Sulopenem

• 120788-07-0
• CP-70429
• 349.5 g/mol, C₁₂H₁₅NO₅S₃
• XX514BJ1XW
• PF-03709270
• PF03709270

(5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(1R,3S)-1-oxothiolan-3-yl]sulfanyl-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

• (5R,6S)-6-((1R)-1-HYDROXYETHYL)-7-OXO-3-(((1R,3S)-1-OXOTETRAHYDRO-1H-1.LAMBA.(SUP 4)-THIOPHEN-3-YL)SULFANYL)-4-THIA-1-AZABICYCLO(3.2.0)HEPT-2-ENE-2-CARBOXYLIC ACID
• (5R,6S)-6-((1R)-1-Hydroxyethyl)-7-oxo-3-(((3S)-tetrahydro-3-thienyl)thio)-4-thia-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid, (R)-S-oxide
• 4-THIA-1-AZABICYCLO(3.2.0)HEPT-2-ENE-2-CARBOXYLIC ACID, 6-((1R)-1-HYDROXYETHYL)-7-OXO-3-(((1R,3S)-TETRAHYDRO-1-OXIDO-3-THIENYL)THIO)-, (5R,6S)-
• 4-THIA-1-AZABICYCLO(3.2.0)HEPT-2-ENE-2-CARBOXYLIC ACID, 6-(1-HYDROXYETHYL)-7-OXO-3-((TETRAHYDRO-3-THIENYL)THIO)-, S-OXIDE, (5R-(3(1R*,3S*),5.ALPHA.,6.ALPHA.(R*)))-

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

Sulopenem (CP-70,429) is a thiopenem antibiotic derivative from the penem family, which unlike most related drugs is orally active. It was developed in Japan in the 1990s, and has been approved to treat uncomplicated urinary tract infections in combination with probenecid (Brand name: Orlynvah). It has reached Phase III clinical trials on several occasions and continues to be the subject of ongoing research into potential applications, especially in the treatment of multiple drug resistant urinary tract infections.^{[1][2][3][4][5]}

In October 2024, the US Food and Drug Administration approved sulopenem etzadroxil with probenecid combination for the treatment of urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult women with limited alternative oral antibiotic options. The combination was developed by Iterum Therapeutics under the trade name ORLYNVAH™.^[6]

JP 1995278137; US 5013729; WO 8808845, J Org Chem 1992,57(16),4352-61

1) The reaction of L-aspartic acid (I) with NaNO2, NaBr and H2SO4 gives 2(S)-bromosuccinic acid (II), which is reduced with methyl sulfide borane complex in THF, yielding 2(S)-bromobutane-1,4-diol (III). The cyclization of (III) with Cs2CO3 in methylene chloride affords (R)-(2-hydroxyethyl)oxirane (IV), which is acylated with methanesulfonyl chloride to the corresponding mesylate (V). The cyclization of (V) with Na2S in acetonitrile/water gives 3(R)-hydroxythiolane (VI), which is acylated with p-toluenesulfonyl chloride, affording the corresponding tosylate (VII). The controlled oxidation of (VII) with potassium peroxymonosulfate (oxone) gives 3(R)-(p-toluenesulfonyloxy)thiolane-1(R)-oxide (VIII), which by reaction with potassium thioacetate in acetone is converted to 3(S)-(acetylthio)thiolane 1(R)-oxide (IX). The reaction of (IX) with NaOEt and CS2 in ethanol yields the trithiocarbonate (X), which is condensed with the chloroazetidinone (XI), yielding the trithiocarbonate ester (XII). The condensation of (XII) with 2-chloroallyloxalyl fluoride (XIII) by means of diisopropylethylamine in methylene chloride affords the substituted oxalamic ester (XIV), which is cyclized by means of triethyl phosphite in refluxing chloroform to the fully protected penem derivative (XV). The reaction of (XV) with tetrabutylammonium fluoride (TBAF) in THF eliminates the protecting tert-butyldimethylsilyl group, yielding the chloroallyl ester (XVI), which is treated with triphenylphosphine and sodium 2-ethylhexanoate in dichloromethane to obtain the corresponding sodium salt (XVII). Finally, this compound is treated with HCl in cool water.

US 4921972

2) The intermediate 3(R)-(p-toluenesulfonyloxy)thiolane (VII) can be obtained by two other synthetic pathways: a) The racemic 2-hydroxy-4-(methylsulfanyl)butyric acid ethyl ester (XVIII) is submitted to optical resolution with Pseudomonas fluorescens lipase in toluene/water, yielding the corresponding 2(R)-hydroxy ester (XIX), which is reduced with NaBH4 in THF/water to afford 4-(methylsulfanyl)butane-1,2(R)-diol (XX). The acylation of (XX) with p-toluenesulfonyl chloride and pyridine yields the ditosylate (XXI), which is cyclized in refluxing benzene to give 1(R)-methyl-3(R)-(p-toluenesulfonyloxy)thiolanium p-toluenesulfonate (XXII). Finally, this compound is treated with trifluoroacetic acid in pyridine to afford the thiolane (VII), already described. b) The reduction of 4-chloro-3(R)-hydroxybutyric acid methyl ester (XXIII) with lithium borohydride in THF gives 4-chlorobutane-1,3(R)-diol (XXIV), which is tosylated as before, yielding the bis(tosyloxy) derivative (XXV). Finally, this compound is cyclized with Na2S in hot acetonitrile/water to afford the thiolane (VII), already described.

https://pubsapp.acs.org/cen/coverstory/88/8836cover.html

References

1. ^ Minamimura M, Taniyama Y, Inoue E, Mitsuhashi S (July 1993). “In vitro antibacterial activity and beta-lactamase stability of CP-70,429 a new penem antibiotic”. Antimicrobial Agents and Chemotherapy. 37 (7): 1547–1551. doi:10.1128/AAC.37.7.1547. PMC 188011. PMID 8363389.
2. ^ Hamilton-Miller JM (November 2003). “Chemical and microbiologic aspects of penems, a distinct class of beta-lactams: focus on faropenem”. Pharmacotherapy. 23 (11): 1497–1507. doi:10.1592/phco.23.14.1497.31937. PMID 14620395. S2CID 43705118.
3. ^ Ednie LM, Appelbaum PC (May 2009). “Antianaerobic activity of sulopenem compared to six other agents”. Antimicrobial Agents and Chemotherapy. 53 (5): 2163–2170. doi:10.1128/AAC.01557-08. PMC 2681565. PMID 19223615.
4. ^ Bader MS, Loeb M, Leto D, Brooks AA (April 2020). “Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents”. Postgraduate Medicine. 132 (3): 234–250. doi:10.1080/00325481.2019.1680052. PMID 31608743. S2CID 204545734.
5. ^ Veeraraghavan B, Bakthavatchalam YD, Sahni RD (December 2021). “Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections”. Infectious Diseases and Therapy. 10 (4): 1815–1835. doi:10.1007/s40121-021-00509-4. PMC 8572892. PMID 34357517.
6. ^ “Iterum Therapeutics Receives U.S. FDA Approval of ORLYNVAH™ (Oral Sulopenem) for the Treatment of Uncomplicated Urinary Tract Infections”. Iterum Therapeutics plc. 2024-10-25. Retrieved 2024-10-25.

//////Sulopenem, Orlynvah, FDA 2024, APPROVALS 2024, CP-70,429, 120788-07-0, CP-70429, XX514BJ1XW, PF-03709270, PF03709270

#Sulopenem, #Orlynvah, #FDA 2024, #APPROVALS 2024, #CP-70,429, #120788-07-0, #CP-70429, #XX514BJ1XW, #PF-03709270, #PF03709270