SYNTHESIS OF POSSIBLE SYNTHESIS OF POSSIBLE ANTICONVULSANT DRUGS ANTICONVULSANT DRUGS

bySROTA DAWN

B.PHARM,4TH YEARREG. NO:ROLL NO:

OFBENGAL SCHOOL OF TECHNOLOOGY

Under the supervisionOf

PROF.(DR) DHANANJAY PALProject submitted for the partial fulfillment of

the degree of B.PHARMUnder

West Bengal University of Technology

SYNTHESIS OF SYNTHESIS OF POSSIBLE POSSIBLE

ANTICONVULSANT ANTICONVULSANT DRUGSDRUGS

Under the GUIDANCE OF……Under the GUIDANCE OF……

Dr. Dhananjay PalDr. Dhananjay Pal M.Pharm,Ph.D. HOD of M.Pharm,Ph.D. HOD of Pharmaceutical chemistryPharmaceutical chemistry

Bengal School Of TechnologySugandha,Delhi road

Hooghly-712102

CERTIFICATECERTIFICATE

THIS IS TO CERTIFY THAT MISS. SROTA DAWN,A THIS IS TO CERTIFY THAT MISS. SROTA DAWN,A CANDIDATE OF B.PHARM,7CANDIDATE OF B.PHARM,7THTH SEM OF BENGAL SEM OF BENGAL

SCHOOL OF TECHNOLOGY HAS CARRIED OUT HER SCHOOL OF TECHNOLOGY HAS CARRIED OUT HER PROJECT WORK ENTITLED PROJECT WORK ENTITLED

““SYNTHESIS OF POSSIBLE SYNTHESIS OF POSSIBLE ANTICONVULSANT”ANTICONVULSANT”

IS A RECORD OF INDEPENDENT WORK UNDER MY IS A RECORD OF INDEPENDENT WORK UNDER MY SUPERVISION.SUPERVISION.

PROF. (DR.) DHANANJAY PAL PROF. (DR.) DHANANJAY PAL BENGAL SCHOOL OF TECHNOLOGYBENGAL SCHOOL OF TECHNOLOGY

DR.GOUTAM CHATTERJEE,DR.GOUTAM CHATTERJEE,PRINCIPALPRINCIPALBENGAL SCHOOL OF TECHNOLOGY BENGAL SCHOOL OF TECHNOLOGY SUGANDHA,DEHLI ROAD,HOOGHLY-712102SUGANDHA,DEHLI ROAD,HOOGHLY-712102

EPILEPSIES (Definition) :These are groups of CENTRAL NERVOUS SYSTEM

disorderscharacterised by PAROXYSMAL CEREBRAL DYSRHYTHMIA ,

manifestation of brief episodes of seizures ,loss and disturbance of consciousness ,with

or with or without characteristic body movements(convulsions) ,

Sensory or psychiatric phenomena.

INTRODUCTION

India is one of the dense populated country, people are attacked

by various kinds of diseases as time goes on . Epilepsy is One of them which is a risk factor for patient in case of any

situation.About 40 million people world-wide suffer from epilepsy.

In 70% of patients who have epilepsy, no specific cause can be determined. Epilepsy can be acquired as a result of

neurological injury and can also occur as a part of Systemic medical illness

Nature of epilepsy

Epilepsy affects about 0.5% of the population. The characteristic event is the seizure, which may be associated with convulsions but often takes other forms. The seizure is caused by an asynchronous high-frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain. In absence seizures, the discharge is regular and oscillatory. Partial seizures affect localised brain regions, and the attack may involve mainly motor, sensory or behavioural phenomena. Unconsciousness occurs when the reticular formation is involved. Generalised seizures affect the whole brain.

•Two common forms of epilepsy are the tonic-clonic fit (grand mal) and the absence seizure (petit mal). Status epilepticus is a life-threatening condition in which seizure activity is uninterrupted. •Many animal models have been devised, including electrically and chemically induced generalised seizures, production of local chemical damage, and kindling. These provide good prediction of antiepileptic drug effects in humans. •The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells. Several susceptibility genes, mainly encoding neuronal ion channels, have been identified. •Repeated epileptic discharge can cause neuronal death (excitotoxicity). •Current drug therapy is effective in 70-80% of patients

Anticonvulsant agentsAnticonvulsant agents

Anticonvulsant agents are those which are use to treat,control or to eliminate convulsions.

Anticonvulsants are the drug which selectively depresses Central Nervous System(C N S).

Types of epilepsyTypes of epilepsy There are four types of epilepsy

1.Grandmal epilepsy 2. Petitmal epilepsy 3.Jacksionian epilepsy4.Psycomotor epilepsy

1.1.Grandmal Grandmal epilepsy epilepsy ::

In which seizures lasts for 2 to 5 minutes. In which seizures lasts for 2 to 5 minutes. It is characterized by sudden loss of It is characterized by sudden loss of consiousness.The patientsconsiousness.The patients

has tonic as well as clonic convulsions of all muscles has tonic as well as clonic convulsions of all muscles and there is urinary incontinence.and there is urinary incontinence.

In this type of epilepsy the person In this type of epilepsy the person experiencesexperiences

an an aura aura (this consists of certain sounds , fear and (this consists of certain sounds , fear and discomfortdiscomfort

immediately before a seizure)immediately before a seizure)

2.2.Petitmal Petitmal epilepsyepilepsy : :

The seizures lasts for 5 to 30 seconds The seizures lasts for 5 to 30 seconds being being characterized by brief attacks of unconsciousness. characterized by brief attacks of unconsciousness. This type of epilepsy is most frequently found in This type of epilepsy is most frequently found in children at age of 4 to 8 years.children at age of 4 to 8 years.

3.3.Jacksonian epilepsy Jacksonian epilepsy :: It is usually associated with lesion of a certain partIt is usually associated with lesion of a certain partof the brain(cerebral cortex).Jacksionian epilepsy is characterizedof the brain(cerebral cortex).Jacksionian epilepsy is characterized by local clonic type convulsions (thumb, big toe etc.)The seizureby local clonic type convulsions (thumb, big toe etc.)The seizure normally lasts fromnormally lasts from1 to 2 minutes.1 to 2 minutes.

44..Psychomotor epilepsy Psychomotor epilepsy :: It is characterized by attacks without It is characterized by attacks without convulsionsconvulsionslasting from 2 to 3 minutes. The individual may experience an auralasting from 2 to 3 minutes. The individual may experience an aura(such as hallucinations or a sense of fear). (such as hallucinations or a sense of fear).

Mechanism of action of antiepileptic drugs

•Current antiepileptic drugs are thought to act mainly by three main mechanisms: • reducing electrical excitability of cell

membranes, mainly through use-dependent block of sodium channels

• enhancing GABA-mediated synaptic inhibition; this may be achieved by an enhanced

postsynaptic action of GABA, by inhibiting GABA transaminase, or by drugs with direct GABA

agonist properties • inhibiting T-type calcium channels (important in

controlling absence seizures). •Newer drugs act by other mechanisms yet to be

elucidated. •Drugs that block glutamate receptors are effective in animal models but are unsuitable for clinical use.

1.BARBITURATES Phenobarbitone

2.DEOXYBARBITURATES Primidone

3.HYDANTOINS Phenytoin,Phosphenytoin

4.IMINOSTILBENES Carbamazepine,Oxcarbamazepine

5.SUCCINIMIDES Ethosuximide

6.ALIPHATIC CARBOXYLIC ACIDS

Valproic acid(sodium valproate),Divalproex

7.BENZODIAZEPINES Clonazepam,Diazepam,Lorazepam,Clobazepam

8.PHENYLTRIAZINE Lamotrigine

9.CYCLIC GABA ANALOGUE Gabapentin

10.NEWER DRUGS Vigabatrin,Topiramate,Tiagabine,Zonisamide,Levetiracetam

Structure of some important Structure of some important AnticonvulsantsAnticonvulsants

N

N O

O

RR 2

1

R

H

Generral structure ofHYDANTOINderivatives

ON

N

O

O

H

RR

R1

2

General structure of BARBTTURATES

N O

O

O

CH

R R 1

3

General structure of Oxazolidinediones

N

O

O

RR 2

1

R

Generral structure of

Succinimides

From the above structures we can conclude that,Most anticonvulsants drugs like HYDANTOIN (eg.PHENYTOIN);

BARBITURATES(eg.PHENOBARBITAL);OXAZOLIDINEDIONES;SUCCNIMIDES contains the

following group:

We assume that THIS GROUP MAY ACTS AS A PHARMACOPHORE FOR

ANTICONVULSANT DRUGS

PROJECT SCHEME

PRESENT PROJECT WORK

Synthesis of Butyl derivative of Phthalimide

Step 1: preparation of Phthalic Anhydride

Theory:

In the first step we have to prepare Phthalic anhydride from

Phthalic acid in the presence of acetic anhydride. Acetic anhydride take

One molecule of water from Phthalic acid and formation of phthalic anhydride takes place.

Physical characteristics of Phthalic acid

Physical characteristics of phthalic anhydride

Molecular wt=(96+6+64)= 166

Molecular wt=(48+6+48)=102

Melting point=230◦c Melting point=130◦c

Reaction:

Physical characteristics of Phthalic acid

Physical characteristics of phthalic anhydride

Solubility: Dissolve , 1gm in 160ml. Water; 10ml. Alcohol; 250ml.ether; 5.3ml. methanol

Solubility: Dissolve, 1gm in 162 parts water;

125 parts cs2; soluble in alcohol; sparingly soluble in ether.

PROCEDURE:

1.Phthalic acid and acetic anhydride are taken in a round bottom flask in 1:2 mole ratio. 2.They are heated and refluxed for 2 hours in a water bath. 3. A mass white colored crystalline product is prepared. 4.Obtained product is filtered and then the mass was taken and dried. 5.Measure the melting point of the obtained product .

OBSERVATION:Melting point of the obtained product is 129◦c,which is near to the melting point of phthalic anhydride 130◦c.(according to Mark Index)

CONCLUSION: The obtained product is phthalic anhydride.

Synthesis of Butyl derivative of Phthalimide

Step 2: preparation of Butyl Phthalimide

Theory:

In the second step we have to prepare Butyl phthalimide from Phthalic anhydride in the presence of Butyl amine. Physical characteristics of butyl amine are as follows, Butyl amine:

Molecular wt : 73.14Density : 0.736gm/cc

Phthalimide It is slightly soluble in water,100gm. Of boiling

alcohol dissolves 5gm. Of phthalimide.Almost insoluble in benzene andPet ether . Fairly soluble in boiling acetic acid. Freely soluble in aq.alkali hydroxide.

Reaction:

PROCEDURE:

1. Phthalic anhydride and butyl amine are taken in a round bottom flask in 1:2 mole ratio. Phthalic anhydride taken 5gm,butyl amine taken 6.8 ml.

2. They are heated and refluxed for 2 hours in an oil bath.Temperature of the oil bath is maintained in between140◦c-160◦c

3. A mass white colored crystalline product is prepared.

4.Obtained product is filtered and then the mass was taken and dried.

5.Measure the melting point of the obtained product . RECRYSTALLISATION PROCEDURE:

The crude product is recrystallized to remove the impurities or to remove the other unwanted compounds which are formed during the reaction procedure.

1 . The obtained crude product is 1st taken in a beaker .

2 . Then the product is dissolved in solution of alcohol and water (1:1) .

3 . Heat the drug solution till the drug completely dissolves in the media.

4 . Cool the solution of drug, during cooling recrystallized product is obtained.

5 . Determine the melting point of the filtered material .

6 . This process is repeated until a stable melting point is observed.

PROCEDURE:

OBSERVATION:

Melting point of the obtained crude product 95◦c,AFTER RECRYSTALLIZATION:

After 1ST recrystallization : 97◦c-98◦c After 2nd recrystallization :100◦c

After 3rd recrystallization :102◦c-103◦cAfter 4threcrystallization :106◦c-108◦cAfter 5th recrystallization :106◦c-108◦c

SolubilityThe drug is freely soluble in

boiling water , warm ethyl alcohol,insoluble in water , benzene.

Colour:Off white.

REPORT: The obtained product is phthalic anhydride

Discussion and conclusion

Our project “preparation of possible anticonvulsant” was very challenging project for us . we have prepare The butyl derivative of phthalimide. After proper characterization through proper techniques , our next target is to evaluate the biological activity

Of the compound for anticonvulsant activity.

References

1.Willams David A. ,Lekme thomas l., Foyes Principle of Medicinal Chemistry 5th ed.(2006)2.Tripathi K.D. ,Essentials of Medical Pharmacology,6th ed.(2008)3.Seth S.D., Textbook of Pharmacology,2th ed.(1999)4.The Mark Index,13th ed.(2001)5.Vogel H. Gerhard , Drug Discovery and Evaluation,2nd ed.

MECHANISM MECHANISM of of ACTIONACTION of of ANTICONVULSANTSANTICONVULSANTS

Seizures are caused by abnormal stimulations Seizures are caused by abnormal stimulations of nerves in brain.of nerves in brain.Generally anticonvulsants reduce the Generally anticonvulsants reduce the excitability of neurons (eg.nerve cells) of the excitability of neurons (eg.nerve cells) of the brain . When neurons excitability brain . When neurons excitability decreased ,seizures are reduced in intensity decreased ,seizures are reduced in intensity and frequency of occurrence is virtually and frequency of occurrence is virtually eliminated .It is believed that eliminated .It is believed that anticonvulsants suppress seizure by anticonvulsants suppress seizure by Depressing the cerebral cortex of the brain , Depressing the cerebral cortex of the brain , thereby raising the thereby raising the C N S to convulsive stimuli .C N S to convulsive stimuli .