Probenecid

• 57-66-9
• 4-(Dipropylsulfamoyl)benzoic acid
• Probenecid acid
• Benemid

4-(dipropylsulfamoyl)benzoic acid

C₁₃H₁₉NO₄S, 285.359

• 
  HC 5006
• NSC-18786

FDA APPROVED, 10/25/2024, sulopenem etzadroxil, probenecid, Orlynvah, To treat uncomplicated urinary tract infections (uUTI)
Drug Trial Snapshot

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

Probenecid was developed as an alternative to caronamide^[1] to competitively inhibit renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects.

Experimental Properties

Property	Value	Source
melting point (°C)	195 °C	PhysProp
water solubility	27.1 mg/L	Not Available
logP	3.21	HANSCH,C ET AL. (1995)
pKa	3.4	SANGSTER (1994)

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US12109197	No	2024-10-08	2039-04-01
US11554112	No	2023-01-17	2039-04-01
US11478428	No	2022-10-25	2039-12-23
US7795243	No	2010-09-14	2029-06-03

PATENT

https://patents.google.com/patent/CN103613521A/en

At present, the production technique of probenecid mainly contains two kinds:

(1) p-methyl benzenesulfonic acid-dipropyl amine method

Take p-methyl benzenesulfonic acid as raw material, through potassium bichromate or potassium permanganate oxidation, then react generation with chlorsulfonic acid generation sulfonating chlorinating to carboxyl benzene sulfonyl chloride, amidate action occurs then in organic solvent and obtain the finished product probenecid.Reaction process route is as follows:

This technique in a large number with an organic solvent, seriously polluted; Heavy metal recovery and treatment cost are high; Chlorsulfonic acid transportation, storage and use are dangerous large, and acid mist is obvious.Along with the increasing of environmental protection pressure, people increase severely day by day to the concern of environment, and this route is substantially in end-of-life state.

(2) to methyl benzenesulfonamide-Halopropane method

To methyl benzenesulfonamide, through potassium bichromate or potassium permanganate oxidation, be P―Carboxybenzenesulfonamide, under the effect of alkali, with Halopropane generation alkylated reaction, after acidifying, obtain probenecid.Reaction process route is as follows:

This process using sodium dichromate 99 or potassium permanganate oxidation are to methyl benzenesulfonamide, and yield is on the low side (lower than 50%).In addition, the waste water that contains chromium or manganese is difficult to dispose, and these have all seriously restricted further developing of this technique.

Reaction scheme of the present invention is as follows:

embodiment 1

(1) diazotization reaction

Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 127.4ml hydrochloric acid (31%, 1.25mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to 0-5 ℃, drip sodium nitrite solution (34.5g Sodium Nitrite, 0.5mol, be dissolved in 190g water), control temperature at 10-20 ℃, it is 4 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.

(2) sulfonating chlorinating reaction

In 5000ml there-necked flask, add 250g water, 765ml hydrochloric acid (31%, 7.5mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at-3–1 ℃, when passing into 64g sulfurous gas (1mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.

In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 5 hours, is warming up to gradually 5-10 ℃, continues reaction 8 hours at this temperature; Filtration obtains 121g to carboxyl benzene sulfonyl chloride.

(3) synthetic probenecid reaction

In 1000ml there-necked flask, add 350g water, 152g dipropyl amine (1.5mol), open and stir, when temperature is greater than 15 ℃, start to divide gradually 40 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 3 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filter, obtain 135g probenecid crude product, put in 500ml pure water, agitator treating 1 hour, heavy 122.8g after filtering, being dried, yield 86.2%(is in para-amino benzoic acid), purity 98.2%.

embodiment 2

(1) diazotization reaction

Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 152.9ml hydrochloric acid (31%, 1.5mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to 0-5 ℃, drip sodium nitrite solution (36.0g Sodium Nitrite, 0.52mol, be dissolved in 190g water), control temperature at 0-10 ℃, it is 3 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.

(2) sulfonating chlorinating reaction

In 5000ml there-necked flask, add 250g water, 887ml hydrochloric acid (31%, 8.7mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at 0-5 ℃, when passing into 112g sulfurous gas (1.75mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.

In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 4 hours, is warming up to gradually 5-15 ℃, continues reaction 5 hours at this temperature; Filtration obtains 150g to carboxyl benzene sulfonyl chloride.

(3) synthetic probenecid reaction

In 1000ml there-necked flask, add 350g water, 192g dipropyl amine (1.9mol), open and stir, when temperature is greater than 15 ℃, start to divide gradually 35 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 2 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filter, obtain 155.4g probenecid crude product, put in 500ml pure water, agitator treating 1 hour, heavy 129.5g after filtering, being dried, yield 90.9%(is in para-amino benzoic acid), purity 98.7%.

embodiment 3

(1) diazotization reaction

Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 203.9ml hydrochloric acid (31%, 2mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to-10–5 ℃, drip sodium nitrite solution (38.0g Sodium Nitrite, 0.55mol, be dissolved in 190g water), control temperature at 0-10 ℃, it is 5 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.

(2) sulfonating chlorinating reaction

In 5000ml there-necked flask, add 250g water, 968ml hydrochloric acid (31%, 9.5mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at 5-10 ℃, when passing into 160g sulfurous gas (2.5mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.

In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 3 hours, is warming up to gradually 10-15 ℃, continues reaction 20 hours at this temperature; Filtration obtains 146.7g to carboxyl benzene sulfonyl chloride, needn’t be dried, and directly enters next step reaction.

(3) synthetic probenecid reaction

In 1000ml there-necked flask, add 350g water, 202g dipropyl amine (2mol), open to stir, when temperature is greater than 30 ℃, start to divide gradually 30 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 4 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filtration obtains 151.7g probenecid crude product, puts in 500ml pure water, and agitator treating 1 hour, heavy 128.5g after filtering, being dried, yield 90.2%(is in para-amino benzoic acid), purity 98.8%.Medical uses

Probenecid is primarily used to treat gout and hyperuricemia.

Probenecid is sometimes used to increase the concentration of some antibiotics and to protect the kidneys when given with cidofovir. Specifically, a small amount of evidence supports the use of intravenous cefazolin once rather than three times a day when it is combined with probenecid.^[2]

It has also found use as a masking agent,^[3] potentially helping athletes using performance-enhancing substances to avoid detection by drug tests.

Adverse effects

Mild symptoms such as nausea, loss of appetite, dizziness, vomiting, headache, sore gums, or frequent urination are common with this medication. Life-threatening side effects such as thrombocytopenia, hemolytic anemia, leukemia and encephalopathy are extremely rare.^[4] Theoretically probenecid can increase the risk of uric acid kidney stones.

Drug interactions

Some of the important clinical interactions of probenecid include those with captopril, indomethacin, ketoprofen, ketorolac, naproxen, cephalosporins, quinolones, penicillins, methotrexate, zidovudine, ganciclovir, lorazepam, and acyclovir. In all these interactions, the excretion of these drugs is reduced due to probenecid, which in turn can lead to increased concentrations of these.^[5]

Pharmacology

Pharmacodynamics

In gout, probenecid competitively inhibits the reabsorption of uric acid through the organic anion transporter (OAT) at the proximal tubules. This leads to preferential reabsorption of probenecid back into plasma and excretion of uric acid in urine,^[6] thus reducing blood uric acid levels and reducing its deposition in various tissues.

Probenecid also inhibits pannexin 1.^[7] Pannexin 1 is involved in the activation of inflammasomes and subsequent release of interleukin-1β causing inflammation. Inhibition of pannexin 1 thus reduces inflammation, which is the core pathology of gout.^[7]

Pharmacokinetics

In the kidneys, probenecid is filtered at the glomerulus, secreted in the proximal tubule and reabsorbed in the distal tubule. Probenicid lowers the concentration of certain drugs in urine drug screens by reducing renal excretion of these drugs.

Historically, probenecid has been used to increase the duration of action of drugs such as penicillin and other beta-lactam antibiotics. Penicillins are excreted in the urine at proximal and distal convoluted tubules through the same organic anion transporter (OAT) as seen in gout. Probenecid competes with penicillin for excretion at the OAT, which in turn increases the plasma concentration of penicillin.^[8]

History

During World War II, probenecid was used to extend limited supplies of penicillin. This use exploited probenecid’s interference with drug elimination (via urinary excretion) in the kidneys and allowed lower doses of penicillin to be used.^[9]

Probenecid was added to the International Olympic Committee‘s list of banned substances in January 1988, due to its use as a masking agent.^[10]

References

1. ^ Mason RM (June 1954). “Studies on the effect of probenecid (benemid) in gout”. Annals of the Rheumatic Diseases. 13 (2): 120–130. doi:10.1136/ard.13.2.120. PMC 1030399. PMID 13171805.
2. ^ Cox VC, Zed PJ (March 2004). “Once-daily cefazolin and probenecid for skin and soft tissue infections”. The Annals of Pharmacotherapy. 38 (3): 458–463. doi:10.1345/aph.1d251. PMID 14970368. S2CID 11449580.
3. ^ Morra V, Davit P, Capra P, Vincenti M, Di Stilo A, Botrè F (December 2006). “Fast gas chromatographic/mass spectrometric determination of diuretics and masking agents in human urine: Development and validation of a productive screening protocol for antidoping analysis”. Journal of Chromatography A. 1135 (2): 219–229. doi:10.1016/j.chroma.2006.09.034. hdl:2318/40201. PMID 17027009. S2CID 20282106.
4. ^ Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C (November 2014). “Uricosuric medications for chronic gout”. The Cochrane Database of Systematic Reviews (11): CD010457. doi:10.1002/14651858.CD010457.pub2. PMC 11262558. PMID 25392987.
5. ^ Cunningham RF, Israili ZH, Dayton PG (March–April 1981). “Clinical pharmacokinetics of probenecid”. Clinical Pharmacokinetics. 6 (2): 135–151. doi:10.2165/00003088-198106020-00004. PMID 7011657. S2CID 24497865.
6. ^ “Probenecid”. PubChem. U.S. National Library of Medicine. Retrieved 2022-06-12.
7. ^ Jump up to:^a b Silverman W, Locovei S, Dahl G (September 2008). “Probenecid, a gout remedy, inhibits pannexin 1 channels”. American Journal of Physiology. Cell Physiology. 295 (3): C761 – C767. doi:10.1152/ajpcell.00227.2008. PMC 2544448. PMID 18596212.
8. ^ Ho RH (January 2010). “4.25 – Uptake Transporters”. In McQueen CA, Kim RB (eds.). Comprehensive Toxicology (Second ed.). Oxford: Elsevier. pp. 519–556. doi:10.1016/B978-0-08-046884-6.00425-5. ISBN 978-0-08-046884-6.
9. ^ Butler D (November 2005). “Wartime tactic doubles power of scarce bird-flu drug”. Nature. 438 (7064): 6. Bibcode:2005Natur.438….6B. doi:10.1038/438006a. PMID 16267514.
10. ^ Wilson W, Derse E, eds. (2001). Doping in Elite Sport: The Politics of Drugs in the Olympic Movement. Human Kinetics. p. 86. ISBN 0-7360-0329-0.

Clinical data
Trade names	Probalan
AHFS/Drugs.com	Monograph
MedlinePlus	a682395
Routes of administration	By mouth
ATC code	M04AB01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	75-95%
Elimination half-life	2-6 hours (dose: 0.5-1 g)
Excretion	kidney (77-88%)
Identifiers
showIUPAC name
CAS Number	57-66-9
PubChem CID	4911
IUPHAR/BPS	4357
DrugBank	DB01032
ChemSpider	4742
UNII	PO572Z7917
KEGG	D00475
ChEMBL	ChEMBL897
CompTox Dashboard (EPA)	DTXSID9021188
ECHA InfoCard	100.000.313
Chemical and physical data
Formula	C13H19NO4S
Molar mass	285.36 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI

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