Thesis on
Synthesis and Pharmacological Evaluation of
Compounds Containing Arylpiperazines
Submitted for the Award of
DOCTOR OF PHILOSOPHY
Degree in
Pharmaceutical Sciences
By
Sushil Kumar
M.Pharm.
Registration No.-SU/SPS/Ph.D./ PT/08/01
Under the Supervision of
Prof. Arun Kumar Wahi
Prof. Ranjit Singh
SCHOOL OF PHARMACEUTICAL SCIENCES
SHOBHIT INSTITUTE OF ENGINEERING AND TECHNOLOGY
A DEEMED-TO-BE- UNIVERSITY
MODIPURAM, MEERUT- 250110 (INDIA)
2011
CERTIFICATE
This is to certify that the thesis entitled “Synthesis and Pharmacological
Evaluation of Compounds Containing Arylpiperazines” submitted by Sushil Kumar,
(Reg. No. SU/SPS/Ph.D./PT/08/01) for the award of Degree of Doctor of Philosophy in
Pharmaceutical Sciences of Shobhit Institute of Engineering and Technology, A deemed-tobe University, Meerut is a record of authentic work carried out by him under my
supervision.
The matter embodied in this thesis is the original work of the candidate and has not
been submitted for the award of any other degree or diploma.
It is further certified that he has worked for the required period in College of
Pharmacy, IFTM, Moradabad.
Prof. Ranjit Singh
(Internal Supervisor)
Date:
Place:
CERTIFICATE
This is to certify that the thesis entitled “Synthesis and Pharmacological
Evaluation of Compounds Containing Arylpiperazines” submitted by Sushil Kumar,
(Reg. No. SU/SPS/Ph.D./PT/08/01) for the award of Degree of Doctor of Philosophy in
Pharmaceutical Sciences of Shobhit Institute of Engineering and Technology, A deemed-tobe University, Meerut is a record of authentic work carried out by him under my
supervision.
The matter embodied in this thesis is the original work of the candidate and has not
been submitted for the award of any other degree or diploma.
It is further certified that he has worked for the required period in College of
Pharmacy, IFTM, Moradabad and School of Pharmaceutical Sciences, Shobhit University,
Meerut.
Prof. Arun Kumar Wahi
(External Supervisor)
Date:
Place:
DECLARATION
I, hereby, declare that the work presented in this thesis entitled “Synthesis and
Pharmacological Evaluation of Compounds Containing Arylpiperazines” in fulfillment
of the requirements for the award of Degree of Doctor of Philosophy, submitted in the
School of Pharmaceutical Sciences at Shobhit University, Modipuram, Meerut is an
authentic record of my own research work under the supervision of Prof. Ranjit Singh and
Prof. Arun Kumar Wahi.
I also declare that the work embodied in the present thesis
(i) is my original work/extension of the existing work and has not been copied from any
Journal/thesis/book, and
(ii) has not been submitted by me for any other Degree/Diploma.
Sushil Kumar
Date:
Place:
AKNOWLEDGEMENT
I humbly grab this opportunity to acknowledge reverentially, many people who
deserve special mentions for their varied contributions in assorted ways that helped me
during my Ph.D research and the making of this thesis. I could never have embarked
and finished the same without their kind support and encouragements.
First and foremost, I would like to express my gratitude to supervisor
Prof. Arun Kumar Wahi, Ex. Dean, & Director, College of Pharmacy, IFTM,
Moradabad for his constant support, encouragement and invaluable guidance from the
very early stages of this research work and his originality has triggered and nourished
me in the successful submission of my research work.
I would like to express my gratitude to supervisor Prof. Ranjit Singh,
Director, School of Pharmaceutical Sciences, Shobhit University, Meerut, who has
been the driving force behind this endeavor. His keen interest, constructive criticism,
constant motivation and caring attitude have been indispensable factors in the
successful completion of my research work.
I must place on record my heartfelt thanks to Prof. R.M. Dubey,
Vice Chancellor, IFTM University, Moradabad for their considerate support and
encouragement to me, throughout the tenure of my research work, for allowing me
to utilize so much of valuable time for the research along with my academic duties
and letting me use the lab facilities and extensive library resources at college campus.
It is a pleasure at this point to express my gratitude to Prof. A.K. Ghosh,
Director, College of Pharmacy, IFTM, Moradabad for unflinching encouragement
and support in various ways during the work.
I have also benefited by some genius advice and scholastic suggestions
from Prof. Shailendra K. Saraf, Prof. Shubhini A. Saraf, Prof. Vijay Juyal,
Prof. K. R. Mahadik and Prof. S. H. Bhosale during the research work.
I also warmly acknowledge my colleagues Prof. D.C.P. Singh, Prof. S. R.
Hashim, Prof. DK. Pal, Prof. Anurag Verma, Prof. P. Chattopadhyay,
Prof. S. Jayalakshmi, Prof. Arjun Patra and Prof. G. Islam for always being ready
to help and being accessible for research and teaching assistance and over and above
i
adjusting my academic load, in my absence at college, whenever I had to be away for
my research work.
I also warmly acknowledge my skilled colleagues in field of pharmacology,
Mohd. Abid and Mr. Vishal Jacob for always being ready to help in carrying out
pharmacological activity.
I am thankful to the Head, sophisticated analytical Instrument Facility,
CDRI, Lucknow for the permission to carry out the spectral analysis.
I am grateful to Nitin Sati, Asst. Professor, Dept. Pharmaceutical Sciences,
HNB Garhwal University, Srinagar for his valuable help in spectral interpretation.
I am thankful to Mr. Mahendra Singh Rana, Librarian, for providing all
valuable books and journals during the research work and also thankful to Mr.
Lalbhadur Singh, Mr. Sikandar Azam (office in charge), Mr. Mukesh Mugdal,
Mr. Sado Singh (Store In charge) for their timely help and support.
I am also thankful to Mr. Babban, Mr. Rukesh, Mr. Rajeev, Mr. Amit and
Mr. Bharti and all other non-teaching staff members for their support.
I would also acknowledge to Mr. Arvind Shukla, Mr. Sunil Kumar and
Mr. Anil Kumar for their timely assistance in computer and statistical work.
I want to convey my deepest appreciation to all faculty members and
administrative staff of School of Pharmaceutical Sciences, Shobhit University,
Meerut for their support and help.
Collective and individual acknowledgments are also owed to my colleagues
whose present somehow perpetually refreshed, helpful, and memorable. Many thanks
go in particular to Nardev Singh, Koshy Mamman, Pradeep Yadav, Navneet
Verma, Kavita Gahlot, Munesh Mani, Kamal Mahaur, Prashant Upadhyay
Teerath Kamboj, Najam Ali Khan and Vaibhav.
I am infinitely thankful to my best friends Vikas Mishra, Suchitra Kaushik,
Deepaish Jindal, Ajay Mittal, Anurag Agrawal, Vineet Singh, Saurabah
Vaishnav, Punit Kumar, Sachin Mittal, Nitin Goyel, Amit Shekher and Pankaj
Gupta who have never forgotten me and have been strengthen always.
I am thankful to my childhood friends Pushkal Gupta, Ratan Varshney, and
Deepak Varshney, for their love, encouragement and wishes.
ii
Where would I be without my family? Here, I pay gratitude to my Brothers
Shri Ashok Kumar Varshney and Shri Ram Kumar Varshney for their love, trust,
patience and support, and of course, for bearing all kind of stresses, they could to
make me what I am. I owe every thing to them. My parents deserve special mention
for their indissoluble support and prayers. My Father, Shri Kunvar Pal Varshney, in
the first place is the person who put the fundamental my learning character, showing
me the joy of intellectual pursuit ever since I was a child. I would like to place on
record my gratitude to my mother, Mrs. Prakash Vati, and my Bhabhiji, Mrs.
Pravesh Gupta and Mrs. Simmi Varshney for their support, love and blessings. I
can never forget my nephews Ankit, Shobhit, Prarit, Arpit, my nieces Pragati,
Pratibha and lovely son Harshit for their love and care.
Words fail me to express the heartfelt reverence and gratitude towards my
In-Laws Shri Vidya Shankar Varshney, Mrs. Kamlesh Varshney and Gunjan for
their blessing and support.
Words fail me to express my appreciation to my wife Anshika for her love,
patience, support, and for bearing all the stress during the course of research work.
Finally, thanks to God Almighty, for his grace, wisdom and comfort
throughout my studies. There were times where things were very tough and God was
there to protect and give me strength to overcome heavy storms and strong waves.
This was indeed a very long journey and I praise you God always.
Date:
Place:
Sushil Kumar
iii
ABSTRACT
Series of new arylpiperazines were synthesized and evaluated for antipsychotic activity in
inhibition of apomorphine induced climbing behavior (D2 antagonism), inhibition of 5-HTP
induced head twitches behaviour (5-HT2A antagonism) and induction of catalepsy studies in
mice. The physicochemical properties and similarity of the target compounds with respect to
standard drugs clozapine, ketanserin and risperidone were assessed by using software programs.
The target compounds were prepared by alkylation of salicylamide and chloroacetylation of
amines (diphenylamine, aniline, benzylamine and cyclohexylamine) followed by condensation
with substituted phenylpiperazines. All the reactions were monitored by TLC. The final products
were purified by recrystallization and characterized by spectroscopic methods. The target
compounds showed good structural similarity with respect to standard drugs. All the tested
compounds exhibited good interaction with D2 and 5-HT2A receptors and emerged as lead
compounds showing potential antipsychotic profile.
Key words: Salicylamide, Acetamide, Arylpiperazines, Computational studies, Antipsychotic
activity, 5-HT2A and D2 antagonists.
iv
LIST OF ABBREVIATIONS
CMC
Carboxymethylcellulose
CNS
Central nervous system
CSF
Cerebral spinal fluid
LCAPs
Long chain arylpiperazines
DA
Dopamine
EPS
Extra pyramidal side-effects
HP
Haloperidol
5-HT
5-Hydroxytryptamine
5-HTP
5-Hydroxytryptophan
GABA
γ-aminobutyricacid
NMDA
N-methyl-D-aspartate
IR
Infra red
i.p.
Intraperitoneal
K2CO3
Potassium carbonate
Kg
Kilogram
KI
Potassium iodide
g
Gram
0
C
Centigrade
mg
Milligram
ml
Milliliter
cm
Centimeter
mm
Millimeter
Sec
Second
NMR
Nuclear magnetic resonance
Sr.No.
Serial number
TLC
Thin layer chromatography
m.p.
Melting point
EDmin
Effective dose minimum
LD50
Median lethal dose
v
Cpd. Code
Compound code
ANOVA
Analysis of variance
S.E.M
Standard error mean
Rf
Retention factor
%
Percentage
CDCl3
Deuterated chloroform
DMSO
Dimethylsulphoxide
MHz
Megahertz
TMS
Tetramethylsilane
ppm
Parts per million
FGAs
First generation antipsychotics
Str
Stretching
BBB
Blood brain barrier
vi
Dedicated To
My Lord Hanumanji
CONTENTS
Certificates
Declaration
IAEC Certificate
Acknowledgement
i-iii
Abstract
iv
Abbreviations
v-vi
CHAPTER 1
INTRODUCTION
1.1
Antipsychotics
1.2
Classification of antipsychotics
1.3
Neurochemical hypotheses of schizophrenia
1.4
Mechanism of action of antipsychotics
1.5
Therapeutic uses
1.6
Adverse effects
1.7
Strategies for drug discovery
1.8
Future of research work
1.9
Scope of thesis
1-23
CHAPTER 2
LITERATURE REVIEW
24-38
CHAPTER 3
RESEARCH ENVISAGED AND PLAN OF WORK
39-45
3.1
Research envisaged
3.2
Plan of work
3.2.1 Synthesis of arylpiperazines
3.2.2 Characterization of synthesized compounds
3.2.3 Computational studies
3.2.4 Pharmacological evaluation for antipsychotic effect
CHAPTER 4
EXPERIMENTAL
4.1
Materials and methods
4.2.
Synthesis and characterization of compounds
4.3
Computational studies
4.4
Pharmacological evaluation for antipsychotic effect
46-235
4.4.1 Behavioral symptoms
4.4.2 Inhibition of apomorphine induced climbing behaviour
4.4.3 Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behaviour
4.4.4 Induction of catalepsy
4.4.5 Acute toxicity study
4.4.6 Structure activity relationships (SAR)
CHAPTER 5
SUMMARY AND CONCLUSION
236-238
CHAPTER 6
BIBLIOGRAPHY
239-254
PUBLICATIONS
INTRODUCTION
1
INTRODUCTION
ANTIPSYCHOTICS
1.1
Antipsychotic agents constitute a diverse class of drugs that are effective in the treatment
of major psychoses, including those associated with schizophrenia. These agents were
originally known as “neuroleptics” because of their ability to lessen the reactivity to
emotional and physical stimuli in highly agitated and/or psychotic patients, with little or no
effect on consciousness (Altar et al., 2003).
The term psychosis refers to a variety of mental disorders characterized by none or more
of the following symptoms: diminished and distorted capacity to process information and
draw logical conclusions, hallucinations, delusions, incoherence or marked loosening of
associations, catatonic or disorganized behavior, and aggression or violence (Craig et al.,
2004).
Schizophrenia is a severe, life-long, idiopathic psychiatric disorder with a polygenic
component. It is composed of severe thought disorders, termed psychoses, which are
characterized by illogical, delusional, or paranoid thoughts. Schizophrenia typically has its
onset in early adulthood with remissions and exacerbations throughout life. The disorder
afflicts approximately 1% of most populations (Reynolds, 1992; Jibson et al., 2004). The
signs and symptoms of schizophrenia usually begin in late adolescence or early adulthood and
are manifested in a highly diverse and complex constellation of clinical presentations. These
have been subdivided into two broad categories, positive and negative signs and symptoms.
These positive components are typically the first to draw attention to the disorder and
constitute the more overt manifestations of psychosis. These include false perceptions
including hallucinations (usually auditory), in which the patient’s internal dialogue is
perceived to originate from others or from inanimate source such as radios or cell phones.
Delusions, bizarre and often repetitive behavior patterns that are inappropriate to setting and
disorganized speech characterize other manifestations of schizophrenia. The negative
components are less spectacular, although more enduring and in many respect the more
disabling of the characteristics of the disorder. These include alogia, anhedonia, avolution,
blunted affect, disorganized thoughts, and social withdrawal.
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INTRODUCTION
Impaired cognitive function, including memory and attention defects, may also occur
(Altar et al., 2003).
1.2
CLASSIFICATION OF ANTIPSYCHOTICS
Several classification schemes for the currently available antipsychotic agents have
been proposed. Compounds may be classified based on chemical structure, pharmacological
profiles, potency and nonneurologic side-effect profile, or clinical efficacy and neurologic
side-effect liability. Antipsychotics are mainly classified into following classes.
I. Typical Antipsychotics (First-generation antipsychotics)
Typical antipsychotics came into being with the serendipitous discovery of the
antipsychotic activity of chlorpromazine. The conventional typical antipsychotics are
characterized by the production of extra pyramidal side effects (EPS), roughly approximating
the symptoms of Parkinson’s disease (Altar et al., 2003; Block et al., 2004; Lemke et al.,
2008). These are further divided into following typesPhenothiazines- Phenothiazine is an organic compound that occurs in various antipsychotic
drugs. Phenothiazines are classified into three groups that differ with respect to the substituent
on nitrogen: the aliphatic compounds (bearing acyclic groups), the "piperidines" (bearing
piperidine-derived groups), and the piperazine (bearing piperazine-derived substituents). The
examples
are
Methotrimeprazine,
Promazine,
Promethazine,
Triflupromazine,
Chlorpromazine,
Thioridazine,
Mesoridazine,
Levomepromazine
Prochlorperazine,
Perphenazine, Fluphenazine and Trifluoperazine.
S
N
Cl
(CH2)3N(CH 3)2
Chlorpromazine
Butyrophenones- Butyrophenone is a chemical compound (with a ketone functional group);
some of its derivatives (called commonly butyrophenones) are used to treat various
psychiatric disorders such as schizophrenia.
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INTRODUCTION
The examples of butyrophenone derivatives are Haloperidol, Droperidol, Benperidol,
Triperidol, Bromperidol, Peridol, Methylperidol, Trifluperidol, Melperone, Lenperone,
Haleperidide,
Paraperidide,
Floropipamide,
Spiperone,
Benperidol,
Butropipazone,
Fluanisone, and Azaperone.
Haloperidol is a buytophenones derivatives binds with equally high affinity to
dopamine D2 and serotonin receptors and produces a high incidence of extrapyramidal
reactions (Lemke et al., 2008).
OH
F
COCH2CH2CH2
N
Cl
Haloperidol
Thioxanthenes- Thioxanthene is a chemical compound in which the oxygen atom in
xanthene is replaced with a sulfur atom. It is also related to phenothiazine. Several of its
derivatives are used as typical antipsychotics in the treatment of schizophrenia and other
psychoses. The examples are Thiothixene, Chlorprothixene, Clopenthixol, Flupenthixol, and
Zuclopenthixol.
S
CH3
SO2N
C
CHCH2CH2
N
CH3
N
CH3
Thiothixene
Dihydroindolones
Molindone is a dihydroindolone compound. It works by blocking the effects of
dopamine in the brain.
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3
INTRODUCTION
H
N
O
N
O
Molindone
Dibenzoxazepine
Loxapine is a dibenzoxazepine compound used primarily in the treatment of
schizophrenia.
N
CH3
N
N
Cl
O
Loxapine
Diphenylbutylpiperidine- Diphenylbutylpiperidines are a class of typical antipsychotic
drugs. The examples are Clopimozide, Fluspirilene, Penfluridol, and Pimozide.
F
F
N
N
HN
O
Pimozide
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4
INTRODUCTION
II. Atypical Antipsychotics (Second-generation antipsychotics)
The search for atypical antipsychotic compounds focused initially on maintaining the
generally favorable efficacy while decreasing the severity or incidence of extrapyramidal side
effects (EPS). A large number of structurally diverse compounds have been investigated. The
following drugs are atypical antipsychotics:
Clozapine
Clozapine is a dibenzodiazepine derivative that acts on dopamine and serotonin
receptors. It also acts as an antagonist against adrenergic, muscarinic, histaminergic receptors.
CH3
N
N
Cl
N
N
H
Clozapine
Risperidone
Risperidone is a benzisoxazole derivative with high affinity for 5-HT2 receptors, D2
receptors, and α1-adrenergic receptors, and a lower affinity for other 5-HT receptors, α2receptors and histaminergic receptors.
N
N
N
F
O
O
N
Risperidone
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INTRODUCTION
Paliperidone
Paliperidone is also known as 9-hydroxyrisperidone its mechanism of action is
unknown, it is believed that its therapeutic effect may be due to a combination of D2 and 5HT2A receptor antagonism. The drug has antagonist effect at α1 and α2 adrenergic receptors
and at H1 histamine receptors.
OH
N
N
N
F
O
O
N
Paliperidone
Iloperidone
Iloperidone has been shown to act as an antagonist at multiple dopamine and serotonin
receptor subtypes. It was found to block the sites of dopamine (D2A and D3), serotonin (5HT1A and 5-HT6) and also of noradrenaline (α2C) receptors.
O
N
O
O N
Iloperidone
Bifeprunox
Bifeprunox is a product of Solvay Pharmaceuticals’ drug discovery efforts. It is a
putative full spectrum atypical antipsychotic compound aimed at the treatment of both
positive and negative symptoms of schizophrenia. Its mechanism of action couples a highly
potent partial agonism of the dopamine D2 receptors to an additional 5HT1A receptor partial
agonist effect.
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6
INTRODUCTION
O
O
HN
N
N
Bifeprunox
Ziprasidone
Ziprasidone exhibits high affinity for the D2-3, serotonin 5-HT1A/1D/2A/2C and α-1
adrenergic receptors and moderate affinity for histamine H1 receptors.
H
N
Cl
O
N
N
N
S
Ziprasidone
Olanzapine
Olanzapine is a thienobenzodiazepine derivative with selective monoaminergic
antagonism with high affinity for 5-HT2A/2C, dopamine receptors D1-4, M1-5 muscarinic
receptors, H1 histaminergic receptors and α-1 receptors. It binds with lesser affinity to
GABAA, receptors and β receptors.
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INTRODUCTION
CH3
N
N
N
N
H
CH3
S
Olanzapine
Quetiapine
Quetiapine is a dibenzothiazepine derivative that has affinity for 5-HT1A/2 and
dopamine D1-2 receptors. It also has high affinity for histamine H1 receptors and α-1
receptors, and a lesser affinity for α-2 receptors.
N
O
OH
N
N
S
Quetiapine
Remoxipride
Remoxipride is a substituted benzamide derivative and a selective D2 receptor
antagonist. It has been shown to be effective in the treatment of schizophrenia.
OCH3
O
N
H
N
C 2H 5
Br
Remoxipride
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8
INTRODUCTION
Sulpiride
Sulpiride is a substituted benzamide derivative and a selective dopamine D2
antagonist with antipsychotic and antidepressant activity.
H3CO
O
NH
O
S
N
O
NH2
Sulpiride
Sertindole
Sertindole is an indole-containing compound that behaves as high affinity
serotonin 5-HT2 receptor antagonist with weak affinity for α1-adrenergic receptors.
F
H
N
O
N
N
N
Cl
Sertindole
Zotepine
Zotepine is an atypical antipsychotic indicated for acute and chronic schizophrenia.
The antipsychotic effect of zotepine is thought to be mediated through antagonist activity at
dopamine and serotonin receptors.
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9
INTRODUCTION
N
O
Cl
S
Zotepine
Aripiprazole
Aripiprazole is an arylpiperazine quinolinone derivative exhibits high affinity for
dopamine D2-3, 5-HT1A/2A, moderate affinity for D4, 5-HT2C/7, α-1 adrenergic and H1 receptors
and muscarinic receptors.
Cl
Cl
N
O
N
H
N
O
Aripiprazole
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INTRODUCTION
1.3
NEUROCHEMICAL HYPOTHESES OF SCHIZOPHRENIA
The concept that schizophrenia is a neurochemical disturbance is primarily supported
by the fact that the clinical symptoms of the disorder can be diminished or exacerbated by
medications that exert their actions through specific CNS receptors. It is clear, however, that
schizophrenia is an illness of multiple symptom-defined domains, each with their own biology
that coexist in individualized combinations in patients. Expanding efforts in basic research,
including large-scale mRNA analyses, have identified other receptors, neurotransmitters, and
structural components which contribute to the disease. From these many leads, novel targets
have appeared for medicinal chemistry and clinical development. While these may be loosely
grouped as monoamine (dopamine, adrenergic, serotonin) and amino acid (primarily
glutamate) neurotransmitter systems, the interconnectivity of these systems and increasing
role of structural and synaptic deficiencies within the CNS make it difficult to lay the
causative mantle at the of any one receptor (Altar et al., 2003).
Dopamine Hypothesis
Dopamine (3, 4-dihydroxyphenylethylamine) is utilized as a neurotransmitter in
specific neuronal pathways within the CNS. Three dopaminergic pathways in the brain serve
as primary substrates for the pharmacological effects of these agents (Fig.1.)
Figure 1. Dopaminergic pathways in the human brain
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INTRODUCTION
The nigrostraital system consists of neurons with cell bodies in the substantia nigra that
project to the caudate and putamen, and is primarily involved in the coordination of posture
and voluntary movement. The mesolimbic-mesocortical system projects from cell bodies in
the ventral mesencephalon to the limbic system and neocortex, pathways associated with
higher mental and emotional functions. The tuberoinfundibular system connects arcuate and
periventricular nuclei of the hypothalamus to the mammotropic cells of the anterior pituitary,
thereby physiologically inhibiting prolactin secretion. Basically, the dopamine hypothesis of
schizophrenia posited that the symptoms of the disease are manifestations of a
hyperdopaminergic state of the CNS, in particular the mesolimbic dopamine system. The
antagonism of dopamine in the mesolimbic-mesocortical system is thought to be the basis of
the therapeutic actions of the antipsychotic drugs, while antagonism of the nigrostriatal
system is the major factor in the extrapyramidal side effects seen with these agents. Several
lines of evidence demonstrated long ago that antipsychotic drugs blocked the synaptic actions
of dopamine and should be classified as dopaminergic antagonists. Two subtypes of dopamine
receptors have been described; D1- like receptors and D2-like receptors groups. All have seven
transmembrane domains and are G protein-coupled. The D1- receptor increases cyclic
adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl
cyclase; it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The
other member of this family is the D5- receptor, which also increases cAMP but has a 10 fold
greater affinity for dopamine and is found primarily in limbic regions. The D2- dopaminergic
receptor decreases cAMP production by inhibiting dopamine-sensitive adenylylcyclase and
opens K+ channels but can also block Ca++ channels. It is located both presynaptically and
postsynaptically on neurons in the caudate putamen, nucleus accumbens, and olfactory
tubercle. Another member of this family is the D3–receptor, which also decreases cAMP
formation but which has much lower expression, primarily in limbic and ventral striatal areas.
The D4-receptor also inhibits adenylylcyclase and is found in frontal cortex and amygdale.
The binding affinity of antipsychotic agents to D2-receptors is very strongly correlated with
clinical antipsychotic and extrapyramidal potency (Craig et al., 2004).
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INTRODUCTION
Serotonin Hypothesis
Serotonin (5-hydroxtryptamine, 5-HT) is an essential neurotransmitter synthesized
from dietary tryptophan. Even before the dopamine hypothesis of schizophrenia became
established, a role for overactive serotonin neurotransmission was suspected. This was based
on the psychotogenic and hallucinogenic properties of partial serotonin 5-HT2A receptor
agonist, lysergic acid diethylamide (LSD) and on report of abnormal CSF and circulating
level of serotonin in schizophrenics. Renewed interest in serotonin’s role in schizophrenia was
initiated by three major findings. First, clozapine, thioridazine and newer atypical
antipsychotics were found to more potently antagonize 5-HT2A receptors than D2 receptors.
Second, the identification of 14 serotonin receptor subtypes provided new candidates for
antipsychotic etiology and targets for drug development. Third allelic variations of genes for
the 5-HT2A receptor have been associated with the diagnosis of schizophrenia (Abraham,
2003). The serotonin receptors or 5-hydroxytryptamine receptors (5-HT) are a group of G
protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the
central and peripheral nervous systems (Martin et al., 1994; Roth et al., 1994; Hoyer et al.,
1994), (Fig.2.). Its numerous biological functions are mediated by a variety of serotonin
receptors (Hoyer et al., 1994; Uphouse, 1997). The interaction with these different serotonin
receptors constitutes the mechanism of action of many drugs. In particular, type 2 serotonin
receptors (5-HT2) mediate the actions of several drugs used in treating diseases such as
schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety,
hallucinations and gastrointestinal dysfunctions (Cowen, 1991; Roth et al., 1998). Current
classification and nomenclature of 5-HT receptor subtypes as defined by the serotonin
receptor nomenclature sub-committee of IUPHAR is follow
5-HT2
5-HT1
5-HT3 5-HT4
5-HT6 5-HT7
5-HT5
5-HT2A, 5-HT2B, 5-HT2C
5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F
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5-HT5A 5-HT5B
13
INTRODUCTION
Figure 2. Serotonergic pathways in the human brain
Other Neurotransmitters in Schizophrenia
Since the implication of disturbed neurotransmission in schizophrenia by Carlsson and
Lindqvist, virtually every neurotransmitter of importance in the CNS has been suggested to
play a role in the pathophysiology of the disease. Thus, a noradrenaline hypothesis (Van
Kammen and Kelley, 1991) a glutamate hypothesis (Ishimaru and Toru, 1997), an
acetylcholine hypothesis (Tandon and Greden, 1989), and a γ-amino butyric acid (GABA)
hypothesis (Squires and Saederup, 1991) of schizophrenia have been put forward to account
for the symptoms observed in the disease.
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INTRODUCTION
1.4
MECHANISM OF ACTION OF ANTIPSYCHOTICS
The pathogenesis of schizophrenia and related psychiatric disorders is unknown, it is
perhaps naive to suggest how drugs act the molecular level to relieve the symptoms of these
disorders. Nevertheless, it generally is agreed that the antipsychotic mechanism of action of
neuroleptics involves modulation of dopamine neurotransmission in the mesolimbicmesocortical pathways. This may be achieved via direct interaction with D2-type receptors
and include the functional spectrum of antagonism, inverse agonism, and/or partial agonism.
Antipsychotic drug clinical efficacy, however, is not solely accounted for by D2-type receptor
interactions; other CNS receptors (acetylcholine, histamine, norepinephrine, serotonin and
GABA) appear to be involved, especially for the atypical drugs (Fig.3.).
Figure 3. Mechanism of action of antipsychotics
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INTRODUCTION
1.5
THERAPEUTIC USES
Antipsychotics are primarily used to manage psychosis (including delusions or
hallucinations, as well as disordered thought), particularly in schizophrenia and bipolar
disorder. However, they are effective in other psychotic disorders, such as mania and anxiety.
Antipsychotics are also useful in the treatment of drug induced nausea, intractable hiccoups,
Tourette’s syndrome, Huntington's disease and in the treatment of disruptive behaviour
including aggressive outbursts, hyperactivity, and stereotypies associated with conduct
disorder, attention deficit hyperactivity disorder (ADHD), and autism (Tripathi, 2006; Rang et
al., 2003; Mycek et al., 2000).
1.6
ADVERSE EFFECTS
Many of the side effects associated with antipsychotic agents can be attributed to
their antagonist activity at a variety of CNS receptors, which include histamine H1, adrenergic
α1/ α2, cholinergic M1, serotonin 5-HT2 and dopamine D2 receptors in the brain. For example
sedation, hypotension, sexual dysfunction, and other autonomic effects reflect blockade of
adrenergic and histamine receptors. The parkinsonian-like movement side effects clearly
result from antagonism of D2 receptors in the nigrostriatal pathway, and the severity of these
extrapyramidal side effects increases with the ratio of their antidopaminergic to
anticholinergic potency. Extrapyramidal side effects include acute dystonias (e.g., facial
grimacing, torticollis and oculogyric crisis), akathisia (motor restlessness), and parkinsoniantype symptoms, such as bradykinesia, muscular rigidity, tremor, masked face and shuffling
gait. Tardive dyskinesia occurs in 15-20% of patients after prolong treatment with typical
neuroleptics and is characterized by stereotyped, involuntary, repetitive, choreiform
movements of the face, eyelids, mouth (grimaces), tongue, extremities, and trunk. Metabolic
and endocrinal side effects are observed with neuroleptics, such as weight gain,
hyperprolactinemia, and gynecomastia. Relatively common dermatologic reactions (e.g.,
urticaria and photosensitivity) and agranulocytosis side effects are also associated with
neuroleptics. (Lemke et al., 2008; Munson et al., 1995; Hardman et al., 2001).
Shobhit University Meerut
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INTRODUCTION
1.7
STRATEGIES FOR DRUG DISCOVERY
There is still need for the development of antipsychotic agents with an improved
clinical profile, i.e. antipsychotic agents which combine the superior antipsychotic activity
and low neurological side-effects. Furthermore, such compounds may help to better
understand the exact mode of action of antipsychotic agents and to unravel the etiology of
schizophrenia and related disorders. Since it has been generally accepted that a dopamine D2
antagonistic component is required for antipsychotic activity, most pharmacological
approaches which are currently under investigation rely on the development of compounds
which interfere to some extent with dopamine D2-like receptors. However, newer atypical
antipsychotics, such as clozapine and risperidone, have a weaker affinity for D2 receptors and
bind more strongly to 5-HT2 receptors. Thus, lesser activity at the D2 receptors relative to the
other transmitter receptors may diminish untoward side effects such as extrapyramidal
toxicity (Craig et al., 2004; Altar et al., 2003).
Dopamine Receptor Subtype Approaches
In general, the typical antipsychotics interact with the D2, D3 and D4 receptor subtypes
but are more potent in their affinities at the D2 receptor.
D4 Selective compounds
Clozapine has greatest affinity at the D4 receptor subtype with a Ki of 21 nM, in
contrast to its 230 nM potency at the dopamine D2 receptor. Some compounds like
nemonapride (1) bound equally at all three receptor subtypes, whereas amisulpride and YM43611 bound about equally to the D2 and D3 but not D4 receptor. Isosteric replacement of the
amide functionality with a pyrrole as in (2) leads to a related series that maintained many of
the pharmacological characteristics of the benzamides. Extension of the strategy to the
butyrophenones provided (3) with high affinity for D2 receptors. The analogous of 2phenylimidazole compound (4) also showed strong affinity for D2 as well as D4 receptors.
When the piperazine linked aromatic was either 2-pyrimidyl (5) (NGD 94-1) or 2-pyridyl (6),
the first true selectivity for the D4 receptor subtype emerged. The structural diversity of D4
selective ligands is illustrated further by the examples of compounds (7-10) (Fig.4). While a
true pharmacophore for the D4 receptor is still emerging, aryl or aryl alkyl piperazine and
piperidine substructres are highly represented within this set of examples (Altar et al., 2003).
Shobhit University Meerut
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INTRODUCTION
OCH3
O
N
H
Cl
NH
H3CHN
N
N
1
OCH3
CH3
2
SO2Et
N
N
N
H
OCH3
N
N
3
N
OCH3
N
H
4
N
N
N
N
N
N
N
N
C
H
N
N
H
N
H
5
6
Cl
SO2 NH2
N
N
O
N
N
7
N
N
H
8
N
O
N
O
N
N
H
O
9
NH2
Cl
10
Figure 4. Chemical structure of D4 selective compounds (1-10).
Shobhit University Meerut
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INTRODUCTION
D3 Selective compounds
Essentially, all clinically effective antipsychotic drugs are antagonists of D2 and D3
receptors (Sigmundson, 1994). As with the D4 selective compounds, the search for D3 specific
ligands began with the benzamide, or sulpiride class of drugs that have selective, nanomolar
affinity for D2 and D3 receptors. The azabicyclononane (11) displayed a sixfold preference for
D3 over D2 receptor sites. Nafadotride (12) is a D3 selective antagonist with a D2/ D3 Ki ratio
of 10 (Sautel et al., 1995). The first compounds to show a high degree of D3 specificity were
the biphenylamides exemplified by GR 103691(13) (Murray et al., 1995). The 4-quinoline
carboxamide derivative SB-277011 (14) reported to be a potent and selective D3 receptor
antagonist (Fig.5.). Selective D3 antagonists represent a new, but still unproven, approach to
the treatment of schizophrenia and related disorders. Preferential D3/D2 antagonism is useful
strategy for treating psychoses including those associated with schizophrenia.
OCH3
O
N
OCH3
NH
O
N
NH
12
CN
n-Bu
11
O
Br
N
OCH3
N
H
N
13
O
N
NH
O
N
14
CN
Figure 5. Chemical structure of D3 selective compounds: azabicyclononane (11); Nafadotride
(12); GR 103691(13); SB-277011 (14).
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INTRODUCTION
Dopamine “D2 Plus” Agents
All antipsychotics except amisulpiride interact with a wide array of receptors. The
potent D2 antagonism of all antipsychotics including amisulpiride has kept open the
exploration of novel D2 antagonists that bind to other receptors, such as D3, adrenergic or
serotonergic receptors. This constitutes the “D2 plus” approach for novel, atypical
antipsychotics (Altar et al., 2003).
5-HT2A/D2 Antagonists
The most validated D2 plus approaches are the ones that involve dopamine and
serotonergic receptors. These include 5-HT2A/D2 receptor antagonism (“SDA hypothesis”),
the 5-HT1A partial agonist/D2 antagonist model, and the 5-HT2A antagonist/5-HT1A partial
agonist/D2 antagonist model (coined here as the “5HT-1A/2A/D2” model). The SDA
hypothesis confers atypical properties by virtue of diminished EPS. The ratio of potencies at
these receptors is more relevant than potency alone, because several atypical, e.g., clozapine
show moderate and low affinity at these sites, but still favor 5-HT2A>D2. Arylpiperidines and
arylpiperazines are two major structural classes that confer concomitant 5-HT2A and D2
antagonism. The compounds setoperone, risperidone, ocaperidone, sertindole, tiasperone,
ziprasidone, molindone and zotepine were discovered on SDA hypothesis (Altar et al., 2003).
D2 Partial Agonists
There is now evidence to support the original proposal of Carlsson et al., that partial
D2 agonists can treat psychosis by activating presynaptic D2 autoreceptors and decreasing
dopamine synthesis and release. In support of this bold proposal, D2 agonists, and even partial
agonist, have been shown to improve negative symptoms of schizophrenia. A number of
compounds have been synthesized with the goal of such autoreceptor agonist properties.
These include pramipexole, roxindole, talipexole and terguride.
NON-DOPAMINERGIC APPROACHES
Serotonergic
5-HT2A Antagonist
Clozapine has a high affinity for 5HT2 receptors rekindled interest in the potential
involvement of this receptor in the action of atypical antipsychotics and in the etiology of
schizophrenia.
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INTRODUCTION
The first compound to have a reasonably selective 5-HT2A affinity was ritanserin. Fananserin
is a potent and selective antagonist at the human 5-HT2A receptor with moderate affinity for
α1 and little or no D2 receptor affinity (Altar et al., 2003).
5-HT1A Partial Agonists
5-HT1A receptor agonism can produce anxiolytic effects and diminish the catalepsy
induced by D2 antagonists in rodents and primates. Intrinsic 5-HT1A receptor agonist activity
is a property of mainly the newest antipsychotic drugs. These include aripiprazole
ziprasidone, and clozapine (Altar et al., 2003).
Glutamatergic Approaches
The glutamate NMDA (N-methyl-D-asparate) receptor antagonists such as
phencyclidine, ketamine and dizocilpine produce psychotic symptoms in humans and reduced
glutamate concentration and glutamate receptor densities have been reported in postmortem
brains of schizophrenics (Rang et al., 2003). Deficiencies in the excitatory aminoacid
glutamate have been implicated in the etiology of schizophrenia, and thus its receptors and
biosynthetic enzymes provide novel drug targets.
1.8
Future of Research work
Schizophrenia is a complex psychiatric disorder that affects approximately 1% of the
population (Reynolds, 1992). The use of classical (typical) neuroleptic (e.g., haloperidol) for
the treatment of this disease is associated with severe mechanism-related side effects,
including induction of acute extra pyramidal symptoms (EPS). Furthermore these drugs are
ineffective against the negative symptoms of schizophrenia. The introduction of clozapine for
treatment resistant schizophrenia gave rise to a new group of atypical or nonclassical
antipsychotics that have no EPS at the doses frequently used in therapy and display moderate
efficacy towards negative symptoms. Clozapine exhibits potent affinities for multiple
receptors (Roth et al., 2004). Its action at serotonin (5-HT) receptors is thought to mediate its
beneficial effects on cognition, negative symptoms, and the low incidence of EPS (Meltzer et
al., 1989; Roth et al., 1998). It also displays affinity for dopamine receptors, related to its
efficacy on positive symptoms, as well as for α-adrenergic, muscarinic, and histaminic (H1)
receptors.
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INTRODUCTION
Although clozapine and other atypical antipsychotic drugs such as risperidone have brought
improvement in the treatment of negative symptoms with lower propensity to elicit EPS,
treatment with these drugs can still lead to substantial weight gain, blood dyscrasias, and
some movement disorders. Additionally, negative symptoms and cognitive impairments are
not fully addressed by these drugs. Hence, the discovery of a more effective, side effects free
therapy for the treatment of schizophrenia remains a challenging research goal.
It has been proposed that the interaction between serotonin (5-HT) and dopamine
systems may play a critical role in the mechanism of action of atypical antipsychotics.
Blockade of 5-HT2A receptors coupled with the antagonism of the dopamine D2 receptors
(serotonin–dopamine hypothesis) has become useful model for developing new second
generation antipsychotic drugs to achieve superior antipsychotic efficacy with a lower
incidence of extrapyramidal side effects compared to those with first-generation antipsychotic
drugs such as haloperidol.
Past two decades, drug discovery research has vigorously attempted to develop a novel
antipsychotic drug based on the serotonin–dopamine hypothesis which is the most
important landmark, and has contributed to the development of a number of second
generation antipsychotics. A number of structurally diverse types of drugs were developed on
5-HT2A/D2 receptor antagonism based hypothesis. Clozapine, risperidone, sertindole,
tiaspirone, ziprasidone, zotepine and molindone were discovered but possess undesirable side
effects.
Molecules based on arylpiperazine core were classified as ligands of serotonin (5HT), dopamine and adrenergic receptors and some of them became clinically useful drugs in
the treatment of psychiatric disorders (Lopez-Rodriguez et al., 2002; Obniska et al., 2003;
Santana et al., 2002). Long chain arylpiperazines have been (LCAPs) recognized as the
largest and most diverse classes of compounds exerting actions on the central nervous system
in particularly serotonin (5-HT1A, 5-HT2A) and dopamine affinity (D2, D4) (Kolaczkowski et
al., 2005; Tomic et al., 2004; Gonzalez-Gomez et al., 2003). Their general chemical structure
consists of the arylpiperazine moiety connected by an alkyl chain with the terminal amide or
imide fragment (Obniska et al., 2003) (fig.6).
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INTRODUCTION
Encouraged by the promising concept of mixed dopamine D2 receptor antagonism and
serotonin 5-HT2A receptor antagonism (Serotonin-Dopamine hypothesis) for the
development of potential atypical antipsychotic agents, the idea was raised to design
compounds with such a pharmacological profile using the arylpiperazines as main fragment.
O
N
OCH3
N
N
N
N
N
N
N
N
O
WAY-100635
Buspirone
O
O
OCH3
N
NH
N
O
N
NH
BP 897
N
H3CO
WAY-100135
Figure 6. Structure of some amide and imides based arylpiperazines: Buspirone, WAY100135, WAY-100635, and BP-897.
1.9
Scope of Thesis
Schizophrenia is the most disabling psychiatric disorder and one of the world’s top ten
causes of long-term disability, affecting 1% of the population worldwide. The
pharmacotherapy of schizophrenia has evolved from typical antipsychotics (dopamine D2
receptor antagonists) to atypical antipsychotics (mixed D2 and serotonin 5-HT2A antagonists
with activity at various other receptors) with improved efficacy and side effect profile. The
concept of mixed dopamine D2 receptor antagonism and serotonin 5-HT2A receptor
antagonism (serotonin-dopamine hypothesis) has generated an interest to develop novel
antipsychotics to achieve superior efficacy with a lower incidence of extrapyramidal side
effects compared to first generation antipsychotics. This thesis, deals with the synthesis,
computational studies and pharmacological evaluation of new arylpipearzines at dopamine D2
and serotonin 5-HT2 receptor as potential antipsychotics. It is hoped that the chemistry of the
synthesized compounds could contribute to a better understanding and treatment of
schizophrenia.
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LITERATURE REVIEW
2
LITERATURE REVIEW
Jin et al., (2011) reported design, synthesis and biological evaluation of new arylpiperazine
derivatives bearing a flavone moiety as α1-adrenoceptor antagonists.
R1
R2
N
N
O
O
n
O
Bali et al., (2010) carried out synthesis, evaluation and computational studies on a series of
acetophenone based 1-(aryloxypropy)-4-(chloroaryl) piperazines as potential atypical
antipsychotics. The physicochemical similarity of the new analogs with respect to standard
drugs clozapine, ketanserin, ziprasidone and risperidone was assessed by calculating from a
set of 10 physicochemical properties using software programs.
Dash et al., (2010) carried out synthesis, pharmacological evaluation and QSAR study of 6[3-(4-substituted phenylpiperazin-1-yl) propoxy] benzo[d] [1, 3] oxathiol-2-ones as potential
antipsychotics.
S
O
N
O
O
N
R
Butini et al., (2010) discovered bishomo (hetero) arylpiperazines as novel multifunctional
ligands targeting dopamine D (3) and serotonin 5-HT (1A) and 5-HT (2A) receptors.
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LITERATURE REVIEW
Dash et al., (2010) synthesized and evaluated 6-(4-(4-substituted phenylpiperazin-1-yl)
butoxy) benzo[d] [1, 3] oxathiol-2-one as potential antipsychotic agents. The anti
dopaminergic activity was evaluated by their ability to inhibit apomorphine induced climbing
behavior and the anti-serotonergic activity of synthesized compounds was assessed by
inhibition of 5-HTP induced head twitches behavior in mice. The intensity of catalepsy
induced by synthesized compounds was evaluated against haloperidol induced catalepsy.
Graulich et al., (2010) reported synthesis and in vitro radioligand binding studies on 4arylpiperazine-ethyl carboxamide derivatives differentially modulate affinity for 5-HT1A,
D4.2, and α 2A receptors.
O
N
N
R
N
N
H
N
Frecentese et al., (2010) reported efficient microwave combinatorial synthesis of novel
indolic arylpiperazine derivatives as serotoninergic ligands. The described reactions were
nucleophilic substitutions of several aromatic piperazines in presence of K2CO3. Good
yields and short reaction times were the main aspect of these procedures. Binding assays
showed influence of the LCAPs on the 5-HT1A, 5-HT2A and 5-HT2C receptors affinity and
allowed to disclose three interesting compounds as 5-HT2C, mixed 5-HT2A/5-HT2C and 5HT1A/5-HT2C ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or
atypical antipsychotic agent therapeutical profiles.
X
N
N
O
O
N
H
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O
25
LITERATURE REVIEW
Sati et al., (2009) reported synthesis, structure activity relationship studies and
pharmacological evaluation of 2-phenyl-3-(substituted phenyl)-3H-quinazolin-4-ones as
serotonin 5-HT2 antagonists.
Charan dash et al., (2009) reported synthesis and biological evaluation of benzo[d] [1, 3]
oxathiols as potential atypical antipsychotic agents. Potential antipsychotic activity of these
compounds in terms of D2 antagonism was evaluated by their ability to inhibit apomorphineinduced climbing behavior and 5-HT2 antagonistic activity of synthesized compounds was
assessed by inhibition of 5-HTP-induced head twitches behavior in mice. Non-specific D2
blockade was evaluated by studying propensity of these compounds to produce catalepsy in
mice. All the synthesized compounds were found to exhibit D2 and 5-HT2 antagonist activity
in behavioral models.
Bali et al., (2009) reported synthesis and evaluation of 1-(quinoliloxypropyl)-4-aryl
piperazines for atypical antipsychotic activity in apomorphine induced mesh climbing and
stereotypic behaviour in mice. Employing appropriate physicochemical properties, the
similarity of the compounds was assessed with respect to some atypical antipsychotic drugs as
clozapine, ketanserine, ziprasidone and risperidone.
N
N
N
O
Cl
Carro et al., (2009) synthesized 8 new tetrahydroquinazolinone derivatives and evaluated for
binding affinity to D2 and 5-HT2A human receptors. Some properties related to blood–brain
barrier penetration were also calculated. From the results of these assays, three compounds
were selected for further binding tests on D1, D3, and 5-HT2C human receptors, which are
thought to be involved in schizophrenia.
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LITERATURE REVIEW
Dong et al., (2009) developed YKP1447 as novel potential atypical antipsychotic agent. The
compound selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and
dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10~100-fold selectivity
over the various receptors which exist in the brain. In the behavioral studies, YKP1447
antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced
head twitch (ED50=0.18 mg/kg) behavior in mice. YKP1447 inhibited the hyperactivity
induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg)
in rats. However, unlike other antipsychotic drugs, catalepsy was observed only at much
higher dose (ED50=68.6 mg/kg).
Bojarski et al., (2009) synthesized a set of 36 arylpiperazine derivatives with two novel
complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6] undec-8en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.02,6] undecane-3,5,8-trione and tested
for their affinity for 5-HT1A and 5-HT2A receptors.
Leopoldo et al., (2008) carried out structural modifications of N-(1, 2, 3, 4 tetrahydronap
hthalen-1-yl)-4-aryl-1-piperazinehexanamides and studied its influence on lipophilicity and
5-HT7 receptor activity.
O
N
N
NH
R
O
N
5
R
N
N
n
Ar
n
Awadallah et al., (2008) reported synthesis, pharmacophore modeling, and biological
evaluation of novel 5H-thiazole [3, 2-a] pyrimidin-5-one derivatives linked through an
ethylene bridge to various phenylpiperazines groups as 5-HT2A receptor antagonists.
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LITERATURE REVIEW
R
N
R'
O
N
N
S
N
CH3
Strappaghetti et al., (2008) reported synthesis and biological affinity of new imidazo- and
indol-arylpiperazine derivative and carried out further validation of a pharmacophore model
for α1- adrenoceptor antagonists.
Ibis et al., (2008) reported the reaction of polyhalogenated-2-nitro-1, 3-butadiene with
alkylthio, thiomorpholine and piperazine derivatives.
Kowalski et al., (2008) synthesized 1-arylpiperazine series of N- substituted 1, 3benzoxazine-2, 4-diones as well as O- and N- substituted salicylamides with an n- propyl
chain and explored the effect of cyclic and acyclic salicylamide moieties on their binding
affinity for 5- HT1A, 5-HT2A, and 5-HT7A receptor sites.
Biswas et al., (2008) studied structure-activity relationships of hybrid 7-{[2-(4phenylpiperazin-1-yl) ethyl] propylamino}-5, 6, 7, 8-tetrahydronapthlen-2-ol analogues as
identification of a high affinity D3- preferring agonist with potent in vivo activity with long
duration of action.
Kossakowski et al., (2008) reported synthesis and pharmacological evaluation of 4-[2hydroxy-3-(4-phenyl-piperazin-1-yl)-propoxy]-4-azatricyclo [5.2.1.02, 6] dec-8-ene-3, 5-dione.
Leopoldo et al., (2008) reported N-[ω-[4-(2-Methoxyphenyl)-1-piperazinyl] alkyl]-2quinolinamines as high-affinity fluorescent 5-HT1A receptor ligands.
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LITERATURE REVIEW
Natesan et al., (2007) reported evaluation of N-desmethylclozapine as potential
antipsychotic during preclinical studies. To explore this, N-desmethylclozapine (NDMC) was
compared with a typical (haloperidol), atypical (clozapine), and partial agonist atypical
(aripiprazole) antipsychotic in preclinical models by using brain D2 and 5-HT2 receptor
occupancy.
Leopoldo et al., (2006) reported the synthesis of compounds structurally related to the high
affinity dopamine D3 receptor ligand N-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butyl]-7methoxy-2-benzofurancarboxamide. All compounds were specifically designed as potential
positron emission tomography (PET) radioligands for brain D3 visualization.
Sasikumar et al., (2006) reported hydrazides of clozapine as a new class of D1 dopamine
receptor subtype selective antagonists. The most potent in this series was the 2, 6dimethoxybenzhydrazide with a D1 Ki of 1.6 nM and 212 –fold selectivity over D2 receptor.
Ladduwahetty et al., (2006) designed a novel series of non-basic piperidine sulfonamides
and amides that have high affinity for 5-HT2A receptor antagonists.
Su et al., (2006) carried out modification of the clozapine structure by high-throughput
parallel synthesis. Several focused libraries were designed, synthesized to develop the SAR.
The synthesized compounds showed D1 and D2 receptor activity.
Brea et al., (2006) carried out synthesis, molecular modeling and in vitro and in vivo
pharmacological studies for 2-[4-(6-fluorobenzisoxa-3-yl) piperidinyl] methyl-1, 2, 3, 4tetrahydro-carbazol-4-one (QF2002B), a conformationally constrained butyrophenone
analogue. This compound showed a multi-receptor profile with affinities similar to those of
clozapine for serotonin (5-HT2A, 5-HT1A, and 5-HT2C), dopamine (D1, D2, D3 and D4), alphaadrenergic (α1, α2), muscarinic (M1, M2) and histamine H1 receptors.
Sakuza et al., (2006) reported effect of BD 1047, a sigma1 receptor antagonist, in the animal
models predetective of antipsychotic activity.
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LITERATURE REVIEW
Kolaczkowski et al., (2005) reported synthesis of new arylpiperazines with a four methylene
spacer containing a terminal pyrimido [2, 1-f] theophyllines fragment and binding affinities at
5-HT1A/5-HT2A receptors. All these compounds displayed a high affinity for 5-HT1A receptors
(Ki = 0.5-21.5 nm) and low affinity for 5-HT2A receptor.
O
O
N
N
N
O
(CH2)4
N
N
Shelke et al., (2005) carried out synthesis and pharmacological of 7-[(4-substituted phenyl
piperazin-1-yl)-alokoxyl]-4-methylchromene-2-ones as potential antipsychotics. The atypical
antipsychotic activity of these compounds was evaluated by their ability to inhibit
apomorphine-induced climbing behavior (D2 antagonism) and to inhibit 5-HTP induced head
twitches (5-HT2A antagonism) along with catalepsy studies in albino mice.
CH3
R
O
O
O(CH2)n
N
N
Sukalovi et al., (2005) reported synthesis, dopamine D2 receptor binding studies and docking
analysis of 5-[3-(4-arylpiperazin-1-yl) propyl]-1H-benzimidazole, 5-[2-(4-arylpiperazin-1-yl)
ethoxy]-1H-benzimidazole and their analogs.
H
N
N
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N
N
30
LITERATURE REVIEW
Park et al., (2005) reported rapid synthesis of arylpiperazine derivatives for imaging 5-HT1A
receptor under microwave irradiation and reaction times of the target compounds were
remarkably reduced when compared with the conventional methods.
Konkel et al., (2005) reported synthesis and structure-activity relationship of fluoro
analogues of 8-{2-[4-(4-methoxyphenyl) piperazin-1yl] ethyl}-8-azaspiro [4.5] decane-7, 9dione as selective α1d-adrenergic recepter antagonists.
Jolanta et al., (2005) reported synthesis, anticonvulsant properties and 5-HT1A/5-HT2A
receptor affinity of new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro [4.4] nonane and [4.5]
decane-1, 3-dione derivatives.
N
N
N
Miyamoto et al., (2005) reviewed pharmacology and mechanisms of action of antipsychotic
drugs for the treatments of schizophrenia.
Caro et al., (2004) reported a series of (R) and (S)-3-aminomethyl-1-tetralones,
conformationally constrained analogues of haloperidol by enzymatic resolution of the
corresponding racemic 3-hydroxymethyl-1-tetralones using Pseudomonas fluorescens lipase.
Their binding affinities at dopamine D2 and serotonin 5-HT2A and 5-HT2C receptors were
determined as potential atypical antipsychotics.
Tomic et al., (2004) reported pharmacological evaluation of selected arylpiperazines with
atypical antipsychotic potential. The compounds were evaluated for the binding affinity to rat
dopamine, serotonin and α1 receptors.
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LITERATURE REVIEW
Tacke et al., (2004) reported synthesis, crystal structure analyses, ([D6] DMSO) NMR studies
and pharmacological characterization of sila-haloperidol.
Matulenko et al., (2004) reported synthesis and functional activity of (2-aryl-1-piperazinyl)N-(3-methylphenyl) acetamide as selective dopamine D4 receptor agonist.
Bojarski et al., (2004) reported o-methoxyphenylpiperazine (MPP, series a) and 1, 2, 3, 4tetrahydroisoquinoline (THIQ; series b) derivatives, containing various imide moieties
derived from NAN190 and in vitro studies for their ability to bind to the serotonin 5-HT1A and
5-HT2A receptors.
Hackling et al., (2003) reported N-(ω-(4-(2-methoxyphenyl) piperazin-1-yl) alkyl) carbox
amides as dopamine D2 and D3 receptor ligands.
Lopez-Rodriguez et al., (2003) designed and synthesized s-(-)-2-[[4-(napht-1-yl) piperazin1-yl]-methyl]-1, 4-dioxoperhydropyrrolo [1, 2-a] pyrazine (csp-2503) using computational
simulation as 5-HT1A receptor agonist.
Balle et al., (2003) reported synthesis and structure-affinity relationship investigations of 5aminomethyl and 5-carbamoly analogues of the antipsychotic sertindole as a new class of
selective α1 adrenoceptor antagonists.
Neves et al., (2003) reported dopaminergic profile of new heterocyclic N-phenylpiperazine
derivatives. The compounds were assayed by blockade of amphetamine induced stereotypy in
rats, the catalepsy test and apomorphine induced hypothermia in mice.
Lee et al., (2003) reported novel, highly potent, selective 5-HT2A/D2 receptor antagonists as
potential atypical antipsychotics. The N-substituted-pyridoindolines and their binding
affinities at the 5-HT2A, 5-HT2C and D2 receptors and in vivo efficacy as 5-HT2A antagonists
were described. The structure-activity relationship of a series of core tetracyclic derivatives
with varying butyrophenone side chains was also discussed.
Shobhit University Meerut
32
LITERATURE REVIEW
Obniska et al., (2003) reported synthesis and 5-HT1A/5-HT2A receptor activity of new N-[3(4-phenylpiperazin-1-yl)-propyl] derivatives of 3-spiro-cyclohexanepyrrolidine-2, 5-dione
and 3-spiro-β-tetralonepyrrolidine-2, 5-dione.
A
A=cyclohexane or tetralone
O
O
N
R
(CH2)3
Gonzalez-Gomez et al., (2003) synthesized new arylpiperazines bearing a coumarin fragment
and the compounds were evaluated for their affinity for α1A, D2 and 5-HT2A receptors. Most of
the new compounds showed high affinity for α1A, D2 and 5-HT2A receptors which depends
fundamentally on the substitution of the N4 of the piperazine ring.
Lopez-Rodriguez et al., (2002) reported arylpiperazine derivatives acting at 5-HT1A
receptors.
Leopoldo et al., (2002) studied structure- affinity relationship on N-[4-(4-arylpiperazin-1-yl)
butyl] aryl carboxamide as potent and selective dopamine D3 receptor ligands.
O
Ar
Shobhit University Meerut
NH
(CH2)n
N
N
Ar'
33
LITERATURE REVIEW
Brea et al., (2002) carried out synthesis, pharmacology, 3D-QSAR, and molecular modeling
of (aminoalkyl) benzo and heterocycloalkanones as new serotonin 5-HT2A, 5-HT2B, and 5HT2C receptor antagonists.
Bromidge et al., (2002) reported bicyclic piperazinylbenzenesulphonamides are potent and
selective 5-HT6 recepter antagonists.
Santana et al., (2002) designed and synthesized compounds in which N-phenylpiperazines
were linked by a propyloxy chain to position 6 or 7 of a coumarin ring and evaluated their
affinities for 5-HT1A and D2A receptors by radioligand binding assays.
Campiani et al., (2002) reported synthesis, structure-activity relationship, molecular
modelling, and biological studies of pyrrolo [1, 3] benzothiazepine-based atypical
antipsychotic
agents.
The
compound
(±)-7-chloro-9-(4-methylpiperazin-1-yl)-9,
10-
dihydropyrrolo [2, 1-b] [1, 3] benzo thiazepine was resolved into its R and S enantiomers and
described the binding studies that the (R)-(-) - enantiomer was more potent D2 receptor
antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT2 receptor.
Lopez-Rodriguez et al., (2001) reported synthesis and structure-activity relationships of a
new model arylpiperazines. They studied the physicochemical influence of the
pharmacophore on 5-HT1A/α1- adrenergic receptor affinity and synthesized a new derivative
with mixed 5-HT1A/ D2 antagonist properties.
Rowley et al., (2001) reviewed current and novel approaches to the drug treatment of
schizophrenia.
Mouithys-Mickalad et al., (2001) reported electro-oxidation potential as a tool in the early
screening for new safer clozapine like analogues. In this study, discussed the oxidation profile
(direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation
potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to
clozapine, some of them being described as putative antipsychotics.
Shobhit University Meerut
34
LITERATURE REVIEW
Kowalski et al., (2001) reported biologically active 1-arylpiperazines and synthesized new
N-(4-aryl-1-piperazinyl) alkyl derivatives of quinazolidin-4(3H)-one, 2, 3 dihydrophthalazine1, 4-dione and 1, 2-dihydropyridazine- 3, 6-dione as potential serotonin receptor ligands.
Zhang et al., (2000) reported trans-1-[(2-phenylcyclopropyl) methyl]-4-arylpiperazines
mixed dopamine D2/D4 receptor antagonists as potential antipsychotic agents.
Karan et al., (2000) studied relevance to antipsychotic drugs for D2 and 5-HT2 receptors.
Caliendo et al., (2000) reported synthesis of new 1, 2, 3-benzotriazin-4-one-arylpiperazine
derivatives as 5-HT1A serotonin receptor ligands.
Perrone et al., (1999) reported 1-aryl-4-[(5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl)
alkyl] piperazines and their analogues and studied influence of the stereochemistry of the
tetrahydronaphthalen-1-yl nucleus on 5-HT1A receptor affinity and selectivity versus α1 and
D2 receptors.
Ar
N
N
X
OCH 3
Srinivas et al., (1999) reported synthesis and preliminary binding affinities of 1-(1, 2dihydro-2-acenaphthylenyl) piperazine.
Thomas et al., (1999) reported enantio- and diastereo controlled dopamine D1, D2, D3 and D4
receptor binding of N-(3-Pyrrolidinylmethyl) benzamides and the compounds synthesized
from aspartic acid.
Shobhit University Meerut
35
LITERATURE REVIEW
Nakazato et al., (1999) reported design, synthesis, structure-activity relationship, and
biological characterization of novel arylalkoxyphenylalkylamine σ ligands as potential
antipsychotic drugs.
Hensen et al., (1998) reported mesolimbic selective antipsychotic arylcarbamates. In this
study linked a 3-(6-fluoro-1, 2-benzisoxazol-3-yl) piperidine with an arylcarbamate to get
compounds which bind to dopamine-D1 and D2, serotonin 5-HT2A and α1- adrenergic
receptors.
Belliotti et al., (1998) reported isoindolinone enantiomers having affinity for the dopamine
D4 receptor.
Oshiro et al., (1998) reported synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)
butoxy]-3, 4-dihydro-2(1H)-quinolinone derivatives as novel antipsychotic agents with
dopamine autoreceptor agonist properties.
N
N
O
N
H
O
Gudasheva et al., (1998) reported a series of N-acylprolyltyrosine amides as tripeptoid. The
substituted dipeptides were tested in vivo for antidopamine activity by their ability to inhibit
the apomorphine induced climbing in mice and the dopamine-induced extrapolatory behavior
impairment in rats as potential atypical antipsychotic agents.
Taverne et al., (1998) reported synthesis, screening of novel benzothiazolin-2-one and
benzoxazin-3-one arylpiperazines derivatives with mixed 5HT1A/D2 affinity as potential
atypical antipsychotic agents.
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LITERATURE REVIEW
R
N
O
S
(CH2)n
N
N
(CH2)n
N
N
R
O
N
O
Perrone et al., (1997) reported synthesis of arylpiperazines with a terminal naphthothiazole
group and their evaluation on 5-HT, DA and α receptors.
Diouf et al., (1997) synthesized new benzothiazolin-2-one and benzoxazin-3-one derivatives
and reported their binding profile at 5-HT1A and 5-HT2A, 5-HT2C as well as D2 and α1
receptors. All the compounds displayed high to moderate affinity for both 5-HT1A and 5-HT2A
receptor subtypes.
Griebel et al., (1996) reported preclinical profile of the mixed 5-HT1A/5-HT2A receptor
antagonist S 21357. The drug behaved as antagonist at both 5-HT1A autoreceptors and
postsynaptic 5-HT1A receptors, as it prevented the inhibitory effect of lesopitron on the
electrical discharge of the dorsal raphe nucleus (DRN) 5-HT neuron and the activity of
forskolin-stimulated adenylcyclase in hippocampal homogenates. In addition, S21357 (4 and
128 mg/kg, PO) inhibited 5-HTP-induced head twitches responses in mice.
Hrib et al., (1996) studied structure- activity relationship of a series of novel
(piperazinylbutyl)
thiazolidinone
antipsychotic
agents
related
to
3-[4-[4-(6-
fiuorobenzo[b]thien-3-yl)-1-piperazinyl] butyl]-2, 5, 5-trimethyl-4-thiazolidinone maleate.
The compounds were evaluated in vitro for dopamine D2 and serotonin 5 HT2 and 5HT1A
receptor affinity and in vivo in animal models of potential antipsychotic activity.
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LITERATURE REVIEW
Murray et al., (1995) synthesized a novel series of arylpiperazines with high affinity and
selectivity for the dopamine D-3 receptor.
Fontenla et al., (1994) reported synthesis and atypical antipsychotic profile of some 2-(2piperidinoethyl) benzocycloalkanones as analogues of butyrophenone.
Wustrow et al., (1994) reported studies of the active conformation of a novel series of
benzamide dopamine D2 agonists.
Philllips et al., (1994) reported 5H-dibenzo[b,e[1,4] diazepine, dibenz[b,e] oxaepin, and 5Hdibenzo[a,d]cycloheptene analogues of clozapine [8-chloro-11-(4-methylpiperazino)-5Hdibenzo[b,e] diazepine and their binding affinity to dopamine D-1, D-2, and D-4 and
serotonin S-2A (5-HT2A), S-2C(5-HT2C), and S-3(5-HT3) receptors.
Gilligan et al., (1992) reported novel piperidine σ receptor ligands as potential antipsychotic
drugs.
Hogberg et al., (1990) reported synthesis and antidopaminergic properties of the atypically
highly potent (S)-5-Bromo-2, 3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl] benzamide
and related compounds as potential antipsychotic agents.
O
Y
NH
N
O
X
Z
R
Gupta et al., (1990) reported in vitro antidopaminergic activity of N-[(1-alkyl-2-pyrrolidinyl)
methyl]-6-methoxysalicylamides.
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RESEARCH ENVISAGED AND PLAN OF WORK
3
3.1
RESEARCH ENVISAGED AND PLAN OF WORK
Research Envisaged
Schizophrenia is the most disabling psychiatric disorder and one of the world’s top
ten causes of long-term disability in humans. The use of classical (typical) neuroleptics (e.g.,
haloperidol) for the treatment of this disease is associated with severe mechanism-related side
effects, including induction of acute extrapyramidal symptoms (EPS). Furthermore, these
drugs are ineffective against the negative symptoms of schizophrenia.
In the past decades, drug discovery research has vigorously attempted to develop
novel antipsychotic drugs modelled on serotonin–dopamine hypothesis. Serotonin–dopamine
hypothesis’ has become useful model for developing new second generation antipsychotic
drugs to achieve superior antipsychotic efficacy with a lower incidence of extrapyramidal side
effects compared to those with typical antipsychotic drugs such as haloperidol and
chlorpromazine.
Literature survey reveals that long chain arylpiperazines (LCAPs) are one of the
largest and most diverse classes of compounds exerting actions on the central nervous system.
Their general chemical structure consists of the arylpiperazine moiety connected by an alkyl
chain with the terminal amide or imide motif. Molecules based on arylpiperazine core were
classified as ligands of serotonin (5-HT), dopamine and α- adrenergic receptors and some of
them became clinically useful drugs in the treatment of psychiatric disorders such as anxiety,
depression and psychosis. So we thought it worthwhile to carryout synthesis, computational
studies and pharmacological evaluation of new arylpiperazines for potential antipsychotic
effect.
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RESEARCH ENVISAGED AND PLAN OF WORK
3.2
Plan of Work
The work was carried out on following lines
3.2.1 Synthesis of arylpiperazines
Series A
Synthesis of 2-{n-[4-(aryl substituted) piperazin-1-yl] alkoxy} benzamides
CONH2
CONH2
OH
O(CH2)nX
i
(1)
R
(2a,2b,2c)
HN
n=2,3,4
ii
N
X=Cl,Br
CONH2
R
O(CH2)n
N
N
3a1-6,3b1-2,3c1-2
Scheme 1. Synthesis of the target compounds. Reagents and conditions :(i) Acetonitrile,
Dihaloalkane, K2CO3, reflux, (ii) DMF, K2CO3, KI.
Table 1. Substituent of compounds
Compound
R
3a1
H
3a2
3-CH3
3a3
4-CH3
3a4
2-OCH3
3a5
3-OCH3
3a6
2-Cl
3b1
H
3b2
2-OCH3
3c1
H
3c2
2-OCH3
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40
RESEARCH ENVISAGED AND PLAN OF WORK
Series B
Synthesis of 2–[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides
N
NH
ClCOCH2Cl
COCH2Cl
i
(2)
R
(1)
HN
ii
N
R
N
COCH2
N
N
3a-j
Scheme 2. Synthesis of the target compounds. Reagents and conditions :(i) Toluene, reflux,
4h (ii) Acetonitrile, K2CO3, KI.
Table 2. Substituent of compounds
Compound
R
3a
H
3b
4-CH3
3c
2, 3- (CH3)2
3d
3-CF3
3e
2-OCH3
3f
3-OCH3
3g
3-Cl
3h
3, 4-(Cl)2
3i
4-F
3j
4-NO2
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41
RESEARCH ENVISAGED AND PLAN OF WORK
Series C
Synthesis of 2-[4-(Aryl substituted) piperazin-1-yl]-N-phenylacetamides
HN
NH2
ClCOCH2Cl
COCH2Cl
i
(2)
R
(1)
HN
ii
N
R
HN
COCH2
N
N
3a-j
Scheme 3. Synthesis of the target compounds. Reagents and conditions :(i) NaOH,
Dichloromethane (ii) Acetonitrile, K2CO3, KI.
Table 3. Substituent of compounds
Compound
R
3a
H
3b
3-CH3
3c
4-CH3
3d
2-OCH3
3e
3-OCH3
3f
4-OCH3
3g
2-Cl
3h
3-Cl
3i
4-F
3j
4-NO2
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42
RESEARCH ENVISAGED AND PLAN OF WORK
Series D
Synthesis of 2-[4-(Aryl substituted) piperazin-1-yl]-N-benzylacetamides
CH2NHCOCH2Cl
CH2NH2
ClCOCH2Cl
i
(2)
R
(1)
HN
ii
N
R
CH2NHCOCH2
N
N
3a-j
Scheme 4. Synthesis of the target compounds. Reagents and conditions :(i) NaOH,
Dichloromethane (ii) Acetonitrile, K2CO3, KI.
Table 4. Substituent of compounds
Compound
R
3a
H
3b
2-OCH3
3c
3-OCH3
3d
4-OCH3
3e
3-CH3
3f
4-CH3
3g
2-Cl
3h
3-Cl
3i
4-NO2
3j
4-F
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RESEARCH ENVISAGED AND PLAN OF WORK
Series E
Synthesis of 2-[4-(Aryl substituted) piperazin-1-yl]-N-cyclohexylacetamides
HN
NH2
ClCOCH2Cl
COCH2Cl
i
(2)
R
ii
(1)
HN
N
R
HN
COCH2
N
N
3a-j
Scheme 5. Synthesis of the target compounds. Reagents and conditions: (i) NaOH,
Dichloromethane (ii) Acetonitrile, K2CO3, KI.
Table 5. Substituent of compounds
Compound
R
3a
H
3b
3-CH3
3c
4-CH3
3d
2-OCH3
3e
3-OCH3
3f
4-OCH3
3g
2-Cl
3h
3-Cl
3i
4-F
3j
4-NO2
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44
RESEARCH ENVISAGED AND PLAN OF WORK
3.2.2 Characterization of synthesized compounds
The synthesized compounds were characterized by following methods
Melting point
Thin Layer Chromatography
IR Spectroscopy
1
H NMR Spectroscopy
Mass Spectroscopy
3.2.3 Computational studies
The physicochemical similarity of the target compounds with respect to standard drugs
clozapine, ketanserin and risperidone was assessed by calculating from a set of
physicochemical properties using Chem 3D Ultra version 11.0, 8.0, Novartis JME molecular
editor and Chem Silico online free software programs.
3.2.4 Pharmacological evaluation for antipsychotic effect
The target compounds were subjected to pharmacological evaluation to determine
their antipsychotic effect by using following models:
Behavioral symptoms
Inhibition of apomorphine induced climbing behavior
Inhibition of 5-Hydoxytryptophan (5-HTP) induced head twitches behavior
Induction of catalepsy
Acute toxicity study
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EXPERIMENTAL
4
4.1
EXPERIMENTAL
Materials and Methods
Materials:
The substituted arylpiperazines were purchased from AB fine Chemicals (Nasik,
India). (-)Apomorphine hydrochloride, clozapine, 5-hydroxytryptophan (5-HTP), pargyline
and haloperidol were purchased from Sigma. All other chemicals and solvents were purchased
from CDH. All chemicals used were of analytical grades and purified before used.
Methods:
Melting points of the synthesized compounds were determined by open capillary
method and are uncorrected. The IR spectra of synthesized compounds were recorded in
potassium bromide discs on Perkin Elmer RX1. The 1H NMR spectra were recorded on a
Bruker DRX-300 spectrophometer at 300 MHz in CDCl3 and DMSO containing TMS as
internal standard. All chemical shift values are reported in ppm (δ). The electro spray mass
spectra were recorded on a Thermo Finnigan LCQ Advantage Max ion trap mass
spectrometer. The spectroscopic analysis of synthesized compounds was carried out at SAIF,
CDRI Lucknow.
The reactions progress was monitored by thin-layer chromatography (TLC) using
silica gel G and spots were visualized in an iodine chamber. All the target compounds were
subjected to pharmacological evaluation for behavior symptoms, inhibition of apomorphine
induced climbing behavior, inhibition of 5-hydroxy tryptophan (5-HTP) induced head
twitches behavior and induction of catalepsy studies. Acute toxicity was carried out for the
potent compounds. Prior permission of the Animal Ethics Committee was obtained and all
experiments were conducted according to the approved protocol (837/ac/04/CPCSEA). Swiss
albino mice (six mice in each group) of either sex (20-25 g) were used and housed in standard
laboratory conditions (12 h light/ dark cycle, 22 ± 2 oC room temperature). Food and water
were available ad libitum. Clozapine and haloperidol groups were employed as a standard
(positive control). Statistical analysis of the results in the test group was done by comparison
with the results in the control group employing non-parametric Kruskal Wallis test or one way
ANOVA (Jandel Sigmastat version 2.0). The results are expressed as mean ± S.E.M. Level of
significance was fixed at p<0.05.
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EXPERIMENTAL
4.2. Synthesis and Characterization of Compounds
Series A
Synthesis of 2-{n-[4-(aryl substituted) piperazin-1-yl] alkoxy} benzamides
Step I.
Alkylation of salicylamide (2a, 2b and 2c)
CONH2
CONH2
n =2, 3 , 4
OH
O(CH2)nX
X= Cl , Br
i
(1)
(2a,2b,2c)
Scheme1. Reagents and conditions: (i) Acetonitrile, Dihaloalkane, K2CO3, Reflux.
General procedure
A mixture of salicylamide 1 (5.48 g, 0.04 mol), dihaloalkane (1, 2-dibromoethane or
1-bromo-3-chloropropane or 1, 4-dibromobutane, 0.04 mol) and anhydrous potassium
carbonate (5.52g, 0.04 mol) in acetonitrile (100 ml) was refluxed for 8 h. The solvent was
removed under vacuum. The residue was dissolved in chloroform and washed with water. The
organic extract was dried over sodium sulphate. The solvent was removed and the residue was
recrystallized from methanol and chloroform (1:1) to afford 2a or 2b or 2c.
The physical parameters were of the compounds
2-(2-Bromoethoxy) benzamide (2a)
Yield
:
7.45 g
Percentage yield
:
76.41%
Melting range
:
199-201oC
Rf value
:
0.72
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C9H10BrNO2
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EXPERIMENTAL
2-(3-Chloropropoxy) benzamide (2b)
Yield
:
5.4 g
Percentage yield
:
42.18%
Melting range
:
123-125oC
Rf value
:
0.74
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C10H12ClNO2
Yield
:
4.70 g
Percentage yield
:
43.0%
Melting range
:
211-213oC
Rf value
:
0.67
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C11H14BrNO2
2-(4-Bromobutoxy) benzamide (2c)
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EXPERIMENTAL
Step II.
Synthesis of final compounds (3a1-6, 3b1-2 and 3c1-2)
CONH2
R
O(CH2)nX
(2a,2b,2c)
HN
n=2,3,4
i
N
X=Cl,Br
CONH2
R
O(CH2)n N
N
(3a1-6, 3b1-2 and 3c1-2)
Scheme 1. Synthesis of the target compounds. Reagents and conditions: (i) DMF, K2 CO3, KI,
Reflux.
Table 6.
Substituent of compounds
Compound
R
3a1
H
3a2
3-CH3
3a3
4-CH3
3a4
2-OCH3
3a5
3-OCH3
3a6
2-Cl
3b1
H
3b2
2-OCH3
3c1
H
3c2
2-OCH3
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EXPERIMENTAL
General procedure
A mixture of 2a or 2b or 2c (5 mmol), anhydrous potassium carbonate (0.69g,
5mmol), respective substituted arylpiperazines (5 mmol) and a catalytic amount of potassium
iodide in anhydrous dimethylformamide (100 ml) were mixed and stirred on a magnetic stirrer
at 80 0C temperature for 36 h. The reaction mixture was poured into 200 ml of water and the
precipitate was extracted with chloroform. The organic phase was dried over sodium sulphate
and the solvent was removed. The crude products were recrystallized from methanol to afford
3a1-6, 3b1-2, and 3c1-2.
The physical parameters were of the synthesized compounds
2-[2-(4-Phenylpiperazin-1-yl) ethoxy] benzamide (3a1)
Yield
:
0.50 g
Percentage yield
:
23.0%
Melting range
:
205-207oC
Rf value
:
0.21
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C19H23N3O2
2-{2-[4-(3-Methylphenyl) piperazin-1-yl] ethoxy} benzamide (3a2)
Yield
:
0.54 g
Percentage yield
:
31.95%
Melting range
:
189-190oC
Rf value
:
0.28
Mobile phase
:
ethyl acetate: methanol (2: 0.4)
Molecular formula
:
C20H25N3O2
2-{2-[4-(4-Methylphenyl) piperazin-1-yl] ethoxy} benzamide (3a3)
Yield
:
0.40 g
Percentage yield
:
23.6%
Melting range
:
185-187oC
Rf value
:
0.31
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C20H25N3O2
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EXPERIMENTAL
2-{2-[4-(2-Methoxyphenyl) piperazin-1-yl] ethoxy} benzamide (3a4)
Yield
:
0.31 g
Percentage yield
:
17.5%
Melting range
:
181-183oC
Rf value
:
0.59
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C20H25N3O3
Log P (Experimental)
:
2.28
2-{2-[4-(3-Methoxyphenyl) piperazin-1-yl] ethoxy} benzamide (3a5)
Yield
:
0.38 g
Percentage yield
:
22.0%
Melting range
:
178-180oC
Rf value
:
0.46
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C20H25N3O3
2-{2-[4-(2-Chlorophenyl) piperazin-1-yl] ethoxy} benzamide (3a6)
Yield
:
0.44 g
Percentage yield
:
24.58%
Melting range
:
154-156oC
Rf value
:
0.47
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C19H22ClN3O2
2-[3-(4-Phenylpiperazin-1-yl) propoxy] benzamide (3b1)
Yield
:
0.26 g
Percentage yield
:
30.95%
Melting range
:
150-152oC
Rf value
:
0.30
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C20H25N3O2
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EXPERIMENTAL
2-{3-[4-(2-Methoxyphenyl) piperazin-1-yl] propoxy} benzamide (3b2)
Yield
:
0.28 g
Percentage yield
:
30.43%
Melting range
:
143-145oC
Rf value
:
0.38
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C21H27N3O3
2-[4-(4-Phenylpiperazin-1-yl) butoxy] benzamide (3c1)
Yield
:
0.24 g
Percentage yield
:
27.27%
Melting range
:
184-186oC
Rf value
:
0.39
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C21H27N3O2
2-{4-[4-(2-Methoxyphenyl) piperazine-1-yl] butoxy} benzamide (3c2)
Yield
:
0.28 g
Percentage yield
:
29.47%
Melting range
:
175-178oC
Rf value
:
0.57
Mobile phase
:
ethyl acetate: methanol (2:0.4)
Molecular formula
:
C22H29N3O3
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EXPERIMENTAL
Figure 7.
IR Spectrum of 2-(2-bromoethoxy) benzamide (2a)
O
NH2
CH2CH2Br
O
Table 7.
Shobhit University Meerut
IR Data of 2a
Wave number (cm-1)
Group Assignment
3455
N-H Str
3159
C-H Str Aromatic
2961
C-H Str Aliphatic
1657
C=O Str
1029
C-O-C Str
748
C-Br Str
53
EXPERIMENTAL
Figure 8.
NMR Spectrum of 2-(2-bromoethoxy) benzamide (2a)
Table 8.
1
H NMR Data of 2a
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
3.40
2
CH2Br
4.50
2
OCH2
7.0-7.50
4
Aromatic
7.82
2
CONH2
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EXPERIMENTAL
Figure 9.
IR Spectrum of 2-(3-chloropropoxy) benzamide (2b)
O
NH2
CH2CH2CH2Cl
O
Table 9.
Shobhit University Meerut
IR Data of 2b
Wave number (cm-1)
Group Assignment
3455
N-H Str
3163
C-H Str Aromatic
2958
C-H Str Aliphatic
1645
C=O Str
1029
C-O-C Str
749
C-Cl Str
55
EXPERIMENTAL
Figure 10.
NMR Spectrum of 2-(3-chloropropoxy) benzamide (2b)
Table 10.
1
H NMR Data of 2b
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.92-2.21
2
CH2
3.31
2
CH2Cl
4.21
2
OCH2
7.0-7.48
4
Aromatic
7.80
2
CONH2
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EXPERIMENTAL
Figure 11.
IR Spectrum of 2-(4-bromobutoxy) benzamide (2c)
O
NH2
CH2CH2CH2CH2Br
O
Table 11. IR Data of 2c
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3455
N-H Str
3159
C-H Str Aromatic
2981
C-H Str Aliphatic
1657
C=O Str
1029
C-O-C Str
748
C-Br Str
57
EXPERIMENTAL
Figure 12.
Table 12.
NMR Spectrum of 2-(4-Bromobutoxy) benzamide (2c)
1
H NMR Data of 2c
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.92-2.51
4
CH2CH2
3.36
2
CH2Br
4.21
2
OCH2
7.0-7.51
4
Aromatic
7.80
2
CONH2
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EXPERIMENTAL
Figure 13.
IR Spectrum of 2-[2-(4-phenylpiperazin-1-yl) ethoxy] benzamide (3a1)
O
NH2
N
N
O
Table 13. IR Data of 3a1
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
3165
C-H Str Aromatic
2952
C-H Str Aliphatic
1644
C=O Str
1391
C-N Str Aromatic
1231
C-N Str Aliphatic
1033
C-O-C Str
59
EXPERIMENTAL
Figure 14.
NMR Spectrum of 3a1
Table 14.
1
H NMR Data of 3a1
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.48-2.85
2
CH2N
3.01-3.51
8
Piperazine
4.15
2
OCH2
6.73-7.48
9
Aromatic
7.82
2
CONH2
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EXPERIMENTAL
Figure 15.
Mass Spectrum of 3a1
Mass Data
MS (EI) m/z: 326.10(M+1).
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EXPERIMENTAL
Figure 16.
IR Spectrum of 2-{2-[4-(3-methylphenyl) piperazin-1-yl] ethoxy}
benzamide (3a2)
O
NH2
N
CH3
N
O
Table 15. IR Data of 3a2
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3458
N-H Str
3163
C-H Str Aromatic
2889
C-H Str Aliphatic
1648
C=O Str
1390
C-N Str Aromatic
1228
C-N Str Aliphatic
1033
C-O-C Str
62
EXPERIMENTAL
Figure 17.
NMR spectrum of 3a2
Table 16.
1
H NMR Data of 3a2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.31
3
CH3
2.48-2.85
2
CH2N
3.02-3.51
8
Piperazine
4.15
2
OCH2
6.73-7.48
8
Aromatic
7.82
2
CONH2
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EXPERIMENTAL
Figure 18.
IR Spectrum of 2-{2-[4-(4-methylphenyl) piperazin-1-yl] ethoxy}
benzamide (3a3)
CH3
O
NH2
N
N
O
Table 17. IR Data of 3a3
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3389
N-H Str
3188
C-H Str Aromatic
2885
C-H Str Aliphatic
1643
C=O Str
1390
C-N Str Aromatic
1238
C-N Str Aliphatic
1035
C-O-C Str
64
EXPERIMENTAL
Figure 19. NMR Spectrum of 3a3
Table 18.
1
H NMR Data of 3a3
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.32
3
CH3
2.65-2.68
2
CH2N
3.10-3.55
8
Piperazine
4.15
2
OCH2
6.65-7.37
8
Aromatic
7.80
2
CONH2
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EXPERIMENTAL
Figure 20.
IR Spectrum of 2-{2-[4-(2-methoxyphenyl) piperazin-1-yl] ethoxy}
benzamide (3a4)
O
NH2
N
N
OCH3
O
Table 19. IR Data of 3a4
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3377
N-H Str
3177
C-H Str Aromatic
2883
C-H Str Aliphatic
1641
C=O Str
1400
C-N Str Aromatic
1237
C-N Str Aliphatic
1023
C-O-C Str
66
EXPERIMENTAL
Figure 21. NMR Spectrum of 3a4
Table 20.
1
H NMR Data of 3a4
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.48-2.97
2
CH2N
3.00-3.59
8
Piperazine
3.97
3
OCH3
4.15
2
OCH2
6.65-7.32
8
Aromatic
7.82
2
CONH2
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EXPERIMENTAL
Figure 22.
IR Spectrum of 2-{2-[4-(3-methoxyphenyl) piperazin-1-yl] ethoxy}
benzamide (3a5)
O
NH2
N
OCH3
N
O
Table 21. IR Data of 3a5
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3392
N-H Str
3193
C-H Str Aromatic
2875
C-H Str Aliphatic
1638
C=O Str
1393
C-N Str Aromatic
1235
C-N Str Aliphatic
1047
C-O-C Str
68
EXPERIMENTAL
Figure 23. NMR Spectrum of 3a5
Table 22.
1
H NMR Data of 3a5
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.55-2.98
2
CH2N
3.01-3.54
8
Piperazine
3.94
3
OCH3
4.15
2
OCH2
6.83-7.58
8
Aromatic
7.80
2
CONH2
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EXPERIMENTAL
Figure 24.
IR Spectrum of 2-{2-[4-(2-chlorophenyl) piperazin-1-yl] ethoxy}
benzamide (3a6)
O
NH2
N
N
Cl
O
Table 23. IR Data of 3a6
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
3162
C-H Str Aromatic
2887
C-H Str Aliphatic
1644
C=O Str
1389
C-N Str Aromatic
1229
C-N Str Aliphatic
1033
C-O-C Str
70
EXPERIMENTAL
Figure 25. NMR Spectrum of 3a6
Table 24.
1
H NMR Data of 3a6
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.47-2.97
2
CH2N
3.00-3.59
8
Piperazine
4.15
2
OCH2
6.67-7.37
8
Aromatic
7.82
2
CONH2
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EXPERIMENTAL
Figure 26.
IR Spectrum of 2-[3-(4-phenylpiperazin-1-yl) propoxy] benzamide 3b1
O
NH2
CH2CH2CH2
N
N
O
Table 25. IR Data of 3b1
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3375
N-H Str
3176
C-H Str Aromatic
2931
C-H Str Aliphatic
1648
C=O Str
1390
C-N Str Aromatic
1238
C-N Str Aliphatic
1035
C-O-C Str
72
EXPERIMENTAL
Figure 27. NMR Spectrum of 3b1
Table 26.
1
H NMR Data of 3b1
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.92-1.95
2
CH2
2.21-2.97
2
CH2N
3.00-3.59
8
Piperazine
4.12
2
OCH2
6.84-7.30
9
Aromatic
7.82
2
CONH2
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EXPERIMENTAL
Figure 28.
IR Spectrum of 2-{3-[4-(2-methoxyphenyl) piperazin-1-yl] propoxy}
benzamide (3b2)
Table 27. IR Data of 3b2
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3375
N-H Str
3176
C-H Str Aromatic
2931
C-H Str Aliphatic
1648
C=O Str
1390
C-N Str Aromatic
1238
C-N Str Aliphatic
1035
C-O-C Str
74
EXPERIMENTAL
Figure 29.
NMR Spectrum of 3b2
Table 28.
1
H NMR Data of 3b2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.92
2
CH2
2.35-2.97
2
CH2N
3.00-3.59
8
Piperazine
3.97
3
OCH3
4.12
2
OCH2
6.57-7.32
8
Aromatic
7.81
2
CONH2
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EXPERIMENTAL
Figure 30.
IR Spectrum of 2-[4-(4-phenylpiperazin-1-yl) butoxy] benzamide (3c1)
O
NH2
N
N
O
Table 29. IR Data of 3c1
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
3162
C-H Str Aromatic
2968
C-H Str Aliphatic
1641
C=O Str
1389
C-N Str Aromatic
1229
C-N Str Aliphatic
1033
C-O-C Str
76
EXPERIMENTAL
Figure 31.
NMR Spectrum of 3c1
Table 30.
1
H NMR Data of 3c1
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.20-1.28
4
CH2CH2
2.68-2.71
2
CH2N
3.09-3.48
8
Piperazine
4.10
2
OCH2
6.85-7.45
9
Aromatic
7.81
2
CONH2
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EXPERIMENTAL
Figure 32.
IR Spectrum of 2-{4-[4-(2-methoxyphenyl) piperazine-1-yl] butoxy}
benzamide (3c2)
O
NH2
N
N
OCH3
O
Table 31. IR Data of 3c2
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
3162
C-H Str Aromatic
2968
C-H Str Aliphatic
1641
C=O Str
1389
C-N Str Aromatic
1229
C-N Str Aliphatic
1033
C-O-C Str
78
EXPERIMENTAL
Figure 33.
NMR Spectrum of 3c2
Table 32.
1
H NMR Data of 3c2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.24-1.28
4
CH2CH2
2.68-2.71
2
CH2N
3.09-3.48
8
Piperazine
3.86
3
OCH3
4.10
2
OCH2
6.85-7.45
8
Aromatic
7.81
2
CONH2
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EXPERIMENTAL
Series B
Synthesis of 2–[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides
Step I.
Synthesis of 2-chloro-N, N-diphenylacetamide (2)
NH
ClCOCH2Cl
N
COCH2Cl
i
(2)
(1)
Scheme 2. Reagents and conditions :( i) Toluene, Reflux, 4h.
Procedure
Diphenylamine 1 (6.76 g, 0.04 mol) was dissolved in 200 of toluene in a 250 ml round
bottom flask and chloroacetylchloride (3.18 ml, 0.04 mol) was added. The reaction mixture
was refluxed for 4 hrs. 400 ml of water was then added to the reaction mixture and kept
overnight for precipitation of the product. The precipitate was filtered, washed with water,
dried and recrystallized from ethanol to afford 2 (Shao et al., 2009).
The physical parameters were of the compound
Yield
:
7.21 g
Percentage yield
:
73.49%
Melting range
:
116-118oC
Rf value
:
0.44
Mobile phase
:
ethyl acetate: hexane (1: 5)
Molecular formula
:
C14H12ClNO
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EXPERIMENTAL
Step II.
Synthesis of final compounds (3a-j)
N
COCH2Cl
(2)
R
HN
i
N
R
N
COCH2
N
N
(3a-j)
Scheme 2. Synthesis of the target compounds. Reagents and conditions :( i) Acetonitrile,
K2CO3, KI, Reflux.
Table 33.
Substituent of compounds
Compound
R
3a
H
3b
4-CH3
3c
2, 3-(CH3)2
3d
3-CF3
3e
2-OCH3
3f
3-OCH3
3g
3-Cl
3h
3, 4-(Cl)2
3i
4-F
3j
4-NO2
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EXPERIMENTAL
General procedure
2-Chloro-N, N-diphenylacetamide 2 (1.22 g, 0.005mol) was dissolved in 100ml of
acetonitrile in a 250 ml round bottom flask, anhydrous potassium carbonate (0.69g, 0.005
mol), catalytic amount of potassium iodide and appropriate arylpiperazine (0.005 mol) were
added into above solution. The above mixture was allowed to reflux with continuous stirring
on magnetic stirrer for 10 h. After completion of reaction the solvent was removed by vacuum
distillation and residue was dissolved in 1:1 mixture of chloroform and water. The organic
layer was separated, washed with brine and dried over sodium sulphate. Removal of the
solvent afforded target compounds (3a-j). The final compounds were recrystallized from
ethanol.
The physical parameters were of the synthesized compounds
2-[4-(Phenyl) piperazin-1-yl] N, N-diphenylacetamide (3a)
Yield
:
1.40 g
Percentage yield
:
76.0%
Melting range
:
125-127oC
Rf value
:
0.34
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C24H25N3O
2-[4-(4-Methylphenyl) piperazin-1-yl] N, N- diphenylacetamide (3b)
Yield
:
1.38 g
Percentage yield
:
72.25%
Melting range
:
86-88oC
Rf value
:
0.28
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C25H27N3O
2-[4-(2, 3-Dimethylphenyl) piperazin-1-yl] N, N-diphenylacetamide (3c)
Yield
:
1.2 g
Percentage yield
:
60.60%
Melting range
:
107-109oC
Rf value
:
0.26
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EXPERIMENTAL
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C26H29N3O
2-[4-(3-Trifluoromethylphenyl) piperazin-1-yl] N, N-diphenylacetamide (3d)
Yield
:
1.26 g
Percentage yield
:
57.79%
Melting range
:
60-62oC
Rf value
:
0.27
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C25H24F3N3O
2-[4-(2-Methoxyphenyl) piperazin-1-yl] N, N -diphenylacetamide (3e)
Yield
:
0.82g
Percentage yield
:
41.20%
Melting range
:
79-81oC
Rf value
:
0.22
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C25H27N3O2
Log P (Experimental)
:
3.87
2-[4-(3-Methoxyphenyl) piperazin-1-yl] N, N -diphenylacetamide (3f)
Yield
:
0.92 g
Percentage yield
:
46.23%
Melting range
:
110-112oC
Rf value
:
0.24
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C25H27N3O2
2-[4-(3-Chlorophenyl) piperazin-1-yl] N, N -diphenylacetamide (3g)
Yield
:
1.14 g
Percentage yield
:
56.71%
Melting range
:
102-104oC
Rf value
:
0.32
Mobile phase
:
hexane: ethyl acetate (2:1)
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EXPERIMENTAL
Molecular formula
:
C24H24ClN3O
2-[4-(3, 4-Dichlorophenyl) piperazin-1-yl] N, N -diphenylacetamide (3h)
Yield
:
1.13 g
Percentage yield
:
51.83%
Melting range
:
80-82oC
Rf value
:
0.29
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C24H23Cl2N3O
2-[4-(4-Fluorophenyl) piperazin-1-yl] N, N -diphenylacetamide (3i)
Yield
:
0.60 g
Percentage yield
:
62.5%
Melting range
:
96-98oC
Rf value
:
0.21
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C24H24FN3O
2-[4-(4-Nitrophenyl) piperazin-1-yl] N, N -diphenylacetamide (3j)
Yield
:
0.97 g
Percentage yield
:
47.08 %
Melting range
:
134-136oC
Rf value
:
0.30
Mobile phase
:
hexane: ethyl acetate (2:1)
Molecular formula
:
C24H24N4O3
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EXPERIMENTAL
Figure 34.
IR Spectrum of 2-chloro-N, N-diphenylacetamide (2)
N
C
H2
C
Cl
O
Table 34. IR Data of 2
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3005
C-H Str Aromatic
2942
C-H Str Aliphatic
1678
C=O Str
1364
C-N Str Aromatic
1263
C-N Str Aliphatic
695
C-Cl Str
85
EXPERIMENTAL
Figure 35.
NMR Spectrum of 2-chloro-N, N-diphenylacetamide (2)
Table 35.
1
H NMR Data of 2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
4.02
2
CH2
7.26-7.39
10
Aromatic
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EXPERIMENTAL
Figure 36.
IR Spectrum of 2-[4-(phenyl) piperazin-1-yl] N, N-diphenylacetamide (3a)
N
COCH2
N
N
Table 36. IR Data of 3a
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3056
C-H Str Aromatic
2826
C-H Str Aliphatic
1673
C=O Str
1448
C-N Str Aromatic
1237
C-N Str Aliphatic
87
EXPERIMENTAL
Figure 37.
NMR Spectrum of 3a
Table 37.
1
H NMR Data of 3a
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.64-2.67
4
Piperazine
3.15-3.66
4
Piperazine
4.56
2
COCH2
6.80-7.54
15
Aromatic
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EXPERIMENTAL
Figure 38
Mass Spectrum of 3a
Mass Data:
MS (EI) m/z: 372.23 (M+1).
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EXPERIMENTAL
Figure 39.
IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl] N, N- diphenyl
acetamide (3b)
N
COCH2
N
N
CH3
Table 38. IR Data of 3b
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3014
C-H Str Aromatic
2826
C-H Str Aliphatic
1674
C=O Str
1453
C-N Str Aromatic
1218
C-N Str Aliphatic
90
EXPERIMENTAL
Figure 40.
NMR Spectrum of 3b
Table 39.
1
H NMR Data of 3b
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.25
3
CH3
2.69-2.97
4
Piperazine
3.12-3.77
4
Piperazine
4.47
2
COCH2
6.71-7.48
14
Aromatic
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EXPERIMENTAL
Figure 41.
IR Spectrum of 2-[4-(2, 3-dimethylphenyl) piperazin-1-yl] N, N-diphenyl
acetamide (3c)
H3C
N
COCH2
N
CH3
N
Table 40. IR Data of 3c
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3012
C-H Str Aromatic
2820
C-H Str Aliphatic
1675
C=O Str
1490
C-N Str Aromatic
1219
C-N Str Aliphatic
92
EXPERIMENTAL
Figure 42.
NMR Spectrum of 3c
Table 41.
1
H NMR Data of 3c
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.18
3
CH3
2.24
3
CH3
2.35-2.94
4
Piperazine
3.05-3.97
4
Piperazine
4.57
2
COCH2
6.87-7.56
14
Aromatic
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EXPERIMENTAL
Figure 43.
IR Spectrum of 2-[4-(3-trifluoromethylphenyl) piperazin-1-yl] N, Ndiphenylacetamide (3d)
CF3
N
COCH2
N
N
Table 42. IR Data of 3d
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3016
C-H Str Aromatic
2828
C-H Str Aliphatic
1674
C=O Str
1490
C-N Str Aromatic
1218
C-N Str Aliphatic
94
EXPERIMENTAL
Figure 44.
NMR Spectrum of 3d
Table 43.
1
H NMR Data of 3d
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.64-2.67
4
Piperazine
3.15-3.66
4
Piperazine
4.56
2
COCH2
6.80-7.35
14
Aromatic
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EXPERIMENTAL
Figure 45.
IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl] N, N –diphenyl
acetamide (3e)
H3CO
N
COCH2
N
N
Table 44. IR Data of 3e
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3083
C-H Str Aromatic
2822
C-H Str Aliphatic
1685
C=O Str
1493
C-N Str Aromatic
1218
C-N Str Aliphatic
96
EXPERIMENTAL
Figure 46.
Table 45.
NMR Spectrum of 3e
1
H NMR Data of 3e
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.64-2.68
4
Piperazine
3.15-3.20
4
Piperazine
3.78
3
CH3
4.57
2
COCH2
6.39-7.37
14
Aromatic
Shobhit University Meerut
97
EXPERIMENTAL
Figure 47.
IR Spectrum of 2-[4-(3-methoxyphenyl) piperazin-1-yl] N, N –diphenyl
acetamide (3f)
OCH3
COCH2
N
N
N
Table 46. IR Data of 3f
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3083
C-H Str Aromatic
2822
C-H Str Aliphatic
1685
C=O Str
1493
C-N Str Aromatic
1218
C-N Str Aliphatic
98
EXPERIMENTAL
Figure 48.
NMR Spectrum of 3f
Table 47.
1
H NMR Data of 3f
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.32-2.78
4
Piperazine
3.10-3.22
4
Piperazine
3.77
3
OCH3
4.57
2
COCH2
6.39-7.37
14
Aromatic
Shobhit University Meerut
99
EXPERIMENTAL
Figure 49. IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl] N, N –diphenyl
acetamide (3g)
Cl
COCH2
N
N
N
Table 48. IR Data of 3g
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3016
C-H Str Aromatic
2828
C-H Str Aliphatic
1674
C=O Str
1490
C-N Str Aromatic
1218
C-N Str Aliphatic
100
EXPERIMENTAL
Figure 50. NMR Spectrum of 3g
Table 49.
1
H NMR Data of 3g
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.63-2.66
4
Piperazine
3.15-3.50
4
Piperazine
4.54
2
COCH2
6.73-7.36
14
Aromatic
Shobhit University Meerut
101
EXPERIMENTAL
Figure 51.
IR Spectrum of 2-[4-(3, 4-dichlorophenyl) piperazin-1-yl] N, N –diphenyl
acetamide (3h)
Cl
COCH2
N
N
Cl
N
Table 50. IR Data of 3h
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3016
C-H Str Aromatic
2829
C-H Str Aliphatic
1675
C=O Str
1480
C-N Str Aromatic
1219
C-N Str Aliphatic
102
EXPERIMENTAL
Figure 52.
NMR Spectrum of 3h
Table 51.
1
H NMR Data of 3h
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.06-2.93
4
Piperazine
3.14-3.53
4
Piperazine
4.47
2
COCH2
6.68-7.48
14
Aromatic
Shobhit University Meerut
103
EXPERIMENTAL
Figure 53.
IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl] N, N –diphenyl
acetamide (3i)
COCH2
N
N
F
N
Table 52. IR Data of 3i
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3021
C-H Str Aromatic
2840
C-H Str Aliphatic
1674
C=O Str
1480
C-N Str Aromatic
1217
C-N Str Aliphatic
104
EXPERIMENTAL
Figure 54.
NMR Spectrum of 3i
Table 53.
1
H NMR Data of 3i
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.68-2.71
4
Piperazine
3.09-3.48
4
Piperazine
4.54
2
COCH2
6.67-7.48
14
Aromatic
Shobhit University Meerut
105
EXPERIMENTAL
Figure 55.
IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl] N, N –diphenyl
acetamide (3j)
COCH2
N
N
NO2
N
Table 54. IR Data of 3j
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3020
C-H Str Aromatic
2848
C-H Str Aliphatic
1673
C=O Str
1496
C-N Str Aromatic
1217
C-N Str Aliphatic
106
EXPERIMENTAL
Figure 56.
NMR Spectrum of 3j
Table 55.
1
H NMR Data of 3j
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.68-2.71
4
Piperazine
3.19-3.43
4
Piperazine
4.58
2
COCH2
6.76-8.17
14
Aromatic
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EXPERIMENTAL
Series C
Synthesis of 2-[4-(aryl substituted) piperazin-1-yl]-N-phenylacetamides
Step I.
Synthesis of 2-chloro-N-phenylacetamide (2)
NH2
HN
COCH2Cl
i
ClCOCH2Cl
(1)
(2)
Scheme 3. Reagents and conditions: (i) NaOH, Dichloromethane, 0oC temperature.
Procedure
Aniline 1 (3.65 ml, 0.04 mol) in 2N aqueous sodium hydroxide (150 ml) at 0oC
temperature was treated with chloroacetylchloride (3.18 ml, 0.04 mol) as a solution in
dichloromethane (100 ml). After 1hr, the layers were separated and the aqueous phase was
extracted with additional portion of dichloromethane. The organic phases were combined,
washed with an aqueous solution of 1N hydrochloric acid, saturated sodium bicarbonate, and
dried over sodium sulphate. Removal of the solvent afforded compound 2.
The physical parameters were of the synthesized compound
Yield
:
4.51 g
Percentage yield
:
68.12%
Melting range
:
130-132oC
Rf value
:
0.93
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C8H8ClNO
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EXPERIMENTAL
Step II.
Synthesis of final compounds
HN
COCH2Cl
(2)
R
HN
i
N
R
HN
COCH2
N
N
(3a-j)
Scheme 3. Synthesis of the target compounds. Reagents and conditions: (i) Acetonitrile,
K2CO3, KI, Reflux.
Table 56.
Substituent of compounds
Compound
R
3a
H
3b
3-CH3
3c
4-CH3
3d
2-OCH3
3e
3-OCH3
3f
4-OCH3
3g
2-Cl
3h
3-Cl
3i
4-F
3j
4-NO2
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EXPERIMENTAL
General procedure
2-chloro-N-phenylacetamide 2 (0.84 g, 0.005mol) was dissolved in 100 ml of
acetonitrile in a 250 ml Round bottom flask. Anhydrous K2CO3 (0.69g, 0.005 mol), catalytic
amount of potassium iodide and appropriate arylpiperazine (0.005 mol) were added into
above solution. The above mixture was allowed to reflux with continuous stirring on magnetic
stirrer for 12 h. After completion of reaction the solvent was removed by vacuum distillation
and residue was dissolved in chloroform and water. The organic layer was washed with brine
and dried over sodium sulphate removal of the solvent under vacuum afforded the crude
products which were recrystallized from ethanol to afford 3a-j.
The physical parameters were of the synthesized compounds
2-[4-(Phenyl) piperazin-1-yl]-N-phenylacetamide (3a)
Yield
:
0.90 g
Percentage yield
:
61.64 %
Melting range
:
124-125oC
Rf value
:
0.65
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H21N3O
2-[4-(3-Methylphenyl) piperazin-1-yl]-N-phenylacetamide (3b)
Yield
:
0.95 g
Percentage yield
:
62.09 %
Melting range
:
92-94oC
Rf value
:
0.52
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H23N3O
2-[4-(4-Methylphenyl) piperazin-1-yl]-N-phenylacetamide (3c)
Yield
:
0.84 g
Percentage yield
:
54.90 %
Melting range
:
109-111oC
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EXPERIMENTAL
Rf value
:
0.50
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H23N3O
2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N-phenylacetamide (3d)
Yield
:
0.60 g
Percentage yield
:
37.26%
Melting range
:
119-120oC
Rf value
:
0.54
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H23N3O2
2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N-phenylacetamide (3e)
Yield
:
0.64 g
Percentage yield
:
39.75 %
Melting range
:
86-88oC
Rf value
:
0.58
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H23N3O2
2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N-phenylacetamide (3f)
Yield
:
0.70 g
Percentage yield
:
43.47%
Melting range
:
95-98oC
Rf value
:
0.40
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H23N3O2
2-[4-(2-Chlorophenyl) piperazin-1-yl]-N-phenylacetamide (3g)
Yield
:
0.87 g
Percentage yield
:
53.37%
Melting range
:
126-127oC
Rf value
:
0.63
Mobile phase
:
hexane: ethyl acetate (1:1)
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EXPERIMENTAL
Molecular formula
:
C18H20ClN3O
2-[4-(3-Chlorophenyl) piperazin-1-yl]-N-phenylacetamide (3h)
Yield
:
0.91 g
Percentage yield
:
55.82%
Melting range
:
104-105oC
Rf value
:
0.60
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H20ClN3O
Log P (Experimental)
:
2.91
2-[4-(4-Fluorophenyl) piperazin-1-yl]-N-phenylacetamide (3i)
Yield
:
0.90 g
Percentage yield
:
58.06%
Melting range
:
106-107oC
Rf value
:
0.53
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H20FN3O
2-[4-(4-Nitrophenyl) piperazin-1-yl]-N-phenylacetamide (3j)
Yield
:
0.95 g
Percentage yield
:
56.54%
Melting range
:
168-169oC
Rf value
:
0.57
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H20N4O3
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EXPERIMENTAL
Figure 57.
IR Spectrum of 2-chloro-N-phenylacetamide (2)
HN
COCH2Cl
Table 57. IR Data of 2
Wave number (cm-1)
Group Assignment
3311
N-H Str
3021
C-H Str Aromatic
2862
C-H Str Aliphatic
1681
C=O Str
1217
C-N Str
670
Shobhit University Meerut
C-Cl Str
113
EXPERIMENTAL
Figure 58.
NMR Spectrum of 2-chloro-N-phenylacetamide (2)
Table 58.
1
H NMR Data of 2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
4.19
2
CH2
7.11-7.53
5
Aromatic
8.24
1
NH
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EXPERIMENTAL
Figure 59.
IR Spectrum of 2-[4-(phenyl) piperazin-1-yl]-N-phenylacetamide (3a)
O
N
N
N
H
Table 59. IR Data of 3a
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3311
N-H Str
3013
C-H Str Aromatic
2829
C-H Str Aliphatic
1683
C=O Str
1384
C-N Str Aromatic
1238
C-N Str Aliphatic
115
EXPERIMENTAL
Figure 60.
NMR Spectrum of 3a
Table 60.
1
H NMR Data of 3a
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.65-2.98
4
Piperazine
3.11-3.34
4
Piperazine
4.50
2
CH2
6.83-7.58
10
Aromatic
9.10
1
NH
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EXPERIMENTAL
Figure 61.
Mass Spectrum of 3a
Mass Data
MS (EI) m/z: 296.3 (M+1).
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117
EXPERIMENTAL
Figure 62. IR Spectrum of 2-[4-(3-methylphenyl) piperazin-1-yl]-N-phenylacetamide
(3b)
O
N
CH3
N
N
H
Table 61. IR Data of 3b
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3450
N-H Str
2930
C-H Str Aromatic
2825
C-H Str Aliphatic
1681
C=O Str
1382
C-N Str Aromatic
1238
C-N Str Aliphatic
118
EXPERIMENTAL
Figure 63.
NMR Spectrum of 3b
Table 62.
1
H NMR Data of 3b
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.29
3
CH3
2.78-2.81
4
Piperazine
3.21-3.23
4
Piperazine
4.51
2
CH2
6.85-7.59
9
Aromatic
9.14
1
NH
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EXPERIMENTAL
Figure 64. IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl]-N-phenylacetamide
(3c)
CH3
O
N
N
N
H
Table 63. IR Data of 3c
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3450
N-H Str
2920
C-H Str Aromatic
2825
C-H Str Aliphatic
1681
C=O Str
1382
C-N Str Aromatic
1238
C-N Str Aliphatic
120
EXPERIMENTAL
Figure 65.
NMR Spectrum of 3c
Table 64.
1
H NMR Data of 3c
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.28
3
CH3
2.79-2.82
4
Piperazine
3.11-3.32
4
Piperazine
4.55
2
CH2
6.80-7.74
9
Aromatic
9.15
1
NH
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121
EXPERIMENTAL
Figure 66.
IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl]-N-phenyl
acetamide (3d)
O
N
N
OCH3
N
H
Table 65. IR Data of 3d
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3271
N-H Str
3013
C-H Str Aromatic
2831
C-H Str Aliphatic
1668
C=O Str
1382
C-N Str Aromatic
1237
C-N Str Aliphatic
122
EXPERIMENTAL
Figure 67.
NMR Spectrum of 3d
Table 66.
1
H NMR Data of 3d
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.83-2.98
4
Piperazine
3.15-3.31
4
Piperazine
3.87
3
OCH3
4.55
2
CH2
6.87-7.60
9
Aromatic
9.19
1
NH
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123
EXPERIMENTAL
Figure 68.
IR Spectrum of 2-[4-(3-methoxyphenyl) piperazin-1-yl]-N-phenyl
acetamide (3e)
O
N
OCH3
N
N
H
Table 67. IR Data of 3e
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3271
N-H Str
3013
C-H Str Aromatic
2831
C-H Str Aliphatic
1668
C=O Str
1382
C-N Str Aromatic
1237
C-N Str Aliphatic
124
EXPERIMENTAL
Figure 69.
NMR Spectrum of 3e
Table 68.
1
H NMR Data of 3e
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.83-2.98
4
Piperazine
3.15-3.31
4
Piperazine
3.87
3
OCH3
4.55
2
CH2
6.87-7.60
9
Aromatic
9.19
1
NH
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EXPERIMENTAL
Figure 70.
IR Spectrum of 2-[4-(4-methoxyphenyl) piperazin-1-yl]-N-phenyl
acetamide (3f)
OCH3
O
N
N
N
H
Table 69. IR Data of 3f
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3271
N-H Str
3013
C-H Str Aromatic
2831
C-H Str Aliphatic
1668
C=O Str
1382
C-N Str Aromatic
1237
C-N Str Aliphatic
126
EXPERIMENTAL
Figure 71.
NMR Spectrum of 3f
Table 70.
1
H NMR Data of 3f
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.18-2.94
4
Piperazine
3.23-3.37
4
Piperazine
3.78
3
OCH3
4.52
2
CH2
6.58-7.75
9
Aromatic
9.28
1
NH
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EXPERIMENTAL
Figure 72. IR Spectrum of 2-[4-(2-chlorophenyl) piperazin-1-yl]-N-phenylacetamide
(3g)
O
N
N
Cl
N
H
Table 71. IR Data of 3g
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3311
N-H Str
3013
C-H Str Aromatic
2829
C-H Str Aliphatic
1683
C=O Str
1384
C-N Str Aromatic
1238
C-N Str Aliphatic
128
EXPERIMENTAL
Figure 73.
NMR Spectrum of 3g
Table 72.
1
H NMR Data of 3g
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.64-2.82
4
Piperazine
3.37-3.59
4
Piperazine
4.22
2
CH2
6.56-7.60
9
Aromatic
10.55
1
NH
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EXPERIMENTAL
Figure 74. IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl]-N-phenylacetamide
(3h)
O
N
Cl
N
N
H
Table 73. IR Data of 3h
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3311
N-H Str
3013
C-H Str Aromatic
2829
C-H Str Aliphatic
1683
C=O Str
1384
C-N Str Aromatic
1238
C-N Str Aliphatic
130
EXPERIMENTAL
Figure 75.
NMR Spectrum of 3h
Table 74.
1
H NMR Data of 3h
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.77-2.80
4
Piperazine
3.21-3.29
4
Piperazine
4.55
2
CH2
6.79-7.59
9
Aromatic
9.08
1
NH
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EXPERIMENTAL
Figure 76.
IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl]-N-phenyl acetamide
(3i)
F
O
N
N
N
H
Table 75. IR Data of 3i
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3307
N-H Str
3016
C-H Str Aromatic
2829
C-H Str Aliphatic
1682
C=O Str
1383
C-N Str Aromatic
1219
C-N Str Aliphatic
132
EXPERIMENTAL
Figure 77.
NMR Spectrum of 3i
Table 76.
1
H NMR Data of 3i
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.63-2.83
4
Piperazine
3.18-3.32
4
Piperazine
4.52
2
CH2
6.88-7.74
9
Aromatic
9.12
1
NH
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EXPERIMENTAL
Figure 78. IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl]-N-phenylacetamide (3j)
NO2
O
N
N
N
H
Table 77. IR Data of 3j
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3307
N-H Str
3016
C-H Str Aromatic
2829
C-H Str Aliphatic
1682
C=O Str
1383
C-N Str Aromatic
1219
C-N Str Aliphatic
134
EXPERIMENTAL
Figure 79.
NMR Spectrum of 3j
Table 78.
1
H NMR Data of 3j
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.59-2.82
4
Piperazine
3.48-3.52
4
Piperazine
4.55
2
CH2
6.75-8.16
9
Aromatic
9.08
1
NH
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EXPERIMENTAL
Series D
Synthesis of 2-[4-(aryl substituted) piperazin-1-yl]-N-benzylacetamides
Step I.
Synthesis of 2-chloro-N-benzylacetamide (2)
CH2NH2
CH2NHCOCH2Cl
i
ClCOCH2Cl
(1)
(2)
Scheme 4. Reagents and conditions: (i) NaOH, Dichloromethane, 0oC temperature.
Procedure
Benzylamine 1 (4.37 ml, 0.04 mol) in 2N aqueous sodium hydroxide (150 ml) at 0 oC
temperature was treated with chloroacetylchloride (3.18 ml, 0.04 mol) as a solution in
dichloromethane (100 ml). After 1h, the layers were separated and the aqueous phase was
extracted with additional portion of dichloromethane. The organic phases were combined,
washed with an aqueous solution of 1N hydrochloric acid, saturated sodium bicarbonate dried
over sodium sulphate. Removal of the solvent afforded compound 2.
The physical parameters were of synthesized compound
Yield
:
5.5 g
Percentage yield
:
75.73 %
Melting range
:
94-96oC
Rf value
:
0.72
Mobile phase
:
hexane: ethyl acetate (1: 1)
Molecular formula
:
C9H10ClNO
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EXPERIMENTAL
Step II.
Synthesis of final compounds
CH2NHCOCH2Cl
(2)
R
HN
i
N
R
CH2NHCOCH2
N
N
(3a-j)
Scheme 4. Synthesis of the target compounds. Reagents and conditions: (i) Acetonitrile,
K2CO3, KI, Reflux.
Table 79.
Substituent of compounds
Compound
R
3a
H
3b
2-OCH3
3c
3-OCH3
3d
4-OCH3
3e
3-CH3
3f
4-CH3
3g
2-Cl
3h
3-Cl
3i
4-NO2
3j
4-F
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EXPERIMENTAL
General procedure
2-Chloro-N-benzylacetamide 2 (0.91 g, 0.005 mol) was dissolved in 100 ml of
acetonitrile in a 250 ml Round bottom flask. Anhydrous K2CO3 (0.69 g, 0.005 mol), catalytic
amount of potassium iodide and appropriate arylpiperazine (0.005 mol) were added into
above solution. The above mixture was allowed to reflux with continuous stirring on magnetic
stirrer for 12 h. After completion of reaction the solvent was removed by vacuum distillation
and residue was dissolved in chloroform and water. The organic layer was washed with brine
and dried over sodium sulphate. Removal of the solvent under vacuum afforded the crude
products which were recrystallized from ethanol to afford 3a-j.
The physical parameters were
2-[4-(Phenyl) piperazin-1-yl]-N-benzylacetamide (3a)
Yield
:
0.80 g
Percentage yield
:
52.18 %
Melting range
:
97-100oC
Rf value
:
0.38
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H23N3O
2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3b)
Yield
:
0.72 g
Percentage yield
:
42.85 %
Melting range
:
85-88oC
Rf value
:
0.28
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C20H25N3O2
Log P (Experimental)
:
2.34
2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3c)
Yield
:
0.74 g
Percentage yield
:
44.04 %
Melting range
:
82-85oC
Rf value
:
0.46
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EXPERIMENTAL
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C20H25N3O2
2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3d)
Yield
:
0.62 g
Percentage yield
:
36.90 %
Melting range
:
70-75oC
Rf value
:
0.47
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C20H25N3O2
2-[4-(3-Methylphenyl) piperazin-1-yl]-N-benzylacetamide (3e)
Yield
:
0.80 g
Percentage yield
:
50.0 %
Melting range
:
126-128oC
Rf value
:
0.30
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C20H25N3O
2-[4-(4-Methylphenyl) piperazin-1-yl]-N-benzylacetamide (3f)
Yield
:
0.85 g
Percentage yield
:
53.21 %
Melting range
:
89-91oC
Rf value
:
0.30
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C20H25N3O
2-[4-(2-Chlorophenyl) piperazin-1-yl]-N-benzylacetamide (3g)
Yield
:
0.98 g
Percentage yield
:
56.32 %
Melting range
:
153-155oC
Rf value
:
0.26
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H22ClN3O
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EXPERIMENTAL
2-[4-(3-Chlorophenyl) piperazin-1-yl]-N-benzylacetamide (3h)
Yield
:
0.90 g
Percentage yield
:
52.94 %
Melting range
:
77-80oC
Rf value
:
0.48
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H22ClN3O
2-[4-(4-Nitrophenyl) piperazin-1-yl]-N-benzylacetamide (3i)
Yield
:
1.10 g
Percentage yield
:
62.85 %
Melting range
:
156-158oC
Rf value
:
0.22
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H22N4O3
2-[4-(4-Fluorophenyl) piperazin-1-yl]-N-phenylacetamide (3j)
Yield
:
0.82 g
Percentage yield
:
50.61 %
Melting range
:
123-125oC
Rf value
:
0.20
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H20FN3O
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EXPERIMENTAL
Figure 80.
IR Spectrum of 2-chloro-N-benzylacetamide (2)
CH2NHCOCH2Cl
Table 80. IR Data of 2
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3268
N-H Str
3017
C-H Str Aromatic
2945
C-H Str Aliphatic
1669
C=O Str
1220
C-N Str
699
C-Cl Str
141
EXPERIMENTAL
Figure 81.
NMR Spectrum of 2-chloro-N-benzylacetamide (2)
Table 81.
1
H NMR Data of 2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
4.11
2
COCH2
4.49-4.51
2
CH2
6.88
1
NH
7.26-7.39
5
Aromatic
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EXPERIMENTAL
Figure 82. IR Spectrum of 2-[4-(phenyl) piperazin-1-yl]-N-benzylacetamide (3a)
O
HN
N
N
Table 82. IR Data of 3a
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3301
N-H Str
3030
C-H Str Aromatic
2823
C-H Str Aliphatic
1661
C=O Str
1320
C-N Str Aromatic
1251
C-N Str Aliphatic
143
EXPERIMENTAL
Figure 83.
NMR Spectrum of 3a
Table 83.
1
H NMR Data of 3a
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.67-3.13
4
Piperazine
3.14-3.36
4
Piperazine
4.39
2
COCH2
4.47
2
CH2
6.86-7.33
9
Aromatic
7.51
1
NH
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EXPERIMENTAL
Figure 84.
Mass Spectrum of 3a
Mass Data
MS (EI) m/z: 310.2 (M+1).
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EXPERIMENTAL
Figure 85.
IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl]-N-benzyl
acetamide (3b)
Table 84. IR Data of 3b
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
2995
C-H Str Aromatic
2827
C-H Str Aliphatic
1657
C=O Str
1306
C-N Str Aromatic
1257
C-N Str Aliphatic
146
EXPERIMENTAL
Figure 86.
NMR Spectrum of 3b
O
H3CO
HN
N
Table 85.
1
N
H NMR Data of 3b
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.71-3.06
4
Piperazine
3.14-3.36
4
Piperazine
3.81
3
OCH3
4.39
2
COCH2
4.49
2
CH2
6.84-7.34
9
Aromatic
7.53
1
NH
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EXPERIMENTAL
Figure 87.
IR Spectrum of 2-[4-(3-methoxyphenyl) piperazin-1-yl]-N-benzyl
acetamide (3c)
O
OCH3
HN
N
N
Table 86. IR Data of 3c
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
2995
C-H Str Aromatic
2827
C-H Str Aliphatic
1657
C=O Str
1306
C-N Str Aromatic
1257
C-N Str Aliphatic
148
EXPERIMENTAL
Figure 88.
NMR Spectrum of 3c
Table 87.
1
H NMR Data of 3c
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.62-3.10
4
Piperazine
3.14-3.38
4
Piperazine
3.73
3
OCH3
4.41
2
COCH2
4.53
2
CH2
6.39-7.33
9
Aromatic
7.53
1
NH
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EXPERIMENTAL
Figure 89.
IR Spectrum of 2-[4-(4-methoxyphenyl) piperazin-1-yl]-N-benzyl
acetamide (3d)
O
HN
N
N
OCH3
Table 88. IR Data of 3d
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
2995
C-H Str Aromatic
2827
C-H Str Aliphatic
1657
C=O Str
1306
C-N Str Aromatic
1257
C-N Str Aliphatic
150
EXPERIMENTAL
Figure 90.
NMR Spectrum of 3d
Table 89.
1
H NMR Data of 3d
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.62-3.10
4
Piperazine
3.14-3.38
4
Piperazine
3.73
3
OCH3
4.41
2
COCH2
4.53
2
CH2
6.39-7.33
9
Aromatic
7.53
1
NH
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EXPERIMENTAL
Figure 91.
IR Spectrum of 2-[4-(3-methylphenyl) piperazin-1-yl]-N-benzylacetamide
(3e)
O
CH3
HN
N
N
Table 90. IR Data of 3e
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3456
N-H Str
2940
C-H Str Aromatic
2827
C-H Str Aliphatic
1659
C=O Str
1306
C-N Str Aromatic
1226
C-N Str Aliphatic
152
EXPERIMENTAL
Figure 92.
NMR Spectrum of 3e
Table 91.
1
H NMR Data of 3e
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.26
3
CH3
2.47-3.10
4
Piperazine
3.11-3.35
4
Piperazine
4.41
2
COCH2
4.48
2
CH2
6.80-7.33
9
Aromatic
7.48
1
NH
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EXPERIMENTAL
Figure 93.
IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl]-N-benzylacetamide
(3f)
O
HN
N
N
CH3
Table 92. IR Data of 3f
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3457
N-H Str
2939
C-H Str Aromatic
2827
C-H Str Aliphatic
1639
C=O Str
1302
C-N Str Aromatic
1235
C-N Str Aliphatic
154
EXPERIMENTAL
Figure 94.
NMR Spectrum of 3f
Table 93.
1
H NMR Data of 3f
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.26
3
CH3
2.47-3.10
4
Piperazine
3.11-3.35
4
Piperazine
4.41
2
COCH2
4.48
2
CH2
6.80-7.33
9
Aromatic
7.48
1
NH
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EXPERIMENTAL
Figure 95.
IR Spectrum of 2-[4-(2-chlorophenyl) piperazin-1-yl]-N-benzylacetamide
(3g)
O
Cl
HN
N
N
Table 94. IR Data of 3g
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3456
N-H Str
3035
C-H Str Aromatic
2830
C-H Str Aliphatic
1664
C=O Str
1302
C-N Str Aromatic
1245
C-N Str Aliphatic
156
EXPERIMENTAL
Figure 96.
NMR Spectrum of 3g
Table 95.
1
H NMR Data of 3g
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.47-3.14
4
Piperazine
3.30-3.51
4
Piperazine
4.43
2
COCH2
4.66
2
CH2
7.09-7.31
9
Aromatic
7.43
1
NH
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EXPERIMENTAL
Figure 97.
IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl]-N-benzylacetamide
(3h)
O
Cl
HN
N
N
Table 96. IR Data of 3h
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3456
N-H Str
3035
C-H Str Aromatic
2830
C-H Str Aliphatic
1664
C=O Str
1302
C-N Str Aromatic
1245
C-N Str Aliphatic
158
EXPERIMENTAL
Figure 98.
NMR Spectrum of 3h
Table 97.
1
H NMR Data of 3h
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.47-3.11
4
Piperazine
3.18-3.30
4
Piperazine
4.42
2
COCH2
4.45
2
CH2
6.75-7.29
9
Aromatic
7.43
1
NH
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EXPERIMENTAL
Figure 99.
IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl]-N-benzylacetamide
(3i)
O
HN
N
N
NO2
Table 98. IR Data of 3i
Shobhit University Meerut
Wave number (cm-1)
Group Assignment
3301
N-H Str
3030
C-H Str Aromatic
2823
C-H Str Aliphatic
1661
C=O Str
1320
C-N Str Aromatic
1251
C-N Str Aliphatic
160
EXPERIMENTAL
Figure 100.
NMR Spectrum of 3i
Table 99.
1
H NMR Data of 3i
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.47-3.11
4
Piperazine
3.18-3.30
4
Piperazine
4.44
2
COCH2
4.62
2
CH2
7.00-8.19
9
Aromatic
7.54
1
NH
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EXPERIMENTAL
Figure 101.
IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl]-N- benzylacetamide
(3j)
O
HN
N
Table 100.
Shobhit University Meerut
N
F
IR Data of 3j
Wave number (cm-1)
Group Assignment
3479
N-H Str
2939
C-H Str Aromatic
2827
C-H Str Aliphatic
1639
C=O Str
1302
C-N Str Aromatic
1235
C-N Str Aliphatic
162
EXPERIMENTAL
Figure 102.
NMR Spectrum of 3j
Table 101.
1
H NMR Data of 3j
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
2.63-3.13
4
Piperazine
3.25-3.30
4
Piperazine
4.42
2
COCH2
4.60
2
CH2
6.94-7.37
9
Aromatic
7.54
1
NH
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EXPERIMENTAL
Series E
Synthesis of 2-[4-(aryl substituted) piperazin-1-yl]-N-cyclohexylacetamides
Step I.
Synthesis of 2-chloro-N-cyclohexylacetamide (2)
NH2
ClCOCH2Cl
HN
i
(1)
COCH2Cl
(2)
Scheme 5. Reagents and conditions: (i) NaOH, Dichloromethane, 0 oC temperature.
Procedure
Cyclohexylamine 1 (4.61 ml, 0.04mol) in 2N aqueous sodium hydroxide (150 ml) at
0
o
C temperature was treated with chloroacetylchloride (3.18ml, 0.04mol) as a solution in
dichloromethane (100 ml). After 1h, the layers were separated and the aqueous phase was
extracted with additional portion of dichloromethane. The organic phases were combined,
washed with an aqueous solution of 1N hydrochloric acid, saturated sodium bicarbonate,
dried over sodium sulphate. Removal of the solvent afforded the compound 2.
The physical parameters were of the synthesized compound
Yield
:
7.10 g
Percentage yield
:
75.69 %
Melting range
:
100-102oC
Rf value
:
0.75
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C8H14ClNO
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EXPERIMENTAL
Step II.
Synthesis of final compounds
HN
COCH2Cl
(2)
R
i
HN
N
R
HN
COCH2
N
N
(3a-j)
Scheme 5. Synthesis of the target compounds. Reagents and conditions: (i) Acetonitrile,
K2CO3, KI, Reflux.
Table 102.
Substituent of compounds
Compound
R
3a
H
3b
3-CH3
3c
4-CH3
3d
2-OCH3
3e
3-OCH3
3f
4-OCH3
3g
2-Cl
3h
3-Cl
3i
4-F
3j
4-NO2
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EXPERIMENTAL
General procedure
2-Chloro-N-cyclohexylacetamide 2 (0.87g, 0.005mol) was dissolved in 100 ml of
acetonitrile in a 250ml Round bottom flask. Anhydrous K2CO3 (0.69g, 0.005mol), catalytic
amount of potassium iodide and appropriate arylpiperazine (0.005 mol) were added into
above solution. The mixture was allowed to reflux with continuous stirring on magnetic stirrer
for 12 h. After completion of reaction the solvent was removed by vacuum distillation and
residue was dissolved in chloroform and water. The organic layer was washed with brine and
dried over sodium sulphate. Removal of the solvent under vacuum afforded the crude
products which were recrystallized from ethanol to afford 3a-j.
The physical parameters were
2-[4-(Phenyl) piperazin-1-yl]-N-cyclohexylacetamide (3a)
Yield
:
0.75 g
Percentage yield
:
50.0 %
Melting range
:
87-90oC
Rf value
:
0.27
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H27N3O
2-[4-(3-Methylphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3b)
Yield
:
0.85 g
Percentage yield
:
54.14 %
Melting range
:
78-82oC
Rf value
:
0.23
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H29N3O
2-[4-(4-Methylphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3c)
Yield
:
0.82 g
Percentage yield
:
52.22 %
Melting range
:
76-80oC
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EXPERIMENTAL
Rf value
:
0.21
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C19H29N3O
2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N-cyclohexylacetamide (3d)
Yield
:
0.57 g
Percentage yield
:
34.54 %
Melting range
:
85-89oC
Rf value
:
0.25
Mobile phase
:
hexane: ethyl acetate (1: 1)
Molecular formula
:
C19H29N3O2
2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3e)
Yield
:
0.50 g
Percentage yield
:
30.30 %
Melting range
:
66-70oC
Rf value
:
0.39
Mobile phase
:
hexane: ethyl acetate (1: 1)
Molecular formula
:
C19H29N3O2
2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3f)
Yield
:
0.58 g
Percentage yield
:
35.15 %
Melting range
:
94-98oC
Rf value
:
0.24
Mobile phase
:
hexane: ethyl acetate (1: 1)
Molecular formula
:
C19H29N3O2
2-[4-(2-Chlorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3g)
Yield
:
0.97 g
Percentage yield
:
58.08 %
Melting range
:
72-75oC
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EXPERIMENTAL
Rf value
:
0.54
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H26ClN3O
2-[4-(3-Chlorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3h))
Yield
:
0.95 g
Percentage yield
:
56.88 %
Melting range
:
86-90oC
Rf value
:
0.47
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H26ClN3O
2-[4-(4-Fluorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3i)
Yield
:
1.0 g
Percentage yield
:
62.89 %
Melting range
:
88-91oC
Rf value
:
0.28
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H26FN3O
Log P (Experimental)
:
2.10
2-[4-(4-Nitrophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3j)
Yield
:
0.98 g
Percentage yield
:
56.64 %
Melting range
:
134-136oC
Rf value
:
0.26
Mobile phase
:
hexane: ethyl acetate (1:1)
Molecular formula
:
C18H26N4O3
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EXPERIMENTAL
Figure 103.
IR Spectrum of 2-chloro-N-cyclohexylacetamide (2)
NHCOCH2Cl
Table 103.
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IR Data of 2
Wave number (cm-1)
Group Assignment
3414
N-H Str
2937
C-H Str Aliphatic
1658
C=O Str
1219
C-N Str
668
C-Cl Str
169
EXPERIMENTAL
Figure 104.
NMR Spectrum of 2-chloro-N-cyclohexylacetamide (2)
Table 104.
1
H NMR Data of 2
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.22-1.94
10
Aliphatic
3.73-3.85
1
Aliphatic
4.03
2
COCH2
6.44
1
NH
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EXPERIMENTAL
Figure 105.
IR Spectrum of 2-[4-(phenyl) piperazin-1-yl]-N-cyclohexylacetamide (3a)
O
N
N
N
H
Table 105.
Shobhit University Meerut
IR Data of 3a
Wave number (cm-1)
Group Assignment
3356
N-H Str
3006
C-H Str Aromatic
2936
C-H Str Aliphatic
1664
C=O Str
1382
C-N Str Aromatic
1234
C-N Str Aliphatic
171
EXPERIMENTAL
Figure 106.
NMR Spectrum of 3a
Table 106.
1
H NMR Data of 3a
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.17-1.89
10
Aliphatic
2.41-2.86
4
Piperazine
3.01-3.17
4
Piperazine
3.79-3.82
1
Aliphatic
4.80
2
COCH2
6.82-7.24
5
Aromatic
7.27
1
NH
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EXPERIMENTAL
Figure 107.
Mass Spectrum of 3a
Mass Data
MS (EI) m/z: 302.3 (M+1).
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EXPERIMENTAL
Figure 108.
IR Spectrum of 2-[4-(3-methylphenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3b)
O
N
CH3
N
N
H
Table 107.
Shobhit University Meerut
IR Data of 3b
Wave number (cm-1)
Group Assignment
3246
N-H Str
3006
C-H Str Aromatic
2938
C-H Str Aliphatic
1660
C=O Str
1382
C-N Str Aromatic
1234
C-N Str Aliphatic
174
EXPERIMENTAL
Figure 109.
NMR Spectrum of 3b
Table 108.
1
H NMR Data of 3b
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.20-1.88
10
Aliphatic
2.31
3
CH3
2.49-2.89
4
Piperazine
3.11-3.23
4
Piperazine
3.69-3.96
1
Aliphatic
4.72
2
COCH2
6.40-8.17
4
Aromatic
7.27
1
NH
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EXPERIMENTAL
Figure 110.
IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3c)
CH3
O
N
N
N
H
Table 109.
Shobhit University Meerut
IR Data of 3c
Wave number (cm-1)
Group Assignment
3246
N-H Str
3006
C-H Str Aromatic
2938
C-H Str Aliphatic
1660
C=O Str
1382
C-N Str Aromatic
1234
C-N Str Aliphatic
176
EXPERIMENTAL
Figure 111.
NMR Spectrum of 3c
Table 110.
1
H NMR Data of 3c
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.20-1.88
10
Aliphatic
2.29
3
CH3
2.49-2.80
4
Piperazine
3.11-3.23
4
Piperazine
3.79-3.96
1
Aliphatic
4.72
2
COCH2
6.40-7.94
4
Aromatic
7.27
1
NH
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EXPERIMENTAL
Figure 112.
IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3d)
O
N
N
OCH3
N
H
Table 111.
Shobhit University Meerut
IR Data of 3d
Wave number (cm-1)
Group Assignment
3355
N-H Str
3003
C-H Str Aromatic
2937
C-H Str Aliphatic
1666
C=O Str
1379
C-N Str Aromatic
1242
C-N Str Aliphatic
1036
C-O-C Str
178
EXPERIMENTAL
Figure 113.
NMR Spectrum of 3d
Table 112.
1
H NMR Data of 3d
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.25-1.89
10
Aliphatic
2.17-2.89
4
Piperazine
3.10-3.42
4
Piperazine
3.54
3
OCH3
3.79-3.96
1
Aliphatic
4.69
2
COCH2
6.57-7.94
4
Aromatic
7.26
1
NH
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EXPERIMENTAL
Figure 114.
IR Spectrum of 2-[4-(3-methoxyphenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3e)
O
N
OCH3
N
N
H
Table 113.
Shobhit University Meerut
IR Data of 3e
Wave number (cm-1)
Group Assignment
3353
N-H Str
3003
C-H Str Aromatic
2935
C-H Str Aliphatic
1665
C=O Str
1379
C-N Str Aromatic
1241
C-N Str Aliphatic
1036
C-O-C Str
180
EXPERIMENTAL
Figure 115.
NMR Spectrum of 3e
Table 114.
1
H NMR Data of 3e
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.25-1.89
10
Aliphatic
2.17-2.89
4
Piperazine
3.10-3.42
4
Piperazine
3.54
3
OCH3
3.79-3.96
1
Aliphatic
4.69
2
COCH2
6.57-7.94
4
Aromatic
7.26
1
NH
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181
EXPERIMENTAL
Figure 116. IR Spectrum of 2-[4-(4-methoxyphenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3f)
OCH3
O
N
N
N
H
Table 115.
Shobhit University Meerut
IR Data of 3f
Wave number (cm-1)
Group Assignment
3353
N-H Str
3003
C-H Str Aromatic
2935
C-H Str Aliphatic
1665
C=O Str
1379
C-N Str Aromatic
1241
C-N Str Aliphatic
1036
C-O-C Str
182
EXPERIMENTAL
Figure 117.
NMR Spectrum of 3f
Table 116.
1
H NMR Data of 3f
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.13-1.90
10
Aliphatic
2.67-2.70
4
Piperazine
3.04-3.47
4
Piperazine
3.54
3
OCH3
3.79-3.86
1
Aliphatic
4.67
2
COCH2
6.77-7.09
4
Aromatic
7.26
1
NH
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183
EXPERIMENTAL
Figure 118.
IR Spectrum of 2-[4-(2-chlorophenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3g)
O
N
N
Cl
N
H
Table 117.
Shobhit University Meerut
IR Data of 3g
Wave number (cm-1)
Group Assignment
3349
N-H Str
3008
C-H Str Aromatic
2935
C-H Str Aliphatic
1664
C=O Str
1329
C-N Str Aromatic
1225
C-N Str Aliphatic
184
EXPERIMENTAL
Figure 119.
NMR Spectrum of 3g
Table 118.
1
H NMR Data of 3g
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.25-1.88
10
Aliphatic
2.14-2.95
4
Piperazine
3.01-3.45
4
Piperazine
3.59-3.81
1
Aliphatic
4.68
2
COCH2
6.65-7.94
4
Aromatic
7.26
1
NH
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185
EXPERIMENTAL
Figure 120.
IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3h)
O
N
Cl
N
N
H
Table 119.
Shobhit University Meerut
IR Data of 3h
Wave number (cm-1)
Group Assignment
3349
N-H Str
3008
C-H Str Aromatic
2935
C-H Str Aliphatic
1664
C=O Str
1329
C-N Str Aromatic
1225
C-N Str Aliphatic
186
EXPERIMENTAL
Figure 121.
NMR Spectrum of 3h
Table 120.
1
H NMR Data of 3h
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.25-1.88
10
Aliphatic
2.14-2.95
4
Piperazine
3.01-3.45
4
Piperazine
3.59-3.81
1
Aliphatic
4.68
2
COCH2
6.65-7.94
4
Aromatic
7.26
1
NH
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187
EXPERIMENTAL
Figure 122.
IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3i)
F
O
N
N
N
H
Table 121.
Shobhit University Meerut
IR Data of 3i
Wave number (cm-1)
Group Assignment
3248
N-H Str
3009
C-H Str Aromatic
2935
C-H Str Aliphatic
1662
C=O Str
1329
C-N Str Aromatic
1224
C-N Str Aliphatic
188
EXPERIMENTAL
Figure 123.
NMR Spectrum of 3i
Table 122.
1
H NMR Data of 3i
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.15-1.87
10
Aliphatic
2.63-2.92
4
Piperazine
3.10-3.45
4
Piperazine
3.55-3.97
1
Aliphatic
4.82
2
COCH2
6.74-7.97
4
Aromatic
7.28
1
NH
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189
EXPERIMENTAL
Figure 124. IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl]-N- cyclohexyl
acetamide (3j)
NO2
O
N
N
N
H
Table 123.
Shobhit University Meerut
IR Data of 3j
Wave number (cm-1)
Group Assignment
3249
N-H Str
3008
C-H Str Aromatic
2937
C-H Str Aliphatic
1663
C=O Str
1329
C-N Str Aromatic
1225
C-N Str Aliphatic
190
EXPERIMENTAL
Figure 125.
NMR Spectrum of 3j
Table 124.
1
H NMR Data of 3j
Chemical Shift ‘δ’ (ppm)
Number of Protons
Inferences
1.18-1.91
10
Aliphatic
2.63-2.70
4
Piperazine
3.06-3.46
4
Piperazine
3.55-3.97
1
Aliphatic
4.82
2
COCH2
6.82-8.13
4
Aromatic
7.27
1
NH
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EXPERIMENTAL
4.3
Computational Studies
A set of physicochemical properties was computed for the target compounds as well as
three standard drugs clozapine, ketanserin and risperidone using Chem 3D Ultra version 11.0,
8.0, Novartis JME molecular editor and Chem Silico online free software programs. The
observations are depicted in Tables 125, 127, 129, 131 and 133.
For antipsychotics, as with the great majority of drugs aimed at CNS targets, the
blood–brain barrier (BBB) must be crossed in order for a therapeutic effect to be exerted. To
predict the BBB penetration of a compound, the most important molecular descriptors used
are molecular surface area parameters (e.g., topological polar surface area), log P and volume
parameters. Literature review suggests that TPSA is a measure of a molecule’s hydrogen
bonding capacity and its value should not exceed certain limit if the compound is intended to
be CNS active. Two differing limits have been proposed: van de Waterbeemed et al.
suggested a limit of 90 A2, where, Kelder et al suggested 60-70 A2. Topological polar surface
area (TPSA) values for the test compounds were well within these limits (26.79-87.39).
The log P values of test compounds were (1.28-5.60) within the range of standard
drugs which shows that these compounds have a potential to effectively cross the blood brain
barrier. Steric and molecular surface descriptors computed include Connolly solvent
accessible surface area (SAS, A2), Connolly molecular surface area (MSA, A2), Connolly
solvent excluded volume (SEV, A3), and Ovality. Global physiochemical properties computed
were molecular weight (MW), molar refractivity (MR), molecular topological index (MTI)
and Wiener index (WI) for the test compounds.
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EXPERIMENTAL
Similarity calculations
The physicochemical similarity of the target compounds was calculated with respect to
the standard drugs and shown in Tables 126, 128, 130, 132 and 134. Firstly, the distance di of
a particular target compound j to drug molecules e.g., clozapine was calculated by the
formula:
n
di2 = ∑ (1-Xi,j /Xi,std)2 /n
j=1
Where, Xi, j is the value of molecular parameter ‘i’ for compound ‘j’, Xi, std is the value of the
same molecular parameter for the standard drug, e.g., clozapine, ketanserin and risperidone.
Then, the similarity of compound ‘j’ to the standard drug was calculated as:
Similarity (%) = (1-R) x 100. Where R =√d2 is the quadratic mean (root mean square),
a measure of central tendency (Bali et al., 2010).
The title compounds showed good physicochemical similarity (13.29 - 92.30%, Series
A), (0.22 - 86.39%, Series B), (25.94% - 86.20%, Series C), (18.55 - 83.39%, Series D),
(24.90 - 81.01%, Series E) with respect to standard drugs.
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193
EXPERIMENTAL
SERIES A
Table 125.
Calculation of molecular properties for 2-{n-[4-(aryl substituted) pipera
zin-1-yl] alkoxy} benzamides and standard drugs
SASc
MSAd
SEVe
TPSAf
MTIg
WIh
Ovi
(A2)
(A2)
(A3)
(A2)
96.5
596.869
314.792
281.008
58.8
12122
1607
1.5172
339.43
102.4
628.141
333.488
297.919
58.8
13585
1798
1.5459
3.13
339.43
102.4
628.116
333.469
297.902
58.8
13722
1816
1.5459
-0.02
2.52
355.43
103.75
635.134
338.812
304.225
68.03
14615
1978
1.5488
3a5
-0.15
2.52
355.43
103.75
641.975
340.692
304.338
68.02
14853
2014
1.5570
3a6
0.16
3.2
359.85
101.11
608.65
324.119
292.986
58.8
12926
1780
1.5193
3b1
0.18
2.75
339.43
101.1
629.429
333.603
298.018
58.8
14070
1864
1.5461
3b2
-0.12
2.62
369.46
108.35
667.699
357.203
320.803
68.03
16827
2274
1.5761
3c1
0.11
3.2
353.46
105.7
660.925
352.171
314.99
58.8
16211
2146
1.5730
Log
Code
BBj
3a1
0.23
2.64
325.40
3a2
0.16
3.13
3a3
0.16
3a4
3c2
MRb
-0.26
3.08
383.48
112.95
699.174
376.186
338.223
68.03
19246
2597
1.6024
k
0.75
3.71
326.82
94.58
508.991
259.124
215.892
30.87
8127
1082
1.4889
l
-0.48
2.37
395.43
106.67
589.34
298.729
253.386
69.72
18646
2596
1.542
m
-0.20
2.10
410.48
114.21
690.021
375.09
351.81
57.5
20311
2793
1.5563
CLZ
KET
RIS
Log P
M.Wa
Cpd.
a
Molecular weight
b
Molar refractivity
c
Connolly solvent accessible surface area
d
Connolly molecular surface area
e
Connolly solvent excluded volume
f
Topological polar surface area
g
Molecular topological index
h
Wienner index
i
Ovality
j
Calcd.online (Chemsilico.com/CS_prBBB/BBBdata.html)
k
Clozapine
l
Ketanserin
m
Risperidone
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194
EXPERIMENTAL
Table 126.
Similarity values for 2-{n-[4-(aryl substituted) piperazin-1-yl] alkoxy}
benzamides with respect to standard drugs
Similaritya,b ( in %) to
Cpd.Code.
Clozapine Ketanserin Risperidone
3a1
57.23
79.15
59.55
3a2
50.03
81.86
83.57
3a3
49.47
82.14
80.23
3a4
37.62
85.03
82.05
3a5
36.48
85.36
82.63
3a6
52.26
81.97
78.99
3b1
47.97
82.81
80.91
3b2
26.48
85.99
65.80
3c1
37.14
87.22
86.95
3c2
13.29
83.41
92.30
a
(1 - R) X 100 where R = quadratic mean (root mean square mean).
b
Calcd. from physicochemical properties: Molecular weight; Molar refractivity; Connolly solvent
accessible surface area; Connolly molecular surface area; Connolly solvent excluded volume;
Topological polar surface area; Molecular topological index; Wiener index.
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EXPERIMENTAL
SERIES B
Table 127.
Calculation of molecular properties for 2–[4-(aryl substituted) piperazin1-yl] N, N-diphenylacetamides and standard drugs
MSAd
SEVe
TPSAf
MTIg
WIh
Ovi
(A2)
(A3)
(A2)
641.894
344.355
308.409
26.79
17130
2193
1.5599
119.22
582.422
313.211
291.582
26.79
19148
2450
1.4729
399.53
125.12
679.816
371.123
336.247
26.79
20677
2644
1.5870
5.41
439.47
119.83
690.253
373.577
335.839
26.79
22826
3226
1.5988
0.21
4.36
401.50
120.57
676.27
367.637
333.074
36.02
20277
2648
1.5821
3f
0.27
4.36
401.50
120.57
687.02
370.267
331.754
36.02
20575
2692
1.5976
3g
0.32
5.05
405.92
117.93
666.463
359.201
322.774
26.79
18269
2428
1.5785
3h
0.33
5.6
440.36
122.53
686.713
372.494
336.839
26.79
19519
2688
1.5910
3i
0.31
4.65
389.47
113.73
648.109
348.009
311.631
26.79
18374
2450
1.5655
MRb
Log
Code
BBj
3a
0.25
4.49
371.47
113.32
3b
0.36
4.98
385.50
3c
0.39
5.46
3d
0.41
3e
3j
SASc
(A2)
0.01
4.04
416.47
119.57
686.144
371.22
332.383
78.60
22209
3024
1.5997
k
0.75
3.71
326.82
94.58
508.991
259.124
215.892
30.87
8127
1082
1.4889
l
-0.48
2.37
395.43
106.67
589.34
298.729
253.386
69.72
18646
2596
1.542
m
-0.20
2.10
410.48
114.21
690.021
375.09
351.81
57.50
20311
2793
1.5563
CLZ
KET
RIS
Log P
M.Wa
Cpd.
a
Molecular weight
b
Molar refractivity
c
Connolly solvent accessible surface area
d
Connolly molecular surface area
e
Connolly solvent excluded volume
f
Topological polar surface area
g
Molecular topological index
h
Wienner index
i
Ovality
j
Calcd.online (Chemsilico.com/CS_prBBB/BBBdata.html)
k
Clozapine
l
Ketanserin
m
Risperidone
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196
EXPERIMENTAL
Table 128.
Similarity values of 2–[4-(aryl substituted) piperazin-1-yl] N, Ndiphenylacetamides with respect to standard drugs
Similaritya,b ( in %) to
Cpd.Code.
Clozapine Ketanserin Risperidone
3a
41.72
75.10
77.86
3b
32.69
77.01
77.91
3c
18.99
72.37
80.61
3d
0.22
70.12
79.56
3e
20.44
76.74
86.33
3f
16.61
76.45
86.39
3g
31.70
74.29
79.90
3h
20.78
72.28
80.61
3i
32.24
75.57
79.56
3j
8.15
81.27
86.04
a
(1 - R) X 100 where R = quadratic mean (root mean square mean).
b
Calcd. from physicochemical properties: Molecular weight; Molar refractivity; Connolly solvent
accessible surface area; Connolly molecular surface area; Connolly solvent excluded volume;
Topological polar surface area; Molecular topological index; Wiener index.
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197
EXPERIMENTAL
SERIES C
Table 129.
Calculation of molecular properties for 2-[4-(aryl substituted) piperazin1-yl]-N-phenylacetamides
MSAd
SEVe
TPSAf
MTIg
WIh
Ovi
(A2)
(A3)
(A2)
561.908
290.826
253.997
35.58
9668
1248
1.4994
95.14
593.162
309.507
270.893
35.58
10915
1408
1.5286
309.41
95.14
593.187
309.524
270.912
35.58
11038
1424
1.5287
2.46
325.40
96.49
589.697
311.837
279.124
44.81
11801
1559
1.5097
0.33
2.46
325.40
96.49
607.005
316.719
277.316
44.81
12015
1591
1.5400
3f
0.33
2.46
325.40
96.49
607.591
316.995
277.285
44.81
12229
1623
1.5415
3g
0.39
3.15
329.82
93.85
573.692
300.151
265.977
35.58
10357
1392
1.500
3h
0.41
3.15
329.82
93.85
586.465
305.662
268.344
35.58
10432
1408
1.5192
3i
0.36
2.75
313.37
89.65
568.091
294.463
257.022
35.58
10507
1424
1.5055
MRb
Log
Code
BBj
3a
0.36
2.59
295.38
89.24
3b
0.45
3.08
309.41
3c
0.45
3.08
3d
0.32
3e
3j
SASc
(A2)
-0.09
1.62
340.38
95.10
607.004
318.695
279.615
87.39
13142
1824
1.5411
k
0.75
3.71
326.82
94.58
508.991
259.124
215.892
30.87
8127
1082
1.4889
l
-0.48
2.37
395.43
106.67
589.34
298.729
253.386
69.72
18646
2596
1.542
m
-0.20
2.10
410.48
114.21
690.021
375.09
351.81
57.5
20311
2793
1.5563
CLZ
KET
RIS
LogP
M.Wa
Cpd.
a
Molecular weight
b
Molar refractivity
c
Connolly solvent accessible surface area
d
Connolly molecular surface area
e
Connolly solvent excluded volume
f
Topological polar surface area
g
Molecular topological index
h
Wienner index
i
Ovality
j
Calcd.online (Chemsilico.com/CS_prBBB/BBBdata.html)
k
Clozapine
l
Ketanserin
m
Risperidone
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198
EXPERIMENTAL
Table 130.
Similarity values of 2-[4-(aryl substituted) piperazin-1-yl]-N-phenyl
acetamides with respect to standard drugs
Similaritya,b ( in %) to
Cpd.Code
Clozapine Ketanserin Risperidone
3a
86.20
67.69
64.39
3b
78.64
70.71
68.44
3c
78.08
70.95
68.66
3d
69.27
75.64
73.10
3e
55.77
76.08
73.55
3f
66.88
76.55
74.19
3g
81.43
70.47
70.32
3h
80.62
70.65
68.15
3i
80.91
70.35
67.17
3j
25.94
81.06
71.46
a
(1 - R) X 100 where R = quadratic mean (root mean square mean).
b
Calcd. from physicochemical properties: Molecular weight; Molar refractivity; Connolly solvent
accessible surface area; Connolly molecular surface area; Connolly solvent excluded volume;
Topological polar surface area; Molecular topological index; Wiener index.
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EXPERIMENTAL
SERIES D
Table 131.
Calculation of molecular properties for 2-[4-(aryl substituted) piperazin1-yl]-N-benzylacetamides (3a-j) and standard drugs
SASc
MSAd
SEVe
TPSAf
MTIg
WIh
OVi
(A2)
(A2)
(A3)
(A2)
94.66
575.217
307.199
280.758
35.58
11308
1458
1.481
339.43
101.91
638.833
338.01
301.468
44.81
13673
1802
1.554
2.53
339.43
101.91
650.064
341.557
300.50
44.81
13901
1836
1.574
0.25
2.53
339.43
101.91
650.116
340.422
298.864
44.81
14129
1870
1.574
3e
0.40
3.15
323.43
100.56
606.47
325.882
297.658
35.58
12691
1635
1.511
3f
0.40
3.15
323.43
100.56
635.774
332.971
292.45
35.58
12822
1652
1.562
3g
0.35
3.22
343.85
99.26
614.289
322.626
287.173
35.58
12077
1618
1.532
3h
0.37
3.22
343.85
99.26
623.463
326.608
287.197
35.58
12157
1635
1.551
3i
-0.20
1.28
354.40
98.64
649.164
341.967
300.969
87.39
15135
2090
1.574
0.32
2.82
327.40
95.06
610.728
317.941
278.769
35.58
12237
1652
1.540
CLZ
0.75
3.71
326.82
94.58
508.991
259.124
215.892
30.87
8127
1082
1.488
KETl
-0.48
2.37
395.43
106.67
589.34
298.729
253.338
69.72
18646
2596
1.542
m
-0.20
2.10
410.48
114.21
690.021
375.09
351.81
57.50
20311
2793
1.556
Log
Code
BBj
3a
0.32
2.66
309.41
3b
0.27
2.53
3c
0.25
3d
3j
k
RIS
LogP
M.Wa
Cpd.
MRb
a
Molecular weight
b
Molar refractivity
c
Connolly solvent accessible surface area
d
Connolly molecular surface area
e
Connolly solvent excluded volume
f
Topological polar surface area
g
Molecular topological index
h
Wienner index
i
Ovality
j
Calcd.online (Chemsilico.com/CS_prBBB/BBBdata.html)
k
Clozapine
l
Ketanserin
m
Risperidone
Shobhit University Meerut
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EXPERIMENTAL
Table 132.
Similarity values of 2-[4-(aryl substituted) piperazin-1-yl]-N-benzyl
acetamides (3a-j) with respect to standard drugs
Similaritya,b ( in %) to
Cpd.code
Clozapine Ketanserin Risperidone
3a
76.52
69.90
69.14
3b
57.60
78.35
78.82
3c
56.21
78.61
79.38
3d
55.13
79.11
79.79
3e
67.39
73.66
73.24
3f
66.31
73.95
73.66
3g
69.95
73.69
72.71
3h
69.11
73.78
73.03
3i
18.55
83.39
75.81
3j
69.73
73.84
72.18
a
(1 - R) X 100 where R = quadratic mean (root mean square mean).
b
Calcd. from physicochemical properties: Molecular weight; Molar refractivity; Connolly solvent
accessible surface area; Connolly molecular surface area; Connolly solvent excluded volume;
Topological polar surface area; Molecular topological index; Wiener index.
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EXPERIMENTAL
SERIES E
Table 133.
Calculation of molecular properties for 2-[4-(aryl substituted) piperazin1-yl]-N-cyclohexylacetamides (3a-j) and standard drugs
MSAd
SEVe
TPSAf
MTIg
WIh
Ovi
(A2)
(A3)
(A2)
580.261
309.454
297.083
35.58
9668
1248
1.4372
97.07
611.491
328.118
313.97
35.58
10915
1408
1.468
315.45
97.07
611.47
328.106
313.961
35.58
11038
1424
1.468
2.35
331.45
98.42
633.866
336.437
311.668
44.81
11801
1559
1.5134
0.07
2.35
331.45
98.42
642.357
338.886
311.452
44.81
12015
1591
1.5251
3f
0.07
2.35
331.45
98.42
644.608
339.974
311.78
44.81
12229
1623
1.5289
3g
0.27
3.03
335.87
98.78
588.700
317.124
310.21
35.58
10357
1392
1.43100
3h
0.32
3.03
335.87
95.78
604.782
324.268
311.414
35.58
10432
1408
1.4594
3i
0.24
2.63
319.42
91.58
586.412
313.07
300.277
35.58
10507
1424
1.4436
3j
-0.87
1.6
346.42
95.77
622.699
336.232
321.552
87.39
13142
1824
1.4813
MRb
Log
code
BBj
3a
0.3
2.47
301.43
91.17
3b
0.34
2.96
315.45
3c
0.34
2.96
3d
0.09
3e
CLZk
LogP
M.Wa
Cpd.
SASc
(A2)
0.75
3.71
326.82
94.58
508.991
259.124
215.892
30.87
8127
1082
1.4889
l
-0.48
2.37
395.43
106.67
589.34
298.729
253.386
69.72
18646
2596
1.542
RISm
-0.20
2.10
410.48
114.21
690.021
375.09
351.81
57.5
20311
2793
1.5563
KET
a
Molecular weight
b
Molar refractivity
c
Connolly solvent accessible surface area
d
Connolly molecular surface area
e
Connolly solvent excluded volume
f
Topological polar surface area
g
Molecular topological index
h
Wienner index
i
Ovality
j
Calcd.online (Chemsilico.com/CS_prBBB/BBBdata.html)
k
Clozapine
l
Ketanserin
m
Risperidone
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EXPERIMENTAL
Table 134.
Similarity values of 2-[4-(aryl substituted) piperazin-1-yl]-N-cyclohexyl
acetamides (3a-j) with respect to standard drugs
Similaritya,b ( in %) to
Cpd.Code
Clozapine Ketanserin Risperidone
3a
81.01
67.40
64.74
3b
73.74
69.62
70.13
3c
73.28
69.84
70.36
3d
65.53
74.29
76.03
3e
64.30
74.63
75.39
3f
63.32
75.00
75.89
3g
76.31
69.70
69.42
3h
76.36
69.65
69.71
3i
76.82
69.84
68.80
3j
24.90
78.87
72.76
a
(1 - R) X 100 where R = quadratic mean (root mean square mean).
b
Calcd. from physicochemical properties: Molecular weight; Molar refractivity; Connolly solvent
accessible surface area; Connolly molecular surface area; Connolly solvent excluded volume;
Topological polar surface area; Molecular topological index; Wiener index.
Shobhit University Meerut
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EXPERIMENTAL
4.4
Pharmacological Evaluation for Antipsychotic Effect
All the target compounds were subjected to pharmacological evaluation to determine
their behaviour symptoms, inhibition of apomorphine induced climbing behaviour, inhibition
of 5-hydroxy tryptophan (5-HTP) induced head twitches behaviour and induction of catalepsy
studies. Swiss albino mice (six mice in each group) of either sex (24-26 g) were used and
housed per cage in standard laboratory conditions (12 h light/ dark cycle, 22±2 oC room
temperature). Food and water were available ad libitum. All experiments were approved by
institutional ethical Committee. All synthesized compounds were suspended in 1% solution of
caboxy methyl cellulose (CMC) in distilled water and administered by the intraperitoneal
(i.p.) route.
4.4.1 Behaviour symptoms
Swiss albino mice (six mice in each group) of either sex (24-26g) were used and kept in
plastic cage. All derivatives at their respective doses were given to animals. Each cage
contained one animal only. The changes in the behavior symptoms were noted down for an
interval of 30 minutes for 3 hours and then after 24 hours, the cages were inspected for any
mortality of the animals.
4.4.2 Inhibition of apomorphine induced climbing behaviour
Swiss albino mice (six mice in each group) of either sex (24-26g) were habituated by
individually placing in a circular cage made of wire mesh of diameter 13 cm and height 14
cm. Mice of the test, control and standard groups were injected, with test compound, normal
saline and clozapine intraperitoneally and returned to the home cage. After a gap of 10 min,
Apomorphine (2.5 mg/kg) was injected intraperitoneally. Mesh climbing behavior was noted
at 5 min intervals for up to 20 min, starting 10 min after the apomorphine administration using
the following scoring system: 0-no paws on the cage, 1-one paw on the cage, 2-two paws on
the cage, 3-three paws on the cage, 4-four paws on the cage. The score recorded for each
animal was based on the position of the animal at the moment it was first observed. A
maximum of 20 score is possible. Recording was done by an observer who was unaware of
the specific drug treatments.
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EXPERIMENTAL
4.4.3 Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behaviour
Swiss albino mice in the control group (n=6) was injected with pargyline (75 mg/kg,
i.p) in order to prevent the rapid degradation of 5-HTP. Thirty minutes later, the test
compound was administered. After a further 30 min, the mice received 5-HTP (50 mg/kg,
s.c). The mice were returned to the test cages and then head twitches were assessed at 10 min
intervals for 30 min, starting 20 min after the 5-HTP treatment. Head twitches were monitored
using the following scoring system, 0-absent, 1-moderate, 2-marked. A maximum of 8 score
is possible. An observer made all observations unaware of the specific drug treatments.
4.4.4 Induction of catalepsy
Catalepsy was induced in albino mice (n=6) with haloperidol (1.0 mg/kg, i.p) and was
assessed at 30 min intervals until 120 min and at the end of 240 min by means of a standard
bar test. Catalepsy was assessed in terms of the time (sec) for which the mouse maintained an
imposed position with both front limbs extended and resting on a 4 cm high wooden bar (1.0
cm diameter). The endpoint of catalepsy was considered to occur when both front paws were
removed from the bar or if the animal moved its head in an exploratory manner. Severity of
the cataleptic behavior was scored as 1 if maintained the imposed posture for at least 20 sec
and every additional 20 sec one extra point was given. A cut-off time of 1100 s was applied
during the recording of observations. The animals were returned to their individual home
cages in between determinations. All observations were made between 10.00 and 16.00 hrs in
a quiet room at 23-25ºC. The animals in the test group were administered with test drugs
instead of haloperidol and the remaining procedure for assessment of catalepsy was same as
mentioned above.
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EXPERIMENTAL
Series A
Pharmacological evaluation of 2-{n-[4-(aryl substituted) piperazin-1-yl] alkoxy}
benzamides
The minimum effective dose (EDmin) that produced statistically significant result was
determined in the inhibition of apomorphine induced climbing behaviour, inhibition of
5-hydroxy tryptophan induced head twitches behaviour and in the induction of catalepsy
studies (Tab.135). The behaviour symptoms were observed at EDmin values obtained in the
inhibition of apomorphine induced climbing behaviour test. The test compounds did not show
any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion
(Tab.136). All the target compounds showed significant interaction with D2 and 5-HT2A
receptor (Tabs. 137, 138 and 139 and Figs. 126, 127 and 128). But the compound 3a4 showed
higher interaction with D2 receptor (EDmin = 30 mg/kg) and with 5-HT2A receptor (EDmin =
20 mg/kg) and minimum induction of catalepsy (EDmin = 70 mg/kg).
Table 135.
In vivo studies of compounds for antipsychotic activity
Compound
Inhibition of
apomorphine
induced climbing
behavior
(EDmin, mg/kg, i.p.)
Inhibition of
5-HTP induced head
twitches behavior
(EDmin, mg/kg, i.p.)
Induction of
catalepsy
(EDmin, mg/kg,
i.p.)
3a1
3a2
3a3
3a4
3a5
3a6
3b1
3b2
3c1
3j
Clozapine
Haloperidol
40
40
40
30
30
40
60
60
60
60
6.0
-
40
40
40
20
20
30
40
60
60
60
2.0
-
60
50
50
70
70
70
60
60
60
60
nda
a
nd: Not determined, 1mg/kg dose was used
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EXPERIMENTAL
Table 136.
Behaviour symptoms
Compound
Behavioural symptoms
3a1
Sedation
Sleep
30 min
-
Observation at Interval of
60 min 90 min 120 min 180 min
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
-
-
-
-
-
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
3a2
3a3
3a4
3a5
3a6
3b1
3b2
Hyperactivity
Convulsion
Sedation
3c1
Sleep
Hyperactivity
Convulsion
Sedation
3c2
Sleep
Hyperactivity
Convulsion
+++ Marked effect, ++ Moderate effect, + Mild effect - Absence of effect
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-
-
207
EXPERIMENTAL
Inhibition of apomorphine induced climbing behavior
Total climbing score
Figure 126.
18
16
14
12
10
8
6
4
2
0
1
3a
2
3a
3
3a
4
3a
5
3a
6
3a
1
3b
2
3b
1
3c
Compounds
2
3c
l
e
tro p in
n
a
o
C
oz
Cl
The effect of synthesized compounds (3a1-3a6, 3b1-3b2 and 3c1-3c2) on the apomorphine
induced climbing behavior. Each column represents the mean ± SEM of total climbing score
for group of six mice assessed at 5-min intervals for 20 min, starting 10 min after
apomorphine treatment. A score of 20 is the maximum possible. All values statistically
significant with respect to control at p<0.05.
Table 137.
Inhibition of apomorphine induced climbing behavior
Sr. No. Compound Total Climbing Score
1
3a1
9.83 ± 0.16
2
3a2
11.16 ± 0.40
3
3a3
11.83 ± 0.47
4
3a4
6.33 ± 0.20
5
3a5
7.50 ± 0.22
6
3a6
8.33 ± 0.20
7
3b1
12.16 ± 0.30
8
3b2
10.16 ± 0.30
9
3c1
13.66 ± 0.49
10
3c2
14.16 ± 0.47
11
Control
16.16 ± 0.30
12
Clozapine
4.83 ± 0.30
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EXPERIMENTAL
8
7
6
5
Co
nt
ro
Cl
l
oz
ap
in
e
Compounds
3c
2
3c
1
3b
2
3b
1
3a
6
3a
5
3a
4
3a
3
3a
2
4
3
2
1
0
3a
1
Total head twitches score
Figure 127. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
The effect of synthesized compounds (3a1-3a6, 3b1-3b2 and 3c1-3c2) on the 5-HTP induced
head twitches behavior. Each column represents the mean ± SEM of total head twitches score
for group of six mice assessed at 10-min intervals for 30 min, starting 20 after the 5-HTP
treatment. A score of 8 is the maximum possible. All values statistically significant with
respect to control at p<0.05.
Table 138. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
Sr. No. Compound Total Head Twitches Score
1
3a1
3.36 ± 0.20
2
3a2
4.16 ± 0.16
3
3a3
4.33 ± 0.20
4
3a4
2.50 ± 0.22
5
3a5
2.83 ± 0.30
6
3a6
3.33 ± 0.33
7
3b1
4.66 ± 0.33
8
3b2
5.0 ± 0.25
9
3c1
5.0 ± 0.36
10
3c2
5.33 ± 0.20
11
Control
6.83 ± 0.30
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EXPERIMENTAL
Induction of catalepsy
Mean catalepsy score
Figure 128.
16
14
12
10
8
6
4
2
0
30
60
90
120
240
1
3a
2
3a
3
3a
4
3a
5
3a
1
3b
6
3a
2
3b
1
3c
Compounds
2
ol
3c erid
p
lo
a
H
The effect of synthesized compounds (3a1-3a6, 3b1-3b2 and 3c1-3c2) on induction of catalepsy
in mice. Results are expressed as the mean ± SEM (n=6). All values statistically significant
with respect to control at p<0.05.
Table 139.
Induction of catalepsy
Compound
Sr. No.
Mean catalepsy score
30 min
60 min
90 min
120 min
240 min
1
3a1
2.33 ± 0.20 4.66 ± 0.33 5.16 ± 0.47 6.83 ± 0.30
2.83 ± 0.30
2
3a2
2.33 ± 0.20 4.83 ± 0.30 5.33 ± 0.49 6.83 ± 0.30
3.00 ± 0.36
3
3a3
2.33 ± 0.20 5.16 ± 0.30 5.33 ± 0.20 6.66 ± 0.20
3.16 ± 0.40
4
3a4
1.50 ± 0.22 3.33 ± 0.33 4.16 ± 0.22 5.83 ± 0.30
1.66 ± 0.20
5
3a5
1.83 ± 0.16 4.00 ± 0.25 4.66 ± 0.20 6.50 ± 0.22
2.33 ± 0.20
6
3a6
2.16 ± 0.16 4.33 ± 0.20 4.83 ± 0.30 6.66 ± 0.33
2.66 ± 0.33
7
3b1
2.66 ± 0.33 5.16 ± 0.30 5.66 ± 0.43 7.33 ± 0.33
3.33 ± 0.33
8
3b2
2.66± 0.33
3.50 ± 0.33
9
3c1
2.50 ± 0.22 5.33 ± 0.42 6.50± 0.33
7.66 ± 0.20
3.66 ± 0.33
10
3c2
2.83 ± 0.30 5.66 ± 0.49 7.16 ± 0.30 8.16 ± 0.30
4.16 ± 0.30
11
5.50 ± 0.42 6.16 ± 0.53 7.50 ± 0.22
Haloperidol 2.83 ± 0.30 6.50 ± 0.42 9.16 ± 0.30 12.66 ± 0.33 5.83 ± 0.30
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EXPERIMENTAL
Series B
Pharmacological evaluation of 2–[4-(aryl substituted) piperazin-1-yl] N, Ndiphenyl
acetamides
The minimum effective dose (EDmin) that produced statistically significant result was
determined in the inhibition of apomorphine induced climbing behaviour, inhibition of
5-hydroxy tryptophan induced head twitches behaviour and in the induction of catalepsy
studies (Tab.140). The behaviour symptoms were observed at EDmin values obtained in the
inhibition of apomorphine induced climbing behaviour test. The test compounds did not show
any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion
(Tab.141). All the target compounds showed significant interaction with D2 and 5-HT2A
receptor (Tabs. 142, 143 and 144 and Figs. 129, 130 and 131). But the compound 3e showed
higher interaction with D2 receptor (EDmin = 20 mg/kg) and with 5-HT2A receptor (EDmin =
10 mg/kg) and minimum induction of catalepsy (EDmin = 80 mg/kg).
Table 140.
In vivo studies of compounds for antipsychotic activity
Compound
Inhibition of
apomorphine
induced climbing
behavior
(EDmin, mg/kg, i.p.)
Inhibition of
5-HTP induced head
twitches behavior
(EDmin, mg/kg, i.p.)
Induction of
catalepsy
(EDmin, mg/kg,
i.p.)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Clozapine
Haloperidol
20
30
40
30
20
30
30
40
30
40
5.5
-
20
30
40
20
10
30
40
40
30
40
1.5
-
60
50
50
60
80
60
50
50
60
50
nda
a
nd: Not determined, 1mg/kg dose was used
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EXPERIMENTAL
Table 141.
Behaviour symptoms
Compound
Behavioural symptoms
3a
Sedation
Sleep
30 min
-
Observation at Interval of
60 min 90 min 120 min 180 min
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
-
-
-
-
-
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
3i
Sleep
Hyperactivity
Convulsion
Sedation
3j
Sleep
Hyperactivity
Convulsion
+++ Marked effect, ++ Moderate effect, + Mild effect - Absence of effect
-
3b
3c
3d
3e
3f
3g
3h
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212
EXPERIMENTAL
Inhibition of apomorphine induced climbing behavior
Total mean climbing score
Figure 129.
16
14
12
10
8
6
4
2
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Compounds
l
ro
ne
pi
nt
a
o
C
oz
Cl
The effect of synthesized compounds (3a-j) on the apomorphine induced climbing behavior.
Each column represents the mean ± SEM of total climbing score for group of six mice
assessed at 5-min intervals for 20 min, starting 10 min after apomorphine treatment. A score
of 20 is the maximum possible. All values statistically significant with respect to control at
p<0.05.
Table 142.
Inhibition of apomorphine induced climbing behavior
Sr. No. Compound Total Climbing Score
1
3a
7.83 ± 0.40
2
3b
8.83 ± 0.16
3
3c
9.16 ± 0.16
4
3d
7.16 ± 0.30
5
3e
4.83 ± 0.30
6
3f
6.16 ± 0.16
7
3g
6.83 ± 0.40
8
3h
8.50 ± 0.22
9
3i
7.66 ± 0.20
10
3j
9.50 ± 0.22
11
Control
14.83 ± 0.33
12
Clozapine
4.16 ± 0.33
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8
7
6
5
Compounds
3j
Co
nt
ro
Cl
l
oz
ap
in
e
3i
3h
3g
3f
3e
3d
3c
3b
4
3
2
1
0
3a
Total mean head twitches score
Figure 130. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
The effect of synthesized compounds (3a-j) on the 5-HTP induced head twitches behavior.
Each column represents the mean ± SEM of total head twitches score for group of six mice
assessed at 10-min intervals for 30 min, starting 20 after the 5-HTP treatment. A score of 8 is
the maximum possible. All values statistically significant with respect to control at p<0.05.
Table 143. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
Sr. No. Compound
Total Head Twitches Score
1
3a
3.16 ± 0.16
2
3b
3.83 ± 0.30
3
3c
4.16 ± 0.30
4
3d
2.83 ± 0.30
5
3e
2.16 ± 0.16
6
3f
2.33 ± 0.20
7
3g
2.50 ± 0.22
8
3h
3.50 ± 0.22
9
3i
2.83 ± 0.16
10
3j
4.50 ± 0.33
11
Control
6.50 ± 0.22
12
Clozapine
1.16 ± 0.16
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EXPERIMENTAL
Figure 131.
Induction of catalepsy
12
30
10
60
8
90
6
120
4
240
2
Ha
l
Compounds
3
op j
er
id
ol
3i
3h
3g
3f
3e
3d
3c
3b
0
3a
Mean catalepsy score
14
The effect of synthesized compounds (3a-j) on induction of catalepsy in mice. Results are
expressed as the mean ± SEM. (n=6) p<0.05.
Table 144.
Induction of catalepsy
Compound
Sr. No.
Mean catalepsy score
30 min
60 min
90 min
120 min
240 min
3.50 ± 0.42
1
3a
2.83 ± 0.70
4.50 ± 0.42
5.16 ± 0.53
3.66 ± 0.61
2
3b
3.33 ± 0.42 3.66 ± 0.33 4.66 ± 0.42
5.33 ± 0.55
3.83 ± 0.47
3
3c
3.66 ± 0.33
5.16 ± 0.60
5.66 ± 0.33
6.16 ± 0.30
4.83 ± 0.30
4
3d
4.33 ± 0.42
5.66 ± 0.33
5.83 ± 0.30
6.66 ± 0.49
4.66 ± 0.33
5
3e
0.83 ± 0.40
1.66 ± 0.42
2.33 ± 0.33
2.83 ± 0.40
1.83 ± 0.30
6
3f
1.16 ± 0.30
1.83 ± 0.30
2.83 ± 0.30
3.33 ± 0.33
2.33 ± 0.33
7
3g
2.16 ± 0.30
3.66 ± 0.33
5.50 ± 0.42
5.83 ± 0.47
3.83 ± 0.30
8
3h
2.66 ± 0.33
4.50 ± 0.42
5.66 ± 0.49
6.33 ± 0.55
3.50 ± 0.22
9
3i
2.66 ± 0.33
4.16 ± 0.60
5.50 ± 0.42
5.83 ± 0.47
3.16 ± 0.30
10
3j
3.16 ± 0.30
5.50 ± 0.42
6.33 ± 0.49
6.16 ± 0.40
4.16 ± 0.30
Haloperidol 5.66 ± 0.42
7.33 ± 0.42
10.5 ± 0.42 11.33 ± 0.49 6.66 ± 0.33
11
Shobhit University Meerut
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EXPERIMENTAL
Series C
Pharmacological evaluation of 2-[4-(arylsubstituted) piperazin-1-yl]-N-phenyl
acetamides
The minimum effective dose (EDmin) that produced statistically significant result was
determined in the inhibition of apomorphine induced climbing behaviour, inhibition of
5-hydroxy tryptophan induced head twitches behaviour and in the induction of catalepsy
studies (Tab.145). The behaviour symptoms were observed at EDmin values obtained in the
inhibition of apomorphine induced climbing behaviour test. The test compounds did not show
any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion
(Tab.146). All the target compounds showed significant interaction with D2 and 5-HT2A
receptor (tabs. 147, 148 and 149 and figs. 132, 133 and 134). But the compound 3h showed
higher interaction with D2 receptor (EDmin = 30 mg/kg) and with 5-HT2A receptor (EDmin =
20 mg/kg) and minimum induction of catalepsy (EDmin = 60 mg/kg).
Table 145.
In vivo studies of compounds for antipsychotic activity
Compound
Inhibition of
apomorphine
induced climbing
behavior
(EDmin, mg/kg, i.p.)
Inhibition of
5-HTP induced head
twitches behavior
(EDmin, mg/kg, i.p.)
Induction of
catalepsy
(EDmin, mg/kg,
i.p.)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Clozapine
Haloperidol
30
40
40
40
50
50
30
30
40
40
5.0
-
30
40
30
50
50
50
40
20
50
40
1.5
-
60
60
60
50
50
50
70
60
70
50
nda
a
nd: Not determined, 1mg/kg dose was used
Shobhit University Meerut
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EXPERIMENTAL
Table 146.
Behaviour symptoms
Compound
Behavioural symptoms
3a
Sedation
Sleep
30 min
-
Observation at Interval of
60 min 90 min 120 min 180 min
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
-
-
-
-
-
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
3b
3c
3d
3e
3f
3g
3h
Hyperactivity
Convulsion
Sedation
3i
Sleep
Hyperactivity
Convulsion
Sedation
3j
Sleep
Hyperactivity
Convulsion
+++ Marked effect, ++ Moderate effect, + Mild effect - Absence of effect
Shobhit University Meerut
-
-
217
EXPERIMENTAL
Inhibition of apomorphine induced climbing behavior
Total mean climbing score
Figure 132.
12
10
8
6
4
2
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Compounds
l
e
tro p in
n
a
o
C
oz
Cl
The effect of synthesized compounds (3a-j) on the apomorphine induced climbing behavior.
Each column represents the mean ± SEM of total climbing score for group of six mice
assessed at 5-min intervals for 20 min, starting 10 min after apomorphine treatment. A score
of 20 is the maximum possible. All values statistically significant with respect to control at
p<0.05.
Table 147.
Inhibition of apomorphine induced climbing behavior
Sr. No. Compound
Total Climbing Score
1
3a
5.66 ± 0.20
2
3b
6.83 ± 0.16
3
3c
7.50 ± 0.42
4
3d
4.83 ± 0.20
5
3e
5.16 ± 0.16
6
3f
5.33 ± 0.20
7
3g
4.50 ± 0.22
8
3h
4.16 ± 0.16
9
3i
6.16 ± 0.30
10
3j
8.16 ± 0.30
11
Control
10.16 ± 0.30
12
Clozapine
3.33 ± 0.20
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218
EXPERIMENTAL
8
7
6
5
3j
Co
nt
ro
Cl
l
oz
ap
in
e
Compounds
3i
3h
3g
3f
3e
3d
3c
3b
4
3
2
1
0
3a
Total mean head twitches score
Figure 133. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
The effect of synthesized compounds (3a-j) on the 5-HTP induced head twitches behavior.
Each column represents the mean ± SEM of total head twitches score for group of six mice
assessed at 10-min intervals for 30 min, starting 20 after the 5-HTP treatment. A score of 8 is
the maximum possible. All values statistically significant with respect to control at p<0.05.
Table 148. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behaviour
Sr. No. Compound
Total Head Twitches Score
1
3a
4.83 ± 0.16
2
3b
5.33 ± 0.20
3
3c
5.66 ± 0.20
4
3d
2.83 ± 0.16
5
3e
3.33 ± 0.20
6
3f
3.66 ± 0.20
7
3g
4.33 ± 0.20
8
3h
4.16 ± 0.30
9
3i
4.83 ± 0.30
10
3j
6.33 ± 0.33
11
Control
7.16 ± 0.16
12
Clozapine
0.83 ± 0.16
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EXPERIMENTAL
Induction of catalepsy
16
14
12
10
8
6
4
2
0
30
60
90
120
Ha
l
Compounds
3
op j
er
id
ol
3i
3h
3g
3f
3e
3d
3c
3b
240
3a
Mean catalepsy score
Figure 134.
The effect of synthesized compounds (3a-j) on induction of catalepsy in mice. Results are
expressed as the mean ± SEM. (n=6) p<0.05.
Table 149.
Induction of catalepsy
Compound
Sr. No.
Mean catalepsy score
30 min
60 min
90 min
120 min
240 min
1
3a
2.66 ± 0.42 4.16 ± 0.30
5.50 ± 0.42
5.66 ± 0.71
3.66 ± 0.49
2
3b
2.66 ± 0.42 4.33 ± 0.49
5.83 ± 0.70
6.16 ± 0.47
3.50 ± 0.42
3
3c
2.83 ± 0.53 4.83 ± 0.47
6.16 ± 0.53
6.33 ± 0.42
3.83 ± 0.47
4
3d
1.66 ± 0.42 2.33 ± 0.61
3.66 ± 0.66
3.83 ± 0.60
2.83 ± 0.47
5
3e
2.66 ± 0.33 3.66 ± 0.55
4.66 ± 0.66
4.83 ± 0.53
3.16 ± 0.60
6
3f
2.66 ± 0.42 3.83 ± 0.47
5.16 ± 0.47
5.33 ± 0.49
3.66 ± 0.61
7
3g
2.50 ± 0.49 4.16 ± 0.65
5.66 ± 0.42
6.33 ± 0.55
4.16 ± 0.47
8
3h
1.50 ± 0.44 2.16 ± 0.47
2.83 ± 0.40
3.50 ± 0.49
2.33 ± 0.33
9
3i
2.83 ± 0.30 4.66 ± 0.61
5.83 ± 0.60
6.66 ± 0.55
3.50 ± 0.42
10
3j
3.66 ± 0.49 5.83 ± 0.70
7.33 ± 0.33
6.50 ± 0.55
4.66 ± 0.33
11
Haloperidol 4.66 ± 0.49
Shobhit University Meerut
7.83 ± 0.6
11.16 ± 0.74 13.50 ± 0.71 6.83 ± 0.47
220
EXPERIMENTAL
Series D
Pharmacological evaluation of 2-[4-(Aryl substituted) piperazin-1-yl]-N-benzyl
acetamides
The minimum effective dose (EDmin) that produced statistically significant result was
determined in the inhibition of apomorphine induced climbing behaviour, inhibition of
5-hydroxy tryptophan induced head twitches behaviour and in the induction of catalepsy
studies (Tab.150). The behaviour symptoms were observed at EDmin values obtained in the
inhibition of apomorphine induced climbing behaviour test. The test compounds did not show
any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion
(Tab.151). All the target compounds showed significant interaction with D2 and 5-HT2A
receptor (tabs. 152, 153 and 154 and figs. 135, 136 and 137). But the compound 3b showed
higher interaction with D2 receptor (EDmin = 20 mg/kg) and with 5-HT2A receptor (EDmin =
20 mg/kg) and minimum induction of catalepsy (EDmin = 80 mg/kg).
Table 150.
In vivo studies of compounds for antipsychotic activity
Compound
Inhibition of
apomorphine
induced climbing
behavior
(EDmin, mg/kg, i.p.)
Inhibition of
5-HTP induced head
twitches behavior
(EDmin, mg/kg, i.p.)
Induction of
catalepsy
(EDmin, mg/kg,
i.p.)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Clozapine
Haloperidol
40
20
30
50
40
40
30
30
50
30
6.0
-
30
20
30
50
40
40
20
20
50
40
2.0
-
70
80
70
70
70
60
70
60
60
80
nda
a
nd: Not determined, 1mg/kg dose was used
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221
EXPERIMENTAL
Table 151.
Behaviour symptoms
Compound
Behavioural symptoms
3a
Sedation
Sleep
30 min
-
Observation at Interval of
60 min 90 min 120 min 180 min
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
-
-
-
-
-
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
3i
Sleep
Hyperactivity
Convulsion
Sedation
3j
Sleep
Hyperactivity
Convulsion
+++ Marked effect, ++ Moderate effect, + Mild effect - Absence of effect
-
3b
3c
3d
3e
3f
3g
3h
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-
222
EXPERIMENTAL
Inhibition of apomorphine induced climbing behavior
Total mean climbing score
Figure 135.
16
14
12
10
8
6
4
2
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Compounds
l
e
tro p in
n
a
o
C
oz
Cl
The effect of synthesized compounds (3a-j) on the apomorphine induced climbing behavior.
Each column represents the mean ± SEM of total climbing score for group of six mice
assessed at 5-min intervals for 20 min, starting 10 min after apomorphine treatment. A score
of 20 is the maximum possible. All values statistically significant with respect to control at
p<0.05.
Table 152.
Inhibition of apomorphine induced climbing behavior
Sr. No. Compound
Total Climbing Score
1
3a
6.16 ± 0.30
2
3b
4.16 ± 0.30
3
3c
4.50 ± 0.22
4
3d
5.16 ± 0.30
5
3e
6.83 ± 0.30
6
3f
7.16 ± 0.40
7
3g
5.16 ± 0.40
8
3h
5.50 ± 0.22
9
3i
7.66 ± 0.33
10
3j
5.83 ± 0.30
11
Control
13.83 ± 0.40
12
Clozapine
4.00 ± 0.25
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EXPERIMENTAL
7
6
5
4
3
2
1
3j
Co
nt
ro
Cl
l
oz
ap
in
e
Compounds
3i
3h
3g
3f
3e
3d
3c
3b
0
3a
Total mean head twitches score
Figure 136. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
The effect of synthesized compounds (3a-j) on the 5-HTP induced head twitches behavior.
Each column represents the mean ± SEM of total head twitches score for group of six mice
assessed at 10-min intervals for 30 min, starting 20 after the 5-HTP treatment. A score of 8 is
the maximum possible. All values statistically significant with respect to control at p<0.05.
Table 153. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
Sr. No. Compound
Total Head Twitches Score
1
3a
4.00 ± 0.25
2
3b
2.16 ± 0.30
3
3c
2.66 ± 0.20
4
3d
2.83 ± 0.30
5
3e
4.33 ± 0.20
6
3f
4.33 ± 0.33
7
3g
3.16 ± 0.40
8
3h
3.50 ± 0.33
9
3i
4.50 ± 0.22
10
3j
3.83 ± 0.40
11
Control
6.16 ± 0.30
12
Clozapine
1.33 ± 0.20
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EXPERIMENTAL
Figure 137.
Induction of catalepsy
12
30
10
60
8
90
6
120
4
240
2
Ha
l
Compounds
3
op j
er
id
ol
3i
3h
3g
3f
3e
3d
3c
3b
0
3a
Mean catalepsy score
14
The effect of synthesized compounds (3a-j) on induction of catalepsy in mice. Results are
expressed as the mean ±SEM. (n=6).p<0.05.
Table 154.
Induction of catalepsy
Compound
Sr. No.
Mean catalepsy score
30 min
60 min
90 min
120 min
240 min
1
3a
2.83 ± 0.70 4.16 ± 0.30 4.83 ± 0.47
5.66 ± 0.33
3.16 ± 0.40
2
3b
1.83 ± 0.30 2.83 ± 0.47 3.66 ± 0.49
4.33 ± 0.49
2.16 ± 0.47
3
3c
2.83 ± 0.30 4.50 ± 0.22 5.33 ± 0.55
6.50 ± 0.42
3.66 ± 0.42
4
3d
3.66 ± 0.49 5.33 ± 0.61 7.16 ± 0.47
7.66 ± 0.49
3.83 ± 0.30
5
3e
3.83 ± 0.40 5.16 ± 0.47 6.83 ± 0.47
7.50 ± 0.42
4.33 ± 0.49
6
3f
2.83 ± 0.30 5.50 ± 0.33 7.16 ± 0.47
7.33 ± 0.42
4.16 ± 0.47
7
3g
2.16 ± 0.30 3.50 ± 0.42 4.83 ± 0.47
5.66 ± 0.49
2.50 ± 0.42
8
3h
2.83 ± 0.30 4.83 ± 0.30 5.50 ± 0.47
6.83 ± 0.20
4.16 ± 0.47
9
3i
3.16 ± 0.30 5.16 ± 0.47 6.16 ± 0.42
7.16 ± 0.47
4.33 ± 0.49
10
3j
2.83 ± 0.30 4.83 ± 0.47 5.66 ± 0.33
6.83 ± 0.47
3.83 ± 0.60
11
Haloperidol 4.16 ± 0.40 7.66 ± 0.49 10.16 ± 0.47 11.83 ± 0.60 6.66 ± 0.33
Shobhit University Meerut
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EXPERIMENTAL
Series E
Pharmacological evaluation of 2-[4-(arylsubstituted) piperazin-1-yl]-N-cyclohexyl
acetamides
The minimum effective dose (EDmin) that produced statistically significant result was
determined in the inhibition of apomorphine induced climbing behaviour, inhibition of
5-hydroxy tryptophan induced head twitches behaviour and in the induction of catalepsy
studies (Tab.155). The behaviour symptoms were observed at EDmin values obtained in the
inhibition of apomorphine induced climbing behaviour test. The test compounds did not show
any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion
(Tab.156). All the target compounds showed significant interaction with D2 and 5-HT2A
receptor (tabs. 157, 158 and 159 and figs. 138, 139 and 140). But the compound 3i showed
higher interaction with D2 receptor (EDmin =40 mg/kg) and with 5-HT2A receptor (EDmin =
30 mg/kg) and minimum induction of catalepsy (EDmin = 100 mg/kg).
Table 155.
In vivo studies of compounds for antipsychotic activity
Compound
Inhibition of
apomorphine
induced climbing
behavior
(EDmin, mg/kg, i.p.)
Inhibition of
5-HTP induced head
twitches behavior
(EDmin, mg/kg, i.p.)
Induction of
catalepsy
(EDmin, mg/kg,
i.p.)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Clozapine
Haloperidol
60
50
70
50
50
60
50
40
40
70
5.0
-
50
60
60
50
60
60
40
50
30
70
2.0
-
100
70
80
80
70
70
80
80
100
80
nda
a
nd: Not determined, 1mg/kg dose was used
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EXPERIMENTAL
Table 156.
Behaviour symptoms
Compound
Behavioural symptoms
3a
Sedation
Sleep
30 min
-
Observation at Interval of
60 min 90 min 120 min 180 min
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
Sedation
Sleep
-
-
-
-
-
Hyperactivity
Convulsion
-
-
-
-
-
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
Sleep
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
Hyperactivity
-
-
-
-
-
Convulsion
Sedation
-
-
-
-
-
Sleep
-
-
-
-
-
3b
3c
3d
3e
3f
3g
3h
Hyperactivity
Convulsion
Sedation
3i
Sleep
Hyperactivity
Convulsion
Sedation
3j
Sleep
Hyperactivity
Convulsion
+++ Marked effect, ++ Moderate effect, + Mild effect - Absence of effect
Shobhit University Meerut
-
-
227
EXPERIMENTAL
Inhibition of apomorphine induced climbing behavior
Total mean climbing score
Figure 138.
16
14
12
10
8
6
4
2
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Compounds
l
e
tro p in
n
a
o
C
oz
Cl
The effect of synthesized compounds (3a-j) on the apomorphine induced climbing behavior.
Each column represents the mean ± SEM of total climbing score for group of six mice
assessed at 5-min intervals for 20 min, starting 10 min after apomorphine treatment. A score
of 20 is the maximum possible. All values statistically significant with respect to control at
p<0.05.
Table 157.
Inhibition of apomorphine induced climbing behavior
Sr. No. Compound
Total Climbing Score
1
3a
7.00 ± 0.36
2
3b
7.83 ± 0.30
3
3c
8.50 ± 0.33
4
3d
6.16 ± 0.30
5
3e
6.83 ± 0.30
6
3f
7.50 ± 0.33
7
3g
5.50 ± 0.33
8
3h
5.83 ± 0.30
9
3i
5.16 ± 0.30
10
3j
9.00± 0.36
11
Control
13.83 ± 0.30
12
Clozapine
4.16 ± 0.30
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228
EXPERIMENTAL
7
6
5
4
3
2
1
Compounds
3j
Co
nt
ro
Cl
l
oz
ap
in
e
3i
3h
3g
3f
3e
3d
3c
3b
0
3a
Total mean head twitches score
Figure 139. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
The effect of synthesized compounds (3a-j) on the 5-HTP induced head twitches behavior.
Each column represents the mean ± SEM of total head twitches score for group of six mice
assessed at 10-min intervals for 30 min, starting 20 after the 5-HTP treatment. A score of 8 is
the maximum possible. All values statistically significant with respect to control at p<0.05.
Table 158. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior
Sr. No. Compound
Total Head Twitches Score
1
3a
3.50 ± 0.22
2
3b
4.33 ± 0.20
3
3c
4.83 ± 0.40
4
3d
2.83 ± 0.16
5
3e
3.16 ± 0.16
6
3f
4.00 ± 0.25
7
3g
5.50 ± 0.22
8
3h
2.50 ± 0.22
9
3i
2.16 ± 0.16
10
3j
5.16 ± 0.40
11
Control
6.33 ± 0.20
12
Clozapine
1.50 ± 0.22
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EXPERIMENTAL
Figure 140.
Induction of catalepsy
Mean catalepsy score
14
12
30
10
60
8
90
6
120
4
240
2
0
3a
3b
3c
3d
3f
3e
3g
3h
3i
3j
Ha
r id
pe
o
l
ol
Compounds
The effect of synthesized compounds (3a-j) on induction of catalepsy in mice. Results are
expressed as the mean ± SEM. (n=6) p<0.05.
Table 159.
Induction of catalepsy
Compound
Sr. No.
Mean catalepsy score
30 min
60 min
90 min
120 min
240 min
1
3a
3.50 ± 0.22 6.16 ± 0.40 9.66 ± 0.20
11.50 ± 0.33 4.30 ± 0.33
2
3b
3.33 ± 0.20 6.16 ± 0.30 7.33 ±0.33
10.33 ± 0.33 3.83 ± 0.30
3
3c
3.16 ± 0.30 6.33 ± 0.33 7.66 ± 0.20
8.16 ± 0.30
4.16 ± 0.30
4
3d
2.83 ± 0.30 5.16 ± 0.16 6.50 ± 0.22
7.66 ± 0.49
3.33 ± 0.22
5
3e
4.16 ± 0.30 6.83 ± 0.30 8.16 ± 0.47
8.33 ± 0.33
4.16 ± 0.40
6
3f
3.33 ± 0.20 6.50 ± 0.22 8.50 ± 0.33
9.50 ± 0.22
5.66 ± 0.33
7
3g
4.00 ± 0.44 6.33 ± 0.42 8.66 ± 0.33
8.50 ± 0.42
4.50 ± 0.42
8
3h
3.83 ± 0.30 6.33 ± 0.33 8.16 ± 0.30
8.50 ± 0.22
4.83 ± 0.30
9
3i
4.33 ± 0.30 7.33 ± 0.30 10.16 ± 0.33 11.16 ± 0.20 5.66 ± 0.30
10
3j
3.66 ± 0.20 5.83 ± 0.30 7.50 ± 0.33
9.66 ± 0.33
4.50 ± 0.33
11 Haloperidol 4.50 ± 0.33 7.83 ± 0.40 10.50 ± 0.33 12.83 ± 0.30 6.83 ± 0.30
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4.4.5 Acute Toxicity Study
The acute toxicity study of potent compounds was performed as per the OECD
guidelines (Tab.160). The albino mice of either sex (body weight 24-25 g) were used. The
potent compound was administered by intraperitoneal route (i.p.) at different dose levels in
groups of 3 animals each. Animals were observed individually after administration at least
once during the first 30 minutes, periodically during the first 24 hours, with special attention
given during the first 4 hours and daily thereafter, for a total of 14 days. During the
observations, no tremors, hyperactivity, convulsions, salivation, diarrhoea, sedation, sleep,
coma, weighted changes and mortality were observed.
Table 160.
LD50 (mg/kg, i.p.) of potent compounds
Sr.No.
Series Compound LD50 (mg/kg, i.p.)
1
A
3a4
>2000
2
B
3e
>2000
3
C
3h
>2000
4
D
3b
>2000
5
E
3i
>2000
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EXPERIMENTAL
4.4.6 Structure Activity Relationships (SAR)
Arylpiperazines are one of the most important classes of serotonin and dopamine
receptor ligands. SAR studies of these compounds have shown significant interaction with
serotonin (5-HT2A) and dopamine (D2) receptors that is influenced by the nature of the N-aryl
group of the piperazine ring, length of the alkyl chain and nature of the terminal fragment
(Fig. 141).
R
terminalfragment
N
N
R= H, CH3, Cl, OCH3, F, CF3, NO2.
Where terminal fragment
CONH2
N
COCH2
NHCOCH2
O(CH2)n
Series A
Series B
CH2NHCOCH2
Series D
Series C
NHCOCH2
Series E
Figure 141. The general structure of arylpiperazines
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EXPERIMENTAL
Series A
The compounds possessing methoxy group (3a4 and 3a5) at ortho or meta position of
aryl moiety of piperazine produced statistically significant reversal of apomorphine induced
climbing behaviour than ortho chloro analog (3a6). A significant reduction in activity was
observed, when methyl group was present at meta or para position of aryl moiety of
piperazine (3a2 and 3a3). Other compounds (3a1, 3b1-3b2 and 3c1-3c2,) showed lesser
interaction at the D2 receptor. The data also revealed the compounds with alkyl side chain
length n=2 showed better activity than compounds with chain length n=3 and 4 (Fig.126).
The inhibition of 5-HTP induced head twitches behaviour (5-HT2A antagonism) study
showed that ortho methoxy analog (3a4) with shorter alkyl side chain (n=2) produced
significant activity than para methoxy and chloro analogs (3a5 and 3a6). The methyl analogs
(3a2 and 3a3) showed lesser interaction with receptor. The data also revealed that compounds
with alkyl side chain length n=2 showed better activity than compounds with chain length n=3
and 4 (Fig.127).
The catalepsy results showed that all the compounds were less cataleptogenic than
haloperidol. Among them methoxy analogs (3a4) exhibited lower propensity to produce
catalepsy (Fig.128).
Series B
The compound possessing methoxy group (3e) at ortho position of aryl moiety of
piperazine produced statistically significant reversal of apomorphine induced climbing
behaviour than meta methoxy, meta chloro and meta trifluoromethyl analogs (3f, 3g and 3d).
A significant reduction in activity was observed, when para methyl or ortho, meta dimethyl
group or para nitro group, was present at aryl moiety of piperazine ring (3b, 3c and 3j). Other
compounds (3i, 3a and 3h) have lesser interaction at the D2 receptor (Fig.129).
The inhibition of 5-HTP induced head twitches behaviour (5-HT2A antagonism) study
showed that ortho methoxy analogs (3e) produced significant activity than meta methoxy,
meta chloro and trifluoromethyl analogs (3f, 3g and 3d). The decrease in activity was
observed, when, para methyl, ortho, meta dimethyl and para nitro group was present at aryl
moiety of piperazine ring (3j, 3b and 3c).
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EXPERIMENTAL
The other compounds (3i, 3a and 3h) have lesser interaction at the5-HT2A receptor
(Fig.130).
The catalepsy results showed that all the compounds were less cataleptogenic than
haloperidol. Among them methoxy analogs (3e and 3f) exhibited lower propensity to produce
catalepsy (Fig.131).
Series C
The compounds (3h, 3g) possessing chloro group at meta and para positions of aryl
moiety of piperazine produced statistically significant reversal of apomorphine induced
climbing behaviour than their methoxy analogs (3d, 3e, 3f). While methyl group present at
meta or para position of arylpiperazine (3b and 3c) greatly decreased the activity. A
significant reduction in activity was observed, when nitro group was present at para position
of arylpiperazine (3j). Other compounds (3a and 3i,) showed lesser efficacy at the D2 receptor
(Fig.132).
The inhibition of 5-HTP induced head twitches behaviour (5-HT2A antagonism) study
showed that methoxy analogs (3d, 3e and 3f) produced significant activity than chloro
analogs (3g and 3h). Replacement of chlorine substituent with a more electron withdrawing
nitro group (3j) greatly decreased the activity. The other compounds (3a, 3b, 3c and 3i)
showed lower antagonism of 5-HTP induced head twitches behavior (Fig.133).
The catalepsy results showed that all the compounds (3a-j) were less cataleptogenic
than haloperidol. Among them meta chloro analogs (3h) exhibited lower propensity to
produce catalepsy (Fig.134).
Series D
The compounds bearing a methoxy group at ortho, meta and para position of aryl
moiety of piperazine ring (3b, 3c and 3d) produced statistically significant reduction in
apomorphine induced climbing behaviour than chloro analogues (3g and 3h). A significant
reduction in activity was observed, when nitro group was present at para position of aryl
moiety of piperazine ring (3i). Other compounds (3a, 3e, 3f and 3j) showed lesser efficacy for
the D2 receptor (Fig.135).
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EXPERIMENTAL
Regarding the 5-HT2A receptor the methoxy analogues (3b, 3c and 3d) also showed
higher inhibition of 5-hydroxy tryptophan (5-HTP) induced head twitches behavior than
chloro analogues (3g and 3h). Highest reduction in activity was observed when meta methyl
or para methyl or nitro substituent was present on arylpiperazine ring (3e, 3f and 3i). The
other compounds (3a, and 3j) showed lower activity for the 5-HT2A receptor (Fig.136).
The catalepsy results showed that all the compounds (3a-j) were less cataleptogenic
than haloperidol. Among them the orthomethoxy analog (3b) exhibited lower propensity to
produce catalepsy (Fig.137).
Series E
The compounds bearing a fluoro group at para position of aryl piperazine ring (3i)
produced statistically significant reduction in apomorphine induced climbing behaviour than
ortho and meta chloro analogues (3g and 3h). A significant reduction in activity was
observed, when nitro group was present at para position of aryl moiety of piperazine ring (3j).
The compounds bearing methoxy group (3d, 3e and 3f) exhibited further reduction in
activity. Other compounds (3a, 3b, and 3c) showed lesser efficacy for the D2 receptor
(Fig.138).
Regarding the 5-HT2A receptor the meta chloro analogue (3h) also showed higher
inhibition of 5-hydroxy tryptophan (5-HTP) induced head twitches behavior than methoxy
analogues and ortho chloro analogue (3d, 3e, 3f and 3g). Highest enhancement in activity was
observed when fluoro substituent was present on arylpiperazine ring (3i). The other
compounds (3a, 3b, 3c and 3j) showed lower activity for the 5-HT2A receptor (Fig.139).
The catalepsy results showed that all the compounds (3a-j) were less cataleptogenic
than haloperidol. Among them the fluoro analog (3i) exhibited lower propensity to produce
catalepsy (Fig.140).
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SUMMARY AND CONCLUSION
5
SUMMARY AND CONCLUSION
Series of arylpiperazines were prepared using the pathway shown in schemes (1-5).
The target compounds were prepared by a two step procedure. In series A, the first step was
alkylation of salicylamide (1) with dihaloalkanes (1, 2-dibromoethane, 1-bromo-3chloropropane and 1, 4-dibromobutane) in acetonitrile in the presence of potassium carbonate
followed by condensation of intermediates (2a or 2b or 2c) with substituted
phenylpiperazines in dimethylformamide in the presence of potassium carbonate and
potassium iodide as catalyst which afforded the target compounds (3a1-3a6, 3b1-3b2 and 3c13c2).
In series B, C, D, and E, the first step was chloroacetylation of amines
(diphenylamine, aniline, benzylanline and cyclohexylamine) followed by condensation of
intermediates (2) with substituted phenylpiperazines in acetonitrile in the presence of
potassium carbonate and potassium iodide as catalyst which afforded the target compounds
(3a-j). All the reactions were monitored by TLC. The final products were purified by
recrystallization and characterized by spectroscopic methods.
A set of physicochemical properties was computed for the target compounds as well as
three standard drugs clozapine, ketanserin and risperidone using software programs. The
values of physicochemical properties for the test compounds were found very close to the
standard drugs and shown in Tables 125, 127, 129, 131 and 133. The physicochemical
similarity of the target compounds was calculated with respect to the standard drugs and
shown in Tables 126, 128, 130, 132 and 134. The compounds showed good structural
similarity with respect to standard drugs.
All the target compounds were subjected to pharmacological evaluation for behavior
symptoms, inhibition of apomorphine induced climbing behavior, inhibition of 5-hydroxy
tryptophan (5-HTP) induced head twitches behavior and induction of catalepsy studies. The
acute toxicity of the potent compound in a series was also performed.
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SUMMARY AND CONCLUSION
Series A
The log BB, log P and TPSA values were -0.02, 2.52 and 68.03 respectively for 2-{2[4-(2-methoxyphenyl) piperazin-1-yl] ethoxy} benzamide (3a4). The compound 3a4 showed
good physicochemical similarity with respect to standard drugs (37.62%, 85.03% and 82.05
% with respect to clozapine, ketanserin and risperidone, respectively). The pharmacological
results suggested that the presence of methoxy group in the phenyl group of piperazine ring
and compound with shorter alkoxy side chain (n=2) increased the atypical antipsychotic
activity (higher D2 antagonistic and 5-HT2A antagonistic activity) with minimum induction of
catalepsy. The compound 3a4 did not show any significant behavioral changes viz: sedation,
sleep, hyperactivity and convulsion. Thus, the compound 3a4 emerged as most potent and
contributed to an atypical antipsychotic like profile.
Series B
The log BB, log P and TPSA values were 0.21, 4.36 and 36.02 respectively for 2-[4(2-methoxyphenyl) piperazin-1-yl] N, N -diphenylacetamide (3e). The compound 3e showed
good physicochemical similarity with respect to standard drugs (20.44%, 76.74% and 86.33
% with respect to clozapine, ketanserin and risperidone, respectively). The compound 3e did
not show any significant behavioral changes viz: sedation, sleep, hyperactivity and
convulsion. The compound 3e showed statistically significant inhibition of apomorphine
induced mesh climbing behaviour (EDmin = 20 mg/kg), inhibition of 5-HTP induced head
twitches (EDmin = 10 mg/kg) and minimum induction of catalepsy (EDmin = 80 mg/kg).
Thus, the compound 3e emerged as most potent and contributed to an atypical antipsychotic
like profile.
Series C
The log BB, log P and TPSA values were 0.41, 3.15 and 35.58 respectively for 2-[4(3-chlorophenyl) piperazin-1-yl]-N-phenylacetamide (3h). The compound 3h showed good
physicochemical similarity with respect to standard drugs (80.62%, 70.65% and 68.15 % with
respect to clozapine, ketanserin and risperidone, respectively). The compound 3h did not
show any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion.
The compound 3h showed statistically significant inhibition of apomorphine induced mesh
climbing behaviour (EDmin = 30 mg/kg), inhibition of 5-HTP induced head twitches (EDmin
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SUMMARY AND CONCLUSION
= 20 mg/kg) and minimum induction of catalepsy (EDmin = 60 mg/kg). Thus, the compound
3h emerged as most potent and contributed to an atypical antipsychotic like profile.
Series D
The log BB, log P and TPSA values were 0.27, 2.53 and 44.81 respectively for 2-[4(2-methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3b). The compound 3b showed good
physicochemical similarity with respect to standard drugs (57.60%, 78.35% and 78.82 % with
respect to clozapine, ketanserin and risperidone, respectively). The compound 3b did not
show any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion.
The compound 3b showed statistically significant inhibition of apomorphine induced mesh
climbing behaviour (EDmin = 20 mg/kg), inhibition of 5-HTP induced head twitches (EDmin
= 20 mg/kg) and minimum induction of catalepsy (EDmin = 80 mg/kg). Thus, the compound
3b emerged as most potent and contributed to an atypical antipsychotic like profile.
Series E
The log BB, log P and TPSA values were 0.24, 2.63 and 35.58 respectively for 2-[4(4-fluorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3i). The compound 3i showed good
physicochemical similarity with respect to standard drugs (76.82%, 69.84% and 68.80 % with
respect to clozapine, ketanserin and risperidone, respectively). The compound 3i did not show
any significant behavioral changes viz: sedation, sleep, hyperactivity and convulsion. The
compound 3i showed statistically significant inhibition of apomorphine induced mesh
climbing behaviour (EDmin = 40 mg/kg), inhibition of 5-HTP induced head twitches (EDmin
= 30 mg/kg) and minimum induction of catalepsy (EDmin = 100 mg/kg). Thus, the compound
3i emerged as most potent and contributed to an atypical antipsychotic like profile.
It may be concluded that the series of arylpiperazines were synthesized and their
pharmacological evaluation showed potential antipsychotic activity in animal model.
Computational studies of the test compounds were also carried out to prediction of
physicochemical similarity with respect to standard drugs. Test compounds showed good
similarity with respect to the standard drugs. The log BB, log P and TPSA values indicate
these have a good potential to penetrate the blood brain barrier and show CNS activity. The
compounds 3a4 (Series A), 3e (Series B), 3h (Series C), 3b (Series D) and 3i (Series E) were
most potent and might be useful as antipsychotic drugs.
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antagonists as potential antipsychotic agents. J. Med. Chem. 2000, 43, 3923-3932.
Shobhit University Meerut
254
PUBLICATIONS
1. A research paper entitled “Synthesis, computational studies and preliminary
pharmacological evaluation of new arylpiperazines as potential antipsychotics” has
been accepted for publication in Medicinal Chemistry Research.
2. A research paper entitled “Synthesis and preliminary pharmacological evaluation of
2-[4-(aryl substituted) piperazin-1-yl]-N-phenylacetamides: Potential antipsychotics
has been accepted for publication in Tropical Journal of Pharmaceutical research.
3. A research paper entitled “Synthesis, computational studies and preliminary
pharmacological evaluation of new arylpiperazines” has been accepted for publication
in E-Journal of chemistry.
4. A research paper entitled “Synthesis, computational studies and preliminary
pharmacological evaluation of 2–[4-(aryl substituted) piperazin-1-yl] N, Ndiphenylacetamides as potential antipsychotics” is under review for publication in
European journal of medicinal chemistry.
5. A research paper entitled “Synthesis and preliminary pharmacological evaluation of
2-[4-(arylsubstituted) piperazin-1-yl]-N-benzylacetamides as potential antipsychotics”
is under review for publication in Archives Pharmacal Research.
<>
Mailbox of [email protected]
From: E-Journal of Chemistry <[email protected]>
To: "[email protected]" <[email protected]>
Subject: Articel Details for # 3883R
Date: Wed, 15 Dec 2010 23:10:56 IST
Dear S. Kumar
We are pleased to inform you that the following research article(s) has been accepted for
publication in
our E-Journal of Chemistry.
Article Title:
Article
Title:
Synthesis, Computational studies and Preliminary Pharmacological Evaluation of
New Arylpiperazines
Manus. ID
3883R
:
Authors :
S. Kumar, A. K. Wahi, R. Singh
Authors
Institution
Drug Design & Medicinal Chemistry Research Laboratory,College of
Pharmacy,IFTM (U.P.), Moradabad, INDIA, 244001.
School of Pharmaceutical Sciences, Shobhit University, Meerut (U.P.) India.
Articles will be published in the website and also in the printed version at the same time.
It is requested that each author and co-authors must be a subscribers to E- Journal of
Chemistry.
Here, we are sending the invoice bill (3). Your article will be published in the Volume 8.
We will dispatch the letter and bill by post (ordinary) soon.
With Best Regards,
For E-J.Chem.,
http://www.e-journals.net
From:
"European Journal of Medicinal Chemistry" <[email protected]> | Add to
Address book |This is spam
To: [email protected]
Subject:
Progress Update for your submission (EJMECH-D-10-00427R1) to European Journal of
Medicinal Chemistry
Date: Mon, 16 May 2011 22:42:56 IST
Ms. Ref. No.: EJMECH-D-10-00427R1
Title: Synthesis, computational studies and preliminary pharmacological evaluation of 2-[4-(aryl
substituted) piperazin-1-yl] N, N-diphenylacetamides as potential antipsychotics
European Journal of Medicinal Chemistry
Dear Mr Kumar,
We are pleased to inform you that a reviewer has agreed to review your manuscript EJMECH-D-1000427R1
Please note that in most cases at least two reviews may be required before a decision on a manuscript
is made. Please also note that the length of the review process can vary greatly between manuscripts.
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Mailbox of [email protected]
From: Editorial Office Archives of Pharmacal Research <[email protected]>
To: "Sushil Kumar" <[email protected]>
Subject:
ARPR: A manuscript number has been assigned to Synthesis and Preliminary Pharmacological
Evaluation of 2-[4-(Aryl substituted) piperazin-1-yl]-N-benzylacetamides as Potential Antipsychotics
Date: Mon, 31 Jan 2011 14:01:26 IST
Dear Prof Kumar,
Your submission entitled "Synthesis and Preliminary Pharmacological Evaluation of 2-[4-(Aryl
substituted) piperazin-1-yl]-N-benzylacetamides as Potential Antipsychotics" has been assigned
the following manuscript number: ARPR-D-11-00076.
You will be able to check on the progress of your paper by logging on to Editorial Manager as
an author.
The URL is http://arpr.edmgr.com/.
Thank you for submitting your work to this journal.
Kind regards,
Editorial Office
Archives of Pharmacal Research