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Sulfinpyrazone

Sulfinpyrazone structure

CAS No:
57-96-5
Formula:
C23H20N2O3S
Chemical Name:
Sulfinpyrazone
Synonyms:
3,5-Pyrazolidinedione,1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-;1,2-Diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione;G 28315;Anturan;Anturane;1,2-Diphenyl-4-(2′-phenylsulfinethyl)-3,5-pyrazolidinedione;Diphenylpyrazone;4-(Phenylsulfoxyethyl)-1,2-diphenyl-3,5-pyrazolidinedione;Sulfinpyrazone;Sulfoxyphenylpyrazolidine;Sulphinpyrazone;Sulfinpyrazon;Anturanil;Anturen;Anturidin;Enturan;Enturen;NSC 75925;158920-43-5
Categories:
Active Pharmaceutical Ingredients > Antipyretic Analgesics

Description

White or almost white powder.

Solid

Sulfinpyrazone is a sulfoxide and a member of pyrazolidines. It has a role as a uricosuric drug.|A uricosuric drug that is used to reduce the serum urate levels in gout therapy. It lacks anti-inflammatory, analgesic, and diuretic properties.

Sulfinpyrazone Basic Attributes

Molecular Weight：

404.48

Exact Mass：

404.48

EC Number：

200-357-4

NSC Number：

757332|75925

DSSTox ID：

DTXSID0023618

Color/Form：

WHITE TO OFF-WHITE

ATC Code：

M - Musculo-skeletal system

HScode：

2933990090

Characteristics

PSA：

76.9

XLogP3：

2.3

Appearance：

Solid

Density：

1.4±0.1 g/cm3

Melting Point：

136-137 °C

Boiling Point：

590.8ºC at 760 mmHg

Flash Point：

311.1±27.9 °C

Refractive Index：

1.717

Water Solubility：

2.601g/L(22 ºC)

PKA：

3.25None

Dissociation Constants：

3.25|PKA: 2.8

Collision Cross Section：

193.5 Å² [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Experimental Properties：

CRYSTALS FROM CHLOROFORM & HEPTANE; CRYSTALS FROM ETHANOL /D-FORM/; CRYSTALS /L-FORM/|SPECIFIC OPTICAL ROTATION: +67.1 DEG @ 22 °C/D (C= 2.04 IN ETHANOL); +109.3 DEG @ 25 °C/D (C= 0.5 IN CHLOROFORM) /D-/|SPECIFIC OPTICAL ROTATION: -64.2 DEG @ 23 °C/D (C= 2.14 IN ETHANOL); -104.5 DEG @ 26 °C/D (C= 0.5 IN CHLOROFORM) /L-/

Safety Information

Transport codes：

NONH for all modes of transport

wgk germany：

hazard class code：

safety instructions：

RTECS Number：

UQ8575000

Marks：

Stability/Shelf Life：

STABLE TO LIGHT & AIR

Precautionary statement(s)：

P301 + P312 + P330

Hazard Statements：

H302

GHS Classification：

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 103 companies from 1 notifications to the ECHA C&L Inventory.

Toxicity

Toxicity Summary：

Symptoms of overdose include nausea, vomiting, diarrhea, epigastric pain, ataxia, labored respiration, convulsions, coma. Possible symptoms, seen after overdosage with other pyrazolone derivatives: anemia, jaundice, and ulceration.

Interactions：

...URICOSURIC ACTION /OF SULFINPYRAZONE/ IS ADDITIVE TO THAT OF PROBENECID & PHENYLBUTAZONE BUT IS MUTUALLY ANTAGONISTIC TO THAT OF SALICYLATES. ... POSSESSES ABILITY TO DISPLACE OTHER ORG ANIONS THAT ARE BOUND EXTENSIVELY TO PLASMA PROTEINS...THUS ALTERING THEIR DISTRIBUTION TO TISSUES & THEIR RENAL EXCRETION...|...SULFINPYRAZONE MAY POTENTIATE ACTIONS OF INSULIN & ORAL HYPOGLYCEMIC AGENTS...|SULFINPYRAZONE MAY DISPLACE SULFONAMIDES FROM PLASMA PROTEIN BINDING SITES...

Protein Binding：

98-99%

Drug Information

Drug Indication：

For the treatment of gout and gouty arthritis.

Therapeutic Uses：

Uricosuric Agents|EXPTL USE: SULFINPYRAZONE...PROLONGS PLATELET SURVIVAL IN MAN. ...BLOCK PLATELET AGGREGATION IN RESPONSE TO COLLAGEN & ANTIGEN-ANTIBODY COMPLEXES BUT NOT IN RESPONSE TO ADP OR THROMBIN...APPEARS RELATED TO DIMINISHED RELEASE OF ADP & 5-HYDROXYTRYPTAMINE. ...BEING STUDIED FOR...PROPHYLACTIVE VALUE IN THROMBOEMBOLIC DISORDERS|SULFINPYRAZONE USP...AS OFFICIAL 100-MG TABLETS & 200 MG CAPSULES. FOR... CHRONIC GOUT, INITIAL DOSAGE IS 100-200 MG/DAY. AFTER 1ST WK, DOSE...GRADUALLY INCR UNTIL SATISFACTORY LOWERING OF PLASMA URIC ACID IS ACHIEVED & MAINTAINED...MAY REQUIRE FROM 100-400 MG/DAY, DIVIDED INTO 2-4 DOSES & PREFERABLY GIVEN WITH MEALS.|OCCASIONAL RESISTANT PT HAVE BEEN TREATED SUCCESSFULLY WITH DOSES AS HIGH AS 800 MG/DAY. LARGER DOSES ARE POORLY TOLERATED & UNLIKELY TO PRODUCE FURTHER URICOSURIC EFFECT IN RESISTANT PT. IN RESPONSIVE PT...SINGLE DAILY DOSE OF 100 MG IS SOMETIMES SATISFACTORY FOR MAINTENANCE.|For more Therapeutic Uses (Complete) data for SULFINPYRAZONE (10 total), please visit the HSDB record page.

Drug Warnings：

SULFINPYRAZONE LACKS CLINICALLY-STRIKING ANTI-INFLAMMATORY & ANALGESIC PROPERTIES OF ITS CONGENER, PHENYLBUTAZONE.|GI IRRITATION OCCURS IN 10-15% OF ALL PT...AN OCCASIONAL PT MAY REQUIRE DISCONTINUANCE OF ITS USE. FREQUENCY & SEVERITY INCR WITH DOSAGE...DISTRESS IS LESSENED WHEN DRUG IS TAKEN IN DIVIDED DOSES WITH MEALS. ...GIVEN TO PT WITH HISTORY OF PEPTIC ULCER ONLY WITH GREATEST CAUTION & CAREFUL OBSERVATION.|...ABILITY OF DRUG TO DEPRESS HEMATOPOIESIS HAS BEEN DEMONSTRATED...PERIODIC BLOOD-CELL COUNTS ARE THEREFORE ADVISED DURING PROLONGED THERAPY. ADEQUATE PRECAUTIONS MUST ALSO BE TAKEN TO PREVENT INTRARENAL PPTN OF URATES...|IN CLINICAL USE OF...URICOSURIC DRUGS, IT MUST BE KEPT IN MIND THAT THEY CAN ALTER PLASMA BINDING, DISTRIBUTION, & RENAL EXCRETION OF OTHER ORG ACIDS... WHETHER THESE BE NATURALLY OCCURRING...OR DRUGS & DRUG METABOLITES. /URICOSURICS/|For more Drug Warnings (Complete) data for SULFINPYRAZONE (8 total), please visit the HSDB record page.

Pharmacology：

Sulfinpyrazone's pharmacologic activity is the potentiation of the urinary excretion of uric acid. It is useful for reducing the blood urate levels in patients with chronic tophaceous gout and acute intermittent gout, and for promoting the resorption of tophi.

MeSH：

Gout suppressants that act directly on the renal tubule to increase the excretion of uric acid, thus reducing its concentrations in plasma. (See all compounds classified as Uricosuric Agents.)

Absorption：

...WELL ABSORBED AFTER ORAL ADMIN. ...BOUND TO PLASMA PROTEINS...98-99%. T/2... IN PLASMA AFTER IV INJECTION IS ABOUT 3 HR. AFTER ORAL ADMIN...URICOSURIC EFFECT MAY PERSIST FOR...10 HR. ALTHOUGH LITTLE...IS AVAILABLE FOR FILTRATION @ GLOMERULUS, IT IS SECRETED BY PROXIMAL TUBULE & UNDERGOES LITTLE PASSIVE BACK DIFFUSION...|APPROX HALF OF ORALLY ADMIN DOSE APPEARS IN URINE WITHIN 24 HR. MOST OF DRUG (90%) IN URINE IS UNCHANGED; REMAINDER IS ELIMINATED AS...METABOLITE...|...RAPIDLY EXCRETED IN MAN, TOGETHER WITH P-HYDROXYLATED METABOLITE. PLASMA T/2...IN RATS...16.2 HR, &...18% OF IP DOSE...WAS EXCRETED INTO URINE. PLASMA T/2 IN MAN...BETWEEN 1 & 3 HR. MAIN ROUTE OF ELIMINATION IN RAT...FECES (68% OF DOSE)...CONSIDERABLE PORTION...EXCRETED IN BILE WAS REABSORBED FROM INTESTINAL TRACT.|...SULFINPYRAZONE...IS EXCRETED IN URINE OF RATS TO ONLY A SMALL EXTENT. ... CLEARED FROM CIRCULATION MAINLY THROUGH BILE...NO EVIDENCE OF ENTERO-HEPATIC CIRCULATION MECHANISM.|UNCHANGED DRUG /IN RAT/ WAS PRINCIPAL EXCRETION PRODUCT & ONLY 28%...IN URINE & 24%...IN FECES & BILE WAS FOUND AS P-HYDROXYSULFINPYRAZOLE. FAILURE OF RAT TO EXCRETE A HIGH PROPORTION OF THE DRUG IN URINE MAY BE RELATED TO ITS LACK OF URICOSURIC PROPERTIES IN THIS SPECIES.

Metabolism/Metabolites：

MOST OF DRUG (90%) IN URINE IS UNCHANGED; REMAINDER IS ELIMINATED AS N1-P-HYDROXYPHENYL METABOLITE...|.../IN RAT/ 28%...IN URINE & 24%...IN FECES & BILE WAS FOUND AS P-HYDROXYSULFINPYRAZOLE.|Sulfinpyrazone has known human metabolites that include Sulfinpyrazone sulfone.

Biological Half-Life：

Approximately 4-6 hours

Mechanism of Action：

Sulfinpyrazone is an oral uricosuric agent (pyrazolone derivative) used to treat chronic or intermittent gouty arthritis. Sulfinpyrazone competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby facilitating urinary excretion of uric acid and decreasing plasma urate concentrations. This is likely done through inhibition of the urate anion transporter (hURAT1) as well as the human organic anion transporter 4 (hOAT4). Sulfinpyrazone is not intended for the treatment of acute attacks because it lacks therapeutically useful analgesic and anti-inflammatory effects. Sulfinpyrazone and its sulfide metabolite possess COX inhibitory effects. Sulfinpyrazone has also been shown to be a UDP-glucuronsyltransferase inhibitor and a very potent CYP2C9 inhibitor. Sulfinpyrazone is also known to be a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor as well as an inhibitor of several multridrug resistance proteins (MRPs).|...IN SUFFICIENT DOSAGE IS POTENT INHIBITOR OF RENAL TUBULAR REABSORPTION OF URIC ACID. ...SMALL DOSES MAY REDUCE EXCRETION...PRESUMABLY BY INHIBITING SECRETORY BUT NOT REABSORPTIVE TRANSPORT. BY COMPETITIVE INHIBITION...REDUCES RENAL TUBULAR SECRETION OF OTHER ORG ANIONS...AS PAH /PARA-AMINOHIPPURIC/ & SALICYLIC ACID.

Human Toxicity Excerpts：

HYPERSENSITIVITY REACTIONS, USUALLY A RASH WITH FEVER, DO OCCUR.../OCCASIONALLY/|SIDE EFFECTS INCL UPPER GI DISTURBANCES...&, RARELY, ANEMIA, LEUKOPENIA, AGRANULOCYTOSIS, & THROMBOCYTOPENIA.

MeSH Entry Terms：

Anturan

Sulfinpyrazone Use and Manufacturing

Methods of Manufacturing

0.5 mg anagrelide, 50 mg zomepirac. Sulfinpyrazone:The method of claim 1 wherein said compound is selected from the group consisting of:...4-butyl-1-(p-hydroxyphenyl)-2-phenyl-3, 5-pyrazolidinedione4-(3-hydroxybutyl)-1, 2-diphenyl-3, 5-pyrazolidinedione4-butyl-1-(p-hydroxyphenyl)-2-phenyl-3, 5-pyrazolidinedione4-(3-hydroxy)-1-(p-hydroxyphenyl)-2-phenyl-3, 5-pyrazolidinedione4-[2-(phenylsulfinyl)ethyl]-1, 2-diphenyl-3, 5-pyrazolidinedione4-[2-(phenylthio)ethyl]-1, 2-diphenyl-3, 5-pyrazolidinedione.Examples of compounds coming within the scope of the invention include:...4-butyl-1-(p-hydroxyphenyl)-2-phenyl-3, 5-pyrazolidinedione (oxyphenbutazone)4-(3-hydroxybutyl)-1, 2-diphenyl-3, 5-pyrazolidinedione (hydroxyphenylbutazone)4-butyl-1-(p-hydroxyphenyl)-2-phenyl-3, 5-pyrazolidinedione (gamma-hydroxyphenylbutazone)4-(3-hydroxy)-1-(p-hydroxyphenyl)-2-phenyl-3, 5-pyrazolidinedione (p, gamma-dihydroxyphenylbutazone)4-[2-(phenylsulfinyl)ethyl]-1, 2-diphenyl-3, 5-pyrazolidinedione (sulfinpyrazone)4-[2-(phenylthio)ethyl]-1, 2-diphenyl-3, 5-pyrazolidinedione (thio analogue of sulfinpyrazone) STR4(a) 1, 2-Diphenyl-4-[2-(phenylsulfinyl)ethyl]-4-hydroxymethyl-pyrazolidine-3, 5-dione (II) 40percent Formaline (25 ml) is added to a solution of 20 grams of 1, 2-diphenyl-4-[2-(phenylsulfinyl)-ethyl]-pyrazolidine-3, 5-dione in 120 ml of methanol. The solution, under magnetic stirring, is heated up to 50° C. for one hour and kept, always under a magnetic stirring, at room temperature for 12 hours. At the end the solvent is evaporated under reduced pressure, the residue is washed with water and extracted with dichloromethane. The organic phase is dried on anhydrous sodium sulphate and the crude product obtained after the solvent evaporation is purified on silica gel chromatographic column, eluent ethyl acetate. The product obtained has m.p. 144°-145° C. Elemental analysis: for C24 H22 N2 SO4 (M.W.=434): calc. percent C=66.36; H=5.07; N=6.45. found percent C=66.22; H=5.21; N=6.38.Oxidation of 1, 2-Diphenyl-4-[2-(phenylthio)ethyl]-3, 5-pyrazolidinedione 1, 2-Diphenyl-4-[2-(phenylthio)ethyl]-3, 5-pyrazolidinedione (20 g, 0.052 moles) was dissolved in 400 ml of glacial acetic acid. To this solution, 240 ml of Caro's acid solution (described in Example 1) was added dropwise over a 30 minute period. A TLC taken three hours after the addition was begun showed starting material. The remainder of the Caro's acid solution was added and the reaction mixture was kept at 5° C. for eighteen hours. Thereafter, the reaction mixture was stirred for two more hours while it came to room temperature. TLC showed no starting material. A 5percent sodium bisulfite solution (200 ml) was added to the reaction mixture followed by the addition of 300 ml of ethyl acetate. Water (500 ml) and 300 ml more of ethyl acetate were added. The layers were separated and the organic layer was washed with 500 ml of 5percent sodium bicarbonate solution. The solvent was evaporated under reduced pressure and toluene (150 ml) was added. The toluene was removed by evaporation under reduced pressure to give a residue (20.2 g). The residue was crystallized from ethanol (60 ml) to give 9.7 g of 1, 2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3, 5-pyrazolidinedione. The mother liquors were concentrated to give another 2.8 g of the sulfinyl compound (total 12.5 g, 60percent of theory). The sulfinyl compound exhibited the following characteristics: mp 130°-131.5° C.; nmr(CDCl3)delta 2.45 (m, 2H), 3.3 (m, 3H), 7.25 (m, 10H) and 7.5 (m, 5H); and Anal. Calcd for C23 H20 O 3 N2 S: C, 68.30percent H, 4.99percent N, 6.93percent and Found: C, 67.94percent H, 5.09percent N, 6.84percent.

Uses

uricosuric

Formulations：

ANTURANE (GEIGY). ORAL: CAPSULES 200 MG; TABLETS 100 MG.

Laboratory Methods：

ANALYSIS IN PLASMA & URINE BY HPLC.|DETERMINATION IN PLASMA BY GC.|MICRODETERMINATION OF SULFINPYRAZONE IN BIOLOGICAL FLUIDS (URINE) BY REVERSED PHASE HPLC.

Use Classification：

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

Computed Properties

Molecular Weight:404.5
XLogP3:2.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:6
Exact Mass:404.11946368
Monoisotopic Mass:404.11946368
Topological Polar Surface Area:76.9
Heavy Atom Count:29
Complexity:571
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

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(+/-)-Sulfinpyrazone

CAS No.: 57-96-5

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