Basic information Used in Particular Diseases Safety Supplier Related
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Sulindac

Basic information Used in Particular Diseases Safety Supplier Related

Sulindac Basic information

Product Name:
Sulindac
Synonyms:
  • 1h-indene-3-aceticacid,5-fluoro-2-methyl-1-((4-(methylsulfinyl)phenyl)methyle
  • Aclin
  • arthrocine
  • (z)-5-fluoro-2-methyl-1-((p-(methylsulfinyl)phenyl)methylene)-1h-indene-3-ac
  • sulindacsulfoxide
  • (Z)-5-FLUORO-2-METHYL-1-[P-(METHYLSULFINYL)BENZYLIDENE]INDENE-3-ACETIC ACID
  • 5-FLUORO-2-METHYL-1Z-[[4(METHYLSILFUNYL)PHENYL]METHYLENE]-1H-INDENE-3-ACETIC ACID
  • AFLODAC
CAS:
38194-50-2
MF:
C20H17FO3S
MW:
356.41
EINECS:
253-819-2
Product Categories:
  • pharmaceutical
  • CLINORIL
  • Other APIs
  • Lipid signaling
  • Active Pharmaceutical Ingredients
  • Intermediates & Fine Chemicals
  • Pharmaceuticals
Mol File:
38194-50-2.mol
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Sulindac Chemical Properties

Melting point:
182-185°C
Boiling point:
581.6±50.0 °C(Predicted)
Density 
1.2581 (estimate)
storage temp. 
Store at RT
solubility 
Very slightly soluble in water, soluble in methylene chloride, sparingly soluble in ethanol (96 per cent). It dissolves in dilute solutions of alkali hydroxides.
form 
neat
pka
pKa (25°) 4.7
Water Solubility 
Soluble in water, methanol, ethanol.
λmax
327nm(0.05mol/L methanolic HCl)(lit.)
Merck 
14,8982
CAS DataBase Reference
38194-50-2(CAS DataBase Reference)
NIST Chemistry Reference
Sulindac(38194-50-2)
EPA Substance Registry System
1H-Indene-3-acetic acid, 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-, (1Z)- (38194-50-2)
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Safety Information

Hazard Codes 
Xn
Risk Statements 
22-63-42/43
Safety Statements 
-
RIDADR 
3249
WGK Germany 
3
RTECS 
NK8226000
HazardClass 
6.1(b)
PackingGroup 
III
HS Code 
29309090

MSDS

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Sulindac Usage And Synthesis

Used in Particular Diseases

Acute Gouty Arthritis:
Dosage and Frequency: 200 mg twice daily for 7–10 days

Chemical Properties

Yellow Crystalline Solid

Originator

Imbaral,Sharp and Dohme ,W. Germany,1976

Uses

A non-steroidal anti-inflammatory agent. An anti-inflammatory

Uses

Sulindac is a non-steroidal anti-inflammatory drug.

Definition

ChEBI: A monocarboxylic acid that is 1-benzylidene-1H-indene which is substituted at positions 2, 3, and 5 by methyl, carboxymethyl, and fluorine respectively, and in which the phenyl group of the benzylidene moiety is substituted at the ara position by a methylsulfinyl group. It is a prodrug for the corresponding sulfide, a non-steroidal anti-inflammatory drug, used particularly in the treatment of acute and chronic inflammatory conditions.

Indications

Sulindac (Clinoril) is chemically related to indomethacin and is generally used for the same indications. It is a prodrug that is metabolized to an active sulfide metabolite and an inactive metabolite. The most frequently reported side effects are GI pain, nausea, diarrhea, and constipation. The incidence of these effects is lower than for indomethacin, presumably because sulindac is a prodrug and thus the active metabolite is not highly concentrated at the gastric mucosa. As with indomethacin, a rather high incidence of CNS side effects (dizziness, headache) also occurs.

Manufacturing Process

The following process sequence is described in US Patent 3,654,349:
p-Fluoro-α-Methylcinnamic Acid: 200 grams (1.61 mols) pfluorobenzaldehyde, 3.5 grams (2.42 mols) propionic anhydride and 155 grams (1.61 mols) sodium propionate are mixed in a 1 liter three-necked flask which had been flushed with nitrogen. The flask is heated gradually in an oilbath to 140°C. After 20 hours the flask is cooled to 100°C and the contents are poured into 8 liters of water. The precipitate is dissolved by adding 302 grams potassium hydroxide in 2 liters of water. The aqueous solution is extracted with ether, and the ether extracts washed with potassium hydroxide solution. The combined aqueous layers are filtered, acidified with concentrated HCl, filtered and the collected solid washed with water, thereby producing pfluoro- α-methylcinnamic acid which is used as obtained.p-Fluoro-α-Methylhydrocinnamic Acid: To 177.9 grams (0.987 mol) p-fluoro-α- methylcinnamic acid in 3.6 liters ethanol is added 11.0 grams of 5% Pd/C and the mixture reduced at room temperature under a hydrogen pressure of 40 psi. Uptake is 31/32 pounds (97% of theoretical). After filtering the catalyst, the filtrate is concentrated in vacuo to give the product p-fluoro-α- methylhydrocinnamic acid used without weighing in next step.
6-Fluoro-2-Methylindanone: To 932 grams polyphosphoric acid at 70°C on the steam bath is added 93.2 grams (0.5 mol) p-fluoro-α-methylhydrocinnamic acid slowly with stirring. This temperature is gradually raised to 95°C and the mixture kept at this temperature for 1 hour. The mixture is allowed to cool and added to 2 liters of water. The aqueous layer is extracted with ether, the ether solution washed twice with saturated sodium chloride solution, 5% Na2CO3 solution, water, and then dried. The ether filtrate is concentrated with 200 grams silica-gel, and added to a five pound silica-gel column packed with 5% ether-petroleum ether. The column is eluted with 5 to 10% etherpetroleum ether and followed by TLC to give 6-fluoro-2-methylindanone.
5-Fluoro-2-Methylindene-3-Acetic Acid: A mixture of 18.4 grams (0.112 mol) of 6-fluoro2-methylindanone, 10.5 grams (0.123 mol) cyanacetic acid, 6.6 grams acetic acid and 1.7 grams ammonium acetate in 15.5 ml dry toluene is refluxed with stirring for 21 hours, as the liberated water is collected in a Dean Stark trap. The toluene is concentrated and the residue dissolved in 60 ml of hot ethanol and 14 ml of 2.2 N aqueous potassium hydroxide solution. 22 grams of 85% KOH in 150 ml of water is added and the mixture refluxed for 13 hours under N2. The ethanol is removed under vacuum, 500 ml water added, the aqueous solution washed well with ether and then boiled with charcoal. The aqueous filtrate is acidified to pH 2 with 50% hydrochloric acid, cooled and the precipitate collected in this way dried 5-fluoro-2-methylindenyl- 3-acetic acid (MP 164° to 166°C) is obtained.
5-Fluoro-2-Methyl-1-(p-Methylthiobenzylidene)-3-Indenylacetic Acid: 15 grams (0.072 mol) 5-fluoro-2-methyl-3-indenylacetic acid, 14.0 grams (0.091 mol) p-methylthiobenzaldehyde and 13.0 grams (0.24 mol) sodium methoxide are heated in 200 ml methanol at 60°C under nitrogen with stirring for 6 hours. After cooling the reaction mixture is poured into 750 milliliters of ice-water, acidified with 2.5 N hydrochloric acid and the collected solid triturated with a little ether to produce 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3- indenylacetic acid (MP 187° to 188.2°C).
5-Fluoro-2-Methyl-1-(p-Methylsulfinylbenzylidene)-3-Indenylacetic Acid: To a solution of 3.4 grams (0.01 mol) 5-fluoro-2-methyl-1-(pmethylthiobenzylidene)- 3-indenylacetic acid in a 250 ml mixture of methanol and 100 ml acetone is added a solution of 3.8 grams (0.018 mol) of sodium periodate in 50 ml water with stirring.
450 ml water is added after 18 hours and the organic solvents removed under vacuum below 30°C. The precipitated product is filtered, dried and recrystallized from ethyl acetate to give 5-fluoro-2-methyl-1-(pmethylsulfinylbenzylidene)- 3-indenylacetic acid. Upon repeated recrystallization from ethylacetate there is obtained cis-5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene)-3-indenylacetic acid (MP 184° to 186°C).

brand name

Clinoril (Merck).

Therapeutic Function

Antiinflammatory

General Description

Sulindac, (Z)-5-fluoro-2-methyl-1-([p-(methylsulfinyl)phenyl]methylene)-1H-indene-3-acetic acid (Clinoril), isan NSAID prodrug that contains a chiral sulfoxide moietybut is marketed as the racemate because it undergoes invivo reduction by the hepatic enzymes into its achiral, activemetabolite, methyl sulfide that exhibits potent andnonselective COX inhibition similar to indomethacin.
The parent sulfoxide has a plasma half-life of 8 hours, andthe active methyl sulfide metabolite is 16.4 hours. The morepolar and inactive sulfoxide is virtually the only form excretedinto the renal tubules, thus sulindac is believed to haveminimal nephrotoxicity associated with indomethacin. Thelong half-life of sulindac is caused by the extensive enterohepaticcirculation and reactivation of the inactive sulfoxideexcreted. Coadministration of aspirin is contraindicated becauseit considerably reduces the sulfide blood levels. Carefulmonitoring of patients with a history of ulcers is recommended.Gastric bleeding, nausea, diarrhea, dizziness, andother adverse effects have been noted with sulindac, but witha lower frequency than with aspirin. Sulindac is recommendedfor RA, OA, and ankylosing spondylitis.

Biological Activity

Prodrug. Metabolizes to sulindac sulfide, a cyclooxgenase inhibitor that represses ras signaling, and sulindac sulfone, an antitumor agent, following oral administration in vivo . Widely used anti-inflammatory agent.

Pharmacokinetics

Sulindac is well absorbed on oral administration (90%), reaches peak plasma levels within 2 to 4 hours, and being acidic (pKa = 4.5), is highly bound to serum proteins (93%). The metabolism of sulindac plays a major role in its actions, because all of the pharmacological activity is associated with its major metabolite. Sulindac is, in fact, a pro-drug, the sulfoxide function being reduced to the active sulfide metabolite. Sulindac is absorbed as the sulfoxide, which is not an inhibitor of prostaglandin biosynthesis in the GI tract. Prostaglandins exert a protective effect in the GI tract, and inhibition of their synthesis here leads to many of the GI side effects noted for most NSAIDs. Once sulindac enters the circulatory system, it is reduced to the sulfide, which is an inhibitor of prostaglandin biosynthesis in the joints. Thus, sulindac produces less GI side effects, such as bleeding, ulcerations, and so on, than indomethacin and many other NSAIDs. In addition, the active metabolite has a plasma half-life approximately twice that of the parent compound (~16 hours versus 8 hours), which favorably affects the dosing schedule. In addition to the sulfide metabolite, sulindac is oxidized to the corresponding sulfone, which is inactive. A minor product results from hydroxylation of the benzylidene function and the methyl group at the 2-position. Glucuronides of several metabolites also are found. Sulindac as well as the sulfide and the sulfone metabolites are all highly protein-bound. Despite the fact that the sulfide metabolite is a major activation product and is found in high concentration in human plasma, it is not found in human urine, perhaps because of its high degree of protein binding.

Clinical Use

Sulindac is indicated for long-term use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gouty arthritis. The usual maximum dosage is 400 mg/day, with starting doses recommended at 150 mg twice a day. It is recommended that sulindac be administered with food.

Side effects

Whereas the toxicity of sulindac is lower than that observed for indomethacin and other NSAIDs, the spectrum of adverse reactions is very similar. The most frequent side effects reported are associated with irritation of the GI tract (e.g., nausea, dyspepsia, and diarrhea), although these effects generally are mild. Effects on the CNS (e.g., dizziness and headache) are less common. Dermatological effects are less frequently encountered.

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