Arylalkanoic acids

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Chapter: Medicinal Chemistry : Analgesics, Antipyretics, and NSAIDs

a. Indole acetic acid derivatives i. Indomethacin (Indocin, Indocid) b. Indeneacetic acid derivatives i. Sulindac (Clinoril) c. Pyrrole acetic acid derivative i. Tolmetin Sodium (Tolectin) ii. Zomepirac (Zomax) d. Aryl and heteroaryl acetic/propionic acid derivatives i. Ibuprofen (Brufen, Motrin) ii. Ibufenac iii. Diclofenac (Voltaren, Voveran) iv. Naproxen (Naprosyn) v. Fenoprofen (Nalton) vi. Ketoprofen (Orudis) vii. Ketoprofen viii. Flurbiprofen (Ansaid) viii. Caprofen ix. Ketorolac (Acular, Ketodrops, Ketlur) x. Etodolac


 

Arylalkanoic acids


 

SAR of Arylalkanoic Acids

1.           The centre of acidity is usually located one carbon atom adjacent to a flat surface represented by an aromatic or hetero aromatic ring.

2.           The distance between these centres is critical because increasing this distance to two or three carbons generally decreases activity.

3.           All agents possess a centre of acidity, which can be represented by a carboxylic acid and hydroxamic acid, a sulphonamide or a terazole.

4.           Substitution of a methyl group on the carbon atom separating the aromatic ring leads to enhancement of anti-inflammatory activity.


a. Indole acetic acid derivatives

i. Indomethacin (Indocin, Indocid)

 

Synthesis


Metabolism: It is converted into inactive metabolites, that is, 50% of single dose is 5-O-demethylated and 10% conjugated with glucuronic acid. Nonhepatic enzymes hydrolyze indomethacin to N-deacetylated metabolite.


Properties and uses: It is a white or yellow crystalline powder, insoluble in water and sparingly soluble in alcohol. Indomethacin is more effective than aspirin. The most frequent side effects are gastric distress and headache. It also has been associated with peptic ulceration, blood disorders, and possible death (these side effects appear to be closely related and sometimes can be minimized by reducing the dose). It is not recommended for use in children because of possible interference with the resistance to infection. Used as anti-inflammatory and analgesic in rheumatic arthritis, spondylitis, and to lesser extent in gout.

Assay: Dissolve the sample in acetone and pass nitrogen for 15 min and titrate with 0.1 M sodium hydroxide using phenolphthalein as indicator.

Dose: In gout, usual adult dose orally is 100 mg initially, followed by 50 mg three times a day until pain is relieved. As an antirheumatic by oral route, the dose is 50 mg two or three times a day. And as an antipyretic, the dose is orally 25–50 mg three times a day.

Dosage forms: Indometacin capsules I.P., B.P., Indometacin Suppositories I.P., B.P.

 

b. Indeneacetic acid derivatives

i. Sulindac (Clinoril)


Metabolism: It is a prodrug to form active metabolites of sulphite. In addition to it, sulindac is oxidized to corresponding sulphone and other sulphone-glucuronide conjugates.

Properties and uses: Suindac is a yellow crystalline powder, very slightly soluble in water, soluble in methylene chloride, and dilute solutions of alkali hydroxides, sparingly soluble in alcohol. The (Z) isomer of sulindac showed much more potent anti-inflammatory activity than the corresponding (E)-isomer. The more polar and inactive sulphoxide is virtually the only form excreted. It has analgesic, antipyretic, and anti-inflammatory properties. It is usually employed in the treatment of rheumatic and muscular skeletal disorders, acute gouty arthritis, and osteoarthritis.

Synthesis

Route I. From: 3-(4-fluorophenyl)-2-methyl propanoic acid


Synthesis

Route II. From p-Fluoro benzaldehyde


Assay: Dissolve the sample in methanol and titrate against 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: Usual adult oral dose is 150 mg twice a day with food.

Dosage forms: Sulindac tablets B.P.


 

SAR of Indole Acetic Acid Derivatives


1. Placement of other acidic functionalities instead of the carboxyl group decreases activity and the amide derivatives are inactive.

2. Substituents of R1 useful for increasing anti-inflammatory activity are ranked as C6H4CH2 > alkyl > H.

3. Acylation of the indole nitrogen with aryl/alkyl carboxylic acids results in the decrease of activity.

4. Presence of substituents on the N-benzoyl derivatives in the p-position with F, Cl, CF3, or S-CH3 groups provide greatest activity.

5. X substituents activity are ranked as 5-OCH3 > N (CH3)2 > CH3 > H.

6. The presence of indole ring nitrogen is not essential for activity because the corresponding 1-benzylidenylindene analogue (sulindac) is also active.

7. Alkyl groups especially methyl group at 2nd position is much active than aryl substituted analogues.

8. Substitution of a methyl group at the α position of the acetic acid side chain leads to equiactive analogues.

9. Anti-inflammatory activity was displayed only by the dextrorotatory enantiomer with similar absolute configuration; it has 25 times the activity of phenylbutazone.

 

SAR of Pyrrole Acetic Acid Derivative

c. Pyrrole acetic acid derivative

Replacement of the p-tolyl group with a p-chloro benzoyl moiety produced little effect on activity, whereas introduction of a methyl group in the 4th position and 5-p-chloro benzoyl analogues (zomeapirac) proved to be four times potent as tolmetin.

 

i. Tolmetin Sodium (Tolectin)

From: 1-Methyl pyrrole


Synthesis


Metabolism: It is metabolized extensively first pass, involving hydroxylation of p-methyl group to primary alcohol, which is subsequently oxidized to dicarboxylic acid.

Properties and uses: It is a light yellow, crystalline powder, soluble in water, slightly soluble in alcohol. It has antipyretic, analgesic, and anti-inflammatory actions. It is employed in the treatment of rheumatic and musculoskeletal disorders. The drug is, however, comparable to indomethacin and aspirin in the control and management of disease activity.

Dose: Adult oral dose initially is 400 mg three times a day, subsequently adjusted as per patient’s response.

 

ii. Zomepirac (Zomax)


Properties and uses: A greater degree of analgesia for severe pain is claimed for Zomepirac. It is used as an analgesic and an ant-inflammatory drug. It is four times as potent as tolmetin.

Dose: Dose is 400 to 600 mg of zomepirac daily (zomepirac sodium 1.2 g is approximately equivalent to 1 g of zomepirac).

Synthesis

Route I. From Chloro acetone


Route II. From: Enol of ethyl acetone dicarboxylate


 

d. Aryl and heteroaryl acetic/propionic acid derivatives

i. Ibuprofen (Brufen, Motrin)


Synthesis

Route I. From Isobutyl benzene


Route II. From: Isobutyl benzene


Metabolism: Oxidative metabolite of ibuprofen and unchanged drugs are excreted in urine. Oxidation involves ω, ω , and ω oxidation of the para isobutyl side chain, followed by alcohol oxidation, resulting from ω oxidation to corresponding carboxylic acid.


Properties and uses: Ibuprofen is a white crystalline powder or colourless crystals, practically insoluble in water, soluble in acetone, methanol, methylene chloride, and dilute solutions of alkali hydroxides and carbonates. The precursor Ibufenac, which was abandoned owing to hepatotoxicity, was less potent. Moreover, the activity resides in the (s)–(+) isomer, not only in Ibuprofen but also throughout the arylacetic acid series. Furthermore, these isomers are the more potent inhibitors of PG synthetase. It is an anti-inflammatory drug that possesses antipyretic and analgesic action and is used for the treatment of rheumatoid arthritis and osteoarthritis.

Assay: Dissolve the sample in methanol and titrate against 0.1 M sodium hydroxide using phenolphthalein as indicator, until red colour is obtained. Perform a blank titration

Dose: Usual oral adult dose as an analgesic (dysmenorrhoea) is 200–400 mg four to six times a day; in rheumatoid arthritis and osteoarthritis. The dose is 300–400 mg three or four times a day.

Dosage forms: Ibuprofen tablets I.P., B.P, Ibuprofen cream B.P., Ibuprofen gel B.P., Ibuprofen oral suspension B.P.

 

ii. Ibufenac


Synthesis


Properties and uses: It was formerly employed in the rheumatic conditions, but was found to cause hepatotoxicity. It has analgesic, antipyretic, and anti-inflammatory actions.

 

iii. Diclofenac (Voltaren, Voveran)


Metabolism: There are four major metabolites that are produced by aromatic hydroxylation, that is, 4-hydroxy derivative, 5-hydroxy, 3-hydroxyl, and 4,5-dihydroxy metabolites. Remaining metabolites are excreted as sulphate conjugates.

Properties and uses: Diclofenac sodium is a white or slightly yellowish crystalline slightly hygroscopic powder, sparingly soluble in water, soluble in methanol and alcohol, slightly soluble in acetone. Used in the treatment of rheumatic arthritis.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The usual dose is 20–50 mg three times a day. It can also be given as a suppository.

Dosage forms: Diclofenac tablets I.P., Diclofenac injection I.P., Prolonged-release diclofenac tablets B.P., Gastro-resistant diclofenac tablets B.P., Prolonged-release diclofenac injection B.P., Prolonged-release diclofenac capsules B.P.

Synthesis


 

iv. Naproxen (Naprosyn)


Metabolism: It is converted to 6-O-desmethyl metabolite and then to glucuronide conjugate.

Properties and uses: Naproxen is a white crystalline powder, practically insoluble in water, soluble in ethanol and in methanol. The drug is fairly comparable to aspirin both in the management and control of disease symptoms. Nevertheless, it has relatively lesser frequency and severity of nervous system together with milder GI-effects. It possesses analgesic, anti-inflammatory, and antipyretic actions, and it is used in the treatment of rheumatic arthritis, dysmenorrhea, and acute gout.

Assay: Dissolve the sample in a mixture of water and methanol (1:3) and titrate against 0.1 M sodium hydroxide, using 1 ml of phenolphthalein solution as indicator.

Dose: For adult in rheumatoid arthritis, 250–375 mg as initial dose two times a day; in acute gout, 750 mg as loading dose followed by 250 mg three times a day until relieved.

Dosage forms: Naproxen oral suspension B.P., Naproxen suppositories B.P., Naproxen tablets B.P., Gastroresistant naproxen tablets B.P.

Synthesis


 

v. Fenoprofen (Nalton)


Synthesis


Metabolism: It is metabolized through glucuronide conjugation with a parent drug and CYP2C9 to 4-hydroxy metabolites.

Properties and uses: Fenoprofen calcium is a white crystalline powder, slightly soluble in water and soluble in ethanol. Fenoprofen calcium has anti-inflammatory (antiarthritic) and analgesic properties. It has been shown to inhibit PG synthetase. It is known to reduce joint-swelling, decrease the duration of morning stiffness, and relieve pain. It is also indicated for acute flares and exacerbations and in the long-term management of osteoarthritis and rheumatoid arhrtitis.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically. Perform a blank titration.

Dose: Dose is 50–100 mg twice daily with food.

Dosage forms: Fenoprofen tablets B.P.

 

vi. Ketoprofen (Orudis)


Synthesis

Route I. From:α-Methylene substituted m-benzyl phenyl acetic acid


Route II. From: 2-(4-Aminophenyl) propanoic acid


 

vii. Ketoprofen

Metabolism: It is metabolized by glucuronidation of carboxylic acid, CYP3A4, and CYP2C9 hydroxylation of benzoyl ring and reduction of keto function.

Properties and uses: Ketoprofen is a white crystalline powder, practically insoluble in water, soluble in acetone, in ethanol, and in methylene chloride. It is closely related to fenoprofen in structure, properties, and indications and has a low incidence of side effects and has been approved for counter sale. It is used in the treatment of rheumatoid arthritis and osteoarthritis

Assay: Dissolve the sample in ethanol and dilute with water and titrate against 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: Usual adult oral dose for rheumatoid arthritis is 600 mg four times daily; for osteoarthritis the dose is 300–600 mg four times a day.

Dosage forms: Ketoprofen capsules I.P., B.P., Ketoprofen gel B.P.

 

viii. Flurbiprofen (Ansaid)


Synthesis


Properties and uses: Flurbiprofen is a white crystalline powder, practically insoluble in water, soluble in alcohol, in methylene chloride, and aqueous solutions of alkali hydroxides and carbonates. The drug is structurally and pharmacologically related to fenoprofen, ibuprofen, and ketoprofen. Another hydrotropic acid analogue that is used in the acute or long-term management of rheumatoid arthritis and osteoarthritis, it posses analgesic, anti-inflammatory, and antipyretic activities.

Assay: Dissolve the sample in alcohol and titrate against 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: Usual adult dose is 150–200 mg a day in three to four divided doses.

Dosage forms: Flurbiprofen tablets I.P., B.P, Flurbiprofen suppositories B.P.

 

viii. Caprofen


Synthesis

From: 1-(4-chlorophenyl) hydrazine


Uses: Used as an analgesic and anti-inflammatory agent.

 

ix. Ketorolac (Acular, Ketodrops, Ketlur)


Synthesis


Properties and uses: Ketorolac is a white crystalline powder, soluble in water and in methanol, slightly soluble in ethanol, practically insoluble in methylene chloride. Ketorolac is a potent analgesic indicated for the treatment of moderately severe and acute pain.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The dose for ocular itching, which is associated with seasonal allergic conjunctivitis, for reduction of ocular pain, and for photophobia in patients undergoing incisional refractive sugery, instil one drop of a 0.5% solution into the affected eyes four times daily.

 

x. Etodolac


Synthesis


Metabolism: It is metabolized to 3-hydroxylated metabolite and to glucuronide conjugates.

Properties and uses: Etodolac is a white crystalline powder, practically insoluble in water, soluble in acetone and in ethanol. It has anti-inflammatory activity and inhibits cyclooxygenase. It is used in the treatment of osteoarthritis and rheumatoid arthritis. Gastrointestinal irritation and ulceration is less with this drug than with other drugs.

Assay: Dissolve the sample in methanol and titrate against 0.1 M tetrabutylammonium hydroxide. Determine the end point potentiometrically. Perform a blank titration.

Dosage forms: Etodolac capsules B.P., Etodolac tablets B.P.

 

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