57-66-9 Usage
Uses
Used in Pharmaceutical Industry:
Probenecid is used as a pharmaceutical intermediate for the development of drugs that target gout and hyperuricemia.
Used in Gout Treatment:
Probenecid is used as an anti-gout drug for the treatment of chronic gout, as it is safe and effective in reducing the excretion of other organic acids, thereby decreasing plasma uric acid concentrations. It has no effects on acute gout pain and inflammation and cannot be applied to acute gout.
Used in Rheumatoid Arthritis Treatment:
Probenecid is used for the treatment of rheumatoid arthritis and other chronic diseases, as it helps in reducing serum uric acid concentrations in patients with frequent disabling gout attacks.
Used in Drug Delivery Systems:
Probenecid is used as an inhibitor of several ABC-transporters of the subfamily ABCC or MRP, which can be employed in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells.
Used in Uricosuric Therapy:
Probenecid is used as a uricosuric drug, increasing uric acid excretion in the urine, primarily in treating gout and hyperuricemia. It was developed as an alternative to caronamide to competitively inhibit renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects.
Used in Hyperuricemia Treatment:
Probenecid is used to promote uric acid excretion in hyperuricemia secondary to the administration of certain drugs or due to other medical conditions.
Chemical Properties:
Probenecid is a white crystalline powder with a melting point of 194-196 °C. It is soluble in acetone, slightly soluble in ethanol or chloroform, and almost insoluble in water. It is also soluble in dilute sodium hydroxide solution but almost insoluble in dilute acid.
Brand Names:
Benemid (Merck) and Probalan (Lannett) are some of the brand names under which Probenecid is marketed.
Anti-gout drug
Probenecid is a chemically synthetic sulfa anti-gout drug, also known as oxybenzone sulfonamides, which has dual role of both promoting the excretion of uric acid excretion and inhibiting the excretion of penicillin. Clinically it is used for treating chronic gout and suppressing excretion of penicillin-type drugs in order to increase their clinical plasma concentration as an adjuvant drug of penicillin therapy. Its mechanism of action is inhibiting the re-absorption of renal tubular on uric acid, thus increasing uric acid excretion and further lowering plasma uric acid concentration for reducing the deposition of urate in tissues and prevent the crystallization of urate. This product can also promote the dissolution of the pre-formed urate, thereby reducing its damage on the joint. In addition, the product can also competitively inhibit the secretion of a weak organic acid (such as penicillin, cephalosporins) in the renal tubules, which can increase blood concentrations of these antibiotics and prolong their duration of action. This product is easy for oral administration with a plasma protein binding rate of 85% to 90%. Adults take 1 g orally each time with the plasma concentration reaches peak after 2~4 hour and with a half-life of being 6 to 12 hours. Probenecid is rapidly metabolized in the liver with the major metabolite being probenecid acetyl glucuronic acid. The main metabolite is excreted through the urine. This product has no anti-inflammatory and analgesic effect, and thus being invalid for treating acute gout. Acute toxicity test results: orally: LD50 of rats being 1600mg/kg. After the oral administration, the major adverse reactions are gastrointestinal reactions with others adverse reactions including dizziness, headache, facial flushing, urinary frequency, gingival swelling and pain, skin rash; there are also occasional allergic reactions. It is not suitable for being applied to patients of acute gout and with history of uric acid crystal deposition in kidney and ureter. Patients of peptic ulcer or blood abnormalities and pregnant women should take with caution. Patients of renal dysfunction are not allowed for using it.
clinical pharmacology
Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits.
Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins.
Probenecid also has been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17 –ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas. See also Drug Interactions.
Probenecid decreases both hepatic and renal excretion of sulfobromophtalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals.
Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin.
Indications
1. For treating hyperuricemia with chronic gouty arthritis and tophi, take 2 times per day for adults with the dose of each time being 25 mg, increase the dose to 2 times per day after 1 week with 500 mg each time. Upon the administration, maintain the daily intake of water being at 2500mL to prevent the formation of kidney stones, simultaneously take alkaline urine drug if necessary. But make sure that: 1, the filtration rate of glomerular should be greater than 50~60mL/min; 2, no kidney stones or history of kidney stones; 3, non-acidic urine; 4, patients of non-taking salicylates; 5, have regular tests of blood and urine pH value, liver and kidney function as well as the uric acid levels in blood and urine; 6, adjust the dose according to the clinical and uric acid level and maintain for a long time with the minimum effective amount.
2. As an adjunct drug for antibiotic treatment; it can be combined together with different antibiotics such as penicillin, ampicillin, oxacillin, amoxicillin ortho chlorine, and nafcillin; Probenecid can be used for inhibiting the discharge of these antibiotics, increase their blood concentration and can maintain for a relative long time.
The above information is edited by the lookchem of Dai Xiongfeng.
Indications
When probenecid (ColBENEMID) is given in sufficient
amounts, it will block the active reabsorption of uric acid
in the proximal tubules following its glomerular filtration,
thereby increasing the amount of urate eliminated.
In contrast, low dosages of probenecid appear to compete
preferentially with plasma uric acid for the proximal
tubule anionic transport system and thereby block
its access to this active secretory system. The uricosuric
action of probenecid, however, is accounted for by the
drug’s ability to inhibit the active reabsorption of filtered
urate.
Drug Interactions
When probenecid is used to elevate plasma concentrations of penicillin or other beta-lactams, or when such drugs are given to patients taking probenecid therapeutically, high plasma concentrations of the other drug may increase the incidence of adverse reactions associated with that drug. In the case of penicillin or other beta-lactams, psychic disturbances have been reported.
The use of salicylates antagonizes the uricosuric action of probenecid (see WARNINGS). The uricosuric action of probenecid is also antagonized by pyrazinamide.
Probenecid produces an insignificant increase in free sulfonamide plasma concentrations, but a significant increase in total sulfonamide plasma levels. Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when sulfonamide and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk of hypoglycemia.
It has been reported that patients receiving probenecid require significantly less thiopental for induction of anesthesia. In addition, ketamine and thiopental anesthesia were significantly prolonged in rats receiving probenecid.
The concomitant administration of probenecid increases the mean plasma elimination half-life of a number of drugs which can lead to increased plasma concentrations. These include agents such as indomethacin, acetaminophen, naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the clinical significance of this observation has not been established, a lower dosage of the drug may be required to produce a therapeutic effect, and increases a dosage of the drug in question should be made cautiously and in small increments when probenecid is being coadministered. Although specific instances of toxicity due to this potential interaction have not been observed to date, physicians should be alert to this possibility.
Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances.
In animals and in humans, probenecid has been reported to increase plasma concentrations of methotrexate (see WARNINGS).
Falsely high readings for theophylline have been reported in an in vitro study, using the Schack and Waxler technique, when therapeutic concentrations of theophylline and probenecid were added to human plasma.
Side effects
1. Gastrointestinal reactions: main reactions are that a small number of patients have loss of appetite, nausea, vomiting, and abdominal discomfort.
2. Central nervous system reactions and allergic reactions: occasional headache, facial flushing, fever and some allergic reactions such as itchy skin, dermatitis.
3. Other serious toxicities: for very few patients, they have got bleeding, neutropenia, aplastic anemia, nephrotic syndrome, and liver necrosis. Probenecid belongs to sulfa drugs, so patients with hypersensitivity to sulfa drugs are not allowed for using. Pregnant women, patients of peptic ulcer, liver and kidney dysfunction should use with caution. In addition, patients should drink lots of water for the medication should drink lots of water and add appropriate amount of sodium carbonate for preventing urinary stones. During the medication, people should pay attention to checking the blood.
Side effects
The major side effect is GI distress (e.g., nausea,
vomiting, and anorexia), but these occur in only 2% of patients at low doses. Other effects include headache,
dizziness, urinary frequency, hypersensitivity reactions, sore gums, and anemia.
Production methods
Toluene sulfonamide is oxidized by sodium dichromate to generate carboxylic benzenesulfonamide; then use bromopropane for alkylation, the resulting sodium probenecid is further acidified by acetate to obtain probenecid.
References
Probenecid is used to treat chronic gout and gouty arthritis. It is used to prevent attacks related to gout, not treat them once they occur. It acts on the kidneys to help the body eliminate uric acid. Probenecid is also used to make certain antibiotics more effective by preventing the body from passing them in the urine.
https://medlineplus.gov/druginfo/meds/a682395.html
https://go.drugbank.com/drugs/DB01032
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Probenecid may be light sensitive .
Fire Hazard
Flash point data for Probenecid are not available. Probenecid is probably combustible.
Mechanism of action
Probenecid is rapidly absorbed after oral administration,
with peak plasma levels usually reached in 2 to 4
hours. Its half-life is somewhat variable (6–12 hours) because
of both its extensive plasma protein binding and
its active proximal tubular secretion. Since tubular backdiffusion
is decreased at alkaline urinary pH ranges,
probenecid excretion increases with increasing urinary
pH. Probenecid is rapidly metabolized, with less than
5% of an administered dose being eliminated in 24
hours.The major metabolite is an acyl monoglucuronide.
Pharmacokinetics
Probenecid is essentially completely absorbed from the GI tract on oral administration, with peak plasma levels
observed within 2 to 4 hours. Like most acidic compounds, probenecid (pKa = 3.4) is extensively plasma protein
bound (93–99%). The primary route of elimination of probenecid and its metabolites is the urine. It is extensively
metabolized in humans, with only 5 to 10% being excreted as unchanged drug. The major metabolites detected result
from glucuronide conjugation of the carboxylic acid, ω-oxidation of the n-propyl side chain and subsequent oxidation
of the resulting alcohol to the carboxylic acid derivative, ω1-oxidation of the n-propyl group, and N-dealkylation.
Clinical Use
Probenecid is an effective and relatively safe agent
for controlling hyperuricemia and preventing tophi
deposition in tissues. Chronic administration will decrease
the incidence of acute gouty attacks as well as diminish
the complications usually associated with hyperuricemia,
such as renal damage and tophi deposition.
Probenecid is still used by some physicians to maintain
high blood levels of penicillin, cephalosporin, acyclovir,
and cyclosporine. It is not useful in treating acute attacks
of gouty arthritis. If the total amount of uric acid
excreted is greater than 800 mg/day, the urine should be
alkalinized to prevent kidney stone formation and promote
uric acid.
Veterinary Drugs and Treatments
Although there has been very limited clinical use or research on
probenecid in veterinary medicine, it can be useful in treating gout
(hyperuricemia), particularly in reptiles.
Probenecid’s effect in inhibiting renal tubular secretion of certain
beta-lactam antibiotics and other weak organic acids is of interest
for increasing serum concentrations, or reducing doses and dosing
frequency of these drugs. This may allow greater efficacy (but also
toxic effects) and reduce the cost or dosing frequency of expensive
human drugs. Probenecid has a significantly long elimination halflife
in dogs (about 18 hours), which may make it particularly useful
in this species; however, at present there is little research supporting
this use of probenecid in veterinary patients.
Check Digit Verification of cas no
The CAS Registry Mumber 57-66-9 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 7 respectively; the second part has 2 digits, 6 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 57-66:
(4*5)+(3*7)+(2*6)+(1*6)=59
59 % 10 = 9
So 57-66-9 is a valid CAS Registry Number.
InChI:InChI=1/C13H19NO4S/c1-3-9-14(10-4-2)19(17,18)12-7-5-11(6-8-12)13(15)16/h5-8H,3-4,9-10H2,1-2H3,(H,15,16)/p-1
57-66-9Relevant articles and documents
Debenzylative Sulfonylation of Tertiary Benzylamines Promoted by Visible Light
Fu, Ying,Wu, Qing-Kui,Du, Zhengyin
, p. 1896 - 1900 (2021/04/06)
An efficient, general, inexpensive, and environmentally friendly photosynthesis of sulfonamides via visible light promoted debenzylative sulfonylation of tertiary benzylamines is described. Compared to the traditional S?N coupling reactions, which are promoted by oxidative C?N bond cleavage of symmetrical tertiary alkylamines, this strategy provides a selective C?N bond cleavage protocol and avoids the use of transition-metal, explosive oxidants, and ligands.
Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation
Belsuzarri, Masiel,Carson, Dennis A.,Chan, Michael,Chu, Paul J.,Corr, Maripat,Cottam, Howard B.,Hayashi, Tomoko,Lao, Fitzgerald S.,Nan, Jason,Saito, Tetsuya,Sato-Kaneko, Fumi,Shukla, Nikunj M.,Yao, Shiyin
, (2021/07/19)
In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure–activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1. The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.
A Broad-Spectrum Catalytic Amidation of Sulfonyl Fluorides and Fluorosulfates**
Wei, Mingjie,Liang, Dacheng,Cao, Xiaohui,Luo, Wenjun,Ma, Guojian,Liu, Zeyuan,Li, Le
supporting information, p. 7397 - 7404 (2021/02/16)
A broad-spectrum, catalytic method has been developed for the synthesis of sulfonamides and sulfamates. With the activation by the combination of a catalytic amount of 1-hydroxybenzotriazole (HOBt) and silicon additives, amidations of sulfonyl fluorides and fluorosulfates proceeded smoothly and excellent yields were generally obtained (87–99 %). Noticeably, this protocol is particularly efficient for sterically hindered substrates. Catalyst loading is generally low and only 0.02 mol % of catalyst is required for the multidecagram-scale synthesis of an amantadine derivative. In addition, the potential of this method in medicinal chemistry has been demonstrated by the synthesis of the marketed drug Fedratinib via a key intermediate sulfonyl fluoride 13. Since a large number of amines are commercially available, this route provides a facile entry to access Fedratinib analogues for biological screening.
VACCINE ADJUVANT
-
Page/Page column 81-82, (2020/06/10)
Compounds useful as an adjuvant, e.g., formulas (I)-(VI) and uses thereof, for example, with immunogenic moieties or other adjuvants, are provided.
Room Temperature Deoxyfluorination of Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and Tetramethylammonium Fluoride
Melvin, Patrick R.,Ferguson, Devin M.,Schimler, Sydonie D.,Bland, Douglas C.,Sanford, Melanie S.
supporting information, p. 1350 - 1353 (2019/03/08)
A method for the room temperature deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride and Me4NF is described. A large scope of aryl and heteroaryl substrates is demonstrated, and this method compares favorably to other common deoxyfluorination methods for many substrates.
Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
supporting information, p. 8332 - 8338 (2013/12/04)
The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
Building a sulfonamide library by eco-friendly flow synthesis
Gioiello, Antimo,Rosatelli, Emiliano,Teofrasti, Michela,Filipponi, Paolo,Pellicciari, Roberto
supporting information, p. 235 - 239 (2013/06/27)
A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.
USE OF A COMPOUND CAPABLE OF REDUCING THE URIC ACID LEVEL FOR THE PREVENTION AND/OR THE TREATMENT OF LUNG INFLAMMATION AND FIBROSIS
-
, (2011/10/13)
The present invention is directed to the use of a compound capable of reducing the uric acid level in a mammal for the prevention and/or the treatment of IL-1β driven lung pathology, particularly to treat lung inflammation such as chronic fibrosis, COPD and interstitial fibrosis and other IL-1β driven lung pathologies including those of autoimmune origin. Preferred compounds capable of reducing the uric acid level are selected from the group consisting of xanthine oxidase inhibitors, such as allopurinol, recombinant enzyme uricase and uricosuric compound capable of enhancing uric acid excretion, such as probenecid. The invention further relates to a method for identifying in vitro whether a patient presents an IL-1β driven lung pathology or is at risk to develop an IL-1β driven lung pathology, or for the screening of a compound for treating an IL-1β driven lung pathology.
Use of a compound capable of reducing the uric acid level for the prevention and/or the treatment of lung inflammation and fibrosis
-
, (2010/04/24)
The present invention is directed to the use of a compound capable of reducing the uric acid level in a mammal for the prevention and/or the treatment of IL-1β driven lung pathology, particularly to treat lung inflammation such as chronic fibrosis, COPD and interstitial fibrosis and other IL-1β driven lung pathologies including those of autoimmune origin. Preferred compounds capable of reducing the uric acid level are selected from the group consisting of xanthine oxidase inhibitors, such as allopurinol, recombinant enzyme uricase and uricosuric compound capable of enhancing uric acid excretion, such as probenecid. The invention further relates to a method for identifying in vitro whether a patient presents an IL-1β driven lung pathology or is at risk to develop an IL-1β driven lung pathology.
Discovery and initial development of a novel class of antibacterials: Inhibitors of Staphylococcus aureus transcription/translation
Larsen, Scott D.,Hester, Matthew R.,Craig Ruble,Kamilar, Gregg M.,Romero, Donna L.,Wakefield, Brian,Melchior, Earline P.,Sweeney, Michael T.,Marotti, Keith R.
, p. 6173 - 6177 (2007/10/03)
The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chemistry. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional solution phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8 μg/mL (compound 4l). Subsequent modification of the central aromatic ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a number of potent antibacterials with MICs of ≤1 μg/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one additional mechanism of action is operative.
