Antiepileptics by srota dawn

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Antiepileptics by srota dawn

  1. 1. SYNTHESIS OF POSSIBLESYNTHESIS OF POSSIBLE ANTICONVULSANT DRUGSANTICONVULSANT DRUGS by SROTA DAWN B.PHARM,4TH YEAR REG. NO: ROLL NO: OF BENGAL SCHOOL OF TECHNOLOOGY Under the supervision Of PROF.(DR) DHANANJAY PAL Project submitted for the partial fulfillment of the degree of B.PHARM Under West Bengal University of Technology
  2. 2. SYNTHESIS OFSYNTHESIS OF POSSIBLEPOSSIBLE ANTICONVULSANTANTICONVULSANT DRUGSDRUGS
  3. 3. Under the GUIDANCE OF……Under the GUIDANCE OF…… Dr. Dhananjay PalDr. Dhananjay Pal M.Pharm,Ph.D. HOD ofM.Pharm,Ph.D. HOD of Pharmaceutical chemistryPharmaceutical chemistry Bengal School Of Technology Sugandha,Delhi road Hooghly-712102
  4. 4. CERTIFICATECERTIFICATE THIS IS TO CERTIFY THAT MISS. SROTA DAWN,ATHIS IS TO CERTIFY THAT MISS. SROTA DAWN,A CANDIDATE OF B.PHARM,7CANDIDATE OF B.PHARM,7THTH SEM OF BENGAL SCHOOLSEM OF BENGAL SCHOOL OF TECHNOLOGY HAS CARRIED OUT HER PROJECTOF TECHNOLOGY HAS CARRIED OUT HER PROJECT WORK ENTITLEDWORK ENTITLED ““SYNTHESIS OF POSSIBLE ANTICONVULSANT”SYNTHESIS OF POSSIBLE ANTICONVULSANT” IS A RECORD OF INDEPENDENT WORK UNDER MYIS A RECORD OF INDEPENDENT WORK UNDER MY SUPERVISION.SUPERVISION. PROF. (DR.) DHANANJAY PALPROF. (DR.) DHANANJAY PAL BENGAL SCHOOL OF TECHNOLOGYBENGAL SCHOOL OF TECHNOLOGY DR.GOUTAM CHATTERJEE,DR.GOUTAM CHATTERJEE, PRINCIPALPRINCIPAL BENGAL SCHOOL OF TECHNOLOGYBENGAL SCHOOL OF TECHNOLOGY SUGANDHA,DEHLI ROAD,HOOGHLY-712102SUGANDHA,DEHLI ROAD,HOOGHLY-712102
  5. 5. EPILEPSIES (Definition) : These are groups of CENTRAL NERVOUS SYSTEM disorders characterised 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
  6. 6. 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.
  7. 7. •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
  8. 8. 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 epilepsy 4.Psycomotor epilepsy
  9. 9. 1.1. GrandmalGrandmal epilepsyepilepsy :: In which seizures lasts for 2 to 5 minutes. It isIn which seizures lasts for 2 to 5 minutes. It is characterized by sudden loss of consiousness.Thecharacterized by sudden loss of consiousness.The patientspatients has tonic as well as clonic convulsions of all muscles andhas tonic as well as clonic convulsions of all muscles and there is urinary incontinence.there is urinary incontinence. In this type of epilepsy the person experiencesIn this type of epilepsy the person experiences anan auraaura (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.PetitmalPetitmal epilepsyepilepsy :: The seizures lasts for 5 to 30 seconds beingThe seizures lasts for 5 to 30 seconds being characterized by brief attacks of unconsciousness. Thischaracterized by brief attacks of unconsciousness. This type of epilepsy is most frequently found in children attype of epilepsy is most frequently found in children at age of 4 to 8 years.age of 4 to 8 years.
  10. 10. 3.3.Jacksonian epilepsyJacksonian epilepsy :: It is usually associated with lesion of a certain partIt is usually associated with lesion of a certain part of 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 from 1 to 2 minutes.1 to 2 minutes. 44..Psychomotor epilepsyPsychomotor epilepsy :: It is characterized by attacks without convulsionsIt is characterized by attacks without convulsions lasting 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).
  11. 11. 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.
  12. 12. 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,Cloba zepam 8.PHENYLTRIAZINE Lamotrigine 9.CYCLIC GABA ANALOGUE Gabapentin 10.NEWER DRUGS Vigabatrin,Topiramate,Tiagabine,Z onisamide,Levetiracetam
  13. 13. Structure of some importantStructure of some important AnticonvulsantsAnticonvulsants N N O O R R 2 1 R H Generral structure of HYDANTOIN derivatives ON N O O H R R R1 2 General structure of BARBTTURATES N O O O CH R R 1 3 General structure of Oxazolidinediones N O O R R 2 1 R Generral structure of Succinimides
  14. 14. 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
  15. 15. PROJECT SCHEME
  16. 16. PRESENT PROJECT WORK
  17. 17. 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
  18. 18. 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.
  19. 19. 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.
  20. 20. 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 : 73.14 Density : 0.736gm/cc Phthalimide It is slightly soluble in water,100gm. Of boiling alcohol dissolves 5gm. Of phthalimide.Almost insoluble in benzene and Pet ether . Fairly soluble in boiling acetic acid. Freely soluble in aq.alkali hydroxide.
  21. 21. Reaction:
  22. 22. 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 between 140◦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.
  23. 23. 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:
  24. 24. 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◦c After 4th recrystallization :106◦c-108◦c After 5th recrystallization :106◦c-108◦c Solubility The drug is freely soluble in boiling water , warm ethyl alcohol, insoluble in water , benzene. Colour: Off white. REPORT: The obtained product is phthalic anhydride
  25. 25. 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.
  26. 26. 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.
  27. 27. MECHANISMMECHANISM ofof ACTIONACTION ofof ANTICONVULSANTSANTICONVULSANTS Seizures are caused by abnormal stimulations ofSeizures are caused by abnormal stimulations of nerves in brain.nerves in brain. Generally anticonvulsants reduce the excitabilityGenerally anticonvulsants reduce the excitability of neurons (eg.nerve cells) of the brain . Whenof neurons (eg.nerve cells) of the brain . When neurons excitability decreased ,seizures areneurons excitability decreased ,seizures are reduced in intensity and frequency of occurrencereduced in intensity and frequency of occurrence is virtually eliminated .It is believed thatis virtually eliminated .It is believed that anticonvulsants suppress seizure byanticonvulsants suppress seizure by Depressing the cerebral cortex of the brain ,Depressing the cerebral cortex of the brain , thereby raising thethereby raising the C N S to convulsive stimuli .C N S to convulsive stimuli .

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