synthesis and pharmacological evaluation of compounds...

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-to-

be 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-to-

be 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:

i

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

ii

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.

iii

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

iv

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.

v

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 0C 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

vi

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

Dedicated To My Lord Hanumanji

CONTENTS

Certificates

Declaration

IAEC Certificate

Acknowledgement i-iii

Abstract iv

Abbreviations v-vi

CHAPTER 1 INTRODUCTION 1-23

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

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 46-235

4.1 Materials and methods

4.2. Synthesis and characterization of compounds

4.3 Computational studies

4.4 Pharmacological evaluation for antipsychotic effect

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

Shobhit University Meerut 1

1 INTRODUCTION

1.1 ANTIPSYCHOTICS

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.

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 types-

Phenothiazines- 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 Promazine, Promethazine, Chlorpromazine, Levomepromazine

Methotrimeprazine, Triflupromazine, Thioridazine, Mesoridazine, Prochlorperazine,

Perphenazine, Fluphenazine and Trifluoperazine.

N

S

(CH2)3N(CH3)2

Cl

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.

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).

F COCH2CH2CH2 N

OH

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.

C

S

CHCH2CH2

SO2NCH3

NN CH3

CH3

Thiothixene

Dihydroindolones

Molindone is a dihydroindolone compound. It works by blocking the effects of

dopamine in the brain.

INTRODUCTION


HN

ON

O

Molindone

Dibenzoxazepine

Loxapine is a dibenzoxazepine compound used primarily in the treatment of

schizophrenia.

O

N NN

CH3

Cl

Loxapine

Diphenylbutylpiperidine- Diphenylbutylpiperidines are a class of typical antipsychotic

drugs. The examples are Clopimozide, Fluspirilene, Penfluridol, and Pimozide.

HNN N

F

F

O Pimozide

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.

NH

NN

Cl

N

CH3

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, α2-

receptors and histaminergic receptors.

N

N

N

ON

F

O

Risperidone

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 5-

HT2A receptor antagonism. The drug has antagonist effect at α1 and α2 adrenergic receptors

and at H1 histamine receptors.

N

N

N

O N

F

O

OH

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 (5-

HT1A and 5-HT6) and also of noradrenaline (α2C) receptors.

ON

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.

INTRODUCTION


N

N

OHN

O

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.

HN

N

N

S

N

O

Cl

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.

INTRODUCTION


NH

N

S

N

N

CH3

CH3 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.

S

N

N

N O OH

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

Br

NH

O

N

C2H5

Remoxipride

INTRODUCTION


Sulpiride Sulpiride is a substituted benzamide derivative and a selective dopamine D2

antagonist with antipsychotic and antidepressant activity.

O

NH

H3CO

N SO

ONH2

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.

N

Cl

F

NN

HNO

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.

INTRODUCTION


S

O

N

Cl

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.

HN OO

N N

Cl Cl

Aripiprazole

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

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).

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-HT1

5-HT25-HT3 5-HT4

5-HT5

5-HT6 5-HT7

5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F

5-HT2A, 5-HT2B, 5-HT2C

5-HT5A 5-HT5B

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.

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 mesolimbic-

mesocortical 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

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 parkinsonian-

type 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).

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 YM-

43611 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 2-

phenylimidazole 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).

INTRODUCTION


Cl

H3CHN OCH3

NH

O

N

CH31

OCH3

SO2Et

NH

N

2

NH

N

N

OCH3

3 N

NH

N

N

OCH3

4

N

NH

N

N N

N

5

N

NH

N

N CH

N

6

N NH

NN

Cl

7

O

N

N

SO2NH2

8

NH

O

N

N

Cl

9

NH2

O

O N

10 Figure 4. Chemical structure of D4 selective compounds (1-10).

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

Br

NH

ON

11CN

OCH3

NH

O

N

n-Bu12

O

O

NH

OCH3

13

N

N

CN

N

NH

O

N

14

Figure 5. Chemical structure of D3 selective compounds: azabicyclononane (11); Nafadotride

(12); GR 103691(13); SB-277011 (14).

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.

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.

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 (5-

HT), 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).

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.

N

NN N

N

O

OBuspirone

N N

OCH3

NH

O

WAY-100135

N N

OCH3

N

N

OWAY-100635

NH

O

N N

H3COBP 897

Figure 6. Structure of some amide and imides based arylpiperazines: Buspirone, WAY-

100135, 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.

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.

N

N O O

O

R1 R2

n

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.

O

S

O

ON

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.

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 4-

arylpiperazine-ethyl carboxamide derivatives differentially modulate affinity for 5-HT1A,

D4.2, and α 2A receptors.

N

NNH

O

N

NR

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 5-

HT1A/5-HT2C ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or

atypical antipsychotic agent therapeutical profiles.

N

N

X

O

NH

O

O

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 apomorphine-

induced 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

ON

N

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.

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-8-

en-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.

N

N

NR

O

n

n

Ar

NHN

N

R

O

5

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.

LITERATURE REVIEW


N

NS CH3

O

R

N

NR'

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, 3-

benzoxazine-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-(4-

phenylpiperazin-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-[2-

hydroxy-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]-2-

quinolinamines as high-affinity fluorescent 5-HT1A receptor ligands.

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]-7-

methoxy-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, 6-

dimethoxybenzhydrazide 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, 4-

tetrahydro-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), alpha-

adrenergic (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.

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.

N

NO

O

N

N

N

(CH2)4

O

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.

OO

CH3

O(CH2)n N N

R

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.

N

HN

N

N

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, 9-

dione 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.

NN

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.

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, 4-

tetrahydroisoquinoline (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) piperazin-

1-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 5-

aminomethyl 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.

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.

NO O

(CH2)3

R

AA=cyclohexane or tetralone

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.

Ar

O

NH (CH2)n N N Ar'

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 5-

HT2C 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.

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 dihydrophthalazine-

1, 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.

OCH3

XN

NAr

Srinivas et al., (1999) reported synthesis and preliminary binding affinities of 1-(1, 2-

dihydro-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.

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.

NH

O ON

N

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.

LITERATURE REVIEW


N

S

R

O

(CH2)n N N

(CH2)n N N

N

O

OR

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.

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-(2-

piperidinoethyl) 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 5H-

dibenzo[a,d]cycloheptene analogues of clozapine [8-chloro-11-(4-methylpiperazino)-5H-

dibenzo[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.

Y

X

Z

NH

O

R

O

N

Gupta et al., (1990) reported in vitro antidopaminergic activity of N-[(1-alkyl-2-pyrrolidinyl)

methyl]-6-methoxysalicylamides.

RESEARCH ENVISAGED AND PLAN OF WORK


3 RESEARCH ENVISAGED AND PLAN OF WORK 3.1 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.



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

OH

(1)

CONH2

O(CH2)nX

(2a,2b,2c)n=2,3,4

HN N

R

CONH2

O(CH2)n N N

R

3a1-6,3b1-2,3c1-2

i

X=Cl,Brii

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



Series B

Synthesis of 2–[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides

NH ClCOCH2Cli

N COCH2Cl

(2)

(1)HN Nii

N COCH2 N N

3a-j

R

R

Scheme 2. Synthesis of the target compounds. Reagents and conditions :(i) Toluene, reflux,

4h (ii) Acetonitrile, K2CO3, KI.


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



Series C

Synthesis of 2-[4-(Aryl substituted) piperazin-1-yl]-N-phenylacetamides

NH2 ClCOCH2Cli

HN COCH2Cl

(2)

(1)HN Nii

HN COCH2 N N

3a-j

R

R

Scheme 3. Synthesis of the target compounds. Reagents and conditions :(i) NaOH,

Dichloromethane (ii) Acetonitrile, K2CO3, KI.


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



Series D

Synthesis of 2-[4-(Aryl substituted) piperazin-1-yl]-N-benzylacetamides

CH2NH2 ClCOCH2Cli

CH2NHCOCH2Cl

(2)

(1)HN Nii

CH2NHCOCH2 N N

3a-j

R

R

Scheme 4. Synthesis of the target compounds. Reagents and conditions :(i) NaOH,



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



Series E

Synthesis of 2-[4-(Aryl substituted) piperazin-1-yl]-N-cyclohexylacetamides

NH2 ClCOCH2Cli

HN COCH2Cl

(2)

(1) HN Nii

HN COCH2 N N

3a-j

R

R

Scheme 5. Synthesis of the target compounds. Reagents and conditions: (i) NaOH,



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



3.2.2 Characterization of synthesized compounds

The synthesized compounds were characterized by following methods

Melting point

Thin Layer Chromatography

IR Spectroscopy 1H 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

EXPERIMENTAL


4 EXPERIMENTAL

4.1 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.

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

OH

(1)

CONH2

O(CH2)nX

(2a,2b,2c)

n =2, 3 , 4

X= Cl , Br

i

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

EXPERIMENTAL


2-(3-Chloropropoxy) benzamide (2b)

Yield : 5.4 g



Rf value : 0.74


Molecular formula : C10H12ClNO2

2-(4-Bromobutoxy) benzamide (2c)

Yield : 4.70 g



Rf value : 0.67


Molecular formula : C11H14BrNO2

EXPERIMENTAL


Step II. Synthesis of final compounds (3a1-6, 3b1-2 and 3c1-2)

CONH2

O(CH2)nX

(2a,2b,2c)n=2,3,4

HN N

R

CONH2

O(CH2)n N N

R

(3a1-6, 3b1-2 and 3c1-2)

X=Cl,Bri

Scheme 1. Synthesis of the target compounds. Reagents and conditions: (i) DMF, K2CO3, KI,

Reflux.


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

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



Rf value : 0.21


Molecular formula : C19H23N3O2

2-{2-[4-(3-Methylphenyl) piperazin-1-yl] ethoxy} benzamide (3a2)

Yield : 0.54 g



Rf value : 0.28

Mobile phase : ethyl acetate: methanol (2: 0.4)


2-{2-[4-(4-Methylphenyl) piperazin-1-yl] ethoxy} benzamide (3a3)

Yield : 0.40 g



Rf value : 0.31



EXPERIMENTAL


2-{2-[4-(2-Methoxyphenyl) piperazin-1-yl] ethoxy} benzamide (3a4)

Yield : 0.31 g



Rf value : 0.59



Log P (Experimental) : 2.28

2-{2-[4-(3-Methoxyphenyl) piperazin-1-yl] ethoxy} benzamide (3a5)

Yield : 0.38 g



Rf value : 0.46



2-{2-[4-(2-Chlorophenyl) piperazin-1-yl] ethoxy} benzamide (3a6)

Yield : 0.44 g



Rf value : 0.47


Molecular formula : C19H22ClN3O2

2-[3-(4-Phenylpiperazin-1-yl) propoxy] benzamide (3b1)

Yield : 0.26 g



Rf value : 0.30



EXPERIMENTAL


2-{3-[4-(2-Methoxyphenyl) piperazin-1-yl] propoxy} benzamide (3b2)

Yield : 0.28 g



Rf value : 0.38



2-[4-(4-Phenylpiperazin-1-yl) butoxy] benzamide (3c1)

Yield : 0.24 g



Rf value : 0.39



2-{4-[4-(2-Methoxyphenyl) piperazine-1-yl] butoxy} benzamide (3c2)

Yield : 0.28 g



Rf value : 0.57



EXPERIMENTAL


Figure 7. IR Spectrum of 2-(2-bromoethoxy) benzamide (2a)

NH2

OCH2CH2Br

O

Table 7. 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

EXPERIMENTAL


Figure 8. NMR Spectrum of 2-(2-bromoethoxy) benzamide (2a)

Table 8. 1H 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

EXPERIMENTAL


Figure 9. IR Spectrum of 2-(3-chloropropoxy) benzamide (2b)

NH2

OCH2CH2CH2Cl

O

Table 9. IR Data of 2b


3455 N-H Str



1645 C=O Str

1029 C-O-C Str

749 C-Cl Str

EXPERIMENTAL


Figure 10. NMR Spectrum of 2-(3-chloropropoxy) benzamide (2b)

Table 10. 1H NMR Data of 2b


1.92-2.21 2 CH2

3.31 2 CH2Cl

4.21 2 OCH2

7.0-7.48 4 Aromatic

7.80 2 CONH2

EXPERIMENTAL


Figure 11. IR Spectrum of 2-(4-bromobutoxy) benzamide (2c)

NH2

OCH2CH2CH2CH2Br

O

Table 11. IR Data of 2c


3455 N-H Str



1657 C=O Str

1029 C-O-C Str

748 C-Br Str

EXPERIMENTAL


Figure 12. NMR Spectrum of 2-(4-Bromobutoxy) benzamide (2c)

Table 12. 1H NMR Data of 2c


1.92-2.51 4 CH2CH2

3.36 2 CH2Br

4.21 2 OCH2

7.0-7.51 4 Aromatic

7.80 2 CONH2

EXPERIMENTAL


Figure 13. IR Spectrum of 2-[2-(4-phenylpiperazin-1-yl) ethoxy] benzamide (3a1)

O

NH2

ON

N

Table 13. IR Data of 3a1


3457 N-H Str



1644 C=O Str

1391 C-N Str Aromatic

1231 C-N Str Aliphatic

1033 C-O-C Str

EXPERIMENTAL


Figure 14. NMR Spectrum of 3a1

Table 14. 1H NMR Data of 3a1


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

EXPERIMENTAL


Figure 15. Mass Spectrum of 3a1

Mass Data

MS (EI) m/z: 326.10(M+1).

EXPERIMENTAL


Figure 16. IR Spectrum of 2-{2-[4-(3-methylphenyl) piperazin-1-yl] ethoxy}

benzamide (3a2)

O

NH2

ON

N CH3



3458 N-H Str



1648 C=O Str



1033 C-O-C Str

EXPERIMENTAL


Figure 17. NMR spectrum of 3a2



2.31 3 CH3

2.48-2.85 2 CH2N


4.15 2 OCH2


7.82 2 CONH2

EXPERIMENTAL


Figure 18. IR Spectrum of 2-{2-[4-(4-methylphenyl) piperazin-1-yl] ethoxy}

benzamide (3a3)

O

NH2

ON

N

CH3



3389 N-H Str



1643 C=O Str



1035 C-O-C Str

EXPERIMENTAL





2.32 3 CH3

2.65-2.68 2 CH2N


4.15 2 OCH2


7.80 2 CONH2

EXPERIMENTAL


Figure 20. IR Spectrum of 2-{2-[4-(2-methoxyphenyl) piperazin-1-yl] ethoxy}

benzamide (3a4)

O

NH2

ON

N

OCH3



3377 N-H Str



1641 C=O Str



1023 C-O-C Str

EXPERIMENTAL





2.48-2.97 2 CH2N


3.97 3 OCH3

4.15 2 OCH2


7.82 2 CONH2

EXPERIMENTAL


Figure 22. IR Spectrum of 2-{2-[4-(3-methoxyphenyl) piperazin-1-yl] ethoxy}

benzamide (3a5)

O

NH2

ON

N OCH3



3392 N-H Str



1638 C=O Str



1047 C-O-C Str

EXPERIMENTAL





2.55-2.98 2 CH2N


3.94 3 OCH3

4.15 2 OCH2


7.80 2 CONH2

EXPERIMENTAL


Figure 24. IR Spectrum of 2-{2-[4-(2-chlorophenyl) piperazin-1-yl] ethoxy}

benzamide (3a6)

O

NH2

ON

N

Cl



3457 N-H Str



1644 C=O Str



1033 C-O-C Str

EXPERIMENTAL





2.47-2.97 2 CH2N


4.15 2 OCH2


7.82 2 CONH2

EXPERIMENTAL


Figure 26. IR Spectrum of 2-[3-(4-phenylpiperazin-1-yl) propoxy] benzamide 3b1

NH2

OCH2CH2CH2

O

N N

Table 25. IR Data of 3b1


3375 N-H Str



1648 C=O Str



1035 C-O-C Str

EXPERIMENTAL


Figure 27. NMR Spectrum of 3b1

Table 26. 1H NMR Data of 3b1


1.92-1.95 2 CH2

2.21-2.97 2 CH2N


4.12 2 OCH2


7.82 2 CONH2

EXPERIMENTAL


Figure 28. IR Spectrum of 2-{3-[4-(2-methoxyphenyl) piperazin-1-yl] propoxy}

benzamide (3b2)

Table 27. IR Data of 3b2


3375 N-H Str



1648 C=O Str



1035 C-O-C Str

EXPERIMENTAL


Figure 29. NMR Spectrum of 3b2

Table 28. 1H NMR Data of 3b2


1.92 2 CH2

2.35-2.97 2 CH2N


3.97 3 OCH3

4.12 2 OCH2


7.81 2 CONH2

EXPERIMENTAL


Figure 30. IR Spectrum of 2-[4-(4-phenylpiperazin-1-yl) butoxy] benzamide (3c1)

O

NH2

ON

N

Table 29. IR Data of 3c1


3457 N-H Str



1641 C=O Str



1033 C-O-C Str

EXPERIMENTAL


Figure 31. NMR Spectrum of 3c1

Table 30. 1H NMR Data of 3c1


1.20-1.28 4 CH2CH2

2.68-2.71 2 CH2N


4.10 2 OCH2


7.81 2 CONH2

EXPERIMENTAL


Figure 32. IR Spectrum of 2-{4-[4-(2-methoxyphenyl) piperazine-1-yl] butoxy}

benzamide (3c2)

O

NH2

ON

N

OCH3

Table 31. IR Data of 3c2


3457 N-H Str



1641 C=O Str



1033 C-O-C Str

EXPERIMENTAL


Figure 33. NMR Spectrum of 3c2

Table 32. 1H NMR Data of 3c2


1.24-1.28 4 CH2CH2

2.68-2.71 2 CH2N


3.86 3 OCH3

4.10 2 OCH2


7.81 2 CONH2

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 ClCOCH2Cli

N COCH2Cl

(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



Rf value : 0.44

Mobile phase : ethyl acetate: hexane (1: 5)

Molecular formula : C14H12ClNO

EXPERIMENTAL


Step II. Synthesis of final compounds (3a-j)

N COCH2Cl

(2)

HN Ni

N COCH2 N N

(3a-j)

R

R

Scheme 2. Synthesis of the target compounds. Reagents and conditions :( i) Acetonitrile,

K2CO3, KI, Reflux.


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

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.


2-[4-(Phenyl) piperazin-1-yl] N, N-diphenylacetamide (3a)

Yield : 1.40 g



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



Rf value : 0.28



2-[4-(2, 3-Dimethylphenyl) piperazin-1-yl] N, N-diphenylacetamide (3c)

Yield : 1.2 g



Rf value : 0.26

EXPERIMENTAL




2-[4-(3-Trifluoromethylphenyl) piperazin-1-yl] N, N-diphenylacetamide (3d)

Yield : 1.26 g



Rf value : 0.27


Molecular formula : C25H24F3N3O

2-[4-(2-Methoxyphenyl) piperazin-1-yl] N, N -diphenylacetamide (3e)

Yield : 0.82g



Rf value : 0.22




2-[4-(3-Methoxyphenyl) piperazin-1-yl] N, N -diphenylacetamide (3f)

Yield : 0.92 g



Rf value : 0.24



2-[4-(3-Chlorophenyl) piperazin-1-yl] N, N -diphenylacetamide (3g)

Yield : 1.14 g



Rf value : 0.32


EXPERIMENTAL


Molecular formula : C24H24ClN3O

2-[4-(3, 4-Dichlorophenyl) piperazin-1-yl] N, N -diphenylacetamide (3h)

Yield : 1.13 g



Rf value : 0.29


Molecular formula : C24H23Cl2N3O

2-[4-(4-Fluorophenyl) piperazin-1-yl] N, N -diphenylacetamide (3i)

Yield : 0.60 g



Rf value : 0.21


Molecular formula : C24H24FN3O

2-[4-(4-Nitrophenyl) piperazin-1-yl] N, N -diphenylacetamide (3j)

Yield : 0.97 g

Percentage yield : 47.08 %


Rf value : 0.30



EXPERIMENTAL


Figure 34. IR Spectrum of 2-chloro-N, N-diphenylacetamide (2)

N C

O

H2C Cl

Table 34. IR Data of 2




1678 C=O Str



695 C-Cl Str

EXPERIMENTAL


Figure 35. NMR Spectrum of 2-chloro-N, N-diphenylacetamide (2)

Table 35. 1H NMR Data of 2


4.02 2 CH2

7.26-7.39 10 Aromatic

EXPERIMENTAL


Figure 36. IR Spectrum of 2-[4-(phenyl) piperazin-1-yl] N, N-diphenylacetamide (3a)

N COCH2 N N





1673 C=O Str



EXPERIMENTAL


Figure 37. NMR Spectrum of 3a





4.56 2 COCH2

6.80-7.54 15 Aromatic

EXPERIMENTAL


Figure 38 Mass Spectrum of 3a

Mass Data:

MS (EI) m/z: 372.23 (M+1).

EXPERIMENTAL


Figure 39. IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl] N, N- diphenyl

acetamide (3b)

N COCH2 N N CH3





1674 C=O Str



EXPERIMENTAL


Figure 40. NMR Spectrum of 3b



2.25 3 CH3



4.47 2 COCH2

6.71-7.48 14 Aromatic

EXPERIMENTAL


Figure 41. IR Spectrum of 2-[4-(2, 3-dimethylphenyl) piperazin-1-yl] N, N-diphenyl

acetamide (3c)

N COCH2 N N

H3C CH3





1675 C=O Str



EXPERIMENTAL


Figure 42. NMR Spectrum of 3c



2.18 3 CH3

2.24 3 CH3



4.57 2 COCH2

6.87-7.56 14 Aromatic

EXPERIMENTAL


Figure 43. IR Spectrum of 2-[4-(3-trifluoromethylphenyl) piperazin-1-yl] N, N-

diphenylacetamide (3d)

N COCH2 N N

CF3

Table 42. IR Data of 3d




1674 C=O Str



EXPERIMENTAL


Figure 44. NMR Spectrum of 3d

Table 43. 1H NMR Data of 3d




4.56 2 COCH2

6.80-7.35 14 Aromatic

EXPERIMENTAL


Figure 45. IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl] N, N –diphenyl

acetamide (3e)

N COCH2 N N

H3CO

Table 44. IR Data of 3e




1685 C=O Str



EXPERIMENTAL


Figure 46. NMR Spectrum of 3e

Table 45. 1H NMR Data of 3e




3.78 3 CH3

4.57 2 COCH2

6.39-7.37 14 Aromatic

EXPERIMENTAL


Figure 47. IR Spectrum of 2-[4-(3-methoxyphenyl) piperazin-1-yl] N, N –diphenyl

acetamide (3f)

NCOCH2 N N

OCH3

Table 46. IR Data of 3f




1685 C=O Str



EXPERIMENTAL


Figure 48. NMR Spectrum of 3f

Table 47. 1H NMR Data of 3f




3.77 3 OCH3

4.57 2 COCH2

6.39-7.37 14 Aromatic

EXPERIMENTAL


Figure 49. IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl] N, N –diphenyl

acetamide (3g)

NCOCH2 N N

Cl

Table 48. IR Data of 3g




1674 C=O Str



EXPERIMENTAL


Figure 50. NMR Spectrum of 3g

Table 49. 1H NMR Data of 3g




4.54 2 COCH2

6.73-7.36 14 Aromatic

EXPERIMENTAL


Figure 51. IR Spectrum of 2-[4-(3, 4-dichlorophenyl) piperazin-1-yl] N, N –diphenyl

acetamide (3h)

NCOCH2 N N

Cl

Cl

Table 50. IR Data of 3h




1675 C=O Str



EXPERIMENTAL


Figure 52. NMR Spectrum of 3h

Table 51. 1H NMR Data of 3h




4.47 2 COCH2

6.68-7.48 14 Aromatic

EXPERIMENTAL


Figure 53. IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl] N, N –diphenyl

acetamide (3i)

NCOCH2 N N F

Table 52. IR Data of 3i




1674 C=O Str



EXPERIMENTAL


Figure 54. NMR Spectrum of 3i

Table 53. 1H NMR Data of 3i




4.54 2 COCH2

6.67-7.48 14 Aromatic

EXPERIMENTAL


Figure 55. IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl] N, N –diphenyl

acetamide (3j)

NCOCH2 N N NO2

Table 54. IR Data of 3j




1673 C=O Str



EXPERIMENTAL


Figure 56. NMR Spectrum of 3j

Table 55. 1H NMR Data of 3j




4.58 2 COCH2

6.76-8.17 14 Aromatic

EXPERIMENTAL


Series C

Synthesis of 2-[4-(aryl substituted) piperazin-1-yl]-N-phenylacetamides

Step I. Synthesis of 2-chloro-N-phenylacetamide (2)

NH2

ClCOCH2Cli

HN COCH2Cl

(2)(1)

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



Rf value : 0.93



EXPERIMENTAL


Step II. Synthesis of final compounds

HN COCH2Cl

(2)

HN Ni

HN COCH2 N N

(3a-j)

R

R

Scheme 3. Synthesis of the target compounds. Reagents and conditions: (i) Acetonitrile,

K2CO3, KI, Reflux.


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

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.


2-[4-(Phenyl) piperazin-1-yl]-N-phenylacetamide (3a)

Yield : 0.90 g



Rf value : 0.65



2-[4-(3-Methylphenyl) piperazin-1-yl]-N-phenylacetamide (3b)

Yield : 0.95 g



Rf value : 0.52



2-[4-(4-Methylphenyl) piperazin-1-yl]-N-phenylacetamide (3c)

Yield : 0.84 g



EXPERIMENTAL


Rf value : 0.50



2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N-phenylacetamide (3d)

Yield : 0.60 g



Rf value : 0.54



2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N-phenylacetamide (3e)

Yield : 0.64 g



Rf value : 0.58



2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N-phenylacetamide (3f)

Yield : 0.70 g



Rf value : 0.40



2-[4-(2-Chlorophenyl) piperazin-1-yl]-N-phenylacetamide (3g)

Yield : 0.87 g



Rf value : 0.63


EXPERIMENTAL



2-[4-(3-Chlorophenyl) piperazin-1-yl]-N-phenylacetamide (3h)

Yield : 0.91 g



Rf value : 0.60




2-[4-(4-Fluorophenyl) piperazin-1-yl]-N-phenylacetamide (3i)

Yield : 0.90 g



Rf value : 0.53



2-[4-(4-Nitrophenyl) piperazin-1-yl]-N-phenylacetamide (3j)

Yield : 0.95 g



Rf value : 0.57



EXPERIMENTAL


Figure 57. IR Spectrum of 2-chloro-N-phenylacetamide (2)

HN COCH2Cl



3311 N-H Str



1681 C=O Str

1217 C-N Str

670 C-Cl Str

EXPERIMENTAL


Figure 58. NMR Spectrum of 2-chloro-N-phenylacetamide (2)



4.19 2 CH2


8.24 1 NH

EXPERIMENTAL


Figure 59. IR Spectrum of 2-[4-(phenyl) piperazin-1-yl]-N-phenylacetamide (3a)

O

NH

N

N



3311 N-H Str



1683 C=O Str



EXPERIMENTAL







4.50 2 CH2

6.83-7.58 10 Aromatic

9.10 1 NH

EXPERIMENTAL


Figure 61. Mass Spectrum of 3a

Mass Data

MS (EI) m/z: 296.3 (M+1).

EXPERIMENTAL


Figure 62. IR Spectrum of 2-[4-(3-methylphenyl) piperazin-1-yl]-N-phenylacetamide

(3b)

O

NH

N

N CH3



3450 N-H Str



1681 C=O Str



EXPERIMENTAL





2.29 3 CH3



4.51 2 CH2


9.14 1 NH

EXPERIMENTAL


Figure 64. IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl]-N-phenylacetamide

(3c)

O

NH

N

N

CH3



3450 N-H Str



1681 C=O Str



EXPERIMENTAL





2.28 3 CH3



4.55 2 CH2


9.15 1 NH

EXPERIMENTAL


Figure 66. IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl]-N-phenyl

acetamide (3d)

O

NH

N

N

OCH3



3271 N-H Str



1668 C=O Str



EXPERIMENTAL







3.87 3 OCH3

4.55 2 CH2


9.19 1 NH

EXPERIMENTAL



acetamide (3e)

O

NH

N

N OCH3



3271 N-H Str



1668 C=O Str



EXPERIMENTAL







3.87 3 OCH3

4.55 2 CH2


9.19 1 NH

EXPERIMENTAL



acetamide (3f)

O

NH

N

N

OCH3



3271 N-H Str



1668 C=O Str



EXPERIMENTAL







3.78 3 OCH3

4.52 2 CH2


9.28 1 NH

EXPERIMENTAL


Figure 72. IR Spectrum of 2-[4-(2-chlorophenyl) piperazin-1-yl]-N-phenylacetamide

(3g)

O

NH

N

N

Cl



3311 N-H Str



1683 C=O Str



EXPERIMENTAL







4.22 2 CH2


10.55 1 NH

EXPERIMENTAL


Figure 74. IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl]-N-phenylacetamide

(3h)

O

NH

N

N Cl



3311 N-H Str



1683 C=O Str



EXPERIMENTAL







4.55 2 CH2


9.08 1 NH

EXPERIMENTAL


Figure 76. IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl]-N-phenyl acetamide

(3i)

O

NH

N

N

F



3307 N-H Str



1682 C=O Str



EXPERIMENTAL







4.52 2 CH2


9.12 1 NH

EXPERIMENTAL


Figure 78. IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl]-N-phenylacetamide (3j)

O

NH

N

N

NO2



3307 N-H Str



1682 C=O Str



EXPERIMENTAL







4.55 2 CH2


9.08 1 NH

EXPERIMENTAL


Series D

Synthesis of 2-[4-(aryl substituted) piperazin-1-yl]-N-benzylacetamides

Step I. Synthesis of 2-chloro-N-benzylacetamide (2)

CH2NH2

ClCOCH2Cli

CH2NHCOCH2Cl

(2)(1) 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


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



Rf value : 0.72

Mobile phase : hexane: ethyl acetate (1: 1)


EXPERIMENTAL



CH2NHCOCH2Cl

(2)

HN Ni

CH2NHCOCH2 N N

(3a-j)

R

R


K2CO3, KI, Reflux.


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

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


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


The physical parameters were

2-[4-(Phenyl) piperazin-1-yl]-N-benzylacetamide (3a)

Yield : 0.80 g



Rf value : 0.38



2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3b)

Yield : 0.72 g



Rf value : 0.28




2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3c)

Yield : 0.74 g



Rf value : 0.46

EXPERIMENTAL




2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3d)

Yield : 0.62 g



Rf value : 0.47



2-[4-(3-Methylphenyl) piperazin-1-yl]-N-benzylacetamide (3e)

Yield : 0.80 g



Rf value : 0.30



2-[4-(4-Methylphenyl) piperazin-1-yl]-N-benzylacetamide (3f)

Yield : 0.85 g



Rf value : 0.30



2-[4-(2-Chlorophenyl) piperazin-1-yl]-N-benzylacetamide (3g)

Yield : 0.98 g



Rf value : 0.26



EXPERIMENTAL


2-[4-(3-Chlorophenyl) piperazin-1-yl]-N-benzylacetamide (3h)

Yield : 0.90 g



Rf value : 0.48



2-[4-(4-Nitrophenyl) piperazin-1-yl]-N-benzylacetamide (3i)

Yield : 1.10 g



Rf value : 0.22



2-[4-(4-Fluorophenyl) piperazin-1-yl]-N-phenylacetamide (3j)

Yield : 0.82 g



Rf value : 0.20



EXPERIMENTAL


Figure 80. IR Spectrum of 2-chloro-N-benzylacetamide (2)

CH2NHCOCH2Cl



3268 N-H Str



1669 C=O Str

1220 C-N Str

699 C-Cl Str

EXPERIMENTAL


Figure 81. NMR Spectrum of 2-chloro-N-benzylacetamide (2)



4.11 2 COCH2

4.49-4.51 2 CH2

6.88 1 NH


EXPERIMENTAL


Figure 82. IR Spectrum of 2-[4-(phenyl) piperazin-1-yl]-N-benzylacetamide (3a)

O

HN

N N



3301 N-H Str



1661 C=O Str



EXPERIMENTAL







4.39 2 COCH2

4.47 2 CH2


7.51 1 NH

EXPERIMENTAL



Mass Data

MS (EI) m/z: 310.2 (M+1).

EXPERIMENTAL


Figure 85. IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl]-N-benzyl

acetamide (3b)



3457 N-H Str



1657 C=O Str



EXPERIMENTAL



O

HN

N N

H3CO





3.81 3 OCH3

4.39 2 COCH2

4.49 2 CH2


7.53 1 NH

EXPERIMENTAL



acetamide (3c)

O

HN

N N

OCH3



3457 N-H Str



1657 C=O Str



EXPERIMENTAL







3.73 3 OCH3

4.41 2 COCH2

4.53 2 CH2


7.53 1 NH

EXPERIMENTAL



acetamide (3d)

O

HN

N N OCH3



3457 N-H Str



1657 C=O Str



EXPERIMENTAL







3.73 3 OCH3

4.41 2 COCH2

4.53 2 CH2


7.53 1 NH

EXPERIMENTAL


Figure 91. IR Spectrum of 2-[4-(3-methylphenyl) piperazin-1-yl]-N-benzylacetamide

(3e)

O

HN

N N

CH3



3456 N-H Str



1659 C=O Str



EXPERIMENTAL





2.26 3 CH3



4.41 2 COCH2

4.48 2 CH2


7.48 1 NH

EXPERIMENTAL


Figure 93. IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl]-N-benzylacetamide

(3f)

O

HN

N N CH3



3457 N-H Str



1639 C=O Str



EXPERIMENTAL





2.26 3 CH3



4.41 2 COCH2

4.48 2 CH2


7.48 1 NH

EXPERIMENTAL


Figure 95. IR Spectrum of 2-[4-(2-chlorophenyl) piperazin-1-yl]-N-benzylacetamide

(3g)

O

HN

N N

Cl



3456 N-H Str



1664 C=O Str



EXPERIMENTAL







4.43 2 COCH2

4.66 2 CH2


7.43 1 NH

EXPERIMENTAL


Figure 97. IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl]-N-benzylacetamide

(3h)

O

HN

N N

Cl



3456 N-H Str



1664 C=O Str



EXPERIMENTAL







4.42 2 COCH2

4.45 2 CH2


7.43 1 NH

EXPERIMENTAL


Figure 99. IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl]-N-benzylacetamide

(3i)

O

HN

N N NO2



3301 N-H Str



1661 C=O Str



EXPERIMENTAL







4.44 2 COCH2

4.62 2 CH2


7.54 1 NH

EXPERIMENTAL


Figure 101. IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl]-N- benzylacetamide

(3j)

O

HN

N N F



3479 N-H Str



1639 C=O Str



EXPERIMENTAL







4.42 2 COCH2

4.60 2 CH2


7.54 1 NH

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

iHN COCH2Cl

(2)(1) 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

oC 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


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



Rf value : 0.75



EXPERIMENTAL



HN COCH2Cl

(2)

HN N

HN COCH2 N N

(3a-j)

R

R

i


K2CO3, KI, Reflux.


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

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


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


The physical parameters were

2-[4-(Phenyl) piperazin-1-yl]-N-cyclohexylacetamide (3a)

Yield : 0.75 g



Rf value : 0.27



2-[4-(3-Methylphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3b)

Yield : 0.85 g



Rf value : 0.23



2-[4-(4-Methylphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3c)

Yield : 0.82 g



EXPERIMENTAL


Rf value : 0.21



2-[4-(2-Methoxyphenyl) piperazin-1-yl]-N-cyclohexylacetamide (3d)

Yield : 0.57 g



Rf value : 0.25



2-[4-(3-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3e)

Yield : 0.50 g



Rf value : 0.39



2-[4-(4-Methoxyphenyl) piperazin-1-yl]-N- cyclohexylacetamide (3f)

Yield : 0.58 g



Rf value : 0.24



2-[4-(2-Chlorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3g)

Yield : 0.97 g



EXPERIMENTAL


Rf value : 0.54



2-[4-(3-Chlorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3h))

Yield : 0.95 g



Rf value : 0.47



2-[4-(4-Fluorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3i)

Yield : 1.0 g



Rf value : 0.28




2-[4-(4-Nitrophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3j)

Yield : 0.98 g



Rf value : 0.26



EXPERIMENTAL


Figure 103. IR Spectrum of 2-chloro-N-cyclohexylacetamide (2)

NHCOCH2Cl



3414 N-H Str


1658 C=O Str

1219 C-N Str

668 C-Cl Str

EXPERIMENTAL


Figure 104. NMR Spectrum of 2-chloro-N-cyclohexylacetamide (2)



1.22-1.94 10 Aliphatic


4.03 2 COCH2

6.44 1 NH

EXPERIMENTAL


Figure 105. IR Spectrum of 2-[4-(phenyl) piperazin-1-yl]-N-cyclohexylacetamide (3a)

O

NH

N

N



3356 N-H Str



1664 C=O Str



EXPERIMENTAL









4.80 2 COCH2


7.27 1 NH

EXPERIMENTAL



Mass Data

MS (EI) m/z: 302.3 (M+1).

EXPERIMENTAL


Figure 108. IR Spectrum of 2-[4-(3-methylphenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3b)

O

NH

N

N CH3



3246 N-H Str



1660 C=O Str



EXPERIMENTAL






2.31 3 CH3




4.72 2 COCH2


7.27 1 NH

EXPERIMENTAL


Figure 110. IR Spectrum of 2-[4-(4-methylphenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3c)

O

NH

N

N

CH3



3246 N-H Str



1660 C=O Str



EXPERIMENTAL






2.29 3 CH3




4.72 2 COCH2


7.27 1 NH

EXPERIMENTAL


Figure 112. IR Spectrum of 2-[4-(2-methoxyphenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3d)

O

NH

N

N

OCH3



3355 N-H Str



1666 C=O Str



1036 C-O-C Str

EXPERIMENTAL








3.54 3 OCH3


4.69 2 COCH2


7.26 1 NH

EXPERIMENTAL



acetamide (3e)

O

NH

N

N OCH3



3353 N-H Str



1665 C=O Str



1036 C-O-C Str

EXPERIMENTAL








3.54 3 OCH3


4.69 2 COCH2


7.26 1 NH

EXPERIMENTAL



acetamide (3f)

O

NH

N

N

OCH3



3353 N-H Str



1665 C=O Str



1036 C-O-C Str

EXPERIMENTAL








3.54 3 OCH3


4.67 2 COCH2


7.26 1 NH

EXPERIMENTAL


Figure 118. IR Spectrum of 2-[4-(2-chlorophenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3g)

O

NH

N

N

Cl



3349 N-H Str



1664 C=O Str



EXPERIMENTAL









4.68 2 COCH2


7.26 1 NH

EXPERIMENTAL


Figure 120. IR Spectrum of 2-[4-(3-chlorophenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3h)

O

NH

N

N Cl



3349 N-H Str



1664 C=O Str



EXPERIMENTAL









4.68 2 COCH2


7.26 1 NH

EXPERIMENTAL


Figure 122. IR Spectrum of 2-[4-(4-fluorophenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3i)

O

NH

N

N

F



3248 N-H Str



1662 C=O Str



EXPERIMENTAL









4.82 2 COCH2


7.28 1 NH

EXPERIMENTAL


Figure 124. IR Spectrum of 2-[4-(4-nitrophenyl) piperazin-1-yl]-N- cyclohexyl

acetamide (3j)

O

NH

N

N

NO2



3249 N-H Str



1663 C=O Str



EXPERIMENTAL









4.82 2 COCH2


7.27 1 NH

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.

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.

EXPERIMENTAL


SERIES A

Table 125. Calculation of molecular properties for 2-{n-[4-(aryl substituted) pipera

zin-1-yl] alkoxy} benzamides and standard drugs

aMolecular weight bMolar refractivity cConnolly solvent accessible surface area dConnolly molecular surface area eConnolly solvent excluded volume fTopological polar surface area gMolecular topological index hWienner index iOvality jCalcd.online (Chemsilico.com/CS_prBBB/BBBdata.html) kClozapine lKetanserin mRisperidone

Cpd.

Code

Log

BBj

Log P

M.Wa MRb SASc

(A2)

MSAd

(A2)

SEVe

(A3)

TPSAf

(A2)

MTIg WIh Ovi

3a1 0.23 2.64 325.40 96.5 596.869 314.792 281.008 58.8 12122 1607 1.5172

3a2 0.16 3.13 339.43 102.4 628.141 333.488 297.919 58.8 13585 1798 1.5459

3a3 0.16 3.13 339.43 102.4 628.116 333.469 297.902 58.8 13722 1816 1.5459

3a4 -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

3c2 -0.26 3.08 383.48 112.95 699.174 376.186 338.223 68.03 19246 2597 1.6024

CLZk 0.75 3.71 326.82 94.58 508.991 259.124 215.892 30.87 8127 1082 1.4889

KETl -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

EXPERIMENTAL


Table 126. Similarity values for 2-{n-[4-(aryl substituted) piperazin-1-yl] alkoxy}

benzamides with respect to standard drugs

a(1 - R) X 100 where R = quadratic mean (root mean square mean).

bCalcd. 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.

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

EXPERIMENTAL


SERIES B

Table 127. Calculation of molecular properties for 2–[4-(aryl substituted) piperazin-

1-yl] N, N-diphenylacetamides and standard drugs

aMolecular weight

bMolar refractivity cConnolly solvent accessible surface area dConnolly molecular surface area eConnolly solvent excluded volume fTopological polar surface area gMolecular topological index hWienner index iOvality jCalcd.online (Chemsilico.com/CS_prBBB/BBBdata.html) kClozapine lKetanserin mRisperidone

Cpd.

Code

Log

BBj

Log P

M.Wa MRb SASc

(A2)

MSAd

(A2)

SEVe

(A3)

TPSAf

(A2)

MTIg WIh Ovi

3a 0.25 4.49 371.47 113.32 641.894 344.355 308.409 26.79 17130 2193 1.5599

3b 0.36 4.98 385.50 119.22 582.422 313.211 291.582 26.79 19148 2450 1.4729

3c 0.39 5.46 399.53 125.12 679.816 371.123 336.247 26.79 20677 2644 1.5870

3d 0.41 5.41 439.47 119.83 690.253 373.577 335.839 26.79 22826 3226 1.5988

3e 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

3j 0.01 4.04 416.47 119.57 686.144 371.22 332.383 78.60 22209 3024 1.5997

CLZk 0.75 3.71 326.82 94.58 508.991 259.124 215.892 30.87 8127 1082 1.4889

KETl -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 57.50 20311 2793 1.5563

EXPERIMENTAL


Table 128. Similarity values of 2–[4-(aryl substituted) piperazin-1-yl] N, N-

diphenylacetamides with respect to standard drugs

a(1 - R) X 100 where R = quadratic mean (root mean square mean). bCalcd. from physicochemical properties: Molecular weight; Molar refractivity; Connolly solvent



Similaritya,b ( in %) to Cpd.Code.


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

EXPERIMENTAL


SERIES C

Table 129. Calculation of molecular properties for 2-[4-(aryl substituted) piperazin-

1-yl]-N-phenylacetamides


Cpd.

Code

Log

BBj

LogP

M.Wa MRb SASc

(A2)

MSAd

(A2)

SEVe

(A3)

TPSAf

(A2)

MTIg WIh Ovi

3a 0.36 2.59 295.38 89.24 561.908 290.826 253.997 35.58 9668 1248 1.4994

3b 0.45 3.08 309.41 95.14 593.162 309.507 270.893 35.58 10915 1408 1.5286

3c 0.45 3.08 309.41 95.14 593.187 309.524 270.912 35.58 11038 1424 1.5287

3d 0.32 2.46 325.40 96.49 589.697 311.837 279.124 44.81 11801 1559 1.5097

3e 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

3j -0.09 1.62 340.38 95.10 607.004 318.695 279.615 87.39 13142 1824 1.5411

CLZk 0.75 3.71 326.82 94.58 508.991 259.124 215.892 30.87 8127 1082 1.4889

KETl -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

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


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

EXPERIMENTAL


SERIES D


1-yl]-N-benzylacetamides (3a-j) and standard drugs


Cpd.

Code

Log

BBj

LogP

M.Wa MRb SASc

(A2)

MSAd

(A2)

SEVe

(A3)

TPSAf

(A2)

MTIg WIh OVi

3a 0.32 2.66 309.41 94.66 575.217 307.199 280.758 35.58 11308 1458 1.481

3b 0.27 2.53 339.43 101.91 638.833 338.01 301.468 44.81 13673 1802 1.554

3c 0.25 2.53 339.43 101.91 650.064 341.557 300.50 44.81 13901 1836 1.574

3d 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

3j 0.32 2.82 327.40 95.06 610.728 317.941 278.769 35.58 12237 1652 1.540

CLZk 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

RISm -0.20 2.10 410.48 114.21 690.021 375.09 351.81 57.50 20311 2793 1.556

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


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

EXPERIMENTAL


SERIES E


1-yl]-N-cyclohexylacetamides (3a-j) and standard drugs


Cpd.

code

Log

BBj

LogP

M.Wa MRb SASc

(A2)

MSAd

(A2)

SEVe

(A3)

TPSAf

(A2)

MTIg WIh Ovi

3a 0.3 2.47 301.43 91.17 580.261 309.454 297.083 35.58 9668 1248 1.4372

3b 0.34 2.96 315.45 97.07 611.491 328.118 313.97 35.58 10915 1408 1.468

3c 0.34 2.96 315.45 97.07 611.47 328.106 313.961 35.58 11038 1424 1.468

3d 0.09 2.35 331.45 98.42 633.866 336.437 311.668 44.81 11801 1559 1.5134

3e 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

CLZk 0.75 3.71 326.82 94.58 508.991 259.124 215.892 30.87 8127 1082 1.4889

KETl -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

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


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

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.

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.

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 40 40 60 3a2 40 40 50 3a3 40 40 50 3a4 30 20 70 3a5 30 20 70 3a6 40 30 70 3b1 60 40 60 3b2 60 60 60 3c1 60 60 60 3j 60 60 60 Clozapine 6.0 2.0 - Haloperidol - - nda

and: Not determined, 1mg/kg dose was used

EXPERIMENTAL


Table 136. Behaviour symptoms Observation at Interval of Compound Behavioural symptoms

30 min 60 min 90 min 120 min 180 min Sedation - - - - - Sleep - - - - -

Hyperactivity - - - - -

3a1

Convulsion - - - - - Sedation - - - - - Sleep - - - - -


3a2



3a3



3a4

Convulsion - - - - - Sedation - - - - - Sleep - - - - - Hyperactivity - - - - -

3a5

Convulsion - - - - - Sedation - - - - - Sleep - - - - Hyperactivity - - - - -

3a6


3b1

Convulsion - - - - Sedation - - - - - Sleep - - - - - Hyperactivity - - - - -

3b2


3c1


3c2

Convulsion - - - - - +++ Marked effect, ++ Moderate effect, + Mild effect - Absence of effect

EXPERIMENTAL


Figure 126. Inhibition of apomorphine induced climbing behavior

02468

1012141618

3a1

3a2

3a3

3a4

3a5

3a6

3b1

3b2

3c1

3c2

Control

Clozapine

Compounds

Tota

l clim

bing

sco

re

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

EXPERIMENTAL


Figure 127. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behavior

012345678

3a1

3a2

3a3

3a4

3a5

3a6

3b1

3b2

3c1

3c2

Control

Clozapine

Compounds

Tota

l hea

d tw

itche

s sc

ore

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

EXPERIMENTAL


Figure 128. Induction of catalepsy

02468

10121416

3a1

3a2

3a3

3a4

3a5

3a6

3b1

3b2

3c1

3c2

Haloperi

dol

Compounds

Mea

n ca

tale

psy

scor

e306090120240

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

Mean catalepsy score

Sr. No.

Compound

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 5.50 ± 0.42 6.16 ± 0.53 7.50 ± 0.22 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 Haloperidol 2.83 ± 0.30 6.50 ± 0.42 9.16 ± 0.30 12.66 ± 0.33 5.83 ± 0.30

EXPERIMENTAL


Series B

Pharmacological evaluation of 2–[4-(aryl substituted) piperazin-1-yl] N, N-diphenyl acetamides The minimum effective dose (EDmin) that produced statistically significant result was







receptor (Tabs. 142, 143 and 144 and Figs. 129, 130 and 131). But the compound 3e showed







3a 20 20 60 3b 30 30 50 3c 40 40 50 3d 30 20 60 3e 20 10 80 3f 30 30 60 3g 30 40 50 3h 40 40 50 3i 30 30 60 3j 40 40 50 Clozapine 5.5 1.5 - Haloperidol - - nda


EXPERIMENTAL





3a



3b



3c



3d


3e


3f



3g


3h


3i


3j


EXPERIMENTAL



02468

10121416

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j

Control

Clozapine

Compounds

Tota

l mea

n cl

imbi

ng s

core

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.



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

EXPERIMENTAL



012345678

3a 3b 3c 3d 3e 3f 3g 3h 3i 3jContr

olCloza

pine

Compounds

Tota

l mea

n he

ad tw

itche

s sc

ore

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.



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

EXPERIMENTAL



0246

8101214

3a 3b 3c 3d 3e 3f 3g 3h 3i 3jHalop

eridol

Compounds

Mea

n ca

tale

psy

scor

e306090120240

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.



Sr. No.

Compound


1 3a 2.83 ± 0.70 3.50 ± 0.42 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

11 Haloperidol 5.66 ± 0.42 7.33 ± 0.42 10.5 ± 0.42 11.33 ± 0.49 6.66 ± 0.33

EXPERIMENTAL


Series C

Pharmacological evaluation of 2-[4-(arylsubstituted) piperazin-1-yl]-N-phenyl

acetamides








receptor (tabs. 147, 148 and 149 and figs. 132, 133 and 134). But the compound 3h showed



Table 145. In vivo studies of compounds for antipsychotic activity

Compound






EXPERIMENTAL





3a



3b



3c



3d


3e


3f



3g


3h


3i


3j


EXPERIMENTAL



0

2

4

6

8

10

12

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j

Control

Clozapine

Compounds

Tota

l mea

n cl

imbi

ng s

core





p<0.05.



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

EXPERIMENTAL



012345678


olCloza

pine

Compounds

Tota

l mea

n he

ad tw

itche

s sc

ore





Table 148. Inhibition of 5-hydoxytryptophan (5-HTP) induced head twitches behaviour


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

EXPERIMENTAL



02468

10121416


eridol

Compounds

Mea

n ca

tale

psy

scor

e306090120240





Sr. No.

Compound


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 7.83 ± 0.6 11.16 ± 0.74 13.50 ± 0.71 6.83 ± 0.47

EXPERIMENTAL


Series D

Pharmacological evaluation of 2-[4-(Aryl substituted) piperazin-1-yl]-N-benzyl

acetamides








receptor (tabs. 152, 153 and 154 and figs. 135, 136 and 137). But the compound 3b showed



Table 150. In vivo studies of compounds for antipsychotic activity

Compound






EXPERIMENTAL





3a



3b



3c



3d


3e


3f



3g


3h


3i


3j


EXPERIMENTAL



02468

10121416

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j

Control

Clozapine

Compounds

Tota

l mea

n cl

imbi

ng s

core





p<0.05.



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

EXPERIMENTAL



0

1

2

34

5

6

7


olCloza

pine

Compounds

Tota

l mea

n he

ad tw

itche

s sc

ore







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

EXPERIMENTAL



0246

8101214


eridol

Compounds

Mea

n ca

tale

psy

scor

e306090120240


expressed as the mean ±SEM. (n=6).p<0.05.



Sr. No.

Compound


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

EXPERIMENTAL


Series E

Pharmacological evaluation of 2-[4-(arylsubstituted) piperazin-1-yl]-N-cyclohexyl

acetamides








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 =








EXPERIMENTAL





3a



3b



3c



3d


3e


3f



3g


3h


3i


3j


EXPERIMENTAL



02468

10121416

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j

Control

Clozapine

Compounds

Tota

l mea

n cl

imbi

ng s

core





p<0.05.



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

EXPERIMENTAL



0

1

2

34

5

6

7


olCloza

pine

Compounds

Tota

l mea

n he

ad tw

itche

s sc

ore







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

EXPERIMENTAL



02

468

10

1214

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j

Haloperi

dol

Compounds

Mea

n ca

tale

psy

scor

e306090120240





Sr. No.

Compound


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

EXPERIMENTAL


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

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).

NN

R

terminalfragment

R= H, CH3, Cl, OCH3, F, CF3, NO2.

Where terminal fragment

CONH2

O(CH2)nN COCH2

NHCOCH2

CH2NHCOCH2 NHCOCH2

Series ASeries B Series C

Series D Series E

Figure 141. The general structure of arylpiperazines

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).


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).

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


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).


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).

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).


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).


than haloperidol. Among them the fluoro analog (3i) exhibited lower propensity to produce


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-3-

chloropropane 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 3c1-

3c2).

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.



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


(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



= 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


(2-methoxyphenyl) piperazin-1-yl]-N-benzylacetamide (3b). The compound 3b showed good


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



3b emerged as most potent and contributed to an atypical antipsychotic like profile.

Series E


(4-fluorophenyl) piperazin-1-yl]-N- cyclohexylacetamide (3i). The compound 3i showed good


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



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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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.


pharmacological evaluation of new arylpiperazines” has been accepted for publication

in E-Journal of chemistry.


pharmacological evaluation of 2–[4-(aryl substituted) piperazin-1-yl] N, N-

diphenylacetamides 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.

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Synthesis, Computational studies and Preliminary Pharmacological Evaluation of New Arylpiperazines

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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-10-00427R1 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. Therefore, we appreciate your patience in this regard. To track the progress of your manuscript, please log in to http://ees.elsevier.com/ejmech/ and click on the "Submissions Being Processed" folder. Your username is: sushil Thank you for submitting your manuscript to European Journal of Medicinal Chemistry. Kind regards, European Journal of Medicinal Chemistry For further assistance, please visit our customer support site at http://support.elsevier.com. Here you can search for solutions on a range of topics, find answers to frequently asked questions and learn more about EES via interactive tutorials. You will also find our 24/7 support contact details should you need any further assistance from one of our customer support representatives.

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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

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