(+/-)-Sulfinpyrazone Chemical Properties

Melting point:

136-137°

Boiling point:

590.8±42.0 °C(Predicted)

Density 

1.1890 (rough estimate)

refractive index 

1.6360 (estimate)

storage temp. 

Sealed in dry,Room Temperature

solubility 

Very slightly soluble in water, sparingly soluble in ethanol (96 per cent). It dissolves in dilute solutions of alkali hydroxides.

form 

Solid

pka

pKa 2.8(H2O t = RT I undefined) (Uncertain)

color 

Off-White to Light Brown

Water Solubility 

2.601g/L(22 ºC)

CAS DataBase Reference

57-96-5(CAS DataBase Reference)

NIST Chemistry Reference

Sulfinpyrazone(57-96-5)

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

Safety Statements 

36

WGK Germany 

3

RTECS 

UQ8575000

HS Code 

2933194350

Hazardous Substances Data

57-96-5(Hazardous Substances Data)

MSDS

• Language:English Provider:SigmaAldrich

(+/-)-Sulfinpyrazone Usage And Synthesis

Description

Sulfinpyrazone is soluble in alkaline solutions. Its synthesis is similar to that of phenylbutazone (Fig. 36.33). It produces its uricosuric effect in a manner similar to that of probenecid. A dose of 35 mg produces a uricosuric effect equivalent to that produced by 100 mg of probenecid, whereas 400 mg/day of sulfinpyrazone produces an effect comparable to that obtained with doses of 1.5 to 2 g of probenecid. It also possesses, not surprisingly, some of the properties of phenylbutazone. It is an inhibitor of human platelet prostaglandin synthesis at the cyclooxygenase step, resulting in a decrease in platelet release and a reduction in platelet aggregation. This antiplatelet effect suggests a role for sulfinpyrazone in reducing the incidence of sudden death, which can occur in the first year following a myocardial infarction; however, it lacks the analgetic and anti-inflammatory effects of phenylbutazone.

Description

Sulfinpyrazone is a uricosuric agent that competitively inhibits uric acid reabsorption in kidney proximal tubules, which is a key mechanism targeted in the treatment of gout. It can also inhibit degranulation of platelets, reducing the release of ADP and thromboxane and diminishing platelet aggregation.

Chemical Properties

White or almost white powder.

Originator

Anturane,Geigy,US,1959

Uses

As an anti-inflammatory and uricosuric agent, its side effects were severe enough to preclude its continuous use in the treatment of chronic gout. Evaluation of several chemical congeners indicated that the phenylthioethyl analog of phenylbutazone had promising anti-inflammatory and uricosuric activity. A metabolite, the sulfoxide pyrazone, exhibited enhanced uricosuric activity. Interestingly, the corresponding sulfone does not appear to be a metabolite. Sulfinpyrazone lacks the clinically striking anti-inflammatory and analgesic properties of phenylbutazone.

Uses

Sulfinpyrazone is used in the treatment of gout acting as a uricosuric medication.

Uses

Sulfinpyrazone is used upon exactly the same indications as phenylbutazone.

Indications

Sulfinpyrazone (Anturane), another uricosuric agent, is chemically related to the antiinflammatory and uricosuric compound phenylbutazone. However, it lacks the antiinflammatory, analgesic, and sodium-retaining properties of phenylbutazone and possesses a number of undesirable side effects that limit its therapeutic usefulness.

Definition

ChEBI: Sulfinpyrazone is a sulfoxide and a member of pyrazolidines. It has a role as a uricosuric drug.

Manufacturing Process

296 parts of (β-phenylmercapto-ethyl)-malonic acid diethyl ester and then 203 parts of hydrazobenzene are added while stirring to a warm sodium ethylate solution obtained from 23 parts of sodium and 400 parts by volume of absolute alcohol. About half the alcohol is then distilled off, after which 200 parts by volume of absolute xylene are gradually added without removing the inclined condenser. The temperature of the oil bath is kept at about 130°C for 12 hours while continuously stirring so that the alcohol still present and that which is liberated distills off but the xylene remains as solvent.
After cooling, 400 parts by volume of water are stirred in. The aqueous layer is separated from the xylene, shaken out twice with 40 parts by volume of chloroform and then made acid to Congo red paper with concentrated hydrochloric acid. The oil which separates is taken up in ethyl acetate and the solution obtained is washed with water. After drying over sodium sulfate the solvent is distilled off under reduced pressure and the residue is recrystallized from alcohol. 1,2-diphenyl-3,5-dioxo-4-(β-phenylmercapto-ethyl)-pyrazolidine melts at 106° to 108°C.

Therapeutic Function

Antiarthritic (uricosuric)

General Description

Sulfinpyrazone (Anturane) produces its uricosuric action ina similar manner to that of probenecid and is indicated forthe treatment of chronic and recurrent gouty arthritis. It iswell absorbed with approximately 50% of the administereddose excreted as unchanged drug into the renal tubules. Therest of the drug is primarily metabolized via CYP2C9 intothe corresponding sulfide and sulfone metabolites, thus itcan potentiate the anticoagulant effect of warfarin.

Mechanism of action

The mechanism of sulfinpyrazone’s uricosuric activity is similar to that of probenecid. Sulfinpyrazone is readily absorbed after oral administration, with peak blood levels reached 1 to 2 hours after ingestion. It is more highly bound to plasma protein (98–99%) than is probenecid (84–94%) and is a more potent uricosuric agent. Most of the drug (90%) is eliminated through active proximal tubular secretion of the intact parent compound. Sulfinpyrazone also undergoes p-hydroxylation to form a uricosuric metabolite, the formation of which undoubtedly contributes to the drug’s prolonged activity (about 10 hours) and potency relative to probenecid. In contrast to probenecid, the rate of excretion of sulfinpyrazone is not enhanced by alkalinization of the urine, since the drug is largely ionized at all urinary pH ranges and therefore not a candidate for passive back-diffusion.

Pharmacokinetics

Only the parent sulfinpyrazone and its reduced sulfide metabolite, however, are active as COX inhibitors. Because these compounds are reversible inhibitors, the antithrombotic activity lasts only as long as blood levels of the drug and metabolite persist (half-life, 4–6 hours for parent sulfinpyrazone, 11–14 hours for the sulfide metabolite). Sulfinpyrazone is not yet approved in the United States for use in acute myocardial infarction or for transient ischemic attack prophylaxis.

Pharmacology

Sulfinpyrazone, although less effective than allopurinol in reducing serum uric acid levels, remains useful for the prevention or reduction of the joint changes and tophus deposition that would otherwise occur in chronic gout; it has no antiinflammatory properties. During the initial period of sulfinpyrazone use, acute attacks of gout may increase in frequency and severity. It is recommended, therefore, that either colchicine or a nonsteroidal antiinflammatory agent be coadministered during early sulfinpyrazone therapy. Abdominal pain, nausea, and possible reactivation of peptic ulcer have been reported.

Clinical Use

Sulfinpyrazone is a structural derivative of the anti-inflammatory drug phenylbutazone. Unlike phenylbutazone, however, sulfinpyrazone does not have significant anti-inflammatory activity. It does have potent uricosuric effects and frequently is used in the treatment of gout.

Side effects

The most frequent adverse reactions are GI disturbances; however, the incidence is relatively low.

Synthesis

Sulfinpyrazone, 1,2-diphenyl-4,2-(phenylsulfinil)ethyl-3,5-pyrazolidinedione (3.2.8), is an analog of phenylbutazone that is synthesized in the analogous manner of condensing hydrazobenzol with 2-(2-phenyltioethyl)malonic ester into pyrazolidinedione (3.2.7), and the subsequent oxidation of thiol ether by hydrogen peroxide in acetic acid into the sulfoxide, sulfinpyrazone (3.2.8) [70,71].

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: increased risk of bleeding with apixaban; enhances anticoagulant effect of coumarins; possibly increased risk of bleeding with dabigatran.
Antidiabetics: enhances effect of sulphonylureas.
Antiepileptics: increases concentration of fosphenytoin and phenytoin.
Ciclosporin: may reduce ciclosporin levels.

Metabolism

The metabolites produced result from sulfoxide reduction, sulfur and aromatic oxidation, and C-glucuronidation of the heterocyclic ring in a manner similar to that for phenylbutazone. The metabolite resulting from p-hydroxylation of the aromatic ring possesses uricosuric effects in humans. The sulfide metabolite, a major metabolic product, may contribute to the antiplatelet effects of sulfinpyrazone but not to the uricosuric effects.

(+/-)-Sulfinpyrazone (57-96-5)Related Product Information

• Phenylmethylsulfonyl fluoride
• Phenylbutazone
• Pyrazosulfuron-ethyl
• Sulfanilamide
• Benzenesulfonic acid
• Ethylparaben
• Cefbuperazone
• ISOXADIFEN-ETHYL
• Chlorosulfonyl isocyanate
• Ethyl acrylate
• Tribenuron methyl
• 1,5-Diphenylcarbazide
• Ethanol
• Ethyl acetate
• Ethyl cyanoacetate
• Benzenesulfonyl chloride
• Trinexapac-ethyl
• Biphenyl