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

Isoxicam

IUPAC nomenclature

4-hydroxy-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)-1,1-dioxo-1λ6,2-benzothiazine-3-carboxamide

Classification

  • NSAID
  • Oxicames

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 335.34 g/mol
2 Physical appearance Solid
3 Melting point N/A
4 Solubility 33.9 ug/ml
5 Octanol/water partition coefficient 2.83 (logP)
6 Presence of ring Isoxazole, benzothiazine
7 Number of chiral centers 1

 

 

Mechanism of Action

  • Isoxicam reversibly inhibits cyclooxygenase enzyme which causes peripheral inhibition of prostaglandin synthesis.
  • It also has the platelet inhibitory action.

 

Structure Activity Relationship

General SAR for Oxicams can be summarized as follows:

  • Substitution on the nitrogen atom of the thiazine ring gives optimum activity.
  • Substitution on the caboxamide with aryl group gives compounds with greater activity than when substituents are alkyl groups.
  • N-heterocyclic compounds are more acidic than N-aryl carboxamides.
  • Primary carboxamides are more potent than secondary carboxamides.
  • m-substituted derivatives are more potent than p-substituted derivatives.
  • Maximum activity is found with m-Cl substituent in the aryl series.
  • Substitution on the carboxamide Nitrogen with heteroaryl group gives compound with seven fold greater anti-inflammatory activity than the aryl group substitution. [1]

 

Method of synthesis

i. Reaction of saccharine with sodium hydroxide to give a sodium salt.

ii. Sodium salt so produced is reacted with methyl chloroacetate to give saccharine-substituted acetic acid ethyl ester.

iii. The above formed product undergoes rearrangement on reaction with dimethylsulfoxide to produce 1,1-dioxide-3-methoxycarbonyl-3,4-dihydro-2-H-1,2-benzothiazin-4-one.

iv. Last undergoes methylation at the nitrogen atom using methyl iodide followed by reaction with 3-amino-5-mehylisoxazole to give Isoxicam. [2]

Therapeutic Uses

Isoxicam is used for:

  • Treatment of pain and swelling due to rheumatoid arthritis 

 

Side Effects

Side effects of isoxicam are:

  • Nausea
  • Upset stomach
  • Dizziness
  • Headache
  • Hypertension
  • Easy bleeding
  • Painful swallowing
  • Ringing in ears
  • Mood changes
  • Change in amount of urine
  • Stiff neck
  • Vision problem
  • Swelling ankles
  • Tiredness
  • Weight gain
  • Dark urine
  • Vomiting
  • Loss of appetite
  • Pale skin
  • Allergic reactions 

 

MCQs

Q.1 What can be the correct IUPAC nomenclature of Isoxicam?

a) 4-hydroxy-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)-1,1-dioxo-1λ6,2-benzothiazine-3-carboxamide

b) 4-hydroxy-2-methyl-N-(5-methyl-1,2-oxazol-3-yl)-1,1-dioxo-1λ6,2-benzothiazine-3-Carboxylic acid

c) N-(3-Ethoxyphenyl) benzothiazine-3-carboxamide

d) N-(4-Ethoxyphenyl) benzothiazine-3-carboxamide

Q.2 Which amongst the following statements is/are incorrect related to the SAR of phenacetin?

I. Primary carboxamides are more potent than secondary carboxamides.

II. m-substituted derivatives are less potent than p-substituted derivatives.

III. Minimum activity is found with m-Cl substituent in the aryl series.

IV. Substitution on the carboxamide Nitrogen with heteroaryl group gives compound with seven fold greater anti-inflammatory activity than the aryl group substitution.

a) I, II

b) I, III

c) I

d) II, III

Q.3 Starting materials required by for the synthesis of Isoxicam can be?

I. Saccharine

II. Sodium hydroxide

III. Sulfuric acid

IV. Atropin

a) I, II

b) III, IV

c) I, IV

d) II, II, IV

Q.4 Side effects of drug Isoxicam is/are?

a) Painful swallowing

b) Ringing in ears

c) Vision problems

d) All of the above

Q.5 Match the following drugs with the correct number of the chiral carbons they have in their structure:

i. Isoxicam A. 4
ii. Tolmetin B. 1
iii. Atazanavir C. 2
iv. Thiopental D. 0

 a) i-A, ii-C, iii-D, iv-B

b) i-D, ii-A, iii-C, iv-B

c) i-D, ii-B, iii-A, iv-C

d) i-B, ii-D, iii-A, iv-C

Q.6 An example of drug from class NSAIDs?

a) Tropicamide

b) Isoxicam

c) Methamphetamine

d) All of the above 

Q.7 The type of ring system found in Isoxicam?

a) Isoxazole

b) Benzothiazine

c) Both a) and b)

d) None of the above

 

 

 

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ANSWERS

1-a

2-d

3-a

4-d

5-d

6-b

7-c

 

REFERENCES

[1]  Lemke TL, Williams DA, Roche VF, Zito SW. FOYE. S Principles of Medicinal Chemistry. Seventh Edition Copyright. 2013.

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

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