Cefiderocol, セフィデロコル , цефидерокол , سيفيديروكول , 头孢德罗 ,

Cefiderocol

セフィデロコル;

Antibacterial, Cell wall biosynthesis inhibitor, enicillin binding protein, Siderophore cephalosporin

Fetroja (TN)

FDA, Cefiderocol, APPROVED, 2019/11/14

(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxy-2-propanyl)oxy]imino}acetyl]amino}-3-[(1-{2-[(2-chloro-3,4-dihydroxybenzoyl)amino]ethyl}-1-pyrrolidiniumyl)methyl]-8-oxo-5-thia-1-azabicycl o[4.2.0]oct-2-ene-2-carboxylate

S-649266,  GSK 2696266D

Cefiderocol, sold under the brand name Fetroja, is an antibiotic used to treat complicated urinary tract infections when no other options are available.^[2] It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa.^[3][4][5] It is given by injection into a vein.^[6]

It is in the cephalosporin family of medications.^[2][7] Cefiderocol was approved for medical use in the United States on November 14, 2019.^[2][8]

Cefiderocol, also known as S-649266, is a potent siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. S-649266 shows potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-β-lactamase-producing P. aeruginosa. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type β-lactamases, and P. aeruginosa producing metallo-β-lactamases such as IMP type and VIM type. FDA approved this drug in 11/14/2019 To treat patients with complicated urinary tract infections who have limited or no alternative treatment options

Medical uses

Cefiderocol is used to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.^[2][7]

Mechanism of action

Its mechanism of entry into bacterial cells is by binding to iron, which is actively transported into the bacterial cells along with the cefiderocol.^{[6][9][10][11][12]} It is in a medication class known as siderophores,^[6][7] and was the first siderophore antibiotic to be approved by the U.S. Food and Drug Administration (FDA).^[13] It bypasses the bacterial porin channels by using the bacteria’s own iron-transport system for being transported in.^[14]

History

In 2019, cefiderocol was approved in the United States as an antibacterial drug for treatment of adults 18 years of age or older with complicated urinary tract infections (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.^[2][8]

The safety and effectiveness of cefiderocol was demonstrated in a study of 448 patients with cUTIs.^[2] Of the patients who were administered cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in patients who received an alternative antibiotic.^[2] The clinical response rates were similar between the two treatment groups.^[2]

Labeling for cefiderocol includes a warning regarding the higher all-cause mortality rate observed in cefiderocol-treated patients compared to those treated with other antibiotics in a trial in critically ill patients with multidrug-resistant Gram-negative bacterial infections.^[2] The cause of the increase in mortality has not been established.^[2] Some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities.^[2] The higher all-cause mortality rate was observed in patients treated for hospital-acquired/ventilator-associated pneumonia (i.e.nosocomial pneumonia), bloodstream infections, or sepsis.^[2] The safety and efficacy of cefiderocol has not been established for the treatment of these types of infections.^[2]

Cefiderocol received a Qualified Infectious Disease Product designation from the U.S. Food and Drug Administration (FDA) and was granted priority review.^[2] The FDA granted approval of Fetroja, on November 14, 2019, to Shionogi & Co., Ltd.^[2]

PATENT

WO 2010050468

WO 2016035845

WO 2016035847

PATENT

WO 2017216765,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017216765&tab=PCTDESCRIPTION

Bacterial infections continue to remain one of the major causes contributing towards human diseases. One of the key challenges in treatment of bacterial infections is the ability of bacteria to develop resistance to one or more antibacterial agents over time. Examples of such bacteria that have developed resistance to typical antibacterial agents include: Penicillin-resistant Streptococcus pneumoniae, Vancomycin-resistant Enterococci, and Methicillin-resistant Staphylococcus aureus. The problem of emerging drug-resistance in bacteria is often tackled by switching to newer antibacterial agents, which can be more expensive and sometimes more toxic. Additionally, this may not be a permanent solution as the bacteria often develop resistance to the newer antibacterial agents as well in due course. In general, bacteria are particularly efficient in developing resistance, because of their ability to multiply very rapidly and pass on the resistance genes as they replicate. Therefore, there is a need for development of newer ways to treat infections that are becoming resistant to known therapies and methods.

Surprisingly, it has been found that the compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof, exhibit synergistic antibacterial activity, even against resistant bacterial strains.

Formula (I)

Example 1

Synthesis of Compound of formula (I)

Step-1: Preparation of intermediate (1):

To the clear solution of (Z)-2[(2-tert-butoxycarbonyl amino-thiazol-4-yl)-carboxy-methyleneaminooxy]2-methyl-propionic acid tert-butyl ester (30 gm, 69.93 mmol) in N,N-dimethyl acetamide (300 ml) was charged triethylamine (17.68 ml, 125.87 mmol) under stirring. The reaction mixture was cooled to -15°C. Methane sulfonyl chloride (12.01 gm, 104. 89 mmol) was charged to this cooled reaction mixture via addition funnel while maintaining temperature at about -15°C. The reaction mixture was stirred for 30 minutes at -15°C after the addition. To the reaction mixture was charged (6 ?,75)-4-methoxybenzyl-7-amino-3-chloromethyl-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride salt (28.25 gm, 69.93 mmol) along with N-methyl morpholine (15.5 ml, 139.86 mmol). The reaction mixture was stirred further for 1 hour at -15°C and the reaction progress was monitored using TLC. After completion of reaction, ethyl acetate (1.2 L) was charged followed by IN aqueous hydrochloric acid (1.2 L) under stirring and cooling was removed to warm up reaction mixture to room temperature. Layers were separated and organic layer was washed with saturated aqueous sodium bicarbonate solution (500 ml) followed by brine (500 ml). Organic layer was dried over sodium sulphate and was evaporated under vacuum to provide a crude mass. It was purified using silica gel column chromatography (60-120 mesh, 30% ethyl acetate in hexane) to provide 38 gm of intermediate (1).

Analysis:

1H NMR (CDCls) δ ppm: 8.29 (br s, 1H), 8.17 (d, 1H), 7.35 (d, 2H), 7.31 (s, 1H), 6.91 (d, 2H), 6.21 (dd, 1H), 5.23 (dd, 2H), 5.05 (d, 1H), 4.55 (d, 1H), 4.46 (d, 1H), 3.82 (s, 3H), 3.65 (d, 1H), 3.48 (d, 1H), 1.62 (s, 3H), 1.59 (s, 3H), 1.53 (s, 9H), 1.45 (s, 9H).

Step-2: Preparation of intermediate (2):

The solution of intermediate 1 (45 gm, 57.76 mmol) in dichloro methane (450 ml) was cooled to about -40°C and m-chloroperbenzoic acid (18 gm, 57.76 mmol) was added in three lots at -40°C under stirring. The mixture was stirred for 30 minutes and allowed to warm at -20°C. As TLC showed complete conversion, 5% aqueous sodium thiosulfate solution (1.2 L) was added at -15°C under stirring. The mixture was allowed to warm at room temperature and was charged with ethyl acetate (1.5 L) and stirred for 30 minutes and layers were separated. Organic layer was washed with saturated aqueous sodium bicarbonate solution (1 L) followed by brine (500 ml).

Organic layer was dried over sodium sulphate and evaporated under vacuum to provide 46 gm of intermediate (2).

Analysis:

1H NMR (CDC1₃) δ ppm: 8.48 (br s, 1H), 7.89 (d, 1H), 7.34 (d, 2H), 7.29 (s, 1H), 6.92 (d, 2H), 6.21 (dd, 1H), 5.27 (dd, 2H), 5.04 (br d, 1H), 4.58 (d, 1H), 4.23 (d, 1H), 3.83 (s, 3H), 3.82 (d, 1H), 3.43 (d, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.53 (9H)1.42 (s, 9H).

Step-3: Preparation of intermediate (3):

Part-1: To the clear solution of intermediate 2 (35 gm, 44.02 mmol) in tetrahydrofuran (350 ml) was charged potassium iodide (14.61 gm, 88.05 mmol) under stirring at 25°C. The suspension was stirred for 5 hours at the same temperature and the reaction was monitored using mass spectroscopy. After completion of the reaction ethyl acetate (600 ml) was added to the reaction mixture followed by 5% aqueous sodium thiosulphate (600 ml). The reaction mixture was stirred for 15 minutes and layers were separated. Organic layer was washed with demineralised water (500 ml) followed by brine (500 ml). Organic layer was dried over sodium sulphate and evaporated to dryness under vacuum to provide 38 gm of corresponding iodo-methyl intermediate.

Part-2: To the iodo-methyl intermediate obtained (37.24 gm, 41.98 mmol) in N,N-dimethylformamide (35 ml) was added 2-chloro-3,4-di-(4-methoxybenzyloxy)-N-(pyrrolidin-l-ylethyl)-benzamide (22 gm, 42.98 mmol). The thick mass was stirred at 25°C for 15 hours and the reaction was monitored using mass spectroscopy. Potassium iodide (48.78 gm, 293.8 mmol) was charged to the reaction mass under stirring at 25 °C. The reaction mixture was cooled to -40°C and acetyl chloride (12 ml, 167.9 mmol) was added. After completion of the reaction ethyl acetate (1.2 L) followed by demineralised water (1.2 L) was added to the reaction mass at 0°C. Layers were separated and organic layer was washed with demineralised water (500 ml) followed by brine (500 ml). Organic layer was dried over sodium sulphate and was evaporated to dryness under vacuum to obtain quaternary intermediate (3) as iodide salt.

Step-4: Preparation compound of Formula (I):

Compound (3) (30 gm, 21.5 mmol) was dissolved in dichloro methane (300 ml) and anisole (30 gm, mmol) was added under stirring at 25°C. The mixture was cooled to -40° C and 2M aluminium chloride solution in nitromethane (150 ml) was added over 45 minutes at -40°C. As addition was completed reaction mixture was stirred for 1 hour at 0°C. To the reaction mixture 2M aqueous hydrochloric acid (750 ml) and acetonitrile (750 ml) were added and the stirring was

continued for 15 minutes. Di-isopropyl ether (1.5 L) was charged to the reaction mixture and the reaction mass was stirred for 15 minutes at 25°C, and the layers were separated. Aqueous layer was washed with additional di-isopropyl ether (500 ml). HP-21 resin (150 gm) was charged to the aqueous layer. The aqueous layer along with resin was loaded on a resin HP-21 column. The column was eluted with demineralised water till pH of eluent became neutral. Then the column was eluted with 10% acetonitrile in water mixture. Finally the column was eluted with 20% acetonitrile in water mixture. Evaporation of required fractions below 40°C under vacuum provided 5.5 gm of crude compound (I). The crude compound (I) was purified by dissolving in acetonitrile (200 ml) and demineralised water (200 ml) mixture followed by addition of HP-21 resin (200 gm).The slurry thus obtained was loaded on HP-21 resin column. The column was eluted first with demineralised water (3 L) followed by 10% acetonitrile in water mixture (2 L) then followed by 20% acetonitrile in water mixture till complete pure compound from the column is eluted. Pure fractions were collected and lyophilized under vacuum to provide titled compound (I) in pure form.

Analysis:

1H NMR (DMSO d₆) δ ppm: 12.5 (br s, 2H), 9.42 (br s, 1H), 8.41 (br t, 1H), 7.28 (br s, 3H), 6.78 (s, 2H), 6.73 (s, 1H), 5.73 (dd, 1H), 5.15 (d, 1H), 5.08 (br d, 1H), 3.71-3.91 (m, 4H), 3.21-3.60 (m, 7H), 1.95-2.19 (m, 4H)1.76 (s, 3H), 1.44 (s, 3H).

HPLC purity: 90.80%

PATENT

WO 2019093450

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019093450&tab=FULLTEXT&_cid=P21-K4M68M-79012-1

Prior art documents

Non-patent literature

PAPER

 European Journal of Medicinal Chemistry (2018), 155, 847-868

References

External links

• “Cefiderocol”. Drug Information Portal. U.S. National Library of Medicine.

ADDITIONAL INFORMATION

S-649266 shows potent in vitro activity against the non-fermenting Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, including MDR strains such as carbapenem-resistant A. baumannii and metallo-β-lactamase-producing P. aeruginosa. MIC90s of S-649266 for A. baumannii, P. aeruginosa and S. maltophilia were 2, 1 and 0.5 mg/L, respectively, whereas MIC90s of meropenem were >16 mg/L. S-649266 showed potent in vitro activities against A. baumannii producing carbapenemases such as OXA-type β-lactamases, and P. aeruginosa producing metallo-β-lactamases such as IMP type and VIM type. MIC90 values for these A. baumannii strains and P. aeruginosa strains were 8 and 4 mg/L, respectively.

REFERENCES

1: Yamano Y. In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S544-S551. doi: 10.1093/cid/ciz827. PubMed PMID: 31724049; PubMed Central PMCID: PMC6853761.

2: Echols R, Ariyasu M, Nagata TD. Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S559-S564. doi: 10.1093/cid/ciz829. PubMed PMID: 31724048; PubMed Central PMCID: PMC6853756.

3: Sato T, Yamawaki K. Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S538-S543. doi: 10.1093/cid/ciz826. PubMed PMID: 31724047; PubMed Central PMCID: PMC6853759.

4: Bonomo RA. Cefiderocol: A Novel Siderophore Cephalosporin Defeating Carbapenem-resistant Pathogens. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S519-S520. doi: 10.1093/cid/ciz823. PubMed PMID: 31724046; PubMed Central PMCID: PMC6853757.

5: Katsube T, Echols R, Wajima T. Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S552-S558. doi: 10.1093/cid/ciz828. PubMed PMID: 31724042; PubMed Central PMCID: PMC6853762.

6: Kidd JM, Abdelraouf K, Nicolau DP. Efficacy of Humanized Cefiderocol Exposure is Unaltered by Host Iron Overload in the Thigh Infection Model. Antimicrob Agents Chemother. 2019 Oct 28. pii: AAC.01767-19. doi: 10.1128/AAC.01767-19. [Epub ahead of print] PubMed PMID: 31658966.

7: Chen IH, Kidd JM, Abdelraouf K, Nicolau DP. Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model. Antimicrob Agents Chemother. 2019 Oct 7. pii: AAC.01558-19. doi: 10.1128/AAC.01558-19. [Epub ahead of print] PubMed PMID: 31591126.

8: Stevens RW, Clancy M. Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug-Resistant Pseudomonas aeruginosa: A Case Report. Pharmacotherapy. 2019 Nov;39(11):1113-1118. doi: 10.1002/phar.2334. Epub 2019 Oct 22. PubMed PMID: 31550054.

9: Sanabria C, Migoya E, Mason JW, Stanworth SH, Katsube T, Machida M, Narukawa Y, Den Nagata T. Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects. Clin Ther. 2019 Sep;41(9):1724-1736.e4. doi: 10.1016/j.clinthera.2019.07.006. Epub 2019 Aug 1. PubMed PMID: 31378318.

10: Trecarichi EM, Quirino A, Scaglione V, Longhini F, Garofalo E, Bruni A, Biamonte E, Lionello R, Serapide F, Mazzitelli M, Marascio N, Matera G, Liberto MC, Navalesi P, Torti C; IMAGES Group . Successful treatment with cefiderocol for compassionate use in a critically ill patient with XDR Acinetobacter baumannii and KPC-producing Klebsiella pneumoniae: a case report. J Antimicrob Chemother. 2019 Nov 1;74(11):3399-3401. doi: 10.1093/jac/dkz318. PubMed PMID: 31369095.

11: Nakamura R, Ito-Horiyama T, Takemura M, Toba S, Matsumoto S, Ikehara T, Tsuji M, Sato T, Yamano Y. In Vivo Pharmacodynamic Study of Cefiderocol, a Novel Parenteral Siderophore Cephalosporin, in Murine Thigh and Lung Infection Models. Antimicrob Agents Chemother. 2019 Aug 23;63(9). pii: e02031-18. doi: 10.1128/AAC.02031-18. Print 2019 Sep. PubMed PMID: 31262762; PubMed Central PMCID: PMC6709502.

12: Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019 Jul 1;74(7):1971-1974. doi: 10.1093/jac/dkz123. PubMed PMID: 31220260; PubMed Central PMCID: PMC6587409.

13: Jean SS, Hsueh SC, Lee WS, Hsueh PR. Cefiderocol: a promising antibiotic against multidrug-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther. 2019 May;17(5):307-309. doi: 10.1080/14787210.2019.1612240. Epub 2019 May 6. PubMed PMID: 31055983.

14: Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron-depleted cation-adjusted Mueller-Hinton broth. Diagn Microbiol Infect Dis. 2019 Aug;94(4):321-325. doi: 10.1016/j.diagmicrobio.2019.03.003. Epub 2019 Mar 23. PubMed PMID: 31029489.

15: Miyazaki S, Katsube T, Shen H, Tomek C, Narukawa Y. Metabolism, Excretion, and Pharmacokinetics of [(14) C]-Cefiderocol (S-649266), a Siderophore Cephalosporin, in Healthy Subjects Following Intravenous Administration. J Clin Pharmacol. 2019 Jul;59(7):958-967. doi: 10.1002/jcph.1386. Epub 2019 Feb 7. PubMed PMID: 30730562; PubMed Central PMCID: PMC6593826.

16: Zhanel GG, Golden AR, Zelenitsky S, Wiebe K, Lawrence CK, Adam HJ, Idowu T, Domalaon R, Schweizer F, Zhanel MA, Lagacé-Wiens PRS, Walkty AJ, Noreddin A, Lynch Iii JP, Karlowsky JA. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. 2019 Feb;79(3):271-289. doi: 10.1007/s40265-019-1055-2. Review. PubMed PMID: 30712199.

17: Huttner A. Cefiderocol for treatment of complicated urinary tract infections – Author’s reply. Lancet Infect Dis. 2019 Jan;19(1):24-25. doi: 10.1016/S1473-3099(18)30728-X. PubMed PMID: 30587291.

18: Portsmouth S, Echols R, Den Nagata T. Cefiderocol for treatment of complicated urinary tract infections. Lancet Infect Dis. 2019 Jan;19(1):23-24. doi: 10.1016/S1473-3099(18)30721-7. PubMed PMID: 30587290.

19: Wagenlehner FME, Naber KG. Cefiderocol for treatment of complicated urinary tract infections. Lancet Infect Dis. 2019 Jan;19(1):22-23. doi: 10.1016/S1473-3099(18)30722-9. PubMed PMID: 30587289.

20: Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, Tenke P, Nagata TD. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. doi: 10.1016/S1473-3099(18)30554-1. Epub 2018 Oct 25. PubMed PMID: 30509675.

Cefiderocol

Clinical data
Trade names	Fetroja
Routes of administration	Intravenous infusion
ATC code	none
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	56–58%[1]
Elimination half-life	2.8 hours
Excretion	mainly renal (60–70% unchanged)
Identifiers
IUPAC name[show]
CAS Number	1225208-94-5
PubChem CID	77843966
DrugBank	DB14879
ChemSpider	52084902
UNII	SZ34OMG6E8
KEGG	D11302
ChEMBL	ChEMBL3989974
Chemical and physical data
Formula	C30H34ClN7O10S2
Molar mass	752.21 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] CC(C)(C(=O)O)ON=C(C1=CSC(=N1)N)C(=O)NC2C3N(C2=O)C(=C(CS3)C[N+]4(CCCC4)CCNC(=O)C5=C(C(=C(C=C5)O)O)Cl)C(=O)[O-]

////////////Cefiderocol, セフィデロコル , FDA 2019, цефидерокол , سيفيديروكول , 头孢德罗 , S-649266,  GSK 2696266D