alkyl)m-S(O)(heteroaryl),
-(C1-8alkyl)m-S(O)(heterocyclyl),
-(C1-8alkyl)m-S(O)2(C1-8alkyl),
-(C1-8alkyl)m-S(O)2O(C1-8alkyl),
-(C1-8alkyl)m-SO2(aryl),
-(C1-8alkyl)m -S02(heteroaryl),
-(C1-8alkyl)m-SO2(heterocyclyl),
-N(R9)(SO2-aryl),
-N(R9)(SO2-heteroaryl),
-N(R9)(SO2-heterocyclyl),
-N(R9)C(O)N(R9)(R9),
-N(R9)C(O)N(R9)(aryl),
-N(R9)C(O)N(R9)(heteroaryl),
-N(R9)C(O)N(R9 )(heterocyclyl),
-N(R9)C(O)C(O)N(R9)(R9),
-N(R9)C(O)C(O)N(R9)(aryl),
-NR9C(0)C(0)N(R9)(heteroaryl),
-N(R9)C(0)C(0)N(R9)(heterocyclyl),
-N(R9)C(S)N(R9)(R9),

27

-N(R9)C(S)N(R9)(aryl),
-N(R9)C(S)N(R9)(heteroaryl),
-N(R9)C(S)N(R9)(heterocyclyl),
-N(R9)SO2N(R9) (R9),
-N(R9)SO2N(R9)(aryl),
-N(R9)S02N(R9)(heteroaryl),
-N(R9)S02N(R9)(heterocyclyl),
-S(C1-8alkyl),
-SO2OH,
-NHC(NH)NH2,
-N(R9)(aryl),
-N(R9)(heteroaryl),
-N(R9)(heterocyclyl),
-(C1-8alky)m-aryl,
-(C1-8alkyl)m-heteroaryl,
-(C1-8alkyl)m-heterocyclyl
- oxo, and
-thioxo;
R9 is selected from hydrogen or (C1-8alkyl);
wherein, aryl present as a substituent in R8 is four to seven membered
monocyclic ring and heteroaryl and heterocyclyl present as a further substituent
in R8 is three to seven membered monocyclic ring system which contains one or
more heteroatoms selected froml nitrogen, oxygen and sulphur; wherein the aryl,
heteroaryl and heterocyclyl are unsubstituted or substituted with one to three
substituents independently selected from the group consisting of:
oxo,
halogen,
-OH,
-SH,
-C1-8alkyl,
28

-O(C1-8alkyl),
nitro,
amino,
mono(C1-8alkyl)amino,
di(C1-8alkyl)amino,
-COOH,
-CONH2,
-CF3,
-C(O)CF3,
-SO2CF3,
-S(C1-8alkyl),
-SO2(C1-8alkyl), and
-SO2NH2;
wherein, the above said Ci-8alkyl is straight, branched or cyclic and may contain
one or two double or triple bonds and is substituted with one to two substituents
independently selected from the group consisting of:
-OH,
-SH,
oxo,
thioxo,
amino,
mono(C1-3alkyl)amino,
di(C1-3alkyl)amino,
-S(C1-3alkyl), and
-C1-3alkoxy;
wherein C1-3
alkoxy is straight or branched, may contain one or two double or
triple bonds; C1-3alkyl is straight or branched;
R9 is selected from hydrogen or (C1-C8)alkyl;
m is zero or one;
with the proviso that when R1 is selected from unsubstituted or substituted
a) cyclohexane,
29

b) cyclohexene,
c) six membered monocyclic heteroaryl or heterocyclyl having one to two
heteroatoms selected from nitrogen, oxygen or sulphur, Re is not selected from
hydroxyl and oxo group.
R2 is selected from the group consisting of:
hydrogen,
halogen,
-C1-3alkyl,
-OH,
-SH,
-O(C1-3alkyl),
amino,
mono(C1-3alkyl)amino,
di(C1-3alkyl)amino,
-C(O)CF3,
-C(O)CH3,
-SO2CF3,
-CF3
-S(C1-8alkyl),
-SO2(C1-8alkyl), and
-SO2NH2;
wherein, the above said C1-8alkyl is straight, branched or cyclic and may contain
one or two double or triple bonds and is substituted with one to two substituents
independently selected from the group consisting of:
-OH,
-SH,
oxo,
thioxo,
amino,
mono(C1-3alkyl)amino,
30

di(C1-3alkyl)amino,
-S(C1-3alkyl), and
-C1-3alkoxy;
Wherein, C1-3alkoxy is straight or branched, may contain one or two double or
triple bonds; C1-3alkyl is straight or branched.
R3 is selected from the group consisting of:
halogen,
nitro,
amino,
-OH,
-SH,
-N(R9)C(O)(C1-8alkyl),
-N(R9)C(O)(aryl),
-N(R9)C(O)(heteroaryl),
-N(R9)C(O)(heterocyclyl),
-N(R9)SO2(C1-8alkyl),
-N(R9)SO2(aryl),
-N(R9)SO2(heteroaryl),
-N(R9)SO2(heterocyclyl),
-(C1-3alkyl),
-(C1-3alkyl)m-aryl,
-(C1-3alkyl)m-heteroaryl,
-(C1-3alkyl)m-heterocyclyl,
-C(O)N(R9) (R9),
-C(O)N(R9)(aryl),
-C(O)N (R9) (heteroaryl),
-C(O)N(R9) (heterocyclyl),
-SO2N((R9) (R9),
-SO2N(R9)(aryl),
-SO2N(R9)(heteroaryl),
31

-S02N(R9)(heterocyclyl),
-N(R9)SO2CF3,
-C(O)O-(C1-8alkyl),
-C(O)O-aryl,
-C(O)O-heteroaryl,
-C(O)O-heterocyclyl,
-N(R9)C(O)O-(C1-8alkyl),
-N(R9)C(O)O-aryl,
-N(R9)C(O)O-heteroaryl,
-N(R9)C(O)O-heterocyclyl,
-CF3,
-C(O)CF3,
-SO2CF3l
-COOH,
-(C1-3alkyl)m-O(C1-8alkyl),
-(C1-3alkyl)m-N((R9)(C1-8alkyl),
-(C1-3alkyl)m -C(O)(C1-8alkyl),
-(C1-3alkyl)m-C(O)(aryl),
-(C1-3alkyl)m -C(O)(heteroaryl),
-(Ci.3alkyl)m-C(O)(heterocyclyl),
-C(O)(C1-3alkyl)-aryl,
-C(0)(C1-3alkyl)-heteroaryl,
-C(O)(C1-3alkyl)-heterocyclyl,
-(C1-3alkyl)-C(O)(C1-3alkyl)-aryl,
-(C1-3alkyl)-C(O)(C1-3alkyl)-heteroaryl,
-(C1-3alkyl)-C(O)(C1-3alkyl)-heterocyclyl,
-(C1-3alkyl)m -S(O)(C1-8alkyl),
-(C1-3alkyl)m-S(O)(aryl),
-(C1-3alkyl)m-S(0)(heteroaryl),
-(C1-3alkyl)m-S(O)(heterocyclyl),
-(C1-3alkyl)m -S(O)2(C1-8alkyl),

32

-(C1-3alkyl)m -S(O)2O-(C1-3alkyl),
-(C1-3alkyl)m-SO2(aryl),
-(C1-3alkyl)m -SO2(heteroaryl),
-(C1-3alkyl)m-SO2(heterocyclyl),
-S(O)2-(C1-3alkyl)-aryl,
-S(O)2-(C1-3alkyl)-heteroaryl,
-S(O)2-(C1-3alkyl)-heterocyclyl,
-(C1-3alkyl)SO2-(C1-3alkyl)-aryl
-(C1-3alkyl)S02-(C1-3alkyl)-heteroaryl
-(C1-3alkyl)S02-(C1-3alkyl)-hetrocyclyl,
-N(R9)SO2(aryl),
-N(R9)SO2(heteroaryl),
-N(R9)SO2(heterocyclyl),
-N(R9)C(O)N((R9)(R9),
-N(R9)C(O)N(R9)(aryl),
-N(R9)C(O)N(R9)(heteroaryl),
-N(R9)C(0)N(R9)(heterocyclyl),
-N(R9)C(O)C(O)N((R9)(R9),
-N(R9)C(O)C(O)N(R9)(aryl),
-N(R9)C(O)C(O)N(R9)(heteroaryl),
-N(R9)C(0)C(0)N(R9)(heterocyclyl),
-N(R9)C(S)N(R9)(R9),
-N(R9)C(S)N(R9)(aryl),
-N(R9)C(S)N(R9)(heteroaryl),
-N(R9)C(S)N(R9)(heterocyclyl),
-N(R9)SO2N(R9)(R9),
-N(R9)SO2N(R9)(aryl),
-N(R9)SO2N(R9)(heteroaryl),
-N(R9)S02N(R9)(heterocyclyl),
-S(Ci.8alkyl),
-SO2OH,

33

-NHC(=NH)NH2,
-(C1-3alkyl)m-O(aryl),
-(C1-3alkyl)m -O(heteroaryl),
-(C1-3alkyl)m -O(heterocyclyl),
-(C1-3alkyl)m-N(R9)(aryl),
-(C1-3alkyl)m-N(R9)(heteroaryl),
-(C1-3alkyl)m-N(R9)(heterocyclyl),
-C(O)C(O)(aryl),
-C(0)C(0)(heteroaryl), and
-C(0)C(0)(heterocyclyl);
wherein, said aryl present as a substituent in R3 is four to seven membered
monocyclic ring and heteroaryl and heterocyclyl present as a substituent in R3
are three to seven membered monocyclic ring containing one or more
heteroatoms selected from nitrogen, oxygen and sulphur, wherein the said aryl,
heteroaryl and heterocyclyl are unsubstituted or substituted with one to three
susbstituents independently selected from the group consisting of:
oxo,
-OH,
-SH,
halogen,
-C1-8alkyl,
-O(C1-8alkyl),
nitro,
amino,
mono(C1-8alkyl)amino,
di(C1-8alkyl)amino,
-COOH,
-CONH2
-CF3,
-C(O)CF3,
-SO2CF3,
34

-S(C1-8alkyl),
-SO2(C1-8alkyl), and
-SO2NH2;
Wherein, the above said C1-8alkyl is straight, branched or cyclic, may contain one
or two double or triple bonds and is with one to two substituents independently
selected from the group consisting of:
-OH,
-SH,
Oxo,
thioxo,
amino,
mono(C1-3alkyl)amino,
d(C1-3alky)amino,
-S(C1-3alkyl), and
-C1-3alkoxy;
wherein C1-3alkoxy is straight or branched, may contain one or two double or
triple bonds; C1-3alkyl is straight or branched;
m is zero or one.
R4 and R5 is independently selected at each occurrence from hydrogen or R8 or
either R4 or R5 together with R7 is oxo;
with the proviso that when R 4 is oxo, R 3 is not selected from -C(O)(C1-8alkyl), -
C(O)O(C1-8alkyl), -C(O)(C1-8alkyl)- aryl, -C(O)aryl, -C(O)thienyl, -C(O)furyl ;
R6 is selected from the group consisting of:
-(C1-8alkyl),
-C(O)N(R9)(R9),
-C(O)N(R9)(aryl),
-C(O)N(R9)(heteroaryl),
-C(0)N(R9)(heterocyclyl),
-C(S)N(R9)(R9),
35

-C(S)N(R9)(aryl),
-C(S)N(R9)(heteroaryl),
-C(S)N(R9)(heterocyclyl),
-SO2N(R9)(R9),
-SO2N(R9)(aryl),
-S02N(R9)(heteroaryl),
-SO2N(R9)(heterocyclyl),
-C(O)C(O)N(R9)(R9),
-C(O)C(O)N(R9)(aryl),
-C(0)C(0)N(R9)(heteroaryl),
-C(0)C(0)N(R9)(heterocyclyl),
-C(O)O-C-(C1-8alkyl),
-C(O)O-(C1-8alky)m-aryl,
-C(O)O-(C1-8alky)m-heteroaryl,
-C(0)0-(C1-8alkyl)m-heterocyclyl,
-CF3,
-C(O)CF3,
-SO2CF3,
-(C1-8alkyl)O(C1-8alkyl),
-(C1-8alky)-O(laryl),
-(C1-8alkyl)-O(heteroaryl),
-(C1-8alkyl)-O(heterocyclyl),
-(C1-8alkyl)-N(R9)(C1-8alkyl),
-(C1-8alkyl)-N(R9)(aryl),
-(C1-8alkyl)-N(R9)(heteroaryl),
-(C1-8alkyl)-N(R9)(heterocyclyl),
-(C1-8alkyl)mC(O)(C1-8alkyl),
-(C1-8alkyl)m-C(O)(aryl),
-(C1-8alkyl)m -C(O)(heteroaryl),
-(C1-8alkyl)m-C(O)(heterocyclyl),
-C(O)-(C1-8alkyl)-aryl,

36

-C(O)-(C1-3alkyl)-heteroaryl,
-C(O)-(C1-3alkyl)-heterocyclyl,
-(C1-8alkyl)-C(O)(C1-8alkyl)-aryl,
-(C1-8alkyl)-C(0)(C1-8alkyl)-heteroaryl,
-(C1-8alkyl)-C(0)(C1-8alkyl)-heterocyclyl,
-{C1-8alkyl)m -SO2(C1-8alkyl),
-(C1-8alkyl)m-SO2(aryl),
-(C1-8alkyl)m -SO2(heteroaryl),
-(C1-8alkyl)m-SO2(heterocyclyl),
-(C1-8alkyl)-S(O)(C1-8alkyl),
-(C1-8alkyl)-S(O)(aryl),
-(C1-8alkyl)-S(O)(heteroaryl),
-(C1-8alkyl)-S(O)(heterocyclyl),
-S(O)2(C1-8alkyl)-aryl,
-S(O)2(C1-8alkyl)-heteroaryl,
-S(O)2(C1-8alkyl)-heterocyclyl,
-(C1-8alkyl)-SO2-(C1-8alkyl)-aryl
-(C1-8alkyl)-S02-(C1-8alkyl)-heteroaryl,
-(C1-8alkyl)-SO2-(C1-8alkyl)-heterocyclyl,
-(C1-8alkyl)m-S(C1-8alkyl),
-(C1-8alkyl)-S(C1-8alkyl)-aryl
-(C1-8alkyl)-S(C1-8alkyl)-heteroaryl,
-(C1-8alkyl)-S(C1-8alkyl)-hetrocyclyl,
-(C1-8alkyl)-S(aryl),
-(C1-8alkyl)-S(heteroaryl),,
-(C1-8alkyl)-S(heterocyclyl),
-(C1-8alkyl)m-aryl,
-(C1-8alkyl)m-heteroaryl,
-(C1-8alkyl)m-heterocyclyl,
-C(O)C(0)(heteroaryl),
-C(0)C(0)(heterocyclyl),
37

-C(O)C(O)(aryl);
wherein aryl present as a substituent in R6 is four to seven membered monocyclic
ring and heteroaryl and heterocyclyl present as a substituent in R6 are three to
seven membered monocyclic ring containing one or more heteroatoms selected
from nitrogen, oxygen and sulphur; wherein said aryl, heteroaryl and heterocyclyl
are unsubstituted or substituted with one to three groups independently selected
from:
oxo,
thioxo,
halogen,
-OH,
-SH,
-C1-8alkyl,
-O(C1-8alkyl),
nitro,
amino,
mono(C1-8alkyl)amino ,
di(C1-8alkyl)amino,
-COOH,
-CONH2,
-CF3,
-C(O)CF3,
-S(C1-8alkyl),
- SO2(C1-8alkyl),
-SO2CF3, and
-SO2NH2 ;
wherein, the above said C1-8alkyl is straight, branched or cyclic, may contain one
or two double or triple bonds and may be substituted with one to two substituents
independently selected from:
-OH,
38

-SH,
0X0,
thioxo,
amino,
mono(C1-3alkyl)amino,
di(C1-3alkyl)amino,
-S(C1-3alkyl), and
-C1-3alkoxy;
wherein, C1-3alkoxy is straight or branched, may contain one or two double or
triple bonds; C1-3alkyl is straight or branched; m is independently selected at
each occurrence, from zero to one.
with the proviso that when R6 is selected from methyl and R2 = H or methyl, then
R1 is not selected from:
a. trimethoxyphenyl,
b. benzdioxole or chlorosubstituted benzdioxole or
c. furyl;
With the further proviso that when R4, R5 and R7 are hydrogen and R6 is
selected from the group consisting of
-(C1-8alkyl),
-(C1-8alkyl)-O(C1-8alkyl) ,
-(C1-8alkyl)-O(aryl),
-(C1-8alkyl)-0(heteroaryl),
-(C1-8alkyl)-O(heterocyclyl),
-(C1-8alkyl)-N(R9)(C1-8alkyl),
-(C1-8alkyl)-N(R9)(aryl),
-(C1-8alkyl)-N(R9)(heteroaryl),
-(C1-8alkyl)-N(R9)(heterocyclyl),
-(C1-8alkyl)-C(O)(C1-8alkyl),
-(C1-8alkyl)-C(O)(aryl),
-(C1-8alkyl)-C(O)(heteroaryl),
39

-(C1-8alkyl)-C(O)(heterocyclyl),
-(C1-8alkyl)-C(O)(C1-8alkyl)-aryl,
-(C1-8alkyl)-C(O)(C1-8alkyl)-heteroaryl,
-(C1-8alkyl)-C(0)(C1-8alkyl)-heterocyclyl,
-(C1-8alkyl)m-aryl,
-(C1-8alkyl)m-heteroaryl,
-(C1-8alkyl)m-heterocyclyl,
-C(O)N(R9)(R9),
-(C1-8alkyl)-SO2(C1-8alkyl),
-(C1-8alkyl)-S(O)(C1-8alkyl),
-(C1-8alkyl)-S(O)(aryl),
-(C1-8alkyl)-S(O)(heteroaryl),
-(C1-8alkyl)-S(O)(heterocyclyl),
-(C1-8alkyl)-SO2(C1-8alkyl)-aryl,
-(C1-8alkyl)-SO2(C1-8alkyl)-heteroaryl,
-(C1-8alkyl)-SO2(C1-8alkyl)-hetrocyclyl,
-(C1-8alkyl)-S(C1-8 alkyl),
-(C1-8alkyl)-S(C1-8alkyl)-aryl,
-(C1-8alkyl)-S(C1-8alkyl)-heteroaryl,
-(C1-8alkyl)-S(C1-8alkyl)-hetrocyclyl,
-(C1-8alkyl)-S(aryl),
-(C1-8alkyl)-S(heteroaryl),,
-(C1-8alkyl)-S(heterocyclyl),
-(C1-8alkyl)-SO2(aryl),
-(C1-8alkyl)-SO2(heteroaryl),
-(C1-8alkyl)-SO2(heterocyclyl),
acyl, and
- C(O)O-(C1-8alkyl),
then R3 is not

40

-CH2-aryl, -CH2-substituted aryl, -CH2-pyridyl, -CH2-substituted pyridyl, -CH2-
pyrimidinyl, -CH2- substituted pyrimidinyl wherein the substitution on aryl, pyridyl
and pyrimidinyl is selected from hydroxyl, alkoxy, halogen and CF3;
R7 is selected from the group consisting of:
hydrogen,
halogen,
-OH,
-SH,
-C1-8alkyl,
-O(C1-8alkyl),
nitro,
amino,
mono(C1-8alkyl)amino ,
di(C1-8alkyl)amino,
-COOH,
-CONH2
-CF3,
-C(O)CF3,
-SO2CF3,
-S(C1-8alkyl),
-SO2(C1-8alkyl), and
-SO2NH2 ;
Wherein, the above said C1-8alkyl is straight, branched or cyclic, may containing
one or two double or triple bonds and substituted with one to two substituents
selected from the group consisting of:
-OH,
-SH,
oxo,
thioxo,
amino,
41

mono(C1-8alkyl)amino,
di(C1-3alkyl)amino,
-S(C1-3alkyl),and
-C1-3alkoxy;
wherein, C1-3alkoxy is straight or branched, may containing one or two double or
triple bonds and C1-3alkyl is straight or branched.
In another embodiment, the present invention pertains to a compound as above,
however only including pharmaceutically acceptable salts thereof.
Yet another embodiment of the present invention provides a method of treating
various disease conditions, accompanying pathological stress are selected from
ischemic stroke, myocardial infarction, inflammation, diseases of viral origin,
tumourous diseases, brain haemorrhage, endothelial dysfunctions, diabetic
neuropathy, hepatotoxicity, acute renal failure, glaucoma, sepsis, gastric mucosal
damage, allograft rejection, chronic wounds in diabetics, neurodegenerative
diseases, epilepsy, post-traumatic neuronal damage and aging-related skin
degeneration wherein the underlying mechanism is Heat Shock Protein (HSP)
induction in a mammal, including a human being, by administering to a mammal
in need thereof a therapeutically effective amount of compounds of present
invention.
Yet another embodiment of the instant invention is the use of above compounds
in the manufacture of medicaments, useful for treatment of various disease
conditions accompanying pathological stress selected from ischemic stroke,
myocardial infarction, inflammation, diseases of viral origin, tumourous diseases,
brain haemorrhage, endothelial dysfunctions, diabetic neuropathy, hepatotoxicity,
acute renal failure, glaucoma, sepsis, gastric mucosal damage, allograft
rejection, chronic wounds in diabetics, neurodegenerative diseases, epilepsy,
post-traumatic neuronal damage and aging-related skin degeneration, in a
mammal including human being by induction of HSP.
42

DEFINITIONS:
The following definitions apply to the terms as used throughout this specification,
unless otherwise limited in specific instances:
The term "compound" employed herein refers to any compound encompassed by
the generic formula disclosed herein. The compounds described herein may
contain one or more double bonds and therefore, may exist as stereoisomers,
such as geometric isomers, , E and Z isomers, and may possess asymmetric
carbon atoms (optical centres) such as enantiomers, diastereoisomers.
Accordingly, the chemical structures depicted herein encompass all possible
stereoisomers of the illustrated compounds including the stereoisomerically pure
form (e.g., geometrically or enantiomerically pure) and stereoisomeric mixtures
(racemates). The compound described herein, may exist as a conformational
isomers such as chair or boat form. The compounds may also exist in several
tautomeric forms including the enol form, the keto form and mixtures thereof.
Accordingly, the chemical structures depicted herein encompass all possible
tautomeric forms of the illustrated compounds. The compounds described also
include isotopically labeled compounds where one or more atoms have an
atomic mass different from the atomic mass conventionally found in nature.
Examples of isotopes that may be incorporated into the compounds of the
invention include, but are not limited to 2H, 3H, 13C, 14C, 15N, 18O, 17O, etc.
Compounds may exist in unsolvated forms as well as solvated forms, including
hydrated forms. In general, compounds may be hydrated or solvated. Certain
compounds may exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated herein and are intended
to be within the scope of the present invention.
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to
43

be construed to cover both the singular and the plural, unless otherwise indicated
herein or clearly contradicted by context.
Further, it should be understood, when partial structures of the compounds are
illustrated, a dash (" - ") indicate the point of attachment of the partial structure
to the rest of the molecule.
The nomenclature of the compounds of the present invention as indicated herein
is according to MDL ISIS® Draw Version 2.5.
"Pharmaceutically acceptable salt" refers to a salt of a compound, which
possesses the desired pharmacological activity of the parent compound. Such
salts include: (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid,
phosphoric acid, and the like; or formed with organic acids such as acetic acid,
propionic acid, isobutyric acid, hexanoic acid, cyclopentanepropionic acid, oxalic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic
acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, , phthalic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-
hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-
methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-
phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric
acid, gluconic acid, glucuronic acid, galactunoric acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound is
replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an
aluminum ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like. Also included
are salts of amino acids such as arginate and the like (see, for example, Berge,
44

S.M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977,
66,1-19).
As used herein, the term "polymorphs" pertains to compounds having the same
chemical formula, the same salt type and having the same form of
hydrate/solvate but having different crystallographic properties.
As used herein, the term "hydrates" pertains to a compound having a number of
water molecules bonded to the molecule.
As used herein, the term "solvates" pertains to a compound having a number of
solvent molecules bonded to the molecule.
The present invention also encompasses compounds which are in a prodrug
form. Prodrugs of the compounds described herein are those compounds that
readily undergo chemical changes under physiological conditions (in vivo) to
provide the active compounds of the present invention. Additionaqlly, prodrugs
can be converted to the compounds of the present invention by chemical or
biochemical methods in an ex vivo environment, for example, transdermal patch
reservoir with a suitable enzyme or chemical. Prodrugs are, in some situation,
easier to administer than the active drug. They may, for instance, be bioavailable
by oral administration whereas the active drug is not. The prodrug may also
have improved solubility in pharmacological composition over the active drug.
Esters, peptidyl derivatives and the like, of the compounds are the examples of
prodrugs of the present invention.
In vivo hydrolysable (or cleavable) ester of a compound of the present invention
that contains a carboxy group is, for example, a pharmaceutically acceptable
ester which is hydrolysed in the human or animal body to produce the parent
acid. Suitable pharmaceutically acceptable esters for carboxy include C1-C8
alkoxymethyl esters, for example, methoxymethyl, C1-C8 alkanoloxymethyl ester,
for example, pivaloyloxymethyl; phthalidyl esters; C3-C8 cycloalkoxycarbonyloxy-
45

C1-C8 alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-
onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-C8
alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxymethyl; and
may be formed at any carboxy group in the compounds of the present invention.
The term "substituted", as used herein, means that any one or more hydrogens
on the designated atom is replaced with a selection from the indicated group,
provided that the designated atom' s normal valence is not exceeded, and that
the substitution results in a stable compound, for example when a substituent is
keto, then two hydrogens on the atom are replaced. All substituents (R1, R2....)
and their further substituents described herein may be attached to the main
structure at any heteroatom or carbon atom which results in formation of stable
compound.
As used herein, the term "oxo" or "thioxo" is intended to mean that the group
when bound to a saturated carbon atom may represent C=O or C=S and when
bound to unsaturated carbon atom may be represented in the tautomeric enol
form.
In the present context the term "aryl" is intended to mean a fully or partially
aromatic carbocyclic ring or ring system.
The term "heteroaryl" is intended to mean a fully or partially aromatic carbocyclic
ring or ring system where one or more of the carbon atoms have been replaced
with heteroatoms, e.g. nitrogen (=N- or-NH-), oxygen and sulphur atoms.
The term "heterocyclyl" is intended to mean a non-aromatic carbocyclic ring or
ring system where one or more of the carbon atoms have been replaced with
heteroatoms, e.g. nitrogen (=N- or-NH-), oxygen and sulphur atoms.
46

As used herein, "room temperature" refers to a temperature between 25 ° C and
35 °C.
As used herein, a "halo" or "halogen" substituent is a monovalent halogen radical
chosen from chloro, bromo, iodo and fluoro.
As used herein, the term "mammal" means a human or an animal such as
monkeys, primates, dogs, cats, horses, cows, etc.
"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to
ameliorating the disease or disorder (i.e., arresting or reducing the development
of the disease or at least one of the clinical symptoms thereof). In another
embodiment "treating" or "treatment" refers to ameliorating at least one physical
parameter, which may not be discernible by the patient. In yet another
embodiment, "treating" or "treatment" refers to inhibiting the disease or disorder,
either physically, {e.g., stabilization of a discernible symptom), physiologically,
{e.g., stabilization of a physical parameter) or both. In yet another embodiment,
"treating" or "treatment" refers to delaying the onset of the disease or disorder.
As used herein, amelioration of the symptoms of a particular disorder by
administration of a particular compound or pharmaceutical composition refers to
any lessening, whether permanent or temporary, lasting or transient that can be
attributed to or associated with administration of the composition.
The phrase "a therapeutically effective amount" means the amount of a
compound that, when administered to a patient for treating a disease, is sufficient
to effect such treatment for the disease. The "therapeutically effective amount"
will vary depending on the compound, mode of administration, the disease and
its severity and the age, weight, etc., of the patient to be treated.
47

When used, the expressions "comprise" and "comprising" denote "include" and
"including" but not limited to. Thus, other ingredients, carriers and additives may
be present.
In a further embodiment of the invention there is provided pharmaceutically
acceptable compositions containing compounds of the present invention, in
admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Pharmaceutical compositions
In another embodiment of the invention is provided a pharmaceutical composition
comprising a therapeutically effective amount of one or more of a compound of
general formula (I). While it is possible to administer therapeutically effective
quantity of compounds of formula (I) either individually or in combination, directly
without any formulation, it is common practice to administer the compounds in
the form of pharmaceutical dosage forms comprising pharmaceutically
acceptable excipient(s) and at least one active ingredient. These dosage forms
may be administered by a variety of routes including oral, topical, transdermal,
subcutaneous, intramuscular, intravenous, intranasal, pulmonary etc.
Oral compositions may be in the form of solid or liquid dosage form. Solid
dosage form may comprise pellets, pouches, sachets or discrete units such as
tablets, multi-particulate units, capsules (soft & hard gelatin) etc. Liquid dosage
forms may be in the form of elixirs, suspensions, emulsions, solutions, syrups
etc. The above pharmaceutical compositions may contain in addition to active
ingredients, excipients such as diluents, disintegrating agents, binders,
solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers,
chelating agents, stabilizers, flavours, sweeteners, colours etc. Some example
of suitable excipients include lactose, cellulose and its derivatives such as
microcrystalline cellulose, methylcelulose, hydroxy propyl methyl cellulose,
ethylcellylose, dicalcium phosphate, mannitol, starch, gelatin, polyvinyl
48

pyrolidone, various gums like acadia, tragacanth, xanthan, alginates & its
derivatives, sorbitol, dextrose, xylitol, magnesium Stearate, talc, colloidal silicon
dioxide, mineral oil, glyceryl mono Stearate, glyceryl behenate, sodium starch
glycolate, Cross Povidone, crosslinked carboxymethylcellulose, various
emulsifiers such as polyethylene glycol, sorbitol fattyacid, esters, polyethylene
glycol alkylethers, sugar esters, polyoxyethylene polyoxypropyl block
copolymers, polyethoxylated fatty acid monoesters, diesters and mixtures
thereof.
Sterile compositions for injection can be formulated according to conventional
pharmaceutical practice by dissolving or suspending the active substance in a
vehicle such as water for injection, N-Methyl-2-Pyrrolidone, propylene glycol and
other glycols, alcohols, a naturally occurring vegetable oil like sesame oil,
coconut oil, peanut oil, cottonseed oil or a synthetic fatty vehicle like ethyl oleate
or the like. Buffers, anti-oxidants, preservatives, complexing agents like cellulose
derivatives, peptides, polypeptides and cyclodextrins and the like can be
incorporated as required.
Dose is appropriately decided by its form of preparation, method of
administration, purpose of use and age, body weight and symptom of the patient
to be treated and it is not constant. But, usually, the amount of at least one of the
compound selected from the compound of the present invention, an optically
active substance thereof or a salt thereof contained in the preparation is from 0.1
microgram to 100 mg/kg per day (for adults). Thus, the total quantity of
compound in a particular pharmaceutical composition may range from 1 to 1000
mg, at concentration levels ranging from about 0.5% to about 90% by weight of
the total composition. In a preferred embodiment, the composition may contain
20 to 500 mg of the compound, at concentration levels ranging from about 10%
to about 70% by weight of the total composition. Of course, the dose may vary
depending upon various conditions and, there ore, the dose less than above may
be sufficient in some cases while, in other cases, the dose more than above may
49

be necessary. The dosage form can have a slow, delayed or controlled release
of active ingredients in addition to immediate release dosage forms.
Yet another embodiment of the present invention is to provide a process for the
preparation of the compounds of the present invention.
The following, reaction schemes give the alternate routes for synthesis of the
compounds according to the present invention.
The compounds of formula (I) of the present invention may be prepared as
shown in the schemes below and further described herein after.

The compounds of general formula (I) may be obtained through the intermediate
(III) or (IX), wherein the R1 R2, R3, R4 R5, R6 and R7 are as defined earlier.
50


In one of the specific embodiment of the present invention, as shown in scheme-
I, the compounds of formula (I) can be prepared by reacting, an aldehyde of
formula, RiCHO wherein, R1 is as defined earlier, such as unsubstituted or
substituted benzaldehyde, pyridine carboxaldehyde, pyrrole carboxaldehyde,
quinoline carboxaldehyde, quinoxaline carboxaldehyde or quinazoline
carboxaldehyde, with a substituted piperidone of formula (III) or (IX) in the
presence of a base such as aqueous NaOH or KOH, sodium methoxide, sodium
ethoxide, potassium tertiary-butoxide, in the solvent such as methanol, ethanol,
n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol or sodium hydride in a
solvent like toluene, tetrahydrofuran, dimethylformamide or pyridine and
piperidine in toluene and at a temperature, in the range of 0° C to 110° C, for a
period of 2 to 12 hours. Reference: (Furniss, et al, Vogel's Textbook of Practical
Organic Chemistry, Fifth Edition, New York; John Wiley & Sons, Inc, (1989),
51

Page:1033 and Canadian Journal of Chemistry, 1968, 46, 1952-1956) to obtain
the compound of formula (I), and all other symbols are as defined earlier.
In an alternate process, the compounds of formula (I) can be prepared by
refluxing the solution of aldehyde of formula RiCHO and a substituted
piperidone of formula (III) or (IX) in ethanol containing 10% piperidine and 50%
acetic acid with Soxhlet on 4A° molecular sieves, for a period of 24 to 30 hours.
Alternatively, the compound of formula (III) is dissolved in an appropriate solvent
such as carbon tetrachloride or methanol, containing HBr-acetic acid and treated
with an equimolar quantity of bromine at a temperature of 0° C to 80° C and the
reaction mixture is refluxed for a period of 2 hours. The crude product obtained
is treated with triphenyl phosphine in an appropriate solvent such as toluene. The
triphenylphosphine salt (Ill-a) obtained is treated with R1CHO in a suitable
solvent like pyridine at a temperature in the range of 100° C to 115°C for a period
of 4 to 6 hours to obtain the compound of formula (I).


(a) i) Paraformaldehyde, ii) 3-Methyl-2-butanone, HCI ; (b) R5CHO, NaOH /
KOH ; (c) R1CHO, NaOH / KOH
In another specific embodiment, as shown in scheme-ll, the compounds of
formula (I) is obtained in following manner:
i) By treating the amine of formula R6NH2, such as unsubstituted or substituted
benzylamine, thiophene ethylamine, thiophene methylamine, furyl methylamine,
morpholine ethylamine, piperidine ethylamine, piperazine ethylamine,
cyclopropylamine, cyclopentylamine, 2-amino-5-methyl-isoxazole, with one or
two equivalent amount of paraformaldehyde in the alcoholic solvent like
methanol, ethanol, propanol or butanol at a temperature in the range of 0° C to
110 ° C, for a period of 2 to 16 hours. The reaction mixture thus obtained is added
dropwise to the refluxing solution (1-2 hours) of 2-methyl-3-butanone in alcoholic
solvent containing 10 % to 50 % inorganic acid such as hydrochloric acid,
sulphuric acid, perchloric acid or organic acid such as acetic acid, propanoic
acid, butanoic acid, heptanoic acid and further refluxed for a period of 8-10 hours
to obtain the compound of formula (IV) or (V).
ii) Further, the compound of formula (III) is prepared by dissolving the compound
of formula (IV), in an appropriate solvent such as ethanol, methanol, propanol,
butanol containing base such as sodium hydroxide or potassium hydroxide,
sodium methoxide, sodium ethoxide, potassium tertiary-butoxide; sodium
hydride in the solvent like toluene, tetrahydrofuran, dimethylformamide or
pyridine and piperidine in toluene and treating, with the compound of formula
R5CHO like unsubstituted or substituted benzaldehyde, pyridine carboxaldehyde,
thiophene carboxaldehyde, furyl carboxaldehyde, pyrrole carboxaldehyde at a
temperature from 0° C to 110° C, for a period of 2 to 16 hours.
iii) The compound of formula (I) is prepared from compound of formula (III) or (V)
by the methods as described in Scheme -1.
53


(a) Zn, TMSI ; (b) NaCNBH3; (c) Ethyl acrylate or ethyl-3-bromopropionate ;
(d) NaOEt ; (e) DMSO : H2O, (1:1) ; (f) R1CHO, NaOH / KOH ; (g) R6-
carboxylic acid, EDCI, HOBT, DIEA or BOP, DIEA / R6-carbonyl chloride,
triethylamine ; (h) R6NCO or R6NCS / R6NH2, triphosgene or thiophosgene ; (i)
R6-chloroformate, triethylamine / R6OH, triphosgene, DIEA
In still another specific embodiment, as shown in scheme-Ill, the compounds of
formula (I) can be prepared in follwing manner:
i) The solution of iodotrimethylsilane is added to the suspension of zinc in a
solvent such as dichloromethane, chloroform, carbon tetrachloride,
tetrahydrofuran, toluene, and is stirred at a temperature ranging from 0° C to 110
0 C, for a period of 1 to 6 hours, further the ethyl bromoisobutyrate is added and
stirred for a period of 15 min to 1 hour, followed by addition of the compound of
formula R4CN like unsubstituted or substituted phenylacetonitrile or
benzonitrile.and the stirring is continued for 2 to 8 hours. The reaction mixture is
cooled, filtered over celite and evaporated under vacuo., The crude product is
dissolved in alcohol and the sodium borohydride or sodium cyanoborohydride is
54

added and stirred at a temperature from 0° C to 110 ° C, for a period of 1 to 6
hours provides the compound of formula (VI),
ii) The compound of formula (VII) is prepared by reacting the compound of
formula (VI) with ethyl acrylate in a solvent such as toluene, N-methyl
pyrrolidinone, alcohols at a temperature in the range of 0° C to 160 ° C, for a
period of 1 to 6 hours. Alternatively, by reacting the compound of formula (VI),
with ethyl 3-bromopropionate in a solvent such as toluene, tetrahydrofuran,
dimethylformamide, dichloromethane at a temperature in the range of 0° C to 110
°C, for a period of 1 to 12 hours, also provides the compound of formula (VII),
iii) By treating the compound of formula (VII) in an appropriate solvent such as
ethanol, methanol, butanol, toluene, tetrahydrofuran with base like sodium
methoxide, sodium ethoxide, potassium tertiary-butoxide, sodium hydride, lithium
hexamethyldisilazane, lithium diisopropylamide, n-butyl lithium at a temperature
from -78°C to 110 ° C, for a period of 3 to 12 hours to obtain the compound of
formula (VIII),
iv) Further, by refluxing the compound of formula (VIII) with a mixture of
dimethylsulfoxide (DMSO) : water (1:1) at a temperature from 60° C to 150 ° C,
for 6 to 12 hours, provides the compound of formula (IX).
v) The compound of formula (X) can be prepared from compound of formula
(IX) by the methods as described in Scheme -1.
vi) (a) The compound of formula (I) is prepared by reacting R6 carboxylic acid
with 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) or benzotriazol-1-yl-oxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) in a solvent such as tetrahydrofuran or
dimethylformamide at a temperature from 0° C to 25° C for about 1 hour,
55

followed by addition of N-ethyldiisopropylamine, the compound of formula (X)
and is stirred at a room temperature for a period of 6 to 20 hours.
References: (i) (Sheehan, J. C; Ledis, S.L.; Journal of American Chemical
Society, (1973), 95, 875). (ii)(Keller-Schirlein, W; Muller, A; Hagmann, L;
Schneisler, U; Zahner, H; Helv. Chim. Acta, (1985), 68, 559.; Le Nguyen, D;
Castro, B; Peptide Chemistry (1987); Protein Research Foundation, Osaka,
(1988), 231.; Kiso, Y; Kimura, T; Chemical Abstract, (1991), 114,164722K).
In an alternate method, the R6 carboxylic acid is treated with oxalyl chloride or
thionyl chloride in a solvent like dichloromethane or toluene at a temperature in
the range of 0° C to 110 ° C, for a period of 3 to 4 hours to obtain the intermediate
compound R6 carbonyl chloride., which on further treatment with the compound
of formula (X) in the presence of base, triethylamine or potassium carbonate in a
solvent such as tetrahydrofuran, toluene, dimethylformamide at a temperature in
the range of 0° C to 25° C for a period of 1 to 4 hours gives the compound of
formula (I). Alternatively, by treating the ester of R6 carboxylic acid with the
compound of formula (X), in a solvent such as toluene or xylene at a temperature
in the range of 100° C to 140° C, for a period of 1 to 12 hours provides the
compound of formula (I),
(b)The compound of formula (I) is prepared by refluxing R6 isocyanate or R6
isothiocyanate with the compound of formula (X) in a solvent such as toluene,
xylene or chloroform for a period of 6 to 12 hours.
The R6 isocyanate is prepared by treating R6 carboxylic acid with ethyl
chloroformate, triethylamine or N-ethyl diisopropylamine in a solvent such as
dichloromethane, dichloroethane, tetrahydrofuran, toluene at a temperature in
the range of 0° C to 60° C, for a period of 30 minutes to 3 hours gives mixed
anhydride of R6, which on treatment with sodium azide, dissolved in water, at a
temperature in the range of 25° C to 110° C, for a period of 1 to 12 hours gives
R6 azide.. Further, the R6 azide is refluxed in toluene or xylene for a period of 1 to
56

4 hours. Reference: (Carl Kaiser and Joseph Weinstock, Org. Syn. Coll.
(1988),Vol. 6, 95, 910).. Alternatively, the R6 isocyanate is prepared by treating
the R6 amine with triphosgene or trichloromethyl chloroformate or thiophosgene
in the presence of a base such as triethylamine, N-ethyldiisopropylamine,
sodium bicarbonate, potassium or sodium carbonate in a solvent such as
dichloromethane, chloroform or dichloroethane at a temperature in the range of
0° C to 20° C, for a period of 30 minutes to 2 hours. Reference: (lwakura,Y.,
Uno, K., Kang, S., J.Org. Chem., (1966), 31, 142; Kurita, K., Iwakura, Y., Org.
Syn. Coll. Vol. 6, (1988), 715).
c) The compound of formula (I) is prepared by treating the compound of formula
(X) with ethyl chloroformate or phenyl chloroformate in the presence of a base
such as triethylamine, N-ethyldiisopropylamine, potassium or sodium carbonate
in a solvent such as tetrahydrofuran, acetonitrile, toluene at a temperature in the
range of 0° C to 60° C, for a period of 10 minutes to 8 hours.
Alternatively, by treating the R6 alcohol with phosgene or triphosgene in the
presence of a base such as N-ethyldiisopropylamine, triethylamine, potassium
or sodium carbonate, in a solvent such as dichloromethane, chloroform or
dichloroethane at the temperature in the range of 0° C to 20° C for a period of 1
hour, followed by addition of the compound of formula (X) and is stirred at a
temperature in the range 0° C to 60° C for a period 1 to 6 hours, to obtain the
compound of formula (I). Reference: (Cotarca, L, Detogan, P., Norddli, A., Sunji,
V., Synthesis, (1996)553)
d) The compound of formula (I) is prepared by treating the solution of compound
of formula (X) with ethyl oxalyl chloride in the presence of base such as
triethylamine or potassium carbonate in a solvent such as tetrahydrofuran,
dichloromethane, toluene at a temperature in the range of 0°C to 110° C, for a
period of 3 to 6 hours, followed by treatment with R6 amine in a solvent such as
57

xylene, dimethylacetamide, N-methyl-2-pyrrolidinone at a temperature in the
range of 100° C to 160° C, for a period of 2 to 16 hours

(a) Paraformaldehyde, K2CO3 ; (b) K2CO3 ; (c) Ethyl malonyl chloride, ,
triethylamine / ethyl hydrogen malonate, EDCI, HOBT, DIEA ; (d) Ethyl
acrylate or ethyl-3-bromopropionate, K2CO3; (e) i) NaOEt, ii) DMSO : H2O
(1:1); (f) RiCHO, NaOH / KOH
In still another embodiment, as shown in scheme-IV, the compounds of formula
(I) can be prepared by following procedure:
i) The ester of R3 carboxylic acid is treated with paraformaldehyde in the
presence of a base such as potassium carbonate, sodium carbonate, sodium
hydride, sodium ethoxide, potassium tertiary-butoxide or sodium methoxide, in a
solvents such as N-methyl pyrrolidinone, toluene, dimethylformamide, dimethyl
58

acetamide at a temperature in the range of 0° C to 110° C, for a period of 2 to
12 hours to obtain the compound of the formula (XI),
ii) By treating the compound of the formula (XI) with R6 amine in a solvent such
as toluene, xylene, N-methyl pyrrolidinone, dimethylformamide or dimethyl
acetamide, in the presence of base like potassium carbonate, sodium
carbonate,or sodium hydride at a temperature from 0° C to 110° C for 2 to 12
hours to obtain the compound of the formula (XII).
iii) By reacting the compound of formula (XII) with ethyl malonyl chloride in a
solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, toluene,
dichloromethane containing a base such as potassium carbonate, sodium
carbonate, sodium hydride, triethylamine or N-ethyldiisopropylamine at a
temperature ranging from 0° C to 110° C, for a period of 1 to 8 hours to obtain
the compound of formula (XIII). Alternatively, by treating the ethyl hydrogen
malonate with 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) in a solvent such as tetrahydrofuran or
dimethylformamide at a temperature from 0° C to 25° C for about 1 hour,
followed by addition of N-ethyldiisopropylamine, the compound of formula (XII)
and is stirred at a room temperature for a period of 6 to 20 hours to obatin the
compound of formula (XIII).
iv)The compound of formula (XII) is reacted with unsubstituted or substituted
ethyl acrylate or ethyl-3-bromopropionate in a solvent such as ethanol, methanol,
butanol, acetonitrile, dimethylformamide or toluene containing a base such as
potassium carbonate, sodium carbonate, triethylamine or N-
ethyldiisopropylamine at a temperature in the range of 0° C to 110° C, for a period
of 1 to 12 hours, provides the compound of formula (XIV).
v) Further, the compound of formula (XIII) or (XIV) is treated with an appropriate
base such as sodium methoxide, sodium ethoxide, potassium tertiary-butoxide,
59

sodium hydride, lithium hexamethyldisilazane, lithium diisopropylamide or n-butyl
lithium in an appropriate solvent such as ethanol, methanol, butanol, toluene or
tetrahydrofuran at a temperature in the range of -78° C to 110 ° C, for a period of
3 to 12 hours to obtain the cyclised intermediate, which on treatment with a
mixture of dimethylsulfoxide : water (1:1) at a temperature from 60° C to 150 ° C,
for a period of 6 to 12 hours, provides the compound of formula (XV) or (XVI)
respectively,
vi) By following the procedure as described in Scheme-I the compound of
formula (XV) or (XVI) can be converted to the compound of formula (I).

(a) Diethyl carbonate, NaH ; (b)Xylene, reflux ; (c) Ethyl-
3-bromopropionate or ethyl acrylate, K2CO3; (d) i) NaOEt,
ii) DMSO : H2O, (1:1); e)R1CHO, NaOH / KOH
In a further embodiment of the present invention, as shown in scheme-V, the
compounds of formula (I) is obtained
60

i) By treating the ester of R3 carboxylic acid with diethyl carbonate in the
presence of sodium hydride, potassium or sodium carbonate, in a solvent such
as toluene, xylene, acetonitrile, dimethylformamide, N-methyl pyrrolidinone,
dimethyl acetamide, at a temperature in the range of 60° C to 150° C, for a period
of 6 to 12 hours to obtain the compound of formula (XVII),
ii) Further, the compound of formula (XVII) is treated with R6 amine in a solvent
such as toluene or xylene at a temperature in the range of 100 ° C to 140 ° C, for
a period of 1 to12 hours to obtain the compound of formula (XVIII),
iii) By reacting the compound of formula (XVIII) with unsubstituted or substituted
ethyl acrylate or ethyl-3-bromopropionate in an appropriate base such as
potassium or sodium carbonate, triethylamine, N-ethyldiisopropylamine or
sodium hydride in an appropriate solvent such as ethanol, methanol, butanol,
dichloromethane, tetrahydrofuran, acetonitrile, toluene or dimethylformamide at
a temperature in the range of 0° C to 110° C, for a period of 1 to 8 hours to
obtain the compound of formula (XIX),
iv) Further, the compound of formula (XIX) is treated with an appropriate base
such as sodium methoxide, sodium ethoxide, potassium tertiary-butoxide,
sodium hydride, lithium hexamethyldisilazane, lithium diisopropylamide or n-butyl
lithium in an appropriate solvent such as ethanol, methanol, butanol, toluene or
tetrahydrofuran at a temperature in the range of -78° C to 110 ° C, for a period of
3 to 12 hours to obtain the cyclised intermediate, which on treatment with a
mixture of dimethylsulfoxide : water (1:1) at a temperature from 60° C to 150 ° C,
for a period of 6 to 12 hours, provides the compound of formula (XX)
v) The compound of formula (I) may be obtained from the compound of formula
(XX) by the procedures as described in Scheme -1.
The compounds of general formula (II) can be prepared by one skilled in the art
wherein, the R1 R2, R3, R4, R5 and R6 are as defined earlier.
61


One of the ordinary skill will recognize to substitute appropriately modified
starting material containing the various substituents. One of the ordinary skill
will readily synthesize the disclosed compounds according to the present
invention using conventional synthetic organic techniques and microwave
techniques from starting material which are either purchased or may be readily
prepared using prior art methods.
The compounds of the present invention may have chiral centers and occur as
racemates, as individual diastereoisomers or enantiomers and as conformational
isomers, with all isomeric forms being included in the present invention.
Therefore, when a compound is chiral, the separate enantiomers, substantially
free of the other, are included within the scope of the invention; further included
are all mixtures of the two enantiomers.
The novel compounds of the present invention are not, however, to be construed
as forming the only genus that is considered as the invention, and any
combination of the compounds or their moieties may itself form a genus.
The novel compounds of the present invention were prepared according to the
procedure of the schemes as described hereinabove, using appropriate materials
and are further exemplified by the following specific examples. The examples are
62

not to be considered nor construed as limiting the scope of the invention set forth
in the claims appended thereto.
Example 1
1-Benzvl-3, 3-dimethvl-5-[1-(6-morpholin-4-yl-pyridin-2-yl)-methvlidene]-
piperidin-4-one (Compound No. 22)
Step A: Preparation of 6-morpholin-4-yl-pyridine-2-carboxaldehvde
The suspension of 6-bromo-pyridine-2-carboxaldehyde (1.9 g, 10 mmol),
morpholine (1.75 g, 20 mmol) and potassium carbonate (3 g, 22 mmol) in
acetonitrile (20 ml) was refluxed for 20 hours. The reaction mixture was then
cooled to room temperature, diluted with water (50 ml) and the pH was adjusted
to 7 by the aqueous solution of hydrochloric acid. The mixture was partitioned
between water and ethyl acetate (50 ml x 3). The combined organic layers were
washed with water (25 ml x 2), brine (25 ml x 2), dried over anhydrous sodium
sulphate and evaporated under vacuo. The residue was purified by column
chromatography over silica gel using 40 % ethyl acetate in hexane as the eluent
to afford the titled compound (1.5 g) was obtained as yellow solid.
1HNMR (DMSOd6): d 3.55 - 3.58 (4H, t), 3.91 - 3.94 (4H, t), 7.15 - 7.18 (1H, d),
7.56 -7.61 (1H, d), 7.65 - 7.6 (1H, t), 9.98 (1H, s).
m/e:192(M+)
Step B: Preparation of 1-Benzyl-3. 3-dimethvl-piperidin-4-one.
The solution of benzylamine (12 g, 112 mmol) and paraformaldehyde (2 g, 66.6
mmol) in ethanol (30 ml) was stirred for 30 minutes at room temperature and
then the mixture was added dropwise to the refluxing solution of 3-methyl-2-
butanone (2.8 g, 32.5 mmol) in ethanol containing 10% HCI. The reaction mixture
was refluxed for 8 hours. After completion of reaction, the mixture was cooled to
room temperature, pH was neutralized using aqueous sodium bicarbonate
63

solution and partitioned between water and ethyl acetate (50 ml x 3). The
combined organic layers were washed with water (50 ml x 2), brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo. The residue
was purified by column chromatography on silica gel using the 2% ethyl acetate
in hexane as the eluent to provide the titled compound (2 g) as brown liquid.
1HNMR (DMSOd6): d 1.16 (6H, s), 2.70 - 2.71 (2H, t), 2.72 - 2.77 (2H, t), 3.40 -
3.42 (2H, s), 3.50 - 3.52 (1H, d), 3.56 - 3.66 (1H, d), 7.20 - 7.22 (2H, m), 7.26 -
7.28 (3H, m)
m/e:217(M+)
Step C: Preparation of 1-Benzyl-3,3-dimethyl-5-[1-(6-morpholin-4-yl-pvridin-2-yl)-
methylidene]-piperidin-4-one.
The solution of 0.3 g (1.38 mmol) of the product of example 1, Step B in
methanol (20 ml) was cooled to 0° C. The aqueous solution of sodium hydroxide
(0.16 g, 4 mmol) and the 0.22 g (1.14 mmol) of the product of example 1, Step A
was added to the reaction mixture, stirred at room temperature for 8 hours. After
completion of reaction, the mixture was cooled to 0° C, diluted with water (20 ml).
The solid precipitate obtained was washed with water (10 ml x 2) and dried under
vacuo to afford 1 -Benzyl-3,3-dimethyl-5-[1 -(6-morpholin-4-yl-pyridin-2-yl)-
methylidene]-piperidin-4-one (0.2 g) as yellow solid.
1HNMR (DMSOd6): d 1.12 (6H, s), 2.60 (2H, s), 3.27 - 3.29 (4H, s), 3.64 - 3.66
(6H, m), 4.02 (2H, s), 6.80 - 6.82 (1H, d), 6.95 - 6.97 (1H, d), 7.13 (1H, s), 7.25 -
7.27 (1H, m), 7.31 - 7.37 (4H, m), 7.56 - 7.60 (1H, m)
m/e:391(M+)
Example 2
2-(2-Fluoro-phenyl)-5.5-dimethyl-3-[1-pyridin-2-yl-methvlidene1-1
-thiophen-2-ylmethyl-piperidin-4-one (Compound No. 61)
Step A: Preparation of 3,3-Dimethyl-4-[(thiophen-2-ylmethyl)-amino]-butan-2-one
64

The solution of thiophene-2-methylamine (2 g, 17.7 mmol) and paraformaldehyde
(0.531 g, 17.7 mmol) in ethanol (20 ml) was stirred for 30 minutes at 60° C and
then the mixture was added dropwise to the refluxing solution of 3-Methyl-2-
butanone (1.67 g, 19.4 mmol) in ethanol containing 10% HCI. The reaction
mixture was refluxed for 8 hours. After completion of reaction, the mixture was
cooled to room temperature, pH was neutralized using aqueous sodium
bicarbonate solution and partitioned between water and ethyl acetate (50 ml x 3).
The combined organic layers were washed with water (50 ml x 2), brine (50 ml x
2), dried over anhydrous sodium sulphate and evaporated under vacuo. The
residue was purified by column chromatography on silica gel using the 2% ethyl
acetate in hexane as the eluent to provide the titled compound (0.8 g) as brown
liquid.
1HNMR (DMSOd6): d 1.02 (6H, s), 2.05 (2H, s), 2.12 (1H, bs), 2.59 (3H, s), 3.85
(2H, s), 6.94 - 6.95 (2H, d), 7.36 - 7.37 (1H, m)
m/e:211(M+)
Step B: Preparation of 2-(2-Fluoro-phenyl)-5.5-dimethyl-1-thiophen-2-ylmethyl-
piperidin-4-one.
The solution of 0.5 g (2.4 mmol) of the product of example 2, Step A in methanol
(10 ml) was cooled to 0° C. The aqueous solution of sodium hydroxide (0.114 g,
2.8 mmol) and the 2-fluoro benzaldehyde (0.294 g, 2.4 mmol) was added to the
reaction mixture, stirred at room temperature for 10 hours. After completion of
reaction, the mixture was cooled to 0° C, diluted with water (20 ml) and pH was
neutralized using aqueous hydrochloric acid and partitioned between water and
ethyl acetate (50 ml x 3). The combined organic layers were washed with water
(50 ml x 2), brine (50 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The residue was purified by column chromatography on
silica gel using the 2% ethyl acetate in hexane as the eluent to provide the titled
compound (0.45 g) as brown liquid.
65

1HNMR (DMSOd6):d 0.92 (3H,s), 1.30 (3H, s), 2.29 - 2.34 (2H, dd), 2.75 - 2.82
(2H, m), 3.37 - 3.43 (1H, m), 3.64 - 3.67 (2H, d), 6.89 - 6.90 (1H, d), 6.93 - 6.95
(1H, m), 7.24 - 7.28 (2H, d), 7.41 - 7.46 (3H, d)
m/e:317(M+)
Step C: Preparation of 2-(2-Fluoro-phenyl)-5.5-dimethyl-3-[1-pvridin-2-yl-
methylidene1-1-thiophen-2-ylmethyl-piperidin-4-one
The solution of 0.1 g (0.3 mmol) of the product of example 2, Step B in methanol
(10 ml) was cooled to 0° C. The aqueous solution of sodium hydroxide (0.02 g,
0.5 mmol) and the pyridine-3-carboxaldehyde (0.034 g, 0.3 mmol) was added to
the reaction mixture, stirred at room temperature for 8 hours. After completion of
reaction, the mixture was cooled to 0° C, diluted with water (20 ml) and pH was
neutralized using aqueous hydrochloric acid and partitioned between water and
ethyl acetate (50 ml x 3). The combined organic layers were washed with water
(50 ml x 2), brine (50 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The residue was purified by column chromatography on
silica gel using the 2% ethyl acetate in hexane as the eluent to provide the titled
compound (0.02 g) as white solid.
1HNMR (DMSOd6):d1.14 (6H, s), 3.22 (2H, s), 3.39 - 3.46 (1H, m), 4.01 - 4.04
(1H, d), 5.45 (1H, d), 6.90 - 6.93 (2H, m), 7.21 - 7.26 (2H, m), 7.30 (1H, s), 7.33 -
7.35 (1H, m), 7.36 - 7.41 (1H, m), 7.42 - 7.44 (2H, m), 7.60 - 7.62 (1H, m), 8.41
(1H, s), 8.47 -8.49(1 H, dd)
m/z; 406 (M+)
Example 3
2-(4-Methoxy-benzyl)-3.3-dimethyl-4-oxo-5-H-pyridin-2-yl-methylidene1-
piperidine-1-carboxylic acid (2,6-dimethyl-phenyl)-amide (Compound No.
191
66

Step A: Preparation of 3-(2-Ethoxycarbonyl-ethylamino)-4-(4-methoxy-phenyl)-
2,2-dimethyl-butyric acid ethyl ester.
The solution of ethyl bromoisobutyrate (12.9 g 114.8 mmol) in tetrahydrofuran
(30 ml) was added to the suspension of zinc in dichloromethane (30 ml)
containing iodosotrimethylsilane (10.4 g, 67.5 mmol) under nitrogen atmosphere
and stirred for 1 hour. The 4-methoxyphenylacetonitrile was then added dropwise
and refluxed for 12 hours. The reaction mixture was cooled, filtered over celite
and evaporated under vacuo. The crude product was dissolved in ethanol and
cooled to 0° C and then the sodium cyanoborohydride (2.47 g, 38 mmol) was
added portionwise, stirred for 8 hours. After completion of reaction, the mixture
was cooled to 0° C, the pH was neutralized using ammonia solution (15 ml) and
filtered over celite, evaporated under vacuo. The residue in toluene was washed
with 10% hydrochloric acid (50 ml x 2) and the aqueous phase was neutralized
using ammonia and partitioned between water and dichloromethane (50 ml x 3).
The combined organic layers were washed with water (50 ml x 2), brine (50 ml x
2), dried over anhydrous sodium sulphate and evaporated under vacuo to
provide the 3-amino-4-(4-methoxy-phenyl)-2,2-dimethyl-butyric acid ethyl ester (3
g) as brown liquid. Then this compound (3 g, 11.3 mmol) and ethyl acrylate (1.5
g, 11.3 mmol) was refluxed for 4 hours. The crude product was purified by
column chromatography on silica gel using the 25% ethyl acetate in hexane as
the eluent to provide the titled compound (3.48 g) as brown liquid.
1HNMR (DMSOd6): d 1.1 (3H, s), 1.23 (3H, s), 1.25 - 1.27 (3H, t), 1.29 - 1.37 (3H,
t), 2.09 - 2.16 (2H, m), 2.18 - 2.20 (1H, dd), 2.27 - 2.33 (2H, m), 2.56 - 2.78 (1H,
d), 2.93 - 2.96 (1H, d), 3.67 (1H, bs), 3.81 (3H, s), 4.05 - 4.11 (2H, q), 4.12 - 4.16
(2H, q), 6.83 - 6.85 (2H, d), 7.15 - 7.17 (2H, d)
m/z: 365 (M+)
Step B: Preparation of 2-(4-Methoxy-benzyl)-3. 3-dimethyl-piperidin-4-one.
67

The solution of 3.4 g (9.4 mmol) of the product of example 3, Step A in toluene
(50 ml) was added dropwise to the solution of sodium (0.43 g, 18.6 mmol) in
ethanol (5ml) and refluxed for 4 hours. After completion of reaction, the mixture
was cooled to room temperature, pH was neutralized using aqueous hydrochloric
acid and partitioned between water and ethyl acetate (50 ml x 3). The combined
organic layers were washed with water (50 ml x 2), brine (50 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. The residue was
purified by column chromatography on silica gel using the 40% ethyl acetate in
hexane as the eluent to provide 6-Benzyl-5,5-dimethyl-4-oxo-piperidine-3-
carboxylic acid ethyl ester (2 g). Then this compound (2 g, 3.1 mmol) was
refluxed with aqueous sodium hydroxide (1 g, 25 mmol) in ethanol (10 ml) for 3
hours. The reaction mixture was cooled to room temperature pH was neutralized
using aqueous hydrochloric acid and partitioned between water and ethyl acetate
(50 ml x 3). The combined organic layers were washed with water (50 ml x 2),
brine (50 ml x 2), dried over anhydrous sodium sulphate and evaporated under
vacuo. The residue was purified by column chromatography on silica gel using
the 50% ethyl acetate in hexane as the eluent to provide the titled compound
(0.88 g) as brown liquid.
1HNMR (DMSOd6): d 1.20 (3H, s), 1.25 (3H, s), 2.07 - 2.10 (2H, d), 2.65 - 2.72
(1H, m), 2.98 - 3.05 (1H, m), 3.51 - 3.71 (2H, m), 3.74 (3H, s), 4.12 - 4.15 (2H, d),
6.75 - 6.77 (2H, d), 7.05 - 7.15 (2H, d)
m/z: 247 (M+)
Step C: Preparation of 2-(4-Methoxy-benzyl)-3,3-dimethyl-5-[1-pyridin-2-yl-
methylidene]-piperidin-4-one.
The solution of 0.2 g (0.8 mmol) of the product of example 3, Step B and
potassium tert-butoxide (0.181 g, 1.6 mmol) in tetrahydrofuran (10 ml) was
cooled to -20° C and pyridine-2-carboxaldehyde (0.087 g, 0.8 mmol) was added
after 15 minutes. The reaction mixture was stirred at room temperature for 2
hours. After completion of reaction, the mixture was cooled to 0° C, diluted with
68

water (20 ml) and pH was neutralized using aqueous hydrochloric acid. The
mixture was partitioned between water and ethyl acetate (50 ml x 3). The
combined organic layers were washed with water (50 ml x 2), brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo. The residue
was purified by column chromatography on silica gel using the 60% ethyl acetate
in hexane as the eluent to provide the titled compound (0.092 g) as yellow solid.
1HNMR (DMSOd6):d 1.27 (3H, s), 1.31 (3H, s), 2.41 - 2.47 (1H, q), 2.87 - 2.91
(2H, dd), 2.96 - 3.0 (1H, dd), 3.83 (3H, s), 3.95 - 4.0 (1H, dd), 4.67 - 4.71 (1H,
dd), 6.88 - 6.90 (2H, d), 7.15 - 7.17 (1H, m), 7.18 - 7.20 (2H, m), 7.35 - 7.37 (1H,
m), 7.39 (1H, s), 7.66 - 7.70 (1H, m), 8.61 - 8.62 (1H, d)
m/z: 336 (M+)
Step D: Preparation of 2-(4-Methoxy-benzyl)-3,3-dimethyl-4-oxo-5-[1-pyridin-2-
yl-methylidene]-piperidine-1 -carboxylic acid (2,6-dimethyl-phenyl)-amide.
The suspension of 0.11 g (3.3 mmol) of the product of example 3, Step C and 2,
6-dimethylphenyl isocyanate (0.048 g, 3.3 mmol) in toluene (30 ml) was refluxed
for 12 hours. The precipitate was filtered, washed with water (10 ml x 2) and
dried under vacuo. The residue was purified by column chromatography on silica
gel using the 2% methanol in dichloromethane as the eluent to provide the titled
compound (0.062 g) as yellow solid.
1HNMR (DMSOd6):d 1.27 (6H, s), 1.91 (6H, s), 2.84 - 2.86 (1H, m), 2.88 - 2.92
(1H, m), 3.63 - 3.71 (1H, d), 3.78 (3H, s), 3.83 - 3.86 (1H, d), 4.29 - 4.33 (1H, t),
6.02 (1H, bs), 6.82 - 6.84 (2H, d), 6.98 - 7.03 (2H, m), 7.04 - 7.05 (1H, m), 7.06 -
7.15 (3H, m), 7.37 - 7.39 (1H, d), 7.62 - 7.66 (1H, m), 7.78 (1H, s), 8.51 - 8.52
(1H,dd)
m/z: 483 (M+)
69

Example 4
1-Benzvl-3-[1-(6-morpholin-4-vl-pyridin-2-vl)-methvlidenel-5-phenyl-
piperidine-2.4-dione (Compound No. 116)
Step A: Preparation of 3-benzylamino-2-phenyl-propionic acid ethyl ester
The solution of ethyl phenylacetate (5 g, 30 mmol), potassium carbonate (6.31 g,
45 mmol) and paraformaldehyde (1.37 g, 45 mmol) in 1-methyl-2-pyrrolidinone
(30 ml) was heated at 90° C for 7 hours. The mixture was partitioned between
water and ethyl acetate (50 ml x 3). The combined organic layers were washed
with water (50 ml x 2), brine (50 ml x 2), dried over anhydrous sodium sulphate
and evaporated under vacuo. The residue was purified by column
chromatography on silica gel using the 1% ethyl acetate in hexane as the eluent
to provide 2-phenyl-acrylic acid ethyl ester (3 g) as colourless liquid. Then this
compound (3 g, 17 mmol) and benzylamine (1.82 g, 17 mmol) in toluene was
refluxed for 4 hours. The mixture was partitioned between water and ethyl
acetate (50 ml x 3). The combined organic layers were washed with water (50 ml
x 2), brine (50 ml x 2), dried over anhydrous sodium sulphate and evaporated
under vacuo. The residue was purified by column chromatography on silica gel
using the 5% ethyl acetate in hexane as the eluent to provide the titled
compound (3.5 g) as brown liquid.
1HNMR (DMSOd6):d 1.17 - 1.19 (3H, t), 2.23 (1H, bs), 2.68 - 2.72 (1H, m), 3.06
- 3.11 (1H, t), 3.69 - 3.70 (2H, d), 3.77 - 3.81 (1H, m), 4.02 - 4.09 (2H, q), 7.20 -
7.22 (2H, m), 7.26 - 7.32 (8H, m)
m/z: 283 (M+)
Step B: Preparation of 3-[Benzyl-(2-ethoxycarbonyl-acetyl)-amino]-2-phenyl-
propionic acid ethyl ester
70

The solution of 3-benzylamino-2-phenyl-propionic acid ethyl ester (3.5 g) in
tetrahydrofuran was cooled to 0° C and sodium hydride (1.2 g, 24 mmol) was
added portionwise. After 15 minutes the ethyl malonyl chloride (3.72 g, 24.7
mmol) was added and heated at 60° C for 4 hours. The mixture was partitioned
between water and ethyl acetate (50 ml x 3). The combined organic layers were
washed with water (50 ml x 2), brine (50 ml x 2), dried over anhydrous sodium
sulphate and evaporated under vacuo. The residue was purified by column
chromatography on silica gel using the 5% ethyl acetate in hexane as the eluent
to provide the titled compound (3.5 g) as brown liquid.
1HNMR (DMSOd6): d 1.12 - 1.19 (6H, t), 3.18 (2H, s), 3.58 - 3.61 (2H, m), 3.70 -
3.72 (2H, s), 3.82 - 3.85 (1H, t), 4.03 - 4.11 (4H, q), 7.20 - 7.22 (2H, m), 7.26 -
7.34 (8H, m)
m/z: 397 (M+)
Step C: Preparation of 1-Benzyl-5-phenyl-piperidine-2, 4-dione.
The solution of 3.5 g (8.8 mmol) of the product of example 4, Step B in ethanol
(10 ml) was cooled to at 0° C and potassium tert-butoxide (0.56 g, 5 mmol) was
added. The reaction mixture was stirred at room temperature for 4 hours. After
completion of reaction, the mixture was cooled to 0° C, diluted with water (20 ml)
and pH was neutralized using aqueous hydrochloric acid. The mixture was
partitioned between water and ethyl acetate (50 ml x 3). The combined organic
layers were washed with water (50 ml x 2), brine (50 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo to obtained 1-Benzyl-
2,4-dioxo-5-phenyl-piperidine-3-carboxylic acid ethyl ester (1 g) as colourless
liquid. Then this crude compound (1 g) was dissolved in dimethylsulphoxide :
water (1:1, 10 ml) and heated at 140°C for 8 hours. The mixture was partitioned
between water and ethyl acetate (50 ml x 3). The combined organic layers were
washed with water (100 ml x 2), brine (50 ml x 2), dried over anhydrous sodium
sulphate and evaporated under vacuo. The residue was purified by column
71

chromatography on silica gel using the 40% ethyl acetate in hexane as the eluent
to provide the titled compound (0.6 g) as brown liquid.
1HNMR (DMSOd6):d 3.19 - 3.27 (1H, d), 3.41 - 3.43 (1H, d), 3.74 - 3.79 (1H, m),
3.86 - 3.87 (1H, d), 4.21 - 4.26 (1H, d), 4.34 - 4.38 (1H, d), 4.45 - 4.49 (1H, d),
7.15 - 7.16 (3H, m), 7.20 - 7.26 (2H, m), 7.28 - 7.36 (5H, m)
m/z: 279 (M+)
Step D: Preparation of 1-Benzyl-3-[1-(6-morpholin-4-yl-pyridin-2-yl)-
methylidene]-5-phenyl-piperidine-2,4-dione
The solution of 0.25 g (0.89 mmol) of the product of example 4, Step C in
methanol (20 ml) was cooled to 0° C, sodium hydroxide (0.07 g, 1.7 mmol) and 6-
Morpholin-4-yl-pyridine-2-carboxaldehyde (0.15 g, 0.8 mmol) was added and
stirred at room temperature for 8 hours. After completion of reaction, the mixture
was cooled to 0° C, diluted with water (20 ml) and pH was neutralized using
aqueous hydrochloric acid and partitioned between water and ethyl acetate (50
ml x 3). The combined organic layers were washed with water (50 ml x 2), brine
(50 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The residue was purified by column chromatography on silica gel using the 5%
ethyl acetate in hexane as the eluent to afford the titled compound (0.052 g) as
yellow solid.
1HNMR (DMSOd6): d 3.48 - 3.50 (4H, t), 3.71 - 3.73 (4H, t), 4.37 (2H, s), 4.80
(2H, s), 7.01 - 7.03 (1H, d), 7.13 - 7.15 (1H, d), 7.19 - 7.22 (1H, m), 7.26 - 7.28
(1H, m), 7.30 - 7.35 (6H, m), 7.64 - 7.67 (3H, m), 7.74 - 7.78 (1H, m), 14.65 (1H,
s)
m/z: 453 (M+)
72

The following representative compounds of the present invention were prepared
following the synthetic routes as described above:

Table-1
Comp. Compound Name NMR MASS
No.
1 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.17 (6H, s), m/z: 306
5-[1-pyridin-2-yl- 2.5m (2H, s), 3.69 (2H, s), 4.191 - (M+1)
methylidene]-piperidin- 4.196 (2H,d), 7.18-7.21 (1H, m),
4-one 7.25 - 7.26 (1H, m), 7.27 - 7.29
(1H, m), 7.34-7.35 (2H, m), 7.39
- 7.41 (4H, m), 7.68 - 7.72 (1H,
2 3,3-Dimethyl-4-oxo-5- m)1HNMR (DMSOd6) d: 1.20 (6H, s), m/z: 350
[1-pyridin-2-yl- 3.64 (2H, s), 5.20 (2H, s), 5.27 (M+1)
methylidene]- (2H, s), 7.23-7.28 (1H,m), 7.30-
piperidine-1- 7.31 (1H, m), 7.36-7.38 (4H, m),
carboxylicacid benzyl 7.45 - 7.54 (2H, m), 7.71- 7.72
ester (1H, m), 8.73(1 H,s)
3 3,3-Dimethyl-4-oxo-5- 1HNMR (DMSOd6) d: 1.213 (6H, m/z: 288
[1-pyridin-2-yl- s), 1.30 (3H, t), 3.61 (2H, s), 4.21 (M+1)
methylidene]- (2H, m), 5.18 (2H, d), 7.24- 7.28
piperidine-1- (1H, m), 7.44 - 7.48 (2H, m), 7.73
carboxylicacid ethyl (1H, m), 8.74-8.75(1 H,d)
ester
4 3,3-Dimethyl-4-oxo-5- 1HNMR (DMSOd6) d: 1.31(6H, s), m/z: 336
[1-pyridin-2-yl- 3.72 - 3.81 (2H, d), 5.29 (1H, s), (M+1)
methylidenej- 5.40 (1H, s), 7.12 - 7.15 (2H, m),
piperidine-1- 7.17 - 7.24 (2H, m), 7.36 - 7.40
carboxylicacid phenyl (2H, m), 7.45-7.48 (1H, m), 7.50
ester -7.54(11-1, d), 7.70 -7.75(1 H, m),
8.73 (1H,s)
5 1 -Acetyl-3,3-dimethyl-5- 1HNMR (DMSOde) d: 1.06 (6H, s), m/z: 258
[1-pyridin-2-yl- 2.10 (3H, s), 4.54 - 4.56 (2H, d), (M+1)
methylidene]-piperidin- 5.40 - 5.43 (2H, m), 7.22 - 7.25
4-one (1H, m), 7.45-7.47 (1H,d), 7.76-
7.81 (2H, m), 8.46-8.47(1 H,d)
6 1-Benzyl-3-methyl-5-[1- 1HNMR (DMSOd6) d: 1.11 - 113 m/z: 292
pyridin-2-yl- (3H, d), 2.46-2.53 (1H,m), 3.16- (M+1)
methylidene]-piperidin- 3.19 (2H, d), 3.6 (2H, s), 3.75 -
4-one 3.76 (2H, d), 7.14 - 7.16 (1H, m),
7.28 - 7.32 (2H, m), 7.33 - 7.41
(4H, m), 7.44-7.46 (1H, m), 7.60
73

- 7.63 (1H, m), 8.53 - 8.54 (1H,
dd)
7 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.07 (6H, s), m/z: 418
5-[1-[4-(morpholine-4- 3.57-3.65 (12H, m), 3.75 (2H, s), (M+1)
carbonyl)-phenyl]- 7.23 - 7.26 (1H, m), 7.30 - 7.35
methylidene]-piperidin- (4H, m), 7.36-7.38(1 H, m), 7.44
4-one - 7.50 (4H, m)
8 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.06 (6H, s), m/z: 351
5-[1 -(4-methylsulfanyl- 2.42 - 2.45(2H, m), 2.56 (3H, s), (M+1)
phenyl)-methylidene]- 3.65 (2H, s), 3.73 (2H, s), 7.27 -
piperidin-4-one 7.28 (2H, m), 7.31- 7.35 (3H, m),
7.36 - 7.39 (3H, m), 7.43 - 7.46
(1H, m),7.81 -7.83(11-1, m)
9 1 -Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.08 (6H, s), m/z: 350
5-[1-(4-nitro-phenyl)- 2.51 (2H, s), 3.65 (2H, s), 3.75 (M+1)
methylidene]-piperidin- (2H, s), 7.33 - 7.36 (5H, m), 7.44
4-one (1H, s), 7.68 - 7.70 (2H, d), 8.24 -
8.26 (2H, d)
10 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.069 (6H, m/z: 305
5-[1-phenyl- s), 2.51 (2H, s), 3.64 (2H, s), 3.73 (M+1)
methylidene]-piperidin- (2H, s), 7.22-7.25(1 H, m), 7.30-
4-one 7.37 (6H, m), 7.40 - 7.45 (4H, m)
11 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOde) 5: 1.08 (6H, s), m/z: 325
5-[1-(3-methyl- 2.33 (3H, s), 2.56 (2H, s), 3.63 (M+1)
thiophen-2-yl)- (2H, s), 3.70 (2H, s), 7.09 - 7.11
methylidene]-piperidin- (1H, d), 7.25-7.29(1 H, m), 7.33 -
4-one 7.40 (4H, m), 7.66 (1H, s), 7.81 -
7.83 (1H,d)
12 1-Benzyl-5-[1-(4- 1HNMR (DMSOd6) d: 1.0 (6H, s), m/z: 391
methanesulfonyl- 2.92 (5H, s), 3.06 - 3.09 (2H, t), (+Na )
piperazin-1-yl)- 3.13 - 3.16 (1H, t), 3.22 (3H, s),
methylidene]-3,3- 3.44 - 3.47 (2H, m), 3.65 (2H, s),
dimethyl-piperidin-4- 4.09 - 4.14 (2H, m), 7.21 - 7.23
one (1H, m), 7.29 - 7.30 (3H, m), 7.64
- 7.73 (2H, m)
13 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.24 (3H, s), m/z: 381
3,3-dimethyl-5-[1-(4- 1.31 (3H, s), 2.39 - 2.45 (1H, q), (M+1)
methylsulfanyl-phenyl)- 2.50 (3H, s), 2.88 - 2.98 (3H, m),
methylidenej-piperidin- 3.77 - 3.78 (1H, d), 3.83 (3H, s),
4-one 4.11 - 4.16 (1H, dd), 6.89 - 6.91
(2H, d), 7.17-7.19 (2H,d), 7.21 -
7.25 (3H, m), 7.26 (1H, s), 7.45
(1H,s)
14 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.27 (3H, s), m/z: 336
3,3-dimethyl-5-[1- 1.31 (3H, s), 2.41 - 2.47 (1H, q), (M+1)
74

pyridin-2-yl- 2.87 - 2.91 (2H, dd), 2.96 - 3.0
methylidene]-piperidin- (1H, dd), 3.83 (3H, s), 3.95 - 4.0
4-one (1H, dd), 4.67-4.71 (1H, dd), 6.88
- 6.90 (2H,d), 7.15-7.17 (1H,m),
7.18 - 7.20 (2H, m), 7.35 - 7.37
(1H, m), 7.39 (1H, s), 7.66 - 7.70
1H, m),8.61 -8.62(11-1, d)
15 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 0.94 - 1.05 m/z: 408
3,3-dimethyl-4-oxo-5- (3H, t), 1.35 (6H, s), 2.50 - 2.57 (M+1)
[1-pyridin-2-yl- (1H, m), 2.97-3.09 (1H, m), 3.80
methylidene]- (3H, s), 3.83 - 3.89 (2H, q), 3.92 -
piperidine-1 -carboxylic 4.06 (1H, m), 4.62-4.81 (1H, m),
acid ethyl ester 5.52 - 5.68 (1H, m), 6.79 - 6.82
(2H, m), 7.07-7.09 (1H,d), 7.10-
7.13 (1H, d), 7.22 - 7.28 (1H, m),
7.47 - 7.49 (1H, d), 7.52 - 7.53
(1H, m) 7.57-7.58 (1H, m), 7.71 -
7.71 (1H, m)
16 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d : 1.35 (3H, s), m/z: 456
3,3-dimethyl-4-oxo-5- 1.37 (3H, s), 2.56 - 2.66 (1H, m), (M+1)
[1-pyridin-2-yl- 3.07 - 3.17 (1H, m), 3.81 (3H, s),
methylidenej- 4.59 - 4.63 (1H, m), 4.86 - 4.93
piperidine-1 -carboxylic (1H, m), 5.71 -5.77(11-1, d), 6.64-
acid phenyl ester 6.66 (1H, d), 6.84 - 6.89 (2H, m),
7.13 - 7.16 (3H, m), 7.17- 7.18
(1H, m), 7.19-7.24(1 H, m), 7.25
- 7.33 (2H, m), 7.49 - 7.52 (1H,
m), 7.60 - 7.63 (1H, m), 7.72 -
7.76(11-1, m), 8.73 -8.77(1 H, dd)
17 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 0.826 (3H,
3,3-dimethyl-4-oxo-5- s), 0.84 (3H, s), 1.21 - 1.27 (3H, m/z: 436
[1 -pyridin-2-yl- d), 1.28- 1.30 (3H, d), 1.59- 1.83 (M+1)
methylidene]- (1H, m), 2.25 - 2.29 (1H, m), 2.45
piperidine-1 -carboxylic - 2.59 (1H, m), 2.89 - 2.90 (1H,
acid isobutyl ester m), 2.92 - 2.97 (1H,m), 3.0-3.09
(1H, m), 3.71 - 3.73 (2H, d), 3.78
(3H, s), 6.77 - 6.80 (2H, m), 7.01 -
7.06 (1H, m), 7.08-7.09 (1H, m),
7.11 - 7.13 (1H, m), 7.21 - 7.30
(1H, m), 7.46-7.50(1 H, m), 7.71
- 7.76 (1H, m), 8.71 - 8.79 (1H,
dd)
18 1-(2,2-Dimethyl- 1HNMR (DMSOd6) d: 1.03 (3H, s), m/z: 420
propionyl)-2-(4- 1.05 (3H, s), 1.21 (3H, s), 1.23 (M+1)
methoxy-benzyl)-3,3- (3H, s), 1.32 (3H, s), 2.51 - 2.58
dimethyl-5-[1 -pyridin-2- (2H, m), 3.14 - 3.19(1 H, dd), 3.79
75

yl-methylidene]- (3H, s), 4.29-4.34(1 H,dd), 5.33-
piperidin-4-one 5.37 (1H, dd), 6.29 -6.24(1 H, d),
6.77 - 6.82 (2H, m), 7.15 - 7.18
(1H, d), 7.23-7.30 (1H,m), 7.47-
7.49 (1H, m), 7.50 - 7.51 (1H, m),
7.74 - 7.78 (1H, m), 8.68 - 8.69
MH.dd)
19 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.27 (6H, s), m/z: 483
3,3-dimethyl-4-oxo-5- 1.91 (6H, s), 2.84 - 2.86 (1H, m), (M+1 )
[1-pyridin-2-yl- 2.88 - 2.92 (1H, m), 3.63 - 3.71
methylidenej- (1H, d), 3.78 (3H, s), 3.83 - 3.86
piperidine-1 -carboxylic (1H, d), 4.29 - 4.33 (1H, t), 6.02
acid (2,6-dimethyl- (1H, bs), 6.82-6.84 (2H,d), 6.98-
phenyl)-amide 7.03 (2H, m), 7.04-7.05 (1H, m),
7.06 - 7.15 (3H, m), 7.37 - 7.39
(1H, d), 7.62 - 7.66 (1H, m), 7.78
(1H,s), 8.51 -8.52(11-1, dd)
20 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 2.50 (6H, s), m/z: 356
5-[1 -quinolin-2-yl- 3.02 (2H, s), 3.68 (2H, s), 4.47 (M+1 )
methylidene]-piperidin- (2H, s), 7.11 -7.35(6H, m), 7.54 -
4-one 7.72 (3H, m), 7.91 - 8.03 (2H, m),
8.21 (1H, s)
21 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1-06 (6H, s), m/z: 294
5-[1 -(1 H-pyrrol-2-yl)- 2.51 (2H, s), 3.54 (2H, s), 3.69 (M+1 )
methylidene]-piperidin- (2H, s), 6.26 - 6.29 (2H, dd), 7.10
4-one (1H, s), 7.27-7.28 (1H,m), 7.35-
7.39 (5H, m),11.53(1 H, bs)
22 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.12 (6H, s), m/z: 391
5-[1 -(6-morpholin-4-yl- 2.60 (2H, s), 3.27 - 3.29 (4H, s), (M+1 )
pyridin-2-yl)- 3.64 - 3.66 (6H, m), 4.02 (2H, s),
methylidene]-piperidin- 6.80 - 6.82 (1H, d), 6.95 - 6.97
4-one (1H, d), 7.13 (1H, s), 7.25 - 7.27
(1H, m), 7.31 -7.37(4H, m), 7.56
-7.60(11-1, m)
23 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 0.85 (6H, s), m/z: 357
5-[1-quinoxalin-2-yl- 3.04 (2H, s), 3.73 (2H, s), 4.49 (M+1 )
methylidene]-piperidin- (2H, s), 7.23 - 7.38 (4H, m), 7.46 -
4-one 7.49 (1H, s), 7.73 - 7.80 (1H, m),
7.781 - 7.82 (2H, m), 7.89 - 7.90
(1H, m), 7.99 - 8.05 (1H, m), 8.79
-8.84(11-1, m)
24 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.046 (6H, m/z: 311
5-[1-thiophen-2-yl- s), 2.36 (2H, s), 3.56 (2H, s), 3.72 (M+1 )
methylidene]-piperidin- (2H, s), 6.99-7.03 (1H, m), 7.19-
4-one 7.24 (1H,m), 7.31 - 7.378 (4H, m),
7.61 - 7.64 (1H, m), 7.78 (1H, s),
76

7.90 - 7.94 (1H,m)
25 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.12 (6H, m/z: 389
5-[1-(3,4,5,6-tetrahydro- m), 1.50 - 1.59 (6H, m), 2.51 - (M+1 )
2H-[1,2' ]bipyridinyl6'- 2.57 (6H, m), 3.66 (2H, s), 4.07
yl)-methylidene]- (2H, s), 6.81 - 6.86 (2H, m), 7.12
piperidin-4-one (1H, s), 7.27-7.29(1 H,m), 7.34-
7.38 (4H, m), 7.53(1 H, s),
26 1-Benzyl-5-[1-(3- 1HNMR (DMSOd6) d: 0.89 (6H, s), m/z: 373
hydroxy-quinoxalin-2- 3.05 (2H, s), 3.29 (2H, s), 4.47 (M+1 )
yl)-methylidene]-3,3- (2H, s), 7.24 - 7.30 (3H, m), 7.32 -
dimethyl-pipe riding- 7.36 (2H, m), 7.39 - 7.42 (2H, m),
one 7.44 - 7.50 (1H, m), 7.52 - 7.58
(1H, d), 7.58 -7.65(1 H, dd), 12.26
MH.bs)
27 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.21 (6H, s), m/z: 382
2-phenyl-3-[1-pyridin-2- 2.4-2.51 (1 H,d), 2.67-2.70 (1H, (M+1 )
yl-methylidene]- d), 3.45-3.56 (1H,m), 3.58-3.69
piperidin-4-one (1H, m), 6.08 (1H, s), 7.17 - 7.14
(1H, m), 7.16-7.19 (2H, m), 7.20
- 7.22 (2H, m), 7.23 - 7.24 (3H,
m), 7.24 - 7.34 (5H, m), 7.55 -
7.59 (1H, dd), 8.63-8.64(1 H,d)
28 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 2.46 (6H, s), m/z: 433
2-phenyl-3-[1- 3.43 - 3.45 (1H, q), 3.45 - 3.53 (M+1 )
quinoxalin-2-yl- (1H, m), 3.55-3.62 (1H, m), 3.63
methylidene]-piperidin- - 3.65 (1H, q), 4.00-4.02 (1H, d),
4-one 7.38 - 7.43 (2H, d), 7.51 - 7.52
(1H, m), 7.53-7.54 (1H, m), 7.62
-7.64(11-1, m), 7.82 -7.90 (2H, d),
7.91 - 7.96 (4H, m), 8.12 - 8.15
(3H, m), 9.37 (2H, s)
29 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.05 (3H, s), m/z: 370
2-phenyl-3-[1-(1H- 1.13 (3H, s), 3.24 - 3.28 (2H, d), (M+1 )
pyrrol-2-yl)- 3.31 (1H, s), 3.86 - 3.89 (1H, d),
methylidene]-piperidin- 5.24 (1H, s), 7.15 - 7.17 (2H, d),
4-one 7.19 - 7.21 (1H, bs), 7.22 - 7.24
(3H, d), 7.25 - 7.27 (3H, m), 7.28 -
7.31 (2H, s), 7.32 - 7.34 (2H, d),
7.40 - 7.44 (2H, m)
30 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.06 (3H, s), m/z: 468
3-[1-(6-morpholin-4-yl- 1.22 (3H, s), 2.36 - 2.39 (1H, d), (M+1 )
pyridin-2-ylj- 2.56 - 2.59 (2H, d), 3.04 - 3.09
methylidene]-2,3,5,6- (2H, m), 3.19-3.25 (2H, m), 3.48
tetrahydro-1H- -3.51 (1H, d), 3.57 -3.59 (4H, t),
[2,2' ]bipyridinyl4-one 3.88 - 3.92 (1H, d), 6.49 (1H, s),
6.72 - 6.75 (1H, d), 6.83 - 6.85
77

(1H, d), 7.00 (1H, s), 7.12 - 7.14
(1H, d), 7.23-7.27 (2H,m), 7.28-
7.31 (1H, m), 7.36 - 7.38 (2H, d),
7.50 - 7.54 (1H, m), 7.80 - 7.85
(1H, dd),8.51 -8.52(1H,d)
31 1 -Benzyl-5,5-dimethyl- *HNMR (DMSOd6) d: 1.10 (3H, s), m/z: 383
3-[1-pyridin-2-yl- 1.18 (3H, s), 2.29 - 2.32 (1H, d), (M+1 )
methylidene]-2,3,5,6- 2.51 (1H, d), 2.79 - 2.82 (1H, d),
tetrahydro-1H- 3.21-3.25 (1H,d), 3.90 -3.94(1 H,
[2,2' ]bipyridinyl4-one d), 6.40 (1H,s), 7.12(1 H,s), 7.21
- 7.26 (2H, m), 7.27 - 7.29 (2H,
m), 7.31 - 7.35 (2H, m), 7.42 -
7.44 (1H, d), 7.49 - 7.51 (1H, d),
7.75 - 7.83 (2H, m), 8.49 - 8.52
(2H, m)
32 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 0.89 (3H, s), m/z: 427
3-[1 -(4-methylsulfanyl- 1.29 (3H, s), 2.33-2.38 (1H, dd), (M+1 )
phenyl)-methylidene]-2- 2.56 (3H, s), 2.83 - 2.95 (2H, m),
phenyl-piperidin-4-one 3.59 -3.67 (2H, m), 7.23 - 7.24
(2H, m), 7.28 - 7.33 (6H, m), 7.39
- 7.46 (3H, m), 7.52 - 7.54 (3H, d),
7.81 -7.84(1H,d),
33 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.02 (3H, s), m/z: 467
3-[1 -(6-morpholin-4-yl- 1.23 (3H, s), 2.54 - 2.57 (1H, d), (M+1 )
pyridin-2-yl)- 2.67 - 2.70 (1H, d), 2.96 - 301 (2H,
methylidene]-2-phenyl- m), 3.07 - 3.12 (2H, m), 3.13 -
piperidin-4-one 3.34 (1H, d), 3.37 - 3.49 (4H, t),
3.62 - 3.65 (1H, d), 3.85 - 3.89
(1H, d), 6.38 (1H, s), 6.73 - 6.75
(1H, d), 6.86 - 6.88(1 H,d), 7.082
-7.10 (1H, d), 7.14 (1H, s), 7.21-
7.26 (2H, m), 7.28 - 7.34 (6H, m),
7.51 -7.55(1H, m)
34 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.30 (3H, s), m/z: 388
3-[1-pyridin-2-yl- 1.49 (3H, s), 2.69 - 2.72 (1H, d), (M+1 )
methylidene]-2- 3.76 - 3.77 (1H, m), 4.27 - 4.29
thiophen-2-yl-piperidin- (1H,d), 4.37-4.378 (1H,d), 4.55
4-one -4.57(1H, d), 6.74 (1H, s), 6.94-
6.95 (1H, m), 6.96 - 6.97(1 H, m),
7.05 (1H, s), 7.23 - 7.27 (1H, m),
7.30 - 7.32 (2H, m), 7.34 - 7.37
(2H, m), 7.41 -7.42(1H, d), 7.54-
7.56 (1H, d), 7.78 - 7.83 (1H,dd),
8.61 -8.62(1H, d)
35 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.03 (3H, s), m/z: 473
3-f 1 -(6-morpholin-4-yl- 1.15 (3H, s), 2.51 - 2.53 (2H, d), (M+1 )
78

pyridin-2-yl)- 2.75 - 2.78 (1H, d), 2.94 - 2.98
methylidene]-2- (2H, m), 2.99 - 3.00 (2H, m), 3.50
thiophen-2-yl-piperidin- -3.52(4H, t), 3.74-3.78(1 H,d),
4-one 3.90 - 3.93 (1H, d), 6.71 - 6.72
(1H, d), 6.76-6.78 (1H, m), 6.91 -
6.93 (1H, d), 6.98 - 7.00 (1H, m),
7.07 (1H, s), 7.24 - 7.28 (1H, m),
7.31 - 7.34 (2H, m), 7.37 - 7.41
(2H, m), 7.43 - 7.44 (1H, dd), 7.53
-7.57(11-1, m),
36 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.37 (3H, s), m/z: 466
3-[1-(3,4,5,6-tetrahydro- 1.44 (3H, s), 2.07 - 2.37 (3H, m), (M+1 )
2H-[1,2' ppyridiny6- 2.62 - 2.65 (1H, m), 3.29 - 3.33
yl)-methylidene]- (1H, m), 3.37-3.43 (1H, m), 3.50
2,3,5,6-tetrahydro-1H- -3.54(11-1, d), 3.81 -3.84(11-1, d),
[2,2' ]bipyridinyl4-one 3.93 - 3.96 (1H, dd), 4.02 - 4.05
(1H, d), 4.27-4.29 (1H,d), 4.35-
4.36 (1H, d), 4.44 -4.47 (1H, d),
4.54 - 4.56 (1H, d), 4.65 - 4.67
(1H, dd), 6.52-6.54 (1H, d), 6.66
- 6.67 (1H,d), 7.02-7.18 (2H,m),
7.23 - 7.31 (4H, m), 7.33 - 7.54
(3H, m), 7.54 - 7.65 (1H, m), 8.58
-8.59(1H, m)
37 3,3-Dimethyl-4-oxo-5- 1HNMR (DMSOd6) d: 1.14 (6H, s), m/z: 419
[1-(3,4,5,6-tetrahydro- 1.40 - 1.45 (4H, m), 1.53 - 1.59 (M+1 )
2H-[1,2' ]bipyridinyB'- (4H, m), 3.37 - 3.46 (2H, m), 3.52
yl)-methylidene]- - 3.57 (2H, s), 3.65 (1H, s), 3.81
piperidine-1 -carboxylic (1H, s), 6.85-6.88(1 H,d), 6.94-
acid phenyl ester 6.98 (1H, m), 7.13 - 7.14 (2H, d),
7.24 - 7.26 (1H, m), 7.27 - 7.30
(1H, m), 7.38 - 7.42 (2H, m), 7.56
-7.60(1H, m)
38 3,3-Dimethyl-5-[1-(6- 1HNMR (DMSOd6) d: 1.15 (6H, s), m/z: 421
morpholin-4-yl-pyridin- 3.46 - 3.49 (6H, t), 3.64 (1H, s), (M+1 )
2-yl)-methylidene]-4- 3.69 (2H, s), 3.80 (1H, s), 5.22
oxo-piperidine-1- (1H, s), 5.46 (1H, s), 6.87 - 6.92
carboxylic acid phenyl (1H, m), 7.05-7.09(1 H, m), 7.15
ester -7.16(21-1, d), 7.24 -7.27 (1H, m),
7.32 (1H, s), 7.40 - 7.44 (2H, m),
7.63 - 7.67 (1H,m)
39 2-[1-Benzyl-5,5- 1HNMR (DMSOd6) d: 1.11 (6H, s), m/z: 373
dimethyl-4-oxo- 2.59 (2H, s), 3.69 (2H, s), 4.17 (M+1 )
piperidin-3- (2H, s), 7.01 -7.02 (1H, m), 7.26-
ylidenemethyl]-3H- 7.29 (1H, m), 7.35 - 7.39 (2H, m),
quinazolin-4-one 7.40 - 7.42 (2H, m), 7.52 - 7.59
79

(2H, m), 7.82-7.86 (1H, m), 8.09
-8.11 (1H, dd), 12.47(1 H, bs),
40 1-Benzyl-3,3-dimethyl- 1HNMR (DMSOd6) d: 1.20 (6H, m/z: 306
5-[1-pyridin-3-yl- s),2.59 (2H, s), 3.71 (4H, s), 7.28 (M+1)
methylidene]-piperidin- (1H, s), 7.31 - 7.37 (4H, m), 7.49
4-one (1H, s), 7.65-7.67 (2H,m), 8.57-
8.58 (1H, dd), 8.59-8.63(1 H,d)
41 5'-[1-Benzyl-5,5- 1HNMR (DMSOd6) d: 1.16 (6H, s), m/z: 434
dimethyl-4-oxo- 1.77 - 1.82 (2H, m), 2.04 - 2.12 (M-1)
piperidin-3- (2H, m), 2.51 (2H, s), 2.53 - 2.68
ylidenemethyl]-3,4,5,6- (1H, m), 3.07 - 3.14 (2H, m), 3.68
tetrahydro-2H- (2H, s), 3.77 (2H, s), 4.28 - 4.30
[1,2' ]bipyridiny4- (1H, t), 4.31 - 4.33 (1H,m), 6.65-
carboxylic acid 6.67 (1H, d), 7.26 (1H, s), 7.28 -
7.30 (1H, m), 7.35-7.39 (3H, m),
7.43 (1H, s), 7.48-7.51 (1H, dd),
8.26-8.268 (1H, d), 11.3 (1H, bs)
42 1-Benzyl-2-(4- 1HNMR (DMSOd6) d: 1.09 (6H, s), m/z: 425
dimethylamino-phenyl)- 2.38 - 2.41 (1H, s), 2.51 - 2.59 (M+1)
5,5-dimethyl-3-[1- (1H, s), 2.84 (6H, s), 3.40 - 3.42
pyridin-2-yl- (1H, d), 3.61 -3.64(11-1, d), 4.13 -
methylidene]-piperidin- 4.15 (1H, dd), 6.07 (1H, s), 6.64-
4-one 6.66 (2H, d), 7.01 (1H, s), 7.05 -
7.07 (2H, d), 7.24 - 7.31 (4H,m),
7.45 -7.46 (1H, d), 7.68 - 7.77 (2H,
m), 8.61 -8.62(11-1, d)
43 1-Benzyl-5-[1-[6-(3,5- 1HNMR (DMSOd6) d: 1.17 (6H, s), m/z: 419
dimethyl-morpholin-4- 1.27 - 1.28 (3H, d), 1.30 - 1.31 (M+1)
yl)-pyridin-3-yl]- (3H, d), 2.51 (2H, s), 2.57 - 2.62
methylidene]-3,3- (2H, m), 3.62 (2H, s), 3.69 - 3.73
dimethyl-piperidin-4- (2H, m), 3.75-3.78 (2H,d), 4.13-
one 4.16 (2H, m), 6.6 - 6.69 (1H, d),
7.28 - 7.30 (1H, m), 7.33 - 7.35
(2H, m), 7.36 - 7.40 (2H, m), 7.42
- 7.44 (1H, m), 7.50 - 7.52 (1H,
dd), 8.26-8.27(1 H,d)
44 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.02 (3H, s), m/z: 513
2-(4-methylsulfanyl- 1.23 (3H, s), 2.39 (3H, s), 2.65 - (M+1)
phenyl)-3-[1-(6- 2.71 (2H, m), 2.97 - 3.01 (2H, m),
morpholin-4-yl-pyridin- 3.10 - 3.14 (2H, m), 3.38 - 3.50
2-yl)-methylidene]- (4H, t), 3.60-3.64 (1H, d), 3.82-
piperidin-4-one 3.86 (1H, d), 6.33 (1H, s), 6.73 -
6.75 (1H, d), 6.86 - 6.88 (1H, d),
7.00 - 7.02 (1H, d), 7.12 (1H, s),
7.20 - 7.22 (2H, m), 7.25 - 7.26
(2H, m), 7.28 - 7.31 (4H, m), 7.51
80

-7.55(1H, m)
45 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.26 (6H, s), m/z: 535
3-[1-(6-morpholin-4-yl- 2.92 - 2.93 (2H, m), 2.99 - 3.00 (M+1 )
pyridin-2-ylj- (2H, m), 3.42 - 3.44 (2H, t), 3.54 -
methylidene]-2-(4- 3.62 (2H, m), 3.70 - 3.73 (2H, m),
trifluoromethyl-phenyl)- 4.15 - 4.51 (2H, m), 6.39 (1H, s),
piperidin-4-one 6.74 - 6.76 (1H, d), 6.91 - 6.93
(1H, d), 7.14-7.19 (1H,m), 7.24-
7.37 (7H, m), 7.53-7.57 (1H, m),
7.70 - 7.72 (1H, m), 7.76 - 7.80
(1H,m)
46 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.03 (6H, s), m/z: 450
3-[1 -pyridin-2-yl- 2.50 (1H, m), 2.59 - 2.62 (1H, d), (M+1 )
methylidene]-2-(4- 3.39 - 3.45 (1H, d), 3.63 - 3.67
trifluoromethyl-phenyl)- (1H, d), 6.28 (1H, s), 7.02 (1H, s),
piperidin-4-one 7.13 - 7.31 (6H, m), 7.47 - 7.58
(3H, m), 7.66 - 7.73 (2H, m), 7.73
- 7.80 (1H,m), 8.61 -8.62 (1H, d),
47 1-Benzyl-2-(3,4- 1HNMR (DMSOd6) d: 1.09n (6H, m/z: 451
dichloro-phenyl)-5,5- s), 2.27 - 2.58 (2H, m), 3.27 - 3.41 (M+1 )
dimethyl-3-[1 -pyridin-2- (1H, d), 3.49 - 3.64 (1H, d), 6.17
yl-methylidene]- (1H, s), 7.12 (1H, s), 7.16 - 7.23
piperidin-4-one (2H, m), 7.25 - 7.28 (4H, m), 7.34
- 7.41 (1H, m), 7.52 - 7.58 (3H,
m), 7.78 - 7.82 (1H, m), 8.62 -
8.63 (1H,d)
48 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 0.59 (3H, s), m/z: 428
2-(4-methylsulfanyl- 1.26 (3H, s), 2.45 - 2.51 (1H, d), (M+1 )
phenyl)-3-[1 -pyridin-2- 2.53 (3H, s), 2.68 - 2.74 (1H, d),
yl-methylidene]- 3.17 - 3.25 (1H, d), 3.71 - 3.84
piperidin-4-one (1H, d), 4.43(1 H,s), 6.31 (1H,s),
7.22 - 7.26 (2H, m), 7.30 - 7.34
(2H, m), 7.42 - 7.44 (2H, d), 7.53 -
7.54 (2H, m), 7.90-7.94 (1H, m),
8.09 - 8.11 (1H, d), 8.60 - 8.64
(1H, m), 8.70 (1H, s), 9.21 - 9.22
(1H,d)
81

49 1 -(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.06 (6H, s), m/z: 412
5,5-dimethyl-2-phenyl- 2.43 - 2.46 (1H, d), 2.51 - 2.60 (M+1 )
3-[1-pyridin-2-yl- (1H, d), 3.54 - 3.57 (1H, d), 3.70
methylidene]-piperidin- (3H, s), 3.73 - 3.74 (1H, d), 6.18
4-one (1H, s), 6.83 - 6.87 (2H, d), 7.05
(1H,s), 7.14-7.18 (2H,m), 7.21 -
7.22 (1H, m), 7.25-7.29 (5H, m),
7.47 - 7.49 (1H, d), 7.74 - 7.78
(1H, dd), 8.62-8.63(1 H,d)
50 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.17 (6H,s), m/z: 421
3,3-dimethyl-5-[1-(6- 3.39 - 3.42 (4H, t), 3.67 - 3.69 (4H, (M+1 )
morpholin-4-yl-pyridin- t), 3.76 (3H, s), 3.73 - 3.74 (2H,
2-yl)-methylidene]- m), 4.38 - 4.40 (2H, d), 5.19 - 5.22
piperidin-4-one (1H, t), 6.46 -6.47(1 H, m), 6.48 -
6.52 (2H, dd), 6.65 - 6.69 (2H, d),
6.77 - 6.78 (1H, d), 7.16 - 7.20
(1H, m), 7.53 -7.57 (2H, m)
51 1 -(4-Methoxy-benzyl)- ^HNMR (DMSOd6) d: 1.08 (6H, s), m/z: 418
5,5-dimethyl-3-[1- 2.34 - 2.38 (1H, d), 3.21 - 3.26 (M+1 )
pyridin-2-yl- (1H, d), 3.51 - 3.52 (1H, m), 3.62-
methylidene]-2- 3.64 (1H, m), 3.74 (3H, s), 6.70
thiophen-2-yl-piperidin- (1H, s), 6.83 - 6.86 (2H, d), 6.89-
4-one 6.96 (2H, m), 7.04 (1H, s), 7.25 -
7.31 (2H, d), 7.31 - 7.33 (1H, m),
7.34 - 7.43 (1H, m), 7.44 - 7.53
(1H,d), 7.78-7.82(1 H.m), 8.62-
8.63 (1H, dd)
52 1-Cyclopropyl-3,3- 1HNMR (DMSOd6) d: 0.51 (2H, m/z: 256
dimethyl-5-[1 -pyridin-2- m), 0.52 (2H, m), 1.07 (6H, s), (M+1 )
yl-methylidene]- 2.21 - 2.43 (1H, m), 2.82 (2H, s),
piperidin-4-one 4.17 (2H, s), 7.25 (1H, s), 7.36 -
7.38 (1H, m), 7.65 - 7.88 (1H, d),
7.85 - 7.88 (1H,m), 8.75(1 H, s)
53 3,3-Dimethyl-5-[1-(6- 1HNMR (DMSOde) 5: 1.22 (6H, s), m/z: 397
morpholin-4-yl-pyridin- 2.62 (2H, s), 3.44 - 3.46 (4H, t), (M+1 )
2-yl)-methylidene]-1- 3.81 - 3.84 (4H, t), 3.90 (2H, s),
thiophen-2-ylmethyl- 4.25 (2H, s), 6.58 - 6.60 (1H, d),
piperidin-4-one 6.85 - 6.86 (1H, d), 6.94 - 6.95
(1H, m), 6.96 - 6.98 (1H, m), 7.24
- 7.25 (1H, dd), 7.29 (1H, s), 7.50-
7.54 (1H,m)
54 1-Cyclopropyl-3,3- 1HNMR (DMSOd6) d: 0.33 - 0.34 m/z: 341
dimethyl-5-[1-(6- (2H, m), 0.48-0.49 (2H, m), 1.06 (M+1 )
morpholin-4-yl-pyridin- (6H, s), 1.79 - 1.81 (1H, m), 2.70
2-yl)-methylidene]- (2H, s), 3.51 - 3.53 (4H, t), 3.72 -
piperidin-4-one 3.74 (4H, t), 4.27 (2H, s), 6.85 -
82

6.88 (1H, d), 6.96 - 6.98 (1H, d),
7.11 (1H, s), 7.60-7.64(1 H,m)
55 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.16 (3H, s), m/z: 394
3,3-dimethyl-4-oxo-5- 1.25 (3H, s), 2.42 - 2.45 (1H, m), (M+1)
[1 -pyridin-2-yl- 2.96 - 2.99 (1H, m), 3.31 (3H, s),
methylidenej- 3.69 (3H, s), 4.40 - 4.60 (2H, m),
piperidine-1 -carboxylic 5.47 - 5.52 (1H, m), 6.78 - 6.88
acid methyl ester (2H, m), 7.09-7.14 (2H,d), 7.39-
7.41 (1H, m), 7.42-7.48 (1H, m),
7.75 - 7.77 (1H, d), 7.89 - 7.94
(1H, m), 8.76-8.79(1 H,m)
56 2-(4-Methoxy-benzyl)- ^HNMR (DMSOd6) d: 1.14 (6H, s), m/z: 501
3,3-dimethyl-4-oxo-5- 2.44 (3H, s), 2.66 - 2.72 (1H, m), (M+1)
[1-pyridin-2-yl- 2.77 - 2.81 (1H, m), 3.59 (3H, s),
methylidene]- 3.64 - 3.69 (1H, d), 3.70 - 3.76
piperidine-1 -carboxylic (1H, m), 4.68 - 4.72 (1H, m), 6.68
acid (4-methylsulfanyl- - 6.76 (2H, d), 7.03 - 7.05 (3H, d),
phenyl)-amide 7.12 - 7.14 (2H, d), 7.16 - 7.21
(2H, d), 7.27-7.29 (1H,d), 7.43-
7.51 (2H, d), 7.70 - 7.74 (1H, m),
9.10(1H,bs)
57 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.25 (6H, s), m/z: 515
3,3-dimethyl-4-oxo-5- 2.66 - 2.82 (2H, m), 3.63 (6H, s), (M+1)
[1-pyridin-2-yl- 3.65 - 3.67 (2H, m), 3.68 (3H, s),
methylidenej- 4.57 - 4.58 (1H, m), 6.58 - 6.63
piperidine-1 -carboxylic (1H,m), 6.75-6.77 (2H,d), 6.85-
acid (2,5-dimethoxy- 6.93 (2H, m), 7.07 - 7.09 (2H, d),
phenyl)-amide 7.15 - 7.20 (1H, m), 7.22 - 7.24
(1H, d), 7.47- 7.77 (1H, m), 7.92
1H, s), 8.02(1 H,d), 8.97(1 H,bs)
58 3,3-Dimethyl-1-(5- jHNMR (DMSOd6) d: 1.08 (6H, s), m/z: 382
methyl-isoxazol-3-yl)-5- 2.29 (3H, s), 3.50 (2H, s), 3.52 - (M+1)
[1-(6-morpholin-4-yl- 3.57 (4H, t), 3.60 - 3.76 (4H, t),
pyridin-2-yl)- 4.95 (2H, s), 6.10 (1H, s), 6.88 -
methylidene]-piperidin- 6.92 (1H, d), 7.02 - 7.06 (1H, d),
4-one 7.28 (1H, s), 7.57 -7.67(1 H, m)
59 2-(2-Hydroxy-phenyl)- 1HNMR (DMSOd6) d: 1.18 (6H, s), m/z: 474
5,5-dimethyl-1-(5- 2.20 (3H, s), 3.17 - 3.33 (2H, m), (+Na)
methyl-isoxazol-3-yl)-3- 3.49 - 3.52 (4H, t), 3.68 - 3.73 (4H,
[1-(6- t), 5.62 (1H, s), 5.87 - 5.90 (1H,
morpholin-4-yl-pyridin- m), 6.90 - 6.92 (2H, d), 7.02 - 7.04
2-yl)-methylidene]- (2H, d), 7.36-7.39 (1H, d), 7.55-
piperidin-4-one 7.63 (3H, m), 12.02(1 H, bs)
60 2-(2-Fluoro-phenyl)-5,5- 1HNMR (DMSOd6) d: 1.15 (3H, s), m/z: 491
dimethyl-3-[1-1/6- 1.28 (3H s) 2.55 - 2.64 (3H m) (M+1)
83

dimethyl-3-[1-(6- 1.28 (3H, s), 2.55 - 2.64 (3H, m), (M+1 )
morpholin-4-yl-pyridin- 3.25 (2H, s), 3.37 - 3.80 (2H, t),
2-yl)-methylidene]-1 - 3.68 - 3.69 (5H, m), 4.05 - 4.09
thiophen-2-ylmethyl- (1H, dd), 6.64 (1H, s), 6.78 - 6.79
piperidin-4-one (1H, m), 6.84 (1H,s), 7.02(1 H,s),
7.09 (1H, s), 7.18 (1H, s), 7.23 -
(2H, m), 7.37-7.38 (1H, m), 7.48
-7.50(11-1, m), 7.52 -7.54(1 H, m)
61 (2-Fluoro-phenyl)-5,5- 1HNMR (DMSOd6) d: 1.21 (6H, s), m/z: 406
dimethyl-3-[1 -pyridin-2- 2.39 - 2.45 (2H, m), 2.68 - 2.74 (M+1 )
yl-methylidene]-1- (1H, d), 3.47-3.53 (1H,d), 4.00-
thiophen-2-ylmethyl- 4.06 (1H, d), 6.53 (1H, s), 6.98 -
piperidin-4-one 7.02 (2H, m), 7.15 - 7.21 (2H, m),
7.27 - 7.33 (3H, m), 7.47 - 7.48
(1H, dd), 7.60-7.62 (1H, d), 7.80
-7.84(1H, t), 8.62-8.63(1 H,m),
62 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.17 (3H, s),
3,3-dimethyl-4-oxo-5- 1.27 (3H, s), 2.55 - 2.60 (1H, m), m/z: 511
[1-pyridin-2-yl- 3.04 - 309 (1H, m), 3.71 (3H, s), (M+1 )
methylidene]- 4.45 - 4.52 (1H, m), 4.55 - 4.60
piperidine-1 -carboxylic (1H, m), 4.60-4.62(1 H,d), 5.59-
acid 2,2,2-trichloro- 5.64 (1H, d), 5.91 - 5.95 (1H, d),
ethyl ester 6.77 - 6.83 (2H, m), 7.14 - 7.16
(2H, d), 7.36-7.42(1 H, m), 7.43 -
7.50 (1H, m), 7.71 -7.78(1H, m),
7.87 - 7.94 (1H, m), 8.67 - 8.78
(1H,dd)
63 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 0.86 -1.13 m/z: 461
3,3-dimethyl-4-oxo-5- (8H, m), 1.22- 1.24 (3H, m), 1.53 (M+1 )
[1-pyridin-2-yl- - 1.73 (6H, m), 2.64 - 2.67 (1H,
methylidene]- m), 2.69 - 2.70 (1H, m), 3.10 -
piperidine-1 -carboxylic 3.25 (1H, m), 3.51 (3H, s), 4.27 -
acid cyclohexylamide 4.32 (1H, m), 4.35-4.50(1 H, m),
5.58 - 5.60 (1H, m), 6.73 - 6.84
(2H, m), 6.96 - 6.98 (1H, m), 7.06
- 7.24 (2H, m), 7.32 - 7.40 (1H,
m), 7.67 - 7.71 (1H, m), 7.88 -
7.91 (1H, m), 8.74(1 H,bs)
64 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.16 (6H, s), m/z: 471
3,3-dimethyl-4-oxo-5- 2.55 - 2.66 (2H, m), 3.08 - 3.12 (M+1 )
[1-pyridin-2-yl- (2H, m), 3.72 (3H, s), 4.85 - 4.90
methylidene]- (1H, d), 6.80-6.84 (4H,m), 7.08-
piperidine-1 -carbothioic 7.13 (1H, m), 7.15-7.25 (4H, m),
acid phenylamide 7.32 - 7.38 (1H, m), 7.44 - 7.49
(1H, m), 7.71 -7.56 (1H, m), 7.88
- 7.92 (1 H,m), 9.46 (2H,s)
84

65 5,5-Dimethyl-2-(4- 1HNMR (DMSOd6) d: 1.12 (3H, s), m/z: 434
methylsulfanyl-phenyl)- 1.17 (3H, s), 2.31 (1H, m), 2.41 (M+1 )
3-[1 -pyridin-2-yl- (3H, s), 2.65 - 2.68 (1H,d), 3.48-
methylidene]-1- 3.62 (1H, d), 4.10 - 4.15 (1H, d),
thiophen-2-ylmethyl- 6.25 (1H, s), 6.85 - 6.98 (2H, m),
piperidin-4-one 7.11 (1H, s), 7.17 - 7.22 (4H, m),
7.28 (1H, m), 7.42-7.43 (1H, m),
7.50 - 7.52 (1H, d), 7.70 - 7.80
(1H, m),8.61 -8.63(1H, d)
66 1 -(4-Methoxy-benzyl)- ^HNMR (DMSOde) d: 0.90 (3H, s), m/z: 497
5,5-dimethyl-3-[1-(6- 1.00 (3H, s), 2.68 - 2.69 (1H, m), (M+1 )
morpholin-4-yl-pyridin- 3.01 - 3.08 (2H, m), 3.46 - 3.49
2-yl)-methylidene]-2- (2H, t), 3.57 - 3.61 (2H, m), 3.63 -
phenyl-piperidin-4-one 3.64 (3H, m), 3.73 (3H, s), 3.75 -
3.78 (1H, m), 4.14 -4.15 (1H, m),
6.22 (1H, s), 6.35 (1H, s), 6.66 -
6.68 (1H, d), 6.87 - 6.91 (2H, m),
7.08 - 7.14 (2H, m), 7.17 - 7.21
(2H, m), 7.30-7.33 (1H, m), 7.40
- 7.46 (2H, m), 7.48 - 7.56 (1H,
m), 7.70-7.71 (1H, m)
67 1 -(4-Methoxy-benzyl)- 1HNMR (DMSOde) d: 0.99 (3H, s), m/z: 465
5,5-dimethyl-3-[1-(6- 1.24 (3H, s), 2.68 (2H, s), 2.91 - (M+1 )
morpholin-4-yl-pyridin- 2.98 (4H, m), 3.36 - 3.44 (4H, t),
2-yl)-methylidene]-2-(4- 3.65 - 3.70 (1H, d), 3.73 (3H, s),
trifluoromethyl-phenyl)- 3.83 - 3.86 (1H, d), 6.40 (1H, s),
piperidin-4-one 6.75 - 6.83 (3H, m), 6.92 - 6.94
(1H, d), 7.18 - 7.20 (2H, d), 7.25
(1H, s), 7.32 - 7.34 (2H, d), 7.54-
7.58 (1H, dd), 7.69 -7.71 (2H, d),
68 3,3-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 1-12 (6H, s), m/z: 297
methyl-isoxazol-3-yl)-5- 2.19 (2H, d), 2.38 (3H, s), 3.95 (M+1 )
[1-pyridin-2-yl- (1H, s), 4.89 (1H,s), 6.72(1 H,s),
methylidene]-piperidin- 7.45 (1H, s), 7.65 - 7.74 (1H, m),
4-one 7.89 - 7.96 (1H, m), 8.44 (1H, s),
8.78 - 8.79 (1H,d)
69 5,5-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 1.13 (6H, s), m/z: 458
methyl-isoxazol-3-yl)-3- 2.18 (3H, s), 3.31 - 3.36 (4H, t), (M+1 )
[1-(6-morpholin-4-yl- 3.41 (2H, s), 3.67 - 3.72 (4H, t),
pyridin-2-yl)- 5.62 (1H, s), 5.87 - 5.90 (1H, m),
methylidene]-2-phenyl- 6.89 - 6.92 (1H, d), 7.02 - 7.04
piperidin-4-one (1H, d), 7.35 - 7.39(1 H,d), 7.51 -
7.74 (6H, m)
70 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.18 (3H, s), m/z: 469
3,3-dimethyl-4-oxo-5- 1.29 (3H, s), 2.13 - 2.19 (2H, m), (M+1 )
85

[1 -pyridin-2-yl- 2.97 - 3.01 (1H, m), 3.73 (3H, s),
methylidene]- 4.10 - 4.15 (2H, m), 4.18 (2H, s),
piperidine-1 -carboxylic 6.78 - 6.89 (2H, d), 6.93 - 6.95
acid benzylamide (2H, d), 7.13 - 7.20 (2H, m), 7.23
(5H, s), 7.37 - 7.44 (1H, m), 7.69
(1H, m), 7.87-7.90(1 H, m), 8.73
-8.74(1H, d)
71 2-(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.07 (3H, s), m/z: 473
3,3-dimethyl-4-oxo-5- 1.12 (3H, s), 3.00 - 3.05 (1H, m), (M+1)
[1-pyridin-2-yl- 3.60 - 3.62 (1H, m), 3.66 (3H, s),
methylidene]- 3.68 - 3.73 (1H, m), 4.40 - 4.43
piperidine-1 -carboxylic (1H, m), 4.55 -4.68(1 H, m), 6.19
acid (4-fluoro-phenyl)- - 6.22 (1H, m), 6.53 - 6.69 (1H,
amide m), 6.74 - 6.82 (2H, m), 6.90 -
6.99 (2H, m), 7.01 -7.14(11-1, m),
7.39 - 7.45 (1H, m), 7.47 - 7.53
(1H, m), 7.74-7.76 (1H, m), 7.90
- 7.93 (1H, m), 8.067 - 8.22 (1H,
m), 8.48 (1H,bs), 8.77 -8.78(1 H,m)1HNMR (DMSOd6) d: 0.94 - 0.97
72 2-(4-Methoxy-benzyl)- m/z: 539
3,3-dimethyl-4-oxo-5- (6H, m), 1.01 - 1.07 (6H, m), 1.24 (M+1)
[1-pyridin-2-yl- (6H, s), 2.51 - 2.59 (1H,d), 3.00-
methylidene]- 3.03 (2H, m), 3.14 -3.17 (1H, m),
piperidine-1 -carboxylic 3.73 (3H, s), 4.04 - 4.63 (2H, m),
acid (2,6-diisopropyl- 5.77 - 5.86 (1H, m), 6.79 - 6.85
phenyl)-amide (2H, m), 7.01 - 7.08 (3H, m), 7.21
(1H, s), 7.38 - 7.41 (1H, m), 7.48
(1H, s), 7.59 (1H,s), 7.68(1 H,m),
7.68 - 7.77 (1H, m), 7.89 - 7.92
(1H, m), 8.75 -8.76(1 H, d)
73 3,3-Dimethyl-5-[1-(6- ^HNMR (DMSOd6) d: 1.17 (6H, s), m/z: 411
morpholin-4-yl-pyridin- 2.64 - 2.72 (4H, m), 3.49 - 3.53 (M+1)
2-yl)-methylidene]-1-(2- (4H, t), 3.54 (2H, s), 3.57 (2H, s),
thiophen-2-yl-ethyl)- 3.70 - 3.74 (4H, t), 6.71 -6.73(1H,
piperidin-4 -one d), 6.90 - 6.92 (1H, d), 7.03 -
7.055 (1H, d), 7.23 - 7.26 (1H, d),
7.35 - 7.39 (1H, d), 7.56 - 7.66
(2H, m)
74 2-(2-Fluoro-phenyl)-5,5- 1HNMR (DMSOd6) d: 1.14 (6H, s), m/z: 406
dimethyl-3-[1 -pyridin-3- 3.22 (2H, s), 3.39 - 3.46 (1H, m), (M+1)
yl-methylidene]-1- 4.01 - 4.04 (1H, d), 5.45 (1H, d),
thiophen-2-ylmethyl- 6.90 - 6.93 (2H, m), 7.21 - 7.26
piperidin-4-one (2H, m), 7.30 (1H, s), 7.33 - 7.35
(1H, m), 7.36-7.41 (1H, m), 7.42
- 7.44 (2H, m), 7.60 - 7.62 (1H,
86

m), 8.41 (1H, s), 8.47 - 8.49 (1H,
dd)
75 1 -Benzyl-5,5-dimethyl- 1HNMR (DMSOd6) d: 1.02 (3H, s), m/z: 472
3-[1-pyridin-2-yl- 1.10 (3H, s), 2.06 (1H, s), 2.13 - (M+1)
methylidene]-2-(3,4,5- 2.19 (1H, s), 2.55 - 2.67 (1H, d),
trimethoxy-phenyl)- 3.59 (3H, s), 3.68 (6H, s), 4.13 -
piperidin-4-one 4.15 (1H, m), 6.18 (1H, s), 6.57
(2H, s), 6.98 (1H, s), 7.24 - 7.30
(1H, m), 7.32-7.35 (4H, m), 7.51
- 7.53 (1H, m), 7.69 - 7.73 (1H,
m), 7.78 - 7.82 (1H, m), 8.69 -
8.70 (1H,d)
76 1-(4-Fluoro-benzyl)-3,3- 1HNMR (DMSOd6) d: 1.07 (6H, s), m/z: 324
dimethyl-5-[1 -pyridin-2- 3.21 - 3.29 (1H, m), 3.34 - 3.36 (M+1)
yl-methylidene]- (1H, m), 3.63 (2H, s), 4.08 (2H, s),
piperidin-4-one 7.30 - 7.38 (2H, m), 7.65 - 7.71
(1H, d), 7.93-7.96 (3H,m), 8.66-
8.67 (1H, dd), 8.83 - 8.85 (2H, dd)
77 1-(4-Fluoro-benzyl)-3,3- 1HNMR (DMSOd6) d: 1.12 (6H, s), m/z: 409
dimethyl-5-[1-(6- 2.59 (2H, s), 3.29 - 3.34 (4H, t), (M+1)
morpholin-4-yl-pyridin- 3.65 - 3.67 (6H, m), 4.03 (2H, s),
2-yl)-methylidene]- 6.81 - 6.83 (1H, d), 6.96 - 6.97
piperidin-4-one (1H, d), 7.14-7.19 (3H,m), 7.38-
7.42 (2H, m), 7.57 - 7.61 (1H, m)
78 3,3-Dimethyl-5-[1-(6- 1HNMR (DMSOd6) d: 1.14 (6H, s), m/z: 459
morpholin-4-yl-pyridin- 2.64 (2H, s), 3.24 - 3.30 (4H, t), (M+1)
2-yl)-methylidene]-1 -(4- 3.60 - 3.62 (4H, t), 3.77 (2H, s),
trifluoromethyl-benzyl)- 4.06 (2H, s), 6.97 - 6.99 (1H, m),
piperidin-4-one 7.05 - 7.09 (1H, m), 7.21 (1H, s),
7.60 - 7.62 (3H, m), 7.70 - 7.72
(2H, m)
79 4-({2-(4-Methoxy- fHNMR (DMSOd6) d: 0.88 (3H, s), m/z: 527
benzyl)-3,3-dimethyl-4- 1.04 (3H, s), 1.26 - 1.29 (3H, t), (M+1)
oxo-5-[1 -pyridin-2-yl- 2.52 (1H, s), 2.79 - 2.82 (1H, d),
methylidene]- 3.27 - 3.30 (1H, d), 3.37 - 3.46
piperidine-1 -carbonyl}- (2H, m), 3.69 (3H, s), 4.23 - 4.26
amino)-benzoic acid (2H, q), 6.78-6.80 (1H,d), 6.87-
ethyl ester 6.89 (2H, d), 7.08 - 7.10 (1H, m),
7.11 - 7.12 (1H, m), 7.14 - 7.18
(2H, m), 7.62 - 7.64 (3H, d), 7.89 -
7.91 (2H, d), 8.40 - 8.41 (1H, dd),
9.74 (1H, bs)
80 1 -(4-Fluoro-benzyl)-5,5- 1HNMR (DMSOd6) d: 1.12 (6H, s), m/z: 400
dimethyl-2-phenyl-3-[1- 2.34 - 2.36 (1H, m), 2.56 - 2.62 (M+1)
pyridin-2-yl- (2H, m), 3.35-3.40 (2H, m), 6.17
methylidenel-piperidin- -6.21 (1H, d), 7.07 -7.09(1 H, m),
87

4-one 7.11 - 7.14 (1H, m), 7.19 - 7.20
(1H, m), 7.21 -7.32 (7H, m), 7.49
-7.51 (1H, d), 7.74-7.79(1 H,m),
8.62 - 8.63 (1H,dd)
81 1 -(4-Methoxy-benzyl)- 1HNMR (DMSOd6) d: 1.08 (3H, s), m/z: 480
5,5-dimethyl-3-[1- 1.12 (3H, s), 2.54 - 2.56 (2H, d), (M+1)
pyridin-2-yl- 3.30 - 3.31 (2H, d), 3.71 (3H, s),
methylidene]-2-(4- 6.27 (1H, s), 6.84 - 6.86 (2H, d),
trifluoromethyl-phenyl)- 7.12 - 7.17 (2H, m), 7.30 - 7.33
piperidin-4-one (1H, m), 7.51 -7.56 (4H, m), 7.66
- 7.68 (2H, d), 7.73 - 7.81 (1H, m),
8.63 - 8.64 (1H,dd)
82 2-(2-Fluoro-phenyl)-1- 1HNMR (DMSOd6) d: 1.08 (6H, s), m/z: 430
(4-methoxy-benzyl)-5,5- 2.34 - 2.38 (1H, m), 2.53 - 2.56 (M+1)
dimethyl-3-[1 -pyridin-2- (1H, m), 3.20-3.23 (1H,d), 3.65-
yl-methylidene]- 3.68 (1H, d), 3.72 (3H, s), 6.39
piperidin-4-one (1H, s), 6.84 - 6.86 (2H, d), 7.12-
7.18 (4H, m), 7.21 -7.28 (4H, m),
7.53 - 7.55 (1H, d), 7.74 - 7.78
(1H, m), 8.56-8.57(1 H.dd)
83 3,3-Dimethyl-5-[1- 1HNMR (DMSOd6) d: 1.18 (6H, s), m/z: 326
pyridin-2-yl-meth- 2.26 - 2.64 (4H, t), 2.84 (2H, s), (M+1)
ylidene]-1 -(2-thiophen- 3.53 (2H, s), 6.71 - 6.73 (1H, d),
2-yl-ethyl)-piperidin-4- 7.22 - 7.23 (1H, d), 7.40 - 7.43
one (1H, m), 7.51 -7.55(11-1, d), 7.70-
7.72 (1H, m), 7.78 - 7.80 (1H, m),
7.85 - 7.89 (1H, m), 8.65 - 8.66
(1H,d)
84 5,5-Dimethyl-3-[1-(6- 1HNMR (DMSOd6) d: 0.93(3H, s), m/z: 487
morpholin-4-yl-pyridin- 1.20 (3H, s), 2.68 (2H, s), 2.97 - (M+1)
2-yl)-methylidene]-2- 3.00 (4H ,t), 3.47 - 3.49 (2H, t),
phenyl-1 -(2-thiophen-2- 3.56 - 3.60 (4H, t), 3.59 - 3.65 (2H,
yl-ethyl)-piperidin-4-one t), 6.21 (1H, s), 6.59 - 6.68 (1H,
m), 6.70 - 6.76 (1H, m), 6.86 -
6.92 (1H, m), 7.07-7.12 (3H, m),
7.16 - 7.22 (4H, m), 7.24 - 4.28
(1H, m), 7.37 -7.46(1 H, m)
85 1 -(4-Fluoro-benzyl)-5,5- 1HNMR (DMSOd6) d: 1.01 (3H, s), m/z: 485
dimethyl-3-[1-(6- 1.22 (3H, s), 2.98 - 3.01 (2H, m), (M+1)
morpholin-4-yl-pyridin- 3.08 - 3.12 (2H, t), 3.24 - 3.29 (1H,
2-yl)-methylidene]-2- m), 3.38 - 3.47 (4H, t), 3.62 - 3.67
phenyl-piperidin-4-one (2H, t), 3.85 - 3.89 (2H, m), 6.39
(1H, s), 6.68-6.70 (1H,d), 6.74-
6.76 (1H, d), 7.07 - 7.13 (3H, m),
7.15 - 7.22 (1H, m), 7.24 - 7.25
(1H, m), 7.30 - 7.34 (4H, m), 7.42
88

-7.52(1H, dd)
86 1 -Furan-2-ylmethyl-5,5- 1HNMR (DMSOd6) d: 1.09 (3H, s), m/z: 372
dimethyl-2-phenyl-3-[1- 1.24 (3H, s), 2.51 - 2.54 (1H, d), (M+1)
pyridin-2-yl- 2.67 - 2.70 (1H, d), 3.39 - 3.44
methylidene]-piperidin- (1H, d), 3.67 - 3.71 (1H, d), 6.17
4-one (1H, s), 6.28 -6.29(1 H, dd), 6.39-
36.41 (1H, m), 7.03 -7.04(1 H, m),
7.19 - 7.20 (1H, m), 7.21 - 7.27
(4H, m), 7.47-7.49 (1H,d), 7.60-
7.61 (1H, m), 7.74 - 7.78 (2H, m),
8.63 - 8.64 (1H,m)
87 1-(3,4-Difluoro-benzyl)- 1HNMR (DMSOde) d: 1.07 (6H, s), m/z: 418
5,5-dimethyl-2-phenyl- 2.50 - 2.51 (2H, d), 2.56 - 2.61 (M+1)
3-[1-pyridin-2-yl- (1H, d), 3.37-3.39 (1H,m), 3.66-
methylidene]-piperidin- 3.67 (1H, d), 6.24 (1H, s), 7.09 -
4-one 7.13 (2H, m), 7.21 - 7.24 (3H, m),
7.25 - 7.28 (3H, m), 7.29 - 7.34
(1H, m), 7.50-7.52 (1H, d), 7.75-
7.79 (1H,m), 8.61 -8.62(11-1, m)
88 5,5-Dimethyl-2-phenyl- 1HNMR (DMSOde) d: 1.00 (3H, s), m/z: 402
3-[1-pyridin-2-yl- 1.13 (3H, s), 2.36 - 2.39 (1H, d), (M+1)
methylidene]-1-(2- 2.62 - 2.70 (1H, m), 2.76 - 2.87
thiophen-2-yl-ethyl)- (2H, m), 2.90-2.92 (1H,d), 3.60-
piperidin-4-one 3.63 (1H, m), 4.14 -4.15 (1H, m),
6.70 - 6.71 (1H, d), 6.79 - 6.80
(1H, d), 6.86-6.90 (1H, m), 7.14-
7.19 (1H, m), 7.24-7.28 (3H, m),
7.29 - 7.32 (3H, m), 7.33 - 7.34
(2H, m), 7.52-7.53(1 H,m)
89 1,5,5-Trimethyl-2- ]HNMR (DMSOde) d: 1.18 (6H, s), m/z: 306
phenyl-3-[1 -pyridin-2-yl- 2.19 (3H, s), 3.73 (2H, s), 5.85 (M+1)
methylidene]-piperidin- (1H, s), 6.48 - 6.53 (1H, m), 6.88
4-one (1H, s), 7.02-7.25 (3H, m), 7.26 -
7.27 (1H, m), 7.28 - 7.29 (1H, m),
7.46 - 7.48 (1H, d), 7.69 - 7.76
(1H, m), 8.65-8.66(1 H,d)
90 2-(2-Fluoro-phenyl)-1- ]HNMR (DMSOde) d: 1.04 (3H, s), m/z:
(4-methoxy-benzyl)-5,5- 1.19 (3H, s), 2.41 - 2.46 (1H, m), 515(M+1)
dimethyl-3-[1-(6- 3.14 - 3.21 (2H, d), 3.27 - 3.29
morpholin-4-yl-pyridin- (1H, d), 3.30 (3H, s), 3.58 - 3.61
2-yl)-methylidene]- (4H, t), 3.72 - 3.73 (4H, t), 6.48
piperidin-4-one (1H, s), 6.60-6.61 (1H, d), 6.79-
6.81 (1H, d), 6.86 - 6.88 (2H, d),
6.98 - 7.01 (1H, m), 7.14 - 7.16
(1H, m), 7.17-7.18 (2H, m), 7.20
-7.25(2H, d), 7.28-7.30(1 H,m),
89

7.42-7.52 (1H,m)
91 1-(4-Fluoro-benzyl)-3,3- 1HNMR (DMSOd6) d: 0.96 (6H, s), m/z: 369
dimethyl-5-[1-(4- 2.47 (2H, s), 2.56 (3H, s), 3.64 (M+1 )
methylsulfanyl-phenyl)- (2H, s), 3.73 (2H, s), 7.13 - 7.19
methylidene]-piperidin- (2H, m), 7.29 - 7.34 (3H, m), 7.37
4-one - 7.42 (4H, m)
92 5,5-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 1.00 (3H, s), m/z: 504
methyl-isoxazol-3-yl)-2- 1.12 (3H, s), 2.29 (3H, s), 2.43 (M+1 )
(4-methylsulfanyl- (3H, s), 3.00-3.04(1 H,d), 3.13-
phenyl)-3-[1-(6- 3.14 (2H, m), 3.28 - 3.49 (2H, t),
morpholin-4-yl-pyridin- 3.46 - 3.59 (5H, m), 6.16 (1H, s),
2-yl)-methylidene]- 6.83 - 6.85 (1H, d), 7.00 - 7.02
piperidin-4-one (2H,d), 7.07-7.09(1 H,d), 7.21 -
7.23 (2H, d), 7.29 (1H, s), 7.59 -
7.63 (1H,m), 7.75(1 H, s)
93 3,3-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 1.09 (6H, s), m/z: 342
methyl-isoxazol-3-yl)-5- 2.34 (3H, s), 2.46 (3H, s), 3.16 (M+1 )
[1-(4-methylsulfanyl- (2H,s), 3.89 (2H,s), 6.77(1 H,s),
phenyl)-methylidene]- 7.22 - 7.26 (2H, d), 7.54 - 7.57
piperidin-4-one (2H,d),8.22(1H,s)
94 1 -Furan-2-ylmethyl-5,5- fHNMR (DMSOd6) d: 1.01 (3H, s), m/z: 462
dimethyl-3-[1 -pyridin-2- 1.15 (3H, s), 2.57 - 2.60 (1H, d), (M+1 )
yl-methylidene]-2- 2.67 - 2.71 (1H, d), 3.42 - 3.56
(3,4,5-trimethoxy- (1H, d), 3.60 (3H, s), 3.67 (6H, s),
phenyl)-piperidin-4-one 3.71 -3.76 (1H, d), 6.19 (1H, s),
6.30 - 6.31 (1H, d), 6.04 - 6.41
(1H, d), 6.57 (2H,s), 6.94(1 H,s),
7.32 - 7.35 (1H, m), 7.50 - 7.52
(1H, s), 7.69-7.72(1 H, m), 7.73 -
7.82 (1H,m), 8.70-8.71 (1H, dd)
95 1-Benzyl-2-(2-fluoro-4- 1HNMR (DMSOd6) d: 0.88 (6H, s), m/z: 430
methoxy-phenyl)-5,5- 3.27 - 3.30 (1H, d), 3.55 - 3.56 (M+1 )
dimethyl-3-[1 -pyridin-2- (1H, d), 3.60 - 3.68 (2H, m), 3.72
yl-methylidene]- (3H, s), 6.16 (1H, s), 6.65 - 6.76
piperidin-4-one (1H, m), 7.10 - 7.15 (3H, m), 7.21
- 7.29 (5H, m), 7.31 - 7.34 (1H,
m), 7.40 - 7.41 (1H, m), 7.68 -
7.69 (1H,m), 8.51 -8.52(1H,d)
96 1 -Benzyl-2-(2-fluoro-4- 1HNMR (DMSOd6) d: 1-06 (3H, s), m/z: 515
methoxy-phenyl)-5,5- 1.19 (3H, s), 2.50 - 2.51 (1H, d), (M+1 )
dimethyl-3-[1-(6- 2.55 - 2.58 (1H, d), 3.36 - 3.37
morpholin-4-yl-pyridin- (4H, t), 3.58 - 3.60 (4H, t), 3.74
2-yl)-methylidene]- (3H, s), 3.75 - 3.76 (2H, m), 6.14
piperidin-4-one (1H, s), 6.46 (1H, s), 6.74 - 6.75
(1H, d), 6.76 -6.79 (2H, m), 6.87 -
6.91 (1H, m), 7.10 (1H, s), 7.20 -
90

7.21 (2H, m), 7.27 - 7.35 (3H, m),
7.74- 7.52 (1H, m)
97 5,5-Dimethyl-3-[1-(6- 1HNMR (DMSOd6) d: 1.02 (3H, s), m/z: 557
morpholin-4-yl-pyridin- 1.20 (3H, s), 2.99 - 3.06 (2H, m), (M+1 )
2-yl)-methylidene]-2- 3.44 - 3.46 (4H, t), 3.63 (9H, s),
phenyl-1-(3,4,5- 3.72 - 3.75 (2H, m), 4.13 - 4.15
trimethoxy-benzyl)- (4H, t), 6.45 (1H, s), 6.59 - 6.62
piperidin-4-one (2H, s), 6.73-6.75 (1H, d), 6.89-
6.90 (1H, d), 7.09 - 7.11 (2H, d),
7.16 (1H, d), 7.22 - 7.24 (1H, m),
7.32 - 7.35 (2H, m), 7.54 - 7.56
(1H,m)
98 1-Benzyl-2-(4- 1HNMR (CDCI3) d: 0.88 (3H, s), m/z: 545
methanesulfonyl- 1.02 (3H, s), 2.94 (3H, s), 2.94 - (M+1 )
phenyl)-5,5-dimethyl-3- 3.00 (2H, m), 3.29 - 3.30 (4H, t),
[1-(6-morpholin-4-yl- 3.31 - 3.34 (4H,t), 3.40-3.45 (1H,
pyridin-2-yl)- d), 3.46 - 3.47 (1H, d), 6.38 (1H,
methylidene] -piperidin- s), 6.75-6.77 (1H,d), 6.92-6.94
4-one (1 H,d) ,7.23-7.34 (5H, m), 7.36-
7.38 (2H, d), 7.53 - 7.57 (1H, m),
7.68 - 7.70 (2H, m), 7. 90 - 7.96
(1H,d)
99 5,5-Dimethyl-1- 1HNMR (DMSOd6) d: 1.14 (3H, s), m/z: 396
phenethyl-2-phenyl-3- 1.18 (3H, s), 2.66 - 2.67 (2H, m), (M+1 )
[1 -pyridin-2-yl- 2.68 - 2.69 (1H, m), 2.72 - 2.73
methylidenej-piperidin- (2H, m), 2.74-2.80(1 H, m), 6.26
4-one (1H, s), 7.04 (1H, s), 7.09 - 7.11
(2H, m), 7.15 - 7.17 (4H, m), 7.18
- 7.21 (3H, m), 7.22 - 7.24 (1H,
m), 7.26 - 7.31 (1H, m), 7.48 -
7.50 (1H, d), 7.74 - 7.78 (1H, m),
8.66 - 8.67 (1H,dd)
100 5,5-Dimethyl-3-[1-(6- 1HNMR (DMSOd6) d: 1.06 (3H, s), m/z: 481
morpholin-4-yl-pyridin- 1.16 (3H, s), 2.66 - 2.69 (4H, t), (M+1 )
2-yl)-methylidene]-1- 2.79 (2H, s), 2.94 - 2.99 (2H, t),
phenethyl-2-phenyl- 3.50 - 3.62 (6H, m), 6.43 (1H, s),
piperidin-4-one 6.79 - 6.86 (2H, dd), 6.96 - 7.03
(1H, m), 7.05-7.09 (2H, m), 7.14
- 7.16 (3H, m), 7.22 - 7.30 (5H,
m), 7.47 -7.58(1 H, m),
101 1-Benzyl-5-[1-(4- 1HNMR (CDCl3) d: 1.19 (6H, s), m/z: 383
methanesulfonyl- 2.56 (2H, s), 3.08 (3H, s), 3.65 (M+1 )
phenyl)-methylidene]- (2H, s), 3.71 (2H, s), 7.28 (2H, s),
3,3-dimethyl-piperidin- 7.34 - 7.35 (3H, m), 7.48 - 7.50
4-one (3H, m), 7.94 - 7.96 (2H, d)
91

102 5,5-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 0.99 (3H, s), m/z: 526
methyl-isoxazol-3-yl)-3- 1.10 (3H, s), 2.30 (3H, s), 2.98 - (M+1)
[1-(6-morpholin-4-yl- 3.02 (4H, m), 3.19-3.20 (2H, m),
pyridin-2-yl)- 3.36 - 3.38 (2H, m), 3.39 - 3.41
methylidene]-2-(4- (1H, m), 3.45 - 3.61 (1H, d), 6.22
trifluoromethyl-phenyl)- (1H, s), 6.83-6.86 (1H, d), 7.05-
piperidin-4-one 7.06 (1H, d), 7.36 - 7.38 (3H, d),
7.60 - 7.64 (1H, m), 7.71 - 7.73
(2H,d), 7.85(1 H,s)
103 5,5-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 0.99 (3H, s), m/z: 539
methyl-isoxazol-3-yl)-3- 1.12 (3H, s), 2.04 - 2.06 (2H, m), (M+1)
[1-[6-(4-methyl- 2.09 - 2.12 (5H, m), 2.30 (3H, s),
piperazin-1 -yl)-pyridin- 2.98 - 3.01 (1H, d), 3.06 - 3.10
2-yl]-methylidene]-2-(4- (2H, m), 3.21 - 3.23 (2H, m), 3.61
trifluoromethyl-phenyl)- -3.64(1H, d), 6.17(1H,s), 6.83-
piperidin-4-one 6.85 (1H, d), 7.00 - 7.02 (1H, d),
7.35 - 7.38 (3H, m), 7.56 - 7.60
(1H, m), 7.71 - 7.73 (2H, d), 7.87
(1H,s)
104 5,5-Dimethyl-1-(5- 1HNMR (DMSOd6) d: 1.08 (6H, s), m/z: 441
methyl-isoxazol-3-yl)-3- 2.18 (3H, s), 3.46 (2H, s), 5.61 (M+1)
[1 -pyridin-2-yl- (1H, s), 7.07-7.10 (1H ,d), 7.11 -
methylidene]-2-(4- 7.13 (1H, m), 7.54 - 7.56 (2H, d),
trifluoromethyl-phenyl)- 7.59 - 7.63 (1H, m), 7.68 - 7.71
piperidin-4-one (3H, d), 8.36 -8.37(1 H, dd), 11.99
1H,s)
105 1-Benzyl-2-(4- 1HNMR (CDCI3) d: 1.14 (3H, s), m/z: 460
methanesulfonyl- 1.24 (3H, s), 2.57 - 2.60 (1H, d), (M+1)
phenyl)-5,5-dimethyl-3- 2.65 - 2.68 (1H, d), 3.02 (3H, s),
[1-pyridin-2-yl- 3.50 - 3.57 (2H, d), 6.30 (1H, s),
methylidenej-piperidin- 7.02 - 7.20 (2H, m), 7.24 - 7.28
4-one (4H, m), 7.31 - 7.35 (2H, m), 7.54
-7.57(2H, d), 7.59-7.66(1 H,m),
7.81 - 7.83 (2H, d), 8.62 - 8.63
(1H,d)
106 {5,5-Dimethyl-3-[1-(6- 1HNMR (DMSOd6) d: 1.04 (3H, s), m/z: 435
morpholin-4-yl-pyridin- 1.14 (3H, s), 2.65 - 2.68 (1H, d), (M+1)
2-yl)-methylidene]-4- 2.84 - 2.89 (1H, t), 3.28 - 3.29
oxo-2-phenyl-piperidin- (2H, m), 3.35 - 3.47 (4H, t), 3.60 -
1 -yl}-acetic acid 3.67 (4H, m), 6.55 (1H, s), 6.77 -
6.79 (1H, d), 6.83 - 6.84 (1H, d),
7.00 (1H, s), 7.18 - 7.22 (3H, m),
7.27 - 7.30 (2H, m), 7.51 - 7.55
(1H,m), 12.36-12.39 (1H,bs)
107 {5,5-Dimethyl-4-oxo-2- 1HNMR (DMSOd6) d: 0.96 (3H, s), m/z: 350
phenyl-3-[1 -pyridin-2-yl- 1.36 (3H, s), 2.75 (2H, s), 2.87 (M1)
92

methylidene]-pipendin- (2H, s), 4.10 (1H, d), 7.12 - 7.17
1 -yl}-acetic (2H, m), 7.23 - 7.31 (2H, m), 7.32
- 7.33 (2H, m), 7.38 - 7.41 (4H,
m), 12.20-12.22 (1H,bs)
108 2-(2,5-Dimethoxy- 1HNMR (CDCI3) d: 1.15 (3H, s), m/z: 541
phenyl)-5,5-dimethyl-1 - 1.27 (3H, s), 2.31 (3H, s), 2.71 - (M+1)
(4-methyl-benzyl)-3-[1- 2.74 (1H, d), 3.28 - 3.31 (2H, m),
(6-morpholin-4-yl- 3.32 - 3.42 (3H, m), 3.60 (3H, s),
pyridin-2-yl)- 3.75 (6H, s), 3.79 - 3.82 (2H, m),
methylidene]-piperidin- 4.22 - 4.25 (1H, m), 6.15 (1H, s),
4-one 6.47 - 6.50 (1H, d), 6.61 - 6.65
(2H, m), 6.75 - 6.78(1 H, dd), 6.83
-6.85(1H, d), 7.10 - 7.12 (2H,d),
7.26 - 7.30 (3H, m), 7.37 - 7.41
(1H,m)
109 5,5-Dimethyl-1-(4- 1HNMR (CDCb) d: 1.18 (3H, s), m/z: 396
methyl-benzyl)-2- 1.27 (3H, s), 2.31 (3H, s), 2.46 - (M+1)
phenyl-3-[1 -pyridin-2-yl- 2.53 (1H, d), 2.65 - 2.71 (1H, d),
methylidene]-piperidin- 3.45 - 3.50 (1H, m), 3.58 - 3.61
4-one (1H, d), 6.06 (1H, s), 7.07 - 7.11
(2H, d), 7.12-7.14 (1H,m), 7.15-
7.18 (3H, m), 7.19 - 7.22 (2H, m),
7.23 - 7.28 (4H, m), 7.54 - 7.59
(1H, m), 8.63-8.64(1 H,d)
110 2-(4-Methanesulfonyl- 1HNMR (DMSOd6) d: 0.80 (3H, s), m/z: 455
phenyl)-3,3-dimethyl-5- 0.96 (3H, s), 3.1 (3H, s), 3.47 - (M+1)
[1-(6-morpholin-4-yl- 3.49 (4H, t), 3.69 - 3.73 (5H, t) ,
pyridin-2-yl)- 4.09 - 4.10 (1H, d), 4.15 (1H, s),
methylidene]-piperidin- 4.80 - 4.84 (1H, d), 6.85 - 6.87
4-one (1H, d), 6.99 -7.00 (1H, d), 7.16 -
7.18 (1H, d), 7.57 - 7.61 (2H, d),
7.63 -7.65 (1H, m), 7.89 - 7.91
(2H, d)
111 {2-(4-Fluoro-phenyl)- 1HNMR (DMSOd6) d: 0.98 (3H, s), m/z: 368
5,5-dimethyl-4-oxo-3- 1.08 (3H, s), 3.13 (2H, s), 3.75 (M+1)
[1-pyridin-2-yl- (2H, s), 6.89 - 6.94 (2H, m), 7.18 -
methylidenej-piperidin- 7.22 (2H, m), 7.23 - 7.24 (2H, m)
1 -yl}-acetic acid 7.25 - 7.31 (3H, m), 7.36 - 7.42
(2H, m)
112 {5,5-Dimethyl-3-[1-[6- 1HNMR (DMSOd6) d: 1.10 (3H, s), m/z: 448
(4-methyl-piperazin-1 - 1.20 (3H, s), 2.21 (3H, s), 2.33 - (M+1)
yl)-pyridin-2-yl]- 2.36 (4H, m), 2.65 - 2.68 (2H, m),
methylidene]-4-oxo-2- 2.84 (2H, m), 3.51 - 3.65 (4H, t),
phenyl-piperidin-1-yl}- 6.57 (1H, s), 6.67 - 6.80 (1H, m),
acetic acid 6.98 (1H, s), 7.19 - 7.21 (2H, m),
7.26 - 7.20 (3H, m), 7.36 - 7.37
93

(1H, m), 7.48 - 7.52(1 H,m), 12.30
-12.36 (1H,bs),
113 5,5-Dimethyl-1-(4- 1HNMR (CDCI3) d: 1.10 (3H, s), m/z: 481
methyl-benzyl)-3-[1-(6- 1.33 (3H, s), 2.35 (3H, s), 2.52 - (M+1)
morpholin-4-yl-pyridin- 2.56 (1H, d), 2.79 - 2.83 (1H, d),
2-yl)-methylidene]-2- 3.03 - 3.09 (2H, m), 3.13 - 3.19
phenyl-piperidin-4-one (2H, m), 3.58 - 3.61 (4H, t), 3.69 -
3.72 (1H, d), 3.80 - 3.87 (1H, d),
6.30 (1H, s), 6.49 - 6.51 (1H, d),
6.73 - 6.75 (1H, d), 7.07 - 7.09
(2H, d), 7.18-7.23 (5H,m), 7.25-
7.27(2H, m), 7.28 (1H, s), 7.42 -
7.46 (1H,m)
114 2-(2,5-Dimethoxy- 1HNMR (CDCI3) d: 1.19 (6H, s), m/z: 456
phenyl)-5,5-dimethyl-1 - 2.33 (5H, s), 2.68 - 2.71 (1H, d), (M+1)
(4-methyl-benzyl)-3-[1- 3.28 - 3.31 (1H, t), 3.65 (3H, s),
pyridin-2-yl- 3.78 (3H, s), 6.14 (1H, s), 6.75 -
methylidene]-piperidin- 6.77 (1H, m), 6.78 - 7.84 (2H, m),
4-one 7.07 - 7.15 (3H, m), 7.20 - 7.27
(3H, d), 7.28 (1H, s), 7.54- 7.58
1H, m), 8.59 -8.60(1 H, d)
115 2-(2,5-Dimethoxy- 1HNMR (CDCI3) d: 1.15 (3H, s), m/z: 554
phenyl)-5,5-dimethyl-1 - 1.23 (3H, s), 2.30 - 2.38 (6H, m), (M+1)
(4-methyl-benzyl)-3-[1- 2.50 (3H, s), 2.68 - 2.75 (1H, t),
[6-(4-methyl-piperazin- 3.22 - 3.24 (1H, m), 3.31 - 3.34
1-yl)-pyridin-2-yl]- (2H, t), 3.39 - 3.44 (2H, m), 3.49 -
methylidene]-piperidin- 3.50 (2H, d), 3.66 (3H, s), 3.84
4-one (3H, s), 3.88 - 3.94 (1H, m), 6.01
(1H, s), 6.16 (1H, s), 6.49 - 6.53
(1H, m), 6.56 - 6.63 (1H, m), 6.64
-6.68(11-1, m), 6.69 -6.71(1 H, m),
6.78 - 6.82 (1H, m), 6.83 - 6.85
(1H, m), 7.10-7.11 (1H, m), 7.20
- 7.28 (2H, m), 7.34 - 7.42 (1H, m)
116 1-Benzyl-3-[1-(6- 1HNMR (DMSOd6) d: 3.48 - 3.50 m/z: 453
morpholin-4-yl-pyridin- (4H, t), 3.71 - 3.73 (4H, t), 4.37 (M+1)
2-yl)-meth-ylidene]-5- (2H, s), 4.80 (2H, s), 7.01 - 7.03
phenyl-piperidine-2,4- (1H,d), 7.13-7.15 (1H,d), 7.19-
dione 7.22 (1H, m), 7.26 - 7.28 (1H, m),
7.30 - 7.35 (6H, m), 7.64 - 7.67
(3H, m), 7.74 - 7.78 (1H, m), 14.65
(1H,s)
117 2-(4-Methanesulfonyl- 1HNMR (DMSOd6) d: 0.87 (3H, s), m/z: 590
phenyl)-3,3-dimethyl-5- 1.01 (3H, s), 3.21 (3H, s), 3.27 - (M+1)
[1-pyridin-2-yl- 3.29 (2H, m), 4.06 (1H, s), 4.83 -
methylidenej-piperidin- 4.88 (1H, d), 7.33 (1H, s), 7.57 -
94

4-one 7.61 (2H, d), 7.62 - 7.68 (1H, d),
7.80 - 7.93 (4H, m), 8.70 - 8.71
(1H,d)
118 2-(4-Methanesulfonyl- 1HNMR (DMSOd6) d: 0.98 (3H, s), m/z: 505
phenyl)-3,3-dimethyl-4- 1.36 (3H, s), 3.16 - 3.18 (1H, d), (M-1)
oxo-5-[1 -pyridin-2-yl- 3.21 (3H, s), 3.23 - 3.27 (1H, s),
methylidene]- 3.39 - 3.43 (1H, m), 7.13 - 7.15
piperidine-1 -carbothioic (1H, m), 7.23-7.32 (4H, m), 7.41
acid phenylamide - 7.43 (1H, m), 7.48-7.50 (2H,d),
7.66 (1H, s), 7.83 - 7.91 (2H, m),
7.92 - 8.01 (2H, m), 8.72 - 8.73
(1H,d), 9.46(1 H,s)
119 2-(4-Methanesulfonyl- 1HNMR (DMSOd6) d: 1.00 (3H, s), m/z:
phenyl)-3,3-dimethyl-4- 1.39 (3H, s), 3.21 (3H, s), 4.03 - 503(M+1)
oxo-5-[1-pyridin-2-yl- 4.12 (2H, m), 4.92 - 4.97 (1H, m),
methylidene]- 5.46 (2H, s), 7.18 - 7.20 (2H, m),
piperidine-1 -carboxylic 7.21 - 7.24 (3H, m), 7.32 - 7.42
acid benzylamide (5H, m), 7.80 - 7.93 (4H, m), 8.74
-8.74(11-1, d)
120 1-Benzyl-5-phenyl-3-[1- 1HNMR (DMSOd6) d: 4.11 - 4.17 m/z: 368
pyridin-2-yl-meth- (4H, m), 5.11 (1H, s), 7.21 - 7.33 (M+1)
ylidene]-piperidine-2,4- (8H, m), 7.36 - 7.41 (4H, m), 7.45
dione -7.46(1H, d), 7.77 (1H, s), 8.50 -
8.51 (1H, d)
121 1-Benzyl-3-[1-[6-(4- 1HNMR (DMSOd6) d: 2.17 - 2.24 m/z: 466
methyl-piperazin-1 -yl)- (2H, m), 2.75 - 2.82 (4H, m), 3.16 (M+1)
pyridin-2-yl]- - 3.17 (2H,d), 3.26 (3H,s), 3.40-
methylidene]-5-phenyl- 3.72 (4H, m), 4.10 (1H, m), 6.77-
piperidine-2,4-dione 6.80 (2H, m), 6.91 - 6.94 (4H, m),
7.15-7.34 (7H,m), 8.32(1 H, s)
122 1-(3,4-Dimethoxy- 1HNMR (DMSOd6) d: 1.01 (3H, s), m/z: 442
benzyl)-5,5-dimethyl-2- 1.12 (3H, s), 2.34 - 2.37 (2H, m), (M+1)
phenyl-3-[1 -pyridin-2-yl- 2.55 - 2.57 (2H, m), 3.78 (3H, s),
methylidene]-piperidin- 3.82 (3H, s), 6.22 (1H, s), 6.83 -
4-one 6.84 (1H, m), 7.28 (1H, s), 7.19 -
7.21 (1H, m), 7.25 - 7.31 (4H, m),
7.32 - 7.37 (1H, m), 7.39 - 7.41
(1H, m), 7.43-7.44(1 H,d), 7.49-
7.54 (1H, d), 8.62 -8.63(1 H, d)
123 1-(3,4-Dimethoxy- 1HNMR (CDCI3) d: 1.02 (6H, s), m/z: 527
benzyl)-5,5-dimethyl-3- 2.23 - 2.24 (2H, m), 2.50 - 2.55 (M+1)
[1-(6-morpholin-4-yl- (2H, m), 3.04 - 3.06 (4H, t), 3.62 -
pyridin-2-yl)- 3.64 (4H, t), 3.75 (3H, s), 3.82
methylidene]-2-phenyl- (3H, s), 6.74 - 6.76 (2H, m), 6.92 -
piperidin-4-one 6.97 (2H, d), 7.28 - 7.30 (2H, d),
7.30 - 7.37 (2H, m), 7.45 - 7.57
95

(1H, d), 7.53-7.54 (1H,m), 7.78-
8.04 (1H, m), 8.15-8.16 (1H, d),
9.07 - 9.09 (1H,d)
124 5,5-Dimethyl-1-(4- 1HNMR (DMSOd6) d: 1.45 (6H, s), m/z: 494
methyl-benzyl)-3-[1-[6- 2.29 (3H, s), 2.31 - 2.36 (6H, t), (M+1)
(4-methyl-piperazin-1 - 2.48 - 2.51 (2H, m), 3.21 - 3.63
yl)-pyridin-2-yl]- (2H ,m), 3.36 - 3.48 (3H, t), 3.63 -
methylidene]-2-phenyl- 3.66 (2H, t), 6.34 (1H, s), 6.47 -
piperidin-4-one 6.53 (1H, d), 6.67 - 6.69 (1H, d),
7.00 (1H, s), 7.06 - 7.09 (2H, d),
7.13 - 7.16 (4H, m), 7.21 - 7.25
(1H, m), 7.28-7.32(1 H, m), 7.35
-7.43(1H, m), 7.48 -7.50(1 H, d),
125 2-(4-Methanesulfonyl- 1HNMR (DMSOd6) d: 0.89 (3H, s), m/z: 507
phenyl)-3,3-dimethyl-4- 1.43 (3H, s), 3.20 (3H, s), 3.21 - (M+1)
oxo-5-[1-pyridin-2-yl- 3.29 (2H, m), 5.61 - 5.62 (1H, d),
methylidene]- 7.03 - 7.06 (2H, m), 7.31 - 7.33
piperidine-1 -carboxylic (2H, m), 7.52 (1H, s), 7.83 - 7.90
acid (4-fluoro-phenyl)- (4H, m), 7.94 - 7.96 (2H, m), 8.79
amide - 8.80 (2H, d)
126 2-(4-Methanesulfonyl- 1HNMR (DMSOd6) d: 1.04 (3H, m/z 590
phenyl)-3,3-dimethyl-5- s), 1.44 (3H,s), 3.21 (3H, s), 3.23 (M+1)
[1-(6-morpholin-4-yl- - 3.27 (4H, m), 3.37 - 3.45 (4H,
pyridin-2-yl)-methylid m), 3.64 - 3.69 (2H, m), 5.96 -
ene]-4-oxo-piperidine 5.98 (1H, d), 6.92 - 6.95 (1H, d),
-1-carbothioic 7.11 - 7.15 (1H, m), 7.17 - 7.19
acid phenylamide (1H, m), 7.24 - 7.32 (3H, m), 7.44
- 7.48 (3H, m), 7.62 - 7.71 (2H,
m), 7.86 - 7.88 (2H, d), 9.28 (1H,s)
Method of protecting cells against stress
The present invention relates to a method of inducing the expression of Heat
Shock Protein 70 (HSP-70) in cells, by administering an effective amount of one
or more compound of present invention, represented by the formula (I) or (II),
their pharmaceutically acceptable salts and their hydrates, solvates,
stereoisomers, conformers, tautomers, polymorphs and prodrugs, thereof and
their pharmaceutically acceptable composition.
96

In the present context, "HSP-70" refers to proteins of the HSP family having an
approximate molecular mass of 70 kDa, which are induced in response to a
pathological stress. "Pathological stress" refers to factors which disturb the
homeostasis of the cells thus leading to the increased expression of stress
proteins like HSP-70. Such factors are, for example, metabolic, oxidative,
stresses caused by hypoxia, ischemia, infections, stresses induced by metals
and exogenous substances, immunogenic stresses, cell malignancy,
neurodegeneration, trauma, or aging. Other forms of pathological stresses
include those causing the formation of free radicals or increase in the quantity of
inflammatory cytokines.
In one embodiment of the present invention, diseases accompanying
pathological stress are selected from cerebrovascular, cardiovascular diseases,
neurodegenerative diseases and immune disorders, such as ischemia stroke,
myocardial infarction, inflammatory disorder, hepatotoxicity, sepsis, diseases of
viral origin, allograft rejection, tumourous diseases, gastric mucosal damage,
brain hemorrhage, endothelial dysfunctions, diabetic complications, neuro-
degenerative diseases, epilepsy, post-traumatic neuronal damage, acute renal
failure, glaucoma and aging related skin degeneration. The compounds of the
present invention possess the ability to induce HSP-70 and thereby protect cells
against stress-induced damage in the above disease conditions.
The present invention also relates to a method of inhibiting TNF-a in cells, by
administering an effective amount of one or more compound, represented by the
formula (I) or (II), their pharmaceutically acceptable salts and their hydrates,
solvates, stereoisomers, tautomers, polymorphs and prodrugs, thereof and their
pharmaceutically acceptable composition. Cytokines such as TNF-a produced by
activated monocytes and macrophages play an important role in the regulation of
the immune response. Studies have shown that TNF-a is involved in the
pathogenesis of diabetes, myocardial infarction, liver failure, infectious diseases
like sepsis syndrome, auto immune diseases like rheumatic arthritis, graft
97

rejection, organ transplant rejection, chronic inflammatory disorders such as
rheumatoid diseases, arthritic disorders and connective tissue disorders.
Reference may be made to [Han, H.S. and Yenari, M.A., Current Opinion in
Investigational Drugs, 2003, Vol. 4(5), pp. 522-529]. Treatment with compound of
the instant invention which shows TNF-a inhibitory activity exerts a cytoprotective
effect in the above disease conditions.
In a specific embodiment of the invention, a method of increasing HSP-70
expression in cells is provided.
In still another embodiment of the invention, a method of inhibition of TNF-a
expression is provided.
BIOLOGICAL ACTIVITY:
In vitro activity
(i) Effect of compounds of the instant invention on Cellular Expression of
HSP
Experiments set forth in this section were conducted to determine whether the
compounds of the present invention are able to elevate the expression of HSP-
70 gene in cells.
Hela cell-line or primary mixed neurons derived from neonatal rat cerebellum
were employed. Induction was carried out for the indicated dose(s) for 4hours
duration and total RNA was isolated. Expression of HSP70b mRNA along-with
expression of 18S rRNA was monitored by real-time PCR. HSP70b mRNA
expression was normalized relative to the expression of 18S rRNA. The results
for test compounds were expressed as fold induction of HSP-70 mRNA relative
to vehicle treated control and are as shown in Table 2 & 3.
98

Table-2:Compound HSP Induction in
No. Hela cells
13 (+++)
14 (+++)
15 (+++)
16 (+++)
17 (++++)
18 (++++)
19 (++)
22 (+++)
25 (+++)
27 (++++)
30 (++++)
31 (+++)
32 (+)
33 (++)
35 (+++)
36 (++)
37 (++++)
38 (++++)
39 (++++)
0 indicates < 4 fold; +, ++, +++ and ++++ indicate 4-24 fold, 25-192 fold, 193-
1536 fold, and >1536 fold induction of HSP-70b mRNA, respectively, relative to
the vehicle treated control.
99

Table-3:

Compound HSP Induction in
no. mixed neuron

44 (+++)
45 (+++)
47 (++)
48 (+++)
49 (++++)
55 (++)
60 (+)
61 (+)
64 (++++)
65 (++++)
66 (+)
67 (++)
68 (++++)
69 (+++)
70 (++)
72 (++++)
73 (++++)
77 (+)
80 (+)
83 (+++)
85 (+)
86 (+++)
89 (++)
90 (+)
94 (+)
96 (++)
98 (++++)
100

99 (+)
100 (++)
105 (++)
113 (++)
115 (+++)
116 (+)
118
0 indicates <2 fold while +,++,+++,++++ indicate 2-4 fold , 5-8 fold, 9-16 fold,
and >16 fold induction of HSP70b mRNA, respectively, relative to vehicle treated
control.
Discussion
As seen in Table 2 & 3, HSP-70 mRNA levels were increased over control after
treatment with compounds of the invention. Thus, the compounds of the instant
invention have the ability to induce HSP-70.
(ii) Effect of compounds of the present invention for TNF-g expression
The purpose of the present study was to determine the inhibition of
lipopolysaccharide(LPS)-induced TNF-a expression in phorbol merstyl ester
(PMA) differentiated THP-1 cells.
Human monocytic leukaemia cell line (THP-1), differentiated into macrophage-
like cells by PMA treatment was employed. Differentiated cells were treated with
either LPS (1ug/ml) alone or with LPS (1ug/ml) and compound for 4 hours. Total
RNA was isolated and expression of TNF-a mRNA along-with expression of 18S
rRNA was monitored by real-time PCR. TNF-a mRNA expression was
normalized relative to the expression of 18S rRNA Considering TNF-cx
expression for cells treated with LPS alone as 100%; the results for test
compounds were expressed as % inhibition of TNF-a expression and are as
shown in Table 4
101

Table-4:

CompoundNo. TNF-alphaInhibition
1 (++++)
2 (+++)
7 (+++)
8 (++++)
18 (++++)
22 (++)
44 (++)
45 (++)
48 (++)
49 (+++)
55 (++++)
64 (+++)
65 (+++)
67 (++)
69 (+++)
72 (++++)
73 (+++)
83 (++++)
86 (++++)
89 (+)
94 (++)
98 (++++)
105 (++++)
115 (+++)
116 (+)
118 (++)
102

0 indicates <20 % while +, ++, +++, ++++ indicate 21-40 %, 41-60 %, 61-80 %
and >80 % inhibition of TNF-a expression, respectively.
Discussion
As seen in Table 4, LPS-induced TNF-a expression was inhibited by the
treatment with compounds of the present invention.