FLURAZEPAM Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

FLURAZEPAM Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

Flurazepam

IUPAC nomenclature

7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one

 

Classification

Flurazepam is a benzodiazepine sedative-hypnotic.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 387.9 g/mol
2 Physical appearance Solid; white rods from ether-petroleum ether.
3 Melting point 79.5°C
4 Octanol/water partition coefficient 3.8
5 Solubility Solubility of HCl salt is 500 mg/ml
6 Presence of ring Diazepine, benzene
7 Number of chiral centers Not present
 

 

Mechanism of Action

i. Flurazepam binds with an allosteric site on GABAA

ii. This potentiate the action of GABA on GABAA receptor through opening the chloride channel within the receptor.

iii. This results in hyperpolarisation through chloride influx.

 

Structure Activity Relationship

  • Ring A should include an aromatic or heteroaromatic ring for binding with 5-phenyl-1,4-benzodiazepin-2-one derivatives.
  • An electronegative group at 7-position of the ring A increases the functional anxiolytic activity.
  • Substitutions at 6, 8 or 9 position with electronegative group on ring A will decrease the functional anxiolytic activity.
  • When Heterocycles used as ring A, drug shows poor pharmacological activity.
  • A proton-accepting group is essential on Ring B for binding with GABAA
  • When the proton accepting group is present on the 2-position of the ring B, and is in coplanar spatial orientation with Ring A, maximum activity is observed.
  • Replacement of oxygen with sulfur in ring B results in alteration in the selectivity for binding with GABA BZR subpopulations, but anxiolytic properties are maintained.
  • There is no effect on agonist activity, but the antagonist activity dereases when methylene 3-position or imine nitrogen of the ring B is substituted.
  • Derivatives having the 3-hydroxy moiety are fast excreted.
  • Sterically large substituents on ring B , like tert-butyl group reduces the receptor affinity and the in vivo activity.
  • 4,5-double bond and 4-position nitrogen is not essential for anxiolystic activity.
  • BZR affinity is decreased if C=N bond is replaced with C-N bond.
  • 5-phenyl ring C is not necessary for the binding with BZR.
  • Substitution at the para position of the ring C decreases the agonist activity of the drug.
  • There is no change observed in the agonist property of the drug when there is substitution at ortho position.
  • When 1,2-bond f the ring C is annelated with an additional electron rich ring such as imidazole, affinity of the BZR increases. [1]

 

Method of synthesis

i. Reaction of 2-amino-5-chloro-2’-flourobenzophenone (1) with bromoaetic acid chloride (2) to give 2-(bromoacetyl)amino-5-chloro-2’-flourobenzophenone (3).

ii. This on reaction with diethylamine produces 2-(diethylaminoacetyl)amino-5-chloro-2’-fluorobenzophenone (4).

iii. Reduction of both carbonyl groups of the above formed compound with lithium-aluminum hydride gives –(2’-diethylamino)ethylamino-5-chloro-2’-fluoroben-zhydrol (5).

iv. The amino group of the product is acylated by phthalimidoacetyl chloride (6) to get phthalimido derivative (7).

v. The protective group phthalimido is removed by reaction with hydrazine hydrate to get 2-(2’-diethylamino)ethylaminoacetylamino-5-hloro-2’-fluorobenzohydrol (8).

vi. On treatment of the above formed compound with hydrobromic acid will lead to intermolecular dehydration with ring closure to give a benzodiazepine cycle, 7-chloro-1-[2-(diethylamino)ethyl]-5-(2’-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-3-one (9).

vii. Oxidation of N4-C5 bond with 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (10) gives flurazepam (11). [2]

Therapeutic Uses

Flurazepam is used for:

  • Treatment of insomnia

 

Side Effects

Side effects of flurazepam are:

  • Dizziness
  • Memory loss
  • Behavior changes
  • Mood changes
  • Depression
  • Abnormal thoughts
  • Suicidal thoughts
  • Hallucinations
  • Confusion
  • Agitation
  • Aggressiveness
  • Anxiety

 

 MCQ

Q.1 Match the following with correct SAR of the drug Flurazepam-

i. An electronegative group at 7-position of the ring A A. Increases the functional anxiolytic activity
ii. Substitutions at 6, 8 or 9 position with electronegative group on ring A B. Decreases the functional anxiolytic activity
. C. Decrease the functional anxiolytic activity
  D. Increase the functional anxiolytic activity

 a) i-A, ii-D

b) i-A, ii-C

c) i-B, ii-C

d) i-B, ii-D

Q.2 Correct sequence for the True/False for correct IUPAC names of the drug can be?

  • Benztropin: (3-endo)-3-(Diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane
  • Fesoterodine: [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate
  • Flurazepam: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
  • Midazolam: 7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one

a) TFTF

b) TTFF

c) FFTT

d) TTFT

Q.3 Number of chiral carbons present in the structure of Flurazepam?

a) 0

b) 1

c) 2

d) 3

Q.4 Flurazepam drug shows its action through??

a) Agonizing the acetylcholine receptors

b) Antagonizing the muscarinic receptors

c) Binding with GABAA receptors

d) ß-inhibition

Q.5 Which amongst the following is a therapeutic use of drug flurazepam?

a) Treatment of Insomia

b) Treatment of Alzhiemer’s disease

c) Treatment of Overactive bladder

d) Treatment of Asthma

Q.6 Which of the following drug and their classification are correct?

I. Benztropin: acetylcholine antagonist

II. Fesoterodine: Nitrogen mustard

III. Flurazepam: benzodiazepine sedative hypnotic

IV. Midazolam: Acetylcholine Nicotinic receptor antagonist

a) I, III

b) I, III, IV

c) II, IV

d) I, II, III, IV 

Q.7 Type of ring present in the structure of flurazepam is?

a) Diazepine ring

b) Pyrimidine

c) Pyrolopyrimidine

d) Not present 

 

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ANSWERS

1-a

2-b

3-a

4-c

5-a

6-a

7-a

  

REFERENCES

[1] Lemke TL, Zito SW, Roche VF, Williams DA. Essentials of Foye’s principles of medicinal chemistry. Wolters Kluwer; 2017, 473-474.

[2] Vardanyan R, Hruby V. Synthesis of essential drugs. Elsevier; 2006 Mar 10.

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