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Acoltremon

June 27, 2025 2:43 am / Leave a comment

Acoltremon

AR-15512

CAS 68489-09-8

WeightAverage: 289.419
Monoisotopic: 289.204179113

Chemical FormulaC₁₈H₂₇NO₂

FDA 2025, 5/28/2025, To treat the signs and symptoms of dry eye disease

Tryptyr

WS-12
WS 12
(1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide
Fema No. 4681
N-(4-methoxyphenyl)-p-menthanecarboxamide

1L7BVT4Z4Z

OriginatorInstituto de Neurociencias de Alicante
DeveloperAlcon; AVX Pharma
ClassCyclohexanes; Ethers; Eye disorder therapies; Small molecules
Mechanism of ActionTRPM8 protein stimulants

RegisteredDry eyes
30 May 2025Alcon plans to launch Acoltremon for Dry eyes in USA in the third quarter of 2025
28 May 2025Registered for Dry eyes in USA (Ophthalmic) – First global approval
05 May 2025FDA assigns PDUFA action date of 30/05/2025 for Acoltremon for Dry eyes

Acoltremon sold under the brand name Tryptyr, is a medication used for the treatment of dry eye syndrome.^[1]

PATENT

US 217370

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023114986&_fid=RU437402572

https://patentscope.wipo.int/search/en/detail.jsf?docId=US193167995&_cid=P11-MCE7BB-27500-1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012032209&_fid=US193167995

Medical uses

Acoltremon was approved for medical use in the United States in May 2025, for the treatment of signs and symptoms associated with dry eye disease.^[2]

Pharmacology

Acoltremon acts as a potent and selective activator (opener) of the TRPM8 calcium channel, which is responsible for the sensation of coldness produced by menthol.^[3] It is slightly less potent as a TRPM8 activator compared to icilin, but is a much more selective TRPM8 ligand when compared to menthol.^[4]

Society and culture

Legal status

Acoltremon was approved for medical use in the United States in May 2025.^[5]

References

^ Jump up to:^a ^b https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217370s000lbl.pdf
^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 29 May 2025. Archived from the original on 3 March 2025. Retrieved 29 May 2025.
^ Ma S, Gisselmann G, Vogt-Eisele AK, Doerner JF, Hatt H (October 2008). “Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels”. Pakistan Journal of Pharmaceutical Sciences. 21 (4): 370–378. PMID 18930858.
^ Kühn FJ, Kühn C, Lückhoff A (February 2009). “Inhibition of TRPM8 by icilin distinct from desensitization induced by menthol and menthol derivatives”. The Journal of Biological Chemistry. 284 (7): 4102–4111. doi:10.1074/jbc.M806651200. PMID 19095656.
^ “Alcon Announces FDA Approval of Tryptyr (acoltremon ophthalmic solution) 0.003% for the Treatment of the Signs and Symptoms of Dry Eye Disease” (Press release). Alcon. 28 May 2025. Archived from the original on 29 May 2025. Retrieved 29 May 2025 – via Business Wire.

External links

Clinical trial number NCT05285644 for “Study Evaluating the Safety and Efficacy of AR-15512 (COMET-2)” at ClinicalTrials.gov
Clinical trial number NCT05360966 for “Study Evaluating the Safety and Efficacy of AR-15512 (COMET-3)” at ClinicalTrials.gov

Clinical data
molecular structure
3D representation
Trade names	Tryptyr
Other names	AVX-012, WS-12
License data	US DailyMed: Acoltremon
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	68489-09-8
PubChem CID	11266244
DrugBank	DB19202
ChemSpider	9441255
UNII	1L7BVT4Z4Z
KEGG	D13125
ChEMBL	ChEMBL2441929
CompTox Dashboard (EPA)	DTXSID10460636
Chemical and physical data
Formula	C₁₈H₂₇NO₂
Molar mass	289.419 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

[1]. Beck B, et al. Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators. Cell Calcium. 2007 Mar;41(3):285-94. [Content Brief][2]. Ma S, et al. Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci. 2008 Oct;21(4):370-8. [Content Brief]

///////Acoltremon, FDA 2025, APPROVALS 2025, WS-12, WS 12, Fema No. 4681, Tryptyr, 1L7BVT4Z4Z, AR-15512

Nerandomilast

June 25, 2025 2:45 am / Leave a comment

Nerandomilast

CAS 1423719-30-5

C₂₀H₂₅ClN₆O₂S

Molecular Weight	448.97
Formula	C₂₀H₂₅ClN₆O₂S

I5DGT51IB8

fda 2025, approvals 2025, Jascayd,10/7/2025, To treat idiopathic pulmonary fibrosis

[1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol

Cyclobutanemethanol, 1-[[(5R)-2-[4-(5-chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]-

1-[[(5R)-2-[4-(5-Chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutanemethanol

Nerandomilast (BI 1015550) is an investigational oral medication being studied for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). It is a preferential inhibitor of phosphodiesterase 4B (PDE4B) and has shown potential in slowing lung function decline in patients with IPF.

Key points about nerandomilast:

Mechanism of Action:Nerandomilast inhibits PDE4B, an enzyme that plays a role in inflammation and fibrosis.
Clinical Trials:Phase 3 clinical trials have shown that nerandomilast can slow lung function decline in patients with IPF and PPF.
Efficacy:The trials demonstrated that nerandomilast led to a smaller decline in forced vital capacity (FVC), a measure of lung function, compared to placebo.
Safety:Diarrhea was the most frequent adverse event, but serious adverse events were balanced across treatment groups.
Progressive Fibrosing ILDs:Nerandomilast is also being investigated in other progressive fibrosing interstitial lung diseases (ILDs) beyond IPF.
FDA Designation:Nerandomilast received Breakthrough Therapy Designation from the FDA for the treatment of IPF.
Not a Cure:While nerandomilast can slow disease progression, it does not cure pulmonary fibrosis.
Not Yet Approved:Nerandomilast is still an investigational drug and is not yet approved for use.

Nerandomilast (BI 1015550) is an orally active inhibitor of PDE4B with an IC₅₀ value of 7.2 nM. Nerandomilast has good safety and potential applications in inflammation, allergic diseases, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

SCHEME

1H NMR (400 MHz, DMSO-D6)  1.57–1.84 (m, 2H), 1.96 (br d, J = 12.5 Hz, 2H), 2.10–2.21 (m, 2H), 2.24–
2.41 (m, 2H), 2.82–2.98 (m, 2H), 3.06 (br t, J = 11.7 Hz, 2H), 3.13–3.27 (m, 2H), 3.36–3.47 (m, 1H), 3.71 (d, J =
5.64 Hz, 2H), 4.70 (br d, J = 12.5 Hz, 2H), 4.84 (t, J = 5.7 Hz, 1H), 7.35 (s, 1H), 8.85 (s, 2H).

1H NMR (DMSO-d6, 400 MHz)  1.87–1.92 (m, 2H), 2.12–2.17 (m, 2H), 3.08 (ddd, J = 12.8, 12.8, 2.8 Hz,
2H), 3.21 (m, 1H), 3.34–3.42 (m, 2H), 8.47 (br, 2H), 8.19 (s, 2H).

PATENT

US20150045376

WO2013026797

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.4c00309

A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective S_NAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).

[1]. Pouzet P A, et al. Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma. United States. US9150586.[2]. Herrmann FE, et al. BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022 Apr 20;13:838449. [Content Brief]

//////////Nerandomilast, BI 1015550, I5DGT51IB8, fda 2025, approvals 2025, Jascayd,

ETRIPAMIL

May 28, 2025 2:57 am / Leave a comment

ETRIPAMIL

CAS 1593673-23-4

AS ACETATE 512.64 CAS 2891832-59-8

HCL SALT 2560549-35-9

WeightAverage: 452.595
Monoisotopic: 452.267507647

Chemical FormulaC₂₇H₃₆N₂O₄

12/12/2025, FDA 2025, APPROVALS 2025

Benzoic acid, 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-, methyl ester

methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate

Methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]benzoate
(-)-MSP 2017
MSP 2017

OriginatorMilestone Pharmaceuticals
DeveloperCorxel Pharmaceuticals; Milestone Pharmaceuticals
ClassAmines; Antiarrhythmics; Benzoates; Esters; Ischaemic heart disorder therapies; Small molecules
Mechanism of ActionCalcium channel antagonists

PreregistrationParoxysmal supraventricular tachycardia
Phase IIAtrial fibrillation
Phase IUnspecified
No development reportedAngina pectoris

14 May 2025Milestone Pharmaceuticals has patent protection for etripamil in the USA
28 Mar 2025Milestone pharmaceuticals plans to request a Type A meeting with USFDA to discuss the issues raised in the complete response letter
28 Mar 2025USFDA has issued a Complete Response Letter (CRL) regarding New Drug Application (NDA) for Etripamil for Paroxysmal supraventricular tachycardia

Etripamil has been used in trials studying the treatment of Paroxysmal Supraventricular Tachycardia (PSVT).

Etripamil (MSP-2017) is a short-acting, L-type calcium-channel antagonist. Etripamil inhibits calcium influx through slow calcium channels, thereby slowing AV node conduction and prolonging the AV node refractory period. Etripamil increases heart rate and decreases systolic blood pressure. Etripamil can be used in the study of paroxysmal supraventricular tachycardia (PSVT).

To treat episodes of paroxysmal supraventricular tachycardia

SCHEME

SIDE CHAIN

MAIN

SYN

US20180110752/ U.S. Patent No. 10,117,848,

EXAMPLES

Example 1: Synthesis methyl 3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Part I: Synthesis of 5-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile

(MOL) (CDX)

Method A, Step 1:

To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrile in 141 mL of tetrahydrofuran (THF) at −30° C., was slowly added 56.4 mL (56.4 mmol) of sodium bis(trimethylsilyl)amide ( NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 10.6 mL (113.0 mmol) of 2-bromopropane was added. The mixture was heated to reflux for 2 hours (h) then left at 22° C. for about 16 h. A saturated aqueous solution of NH₄Cl was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried ( Na₂SO₄), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil.

Method A, Step 2:

To a solution of 11.21 g (51.1 mmol) of 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile in 126 mL of tetrahydrofuran (THF) at −30° C., was slowly added 46.0 mL (46.0 mmol) of sodium bis(trimethylsilyl)amide ( NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 9.40 mL (256 mmol) of 1,3-dibromopropane was added dropwise. The mixture was warmed to 22° C. and stirred for about 16 h. A saturated aqueous solution of NH₄Cl was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried ( Na₂SO₄), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile as an oil.

Part II: Synthesis of methyl 3-(2-(methylamino)ethyl)benzoate

(MOL) (CDX)

To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in 36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. The mixture was refluxed for about 16 h, cooled to 22° C. and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 3-(cyanomethyl)benzoate.

To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in 31 mL of THF stirred at −10° C. was slowly added 710 mg (18.7 mmol) of sodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroacetic acid. The mixture was warmed to 22° C. and stirred for about 16 h. About 100 mL of water was carefully added to the mixture (gas evolution). The mixture was extracted with ethyl acetate (5×50 mL). The organic phase was washed with brine, dried ( Na₂SO₄), filtered and evaporated to give methyl 3-(2-aminoethyl)benzoate which was used in the next step without purification.

Method B:

To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mL tetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC ₂O. The mixture was stirred for about 16 h at 22° C. and 100 mL of water was added. The mixture was extracted with ethyl acetate (2×100 mL) and the organic phase was washed with brine, dried ( Na₂SO₄) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 20% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was further converted to III by Method C (described below).

Method C, Step 1:

To a solution of methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate in dry THF under a nitrogen atmosphere was added dropwise NaHMDS (1.0 M in THF) at 0° C. After stirring for 10 min, dimethyl sulfate was added and the reaction was warmed to 22° C. and stirred for about 16 h. The reaction was quenched by adding 25 mL of saturated NaHCO₃ and the mixture was extracted with DCM (2×25 mL). The combined organic extracts were dried ( Na₂SO₄) and evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 10% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate.

Method C, Step 2:

To a solution of methyl 3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate in DCM at 0° C. was added trifluoroacetic acid (TFA). The reaction was warmed to 22° C., stirred for 3 h and the solvents were then evaporated. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N NaOH which had been saturated with NaCl. The aqueous layer was back-extracted with ethyl acetate (6×50 mL) and the combined organics were dried ( Na₂SO₄) and evaporated to give 2c as a colorless oil.

Part III: Reaction of Compound II with Compound III Produced Compound I

Analysis of the product by mass spectrometry revealed a peak with a mass-to-charge ratio (m/z) of 453, corresponding to the M+H molecular ion of compound I.

Example 2: Concentrated Solution of Acetate Salt of Compound I

A concentrated aqueous solution of the acetate salt of compound I is formed according to the following protocol:

An aqueous solution of 7.5 M sulfuric acid is first made by diluting concentrated sulfuric acid in water and manually mixing in a sealed bottle, periodically venting the pressure by releasing the bottle cap. Separately, 175±1.0 g of compound I is dispensed from a pre-heated container into a glass bottle and maintained at a temperature of 50±2° C. in a water bath. Next, 96.7±0.2 mL of a 4.0 M acetic acid solution is added to compound I, followed by 83.3 mL±0.2 mL of a 31.8 mM solution of EDTA. The mixture containing the (−) enantiomer (S-enantiomer) of compound I is maintained at 50±2° C. and stirred using a magnetic stir bar during both additions. Heating and stirring is continued until the compound appears to be fully dispersed throughout the mixture.

Upon complete dispersion of compound I, the solution of 7.5 M sulfuric acid is added drop-wise to the compound I mixture until a pH of 5.0±0.1 is reached. At this point, heating is discontinued and the mixture continues to stir. The mixture is then allowed to cool to within 2° C. of ambient temperature. A solution of 0.9 M sulfuric acid is then added drop-wise to the mixture until a pH of 4.5±0.1 is reached. The mixture containing compound I is then diluted to 90% of the final target volume by the addition of water to the mixture, and the pH is monitored after this dilution. If necessary, the pH is lowered back to 4.5±0.1 by drop-wise addition of 0.9 M sulfuric acid. The mixture is then diluted to the final target volume by the addition of water.

This protocol readily can be adapted to provide a concentrated solution of the methanesulfonate salt of compound I.

PATENT

PRED BY CHIRAL SEPERATION

US20230065401

WO2016165014

EP4119137 chiral sepn done

[0034] In one embodiment the present invention is a kit for treating a cardiac arrhythmia (e.g., PSVT or atrial fibrillation), angina, or a migraine in a subject in need thereof wherein the kit comprises a nasal delivery system comprising two doses of a therapeutically effective amount of compound I having a structure according to the formula:

and instructions for nasally administering to the subject (i) a first dose, and, optionally, (ii) a second dose of an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, or a racemate or enantiomer thereof, wherein the acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of 350 mg/mL± 50 mg/mL, and wherein the second dose of the compound is to be administered between 5 minutes and 60 minutes after the first dose.

Cross ref U.S. Patent No. 10,117,848,

[0336]

1. A method of treating a cardiac arrhythmia in a subject in need thereof with a therapeutically effective amount of compound I having a structure according to the formula:

the method comprising nasally administering to the subject (i) a first dose, and (ii) a second dose of an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, or a racemate or enantiomer thereof, wherein the acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of 350 mg/mL ± 50 mg/mL, and wherein the second dose of the compound is administered between 5 minutes and 25 minutes after the first dose.

PATENT

Journal of the American College of Cardiology (2018), 72(5), 489-497

American Heart Journal (2022), 253, 20-29

Expert Opinion on Investigational Drugs (2020), 29(1), 1-4

EP4119137 WO2016165014

WO2023108146

EP-2170050-B1

US-9737503-B2

US-4968717-A

EP-0231003-A2

[1]. Stambler BS, et al. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm. J Am Coll Cardiol. 2018 Jul 31;72(5):489-497. [Content Brief][2]. Milestone Pharmaceuticals Announces USAN Approval of Generic Name “Etripamil” for its Phase 2 Clinical Development Product for the Treatment of Paroxysmal Supraventricular Tachycardia.[3]. Ascah A, et al. Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys. Int J Toxicol. 2025 Apr 1:10915818251327963. [Content Brief][4]. Pion J, et al. Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia. Int J Toxicol. 2024 Sep-Oct;43(5):503-510. [Content Brief]

//////////ETRIPAMIL, (-)-MSP 2017, MSP 2017, FDA 2025, APPROVALS 2025

Olezarsen

April 14, 2025 2:47 am / Leave a comment

Olezarsen

Olezarsen is an ASO directed inhibitor of Apolipoprotein C-III (apoC-III) mRNA, conjugated to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes.

TRYNGOLZA contains olezarsen sodium as the active ingredient. Olezarsen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of olezarsen sodium is C 296H 419N 71O 154P 20S 19Na 20and the molecular weight is 9124.48 daltons. The chemical name of olezarsen sodium is DNA, d(P-thio) ([2′- O-(2-methoxyethyl)] rA-[2′- O-(2-methoxyethyl)] rG-[2′- O-(2-methoxyethyl)] m5rC-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-m5C-T-T-G-T-m5C-m5C-A-G-m5C-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] rA-[2′- O-(2-methoxyethyl)]m5rU), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20).

Olezarsen

FDA APPROVED 12/19/2024, Tryngolza, To treat familial chylomicronemia syndrome
Drug Trials Snapshot

Synonyms

AKCEA-APOCIII-LRX
ALL-P-AMBO-5′-O-(((6-(5-((TRIS(3-(6-(2-ACETAMIDO-2-DEOXY-.BETA.-D-GALACTOPYRANOSYLOXY)HEXYLAMINO)-3-OXOPROPOXYMETHYL))METHYL)AMINO-5-OXOPENTANAMIDO)HEXYL))PHOSPHO)-2′-O-(2-METHOXYETHYL)-P-THIOADENYLYL-(3′-O->5′-O)-2′-O-(2-METHOXYETHYL)-P-THIOGUANYLYL-(3
DNA, D(P-THIO)((2′-O-(2-METHOXYETHYL))RA-(2′-O-(2-METHOXYETHYL))RG-(2′-O-(2-METHOXYETHYL))M5RC-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETHYL))M5RU-M5C-T-T-G-T-M5C-M5C-A-G-M5C-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETH
IONIS-APOCIII-LRX
ISIS-APOCIII-LRX

External IDs

ISIS-678354

Olezarsen, sold under the brand name Tryngolza, is a medication used in the treatment of familial chylomicronemia syndrome.^[1]^[2] It is given by injection under the skin.^[1]

Olezarsen was approved for medical use in the United States in December 2024.^[1]^[3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[4]

PATENT

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9127276	No	2015-09-08	2034-05-01
US9181549	No	2015-11-10	2034-05-01
US9593333	No	2014-02-14	2034-02-14
US9157082	No	2012-04-27	2032-04-27
US9163239	No	2014-05-01	2034-05-01

Medical uses

Olezarsen is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome.^[1]

Pharmacology

Olezarsen is an apolipoprotein C-III-directed antisense oligonucleotide.^[1] By binding to apolipoprotein C-III mRNA, it causes its degradation, which in turn increases clearance of plasma triglycerides and very low-density lipoprotein (VLDL).^[5]

Adverse effects

In a 66-patient trial, olezarsen was demonstrated to cause following side effects:^[5]^[6]

injection site reactions
hypersensitivity reactions (due to immunogenic potential of the medication)
arthralgia
thrombocytopenia
hyperglycemia
elevation of liver enzymes

History

The US Food and Drug Administration (FDA) granted the application of olezarsen orphan drug designation in February 2024.^[7] In August 2024, European Medicines Agency also granted olezarsen this designation.^[8]

Society and culture

Legal status

Olezarsen was approved for medical use in the United States in December 2024.^[3]^[9]

Names

Olezarsen is the international nonproprietary name.^[10]

Olezarsen is sold under the brand name Tryngolza.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Tryngolza- olezarsen sodium injection, solution”. DailyMed. 19 December 2024. Retrieved 25 January 2025.

^ Spagnuolo, Catherine M; Hegele, Robert A (2023). “Recent advances in treating hypertriglyceridemia in patients at high risk of cardiovascular disease with apolipoprotein C-III inhibitors”. Expert Opinion on Pharmacotherapy. 24 (9): 1013–1020. doi:10.1080/14656566.2023.2206015. PMID 37114828.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ Jump up to:^a ^b Stroes, Erik S.G.; Alexander, Veronica J.; Karwatowska-Prokopczuk, Ewa; Hegele, Robert A.; Arca, Marcello; Ballantyne, Christie M.; et al. (16 May 2024). “Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome”. New England Journal of Medicine. 390 (19): 1781–1792. doi:10.1056/NEJMoa2400201. ISSN 0028-4793.
^ Ionis Pharmaceuticals, Inc. (11 December 2024). A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA-APOCIII-LRx Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS) (Report). clinicaltrials.gov.
^ “Olezarsen Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Retrieved 20 December 2024.
^ “EU/3/24/2973 – orphan designation for treatment of familial chylomicronaemia syndrome | European Medicines Agency (EMA)”. http://www.ema.europa.eu. 21 August 2024. Retrieved 22 February 2025.
^ “Tryngolza (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet” (Press release). Ionis Pharmaceuticals. 19 December 2024. Retrieved 20 December 2024 – via PR Newswire.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.

External links

“Olezarsen (Code C180652)”. NCI Thesaurus.

Clinical trial number NCT04568434 for “A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) Administered to Patients With Familial Chylomicronemia Syndrome (FCS) (BALANCE)” at ClinicalTrials.gov

Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O’Dea LSL, Tsimikas S, Gaudet D: Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820. [Article]
Karwatowska-Prokopczuk E, Tardif JC, Gaudet D, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Amour ES, Alexander VJ, Xia S, Otvos JD, Witztum JL, Tsimikas S: Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia. J Clin Lipidol. 2022 Sep-Oct;16(5):617-625. doi: 10.1016/j.jacl.2022.06.005. Epub 2022 Jun 23. [Article]
Hooper AJ, Bell DA, Burnett JR: Olezarsen, a liver-directed APOC3 ASO therapy for hypertriglyceridemia. Expert Opin Pharmacother. 2024 Oct;25(14):1861-1866. doi: 10.1080/14656566.2024.2408369. Epub 2024 Sep 26. [Article]
Bergmark BA, Marston NA, Prohaska TA, Alexander VJ, Zimerman A, Moura FA, Murphy SA, Goodrich EL, Zhang S, Gaudet D, Karwatowska-Prokopczuk E, Tsimikas S, Giugliano RP, Sabatine MS: Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. N Engl J Med. 2024 May 16;390(19):1770-1780. doi: 10.1056/NEJMoa2402309. Epub 2024 Apr 7. [Article]
FDA News: FDA approves drug to reduce triglycerides in adult patients with familial chylomicronemia syndrome [Link]
FDA Approved Drug Products: TRYNGOLZA (olezarsen) injection, for subcutaneous use [Link]

Clinical data

Trade names	Tryngolza
Other names	IONIS-APOCIII-LRX
License data	US DailyMed: Olezarsen
Routes of administration	Subcutaneous
Drug class	Antisense oligonucleotide
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	2097587-83-0 2298451-31-5
DrugBank	DB18728
UNII	S3RS2SA30L NSY2BY6PSB
KEGG	D13023

////Olezarsen, FDA 2024, APPROVALS 2025, Tryngolza, ISIS-678354, ISIS 678354, familial chylomicronemia syndrome

Fitusiran

April 12, 2025 5:51 am / Leave a comment

Fitusiran
1711.0 g/mol, C₇₈H₁₃₉N₁₁O₃₀

FDA APPROVED 3/28/2025, Qfitlia, To prevent or reduce the frequency of bleeding episodes in hemophilia A or B
Press Release

CAS 1499251-18-1
EX-A12034
DA-53206
N-[1,3-Bis[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]propan-2-yl]-12-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-12-oxododecanamide

Fitusiran Sodium

43 Sodium salt of duplex of [(2S,4R)-1-{1-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]-16,16-bis({3-[(3-{5-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]pentanamido}propyl)amino]-3-oxopropoxy}methyl)-5,11,18-trioxo-14-oxa-6,10,17-triazanonacosan-29-oyl}-4-hydroxypyrrolidin-2-yl]methyl hydrogen all–P–ambo-2′-deoxy-2′-fluoro-P-thioguanylyl-(3’→5′)-2′-O-methyl-P-thioguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methylcytidylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoro-3′-adenylate and all–P–ambo-2′-O-methyl-P-thiouridylyl-(3’→5′)-2′-deoxy-2′-fluoro-P-thiouridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoroguanylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyl-P-thiocytidylyl-(3’→5′)-2′-O-methyl-P-thioadenylyl-(3’→5′)-2′-O-methylguanosine

C₅₂₀H₆₃₆F₂₁N₁₇₅Na₄₃O₃₀₉P₄₃S₆ : 17193.39
[1609016-97-8]

Fitusiran, sold under the brand name Qfitlia, is a medication used for the treatment of hemophilia.^[1] It is an antithrombin-directed small interfering ribonucleic acid.^[1] It is given by subcutaneous injection.^[1] Fitusiran reduces the amount of a protein called antithrombin.^[2]

The most common side effects include viral infection, common cold symptoms (nasopharyngitis) and bacterial infection.^[2]

Fitusiran was approved for medical use in the United States in March 2025.^[2]

PATENT

https://patents.google.com/patent/WO2023240199A2/en

Medical uses

Fitusiran is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in people aged twelve years of age and older with hemophilia A or hemophilia B, with or without factor VIII or IX inhibitors (neutralizing antibodies).^[1]^[2]

Adverse effects

The US Food and Drug Administration prescription label for fitusiran contains a boxed warning for thrombotic events (blood clotting) and gallbladder disease (with some recipients requiring gallbladder removal).^[2] The label also has a warning about liver toxicity and the need to monitor liver blood tests at baseline and then monthly for at least six months after initiating treatment with fitusiran or after a dose increase of fitusiran.^[2]

History

The efficacy and safety of fitusiran were assessed in two multicenter, randomized clinical trials which enrolled a total of 177 adult and pediatric male participants with either hemophilia A or hemophilia B.^[2] In one study, participants had inhibitory antibodies to coagulation factor VIII or coagulation factor IX and previously received on-demand treatment with medicines known as “bypassing agents” for bleeding.^[2] In the second study, participants did not have inhibitory antibodies to coagulation factor VIII or coagulation factor IX and previously received on-demand treatment with clotting factor concentrates.^[2] In the two randomized trials, participants received either a fixed dose of fitusiran monthly or their usual on-demand treatment (bypassing agents or clotting factor concentrates) as needed for nine months.^[2] The fixed dose of fitusiran is not approved because it led to excessive clotting in some participants.^[2]

The US Food and Drug Administration (FDA) granted the application for fitusiran orphan drug and fast track designations. The FDA granted the approval of Qfitlia to Sanofi.

Society and culture

Legal status

Fitusiran was approved for medical use in the United States in March 2025.^[2]^[3]

Names

Fitusiran is the international nonproprietary name.^[4]

Fitusiran is sold under the brand name Qfitlia.^[1]^[2]

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Qfitlia- fitusiran injection, solution”. DailyMed. 26 March 2025. Retrieved 2 April 2025.

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “FDA Approves Novel Treatment for Hemophilia A or B, with or without Factor Inhibitors”. U.S. Food and Drug Administration. 28 March 2025. Retrieved 29 March 2025. This article incorporates text from this source, which is in the public domain.
^ “Qfitlia approved as the first therapy in the US to treat hemophilia A or B with or without inhibitors”. Sanofi (Press release). 28 March 2025. Retrieved 29 March 2025.
^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information. 30 (1). hdl:10665/331046.

External links

Clinical trial number NCT03417102 for “A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors (ATLAS-INH)” at ClinicalTrials.gov
Clinical trial number NCT03417245 for “A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors” at ClinicalTrials.gov
Clinical trial number NCT03754790 for “Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX (ATLAS-OLE)” at ClinicalTrials.gov

Clinical data
Trade names	Qfitlia
Other names	ALN-AT3SC
License data	US DailyMed: Fitusiran
Routes of administration	Subcutaneous
Drug class	Anthithrombin production inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1499251–18–1
DrugBank	DB15002
UNII	SV9W47ZLE1
KEGG	D11810
Chemical and physical data
Formula	C₅₂₀H₆₃₆F₂₁N₁₇₅Na₄₃O₃₀₉P₄₃S₆
Molar mass	17193.48 g·mol⁻¹

////////Fitusiran, Qfitlia, FDA 2025, APPROVALS 2025, EX-A12034, DA-53206

Gepotidacin

April 10, 2025 3:20 am / Leave a comment

Gepotidacin

CAS

1075236-89-3

GSK-2140944
GSK2140944

WeightAverage: 448.527
Monoisotopic: 448.222288786 Chemical FormulaC₂₄H₂₈N₆O₃
(3R)-3-({4-[({2H,3H,4H-pyrano[2,3-c]pyridin-6-yl}methyl)amino]piperidin-1-yl}methyl)-1,4,7-triazatricyclo[6.3.1.0^{4,12}]dodeca-6,8(12),9-triene-5,11-dione

FDA APPROVED 3/25/2025,Blujepa, To treat uncomplicated urinary tract infections

Ingredient	UNII	CAS	InChI Key
Gepotidacin hydrochloride	30Z5B7ACV6	1075235-46-9	DPAHPKBTWARMFG-FSRHSHDFSA-N
Gepotidacin mesylate	5P7X0H2O6B	1624306-20-2	MTLHHQWYERWLIX-RGFWRHHQSA-N

Gepotidacin, sold under the brand name Blujepa, is an antibiotic medication used for the treatment of urinary tract infection.^[1] Gepotidacin is a triazaacenaphthylene bacterial type II topoisomerase inhibitor.^[1]^[2] It is used as the salt gepotidacin mesylate, and is taken by mouth.^[1]

Gepotidacin was approved for medical use in the United States in March 2025.^[1]^[3]

SYNTHESIS

Gepotidacin

Gepotidacin (GSK2140944) is a triazaacenaphtylene developed by GSK and belongs to the class of Novel Bacterial Topoisomerase Inhibitors (NBTI). This new antibiotic is currently being investigated in three phase 3 clinical trials.

Gepotidacin is derived from the analogue GSK299423 described by Bax et al. [9], which results from a medicinal chemistry program initiated after an unbiased antibacterial screening [10].

2.2.1 Chemical synthesis

The synthesis of gepotidacin has been described in two patents in 2008 and 2016 and comprises 11 steps (Fig. 2) [11,12]. First, 2-chloro-6-methoxy-3-nitro-pyridine reacts with 2-amino-propane-1,3-diol through nucleophilic aromatic substitution (S_NAr). The resulting diol is then protected with 2,2-dimethoxypropane in presence of p-toluenesulfonic acid (PTSA) followed by the reduction of the nitro group with hydrogen and 10% Pd/C. The aniline thus formed is then alkylated with ethyl bromoacetate. Cyclization is performed in basic conditions using sodium hydride, followed by oxidation using manganese dioxide. The acetal is then cleaved and the released diol reacts with methanesulfonic anhydride to form the third cycle of the triazaacenaphtylene core. Substitution with Boc-amino-piperidine, followed by deprotection and subsequent purification by chiral chromatography affords the primary amine derivative, which can be condensed by reductive amination with the corresponding aldehyde to give the free base of gepotidacin. The mono-hydrochloride salt is obtained by reaction with one equivalent of HCl 1 M in diethylether [13].

PATENT

WO2021219637A1

https://patents.google.com/patent/WO2021219637A1/en

Gepotidacin mesylate dihydrate (Form 1)

Example la – Preparation Method 1

Acetone (5 ml) was added to gepotidacin (294.14 mg). To the slurry, methanesulfonic acid (3M solution in water, 1 equivalent) was added over a period of 60 minutes. The slurry was heated to 50°C for 3 hours, cooled slowly to 20°C, left stirring at 20°C for 5 hours and cooled further to 5°C. The slurry was stirred at 5°C overnight. The crystalline solids were filtered under vacuum, washed with acetone and dried in a vacuum oven at 60°C to give crystalline gepotidacin mesylate dihydrate (Form 1) in 72.9% yield.

WO2008128942A1

References:

GLAXO GROUP LIMITED WO2008/128942, 2008, A1Yield:-

Steps:

Multi-step reaction with 12 steps
1.1: ethanol; water / 4 h / 0 °C / Heating / reflux
2.1: toluene-4-sulfonic acid / 20 °C
2.2: 0.33 h
3.1: hydrogen / palladium 10% on activated carbon / 1,4-dioxane / 20 °C / 760.05 Torr
4.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C
5.1: sodium hydride / tetrahydrofuran / 3.25 h / 0 – 20 °C
6.1: manganese(IV) oxide / dichloromethane / 2 h / 20 °C
7.1: hydrogenchloride; water / tetrahydrofuran / 1 h / 20 °C
7.2: pH ~ 8
8.1: triethylamine / chloroform / 4.5 h / Heating / reflux
9.1: pyridine / acetonitrile / 5 h / 50 – 90 °C
10.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 20 °C
11.1: isopropylamine / methanol; acetonitrile / Resolution of racemate
12.1: methanol; chloroform / 20 °C
12.2: 0.5 h / 20 °C

Example 10 (lR)-l-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]- l-piperidinyl}methyl)-l,2-dihydro-4H,9H-imidazo[l,2,3-//]-l,8-naphthyridine-4,9- dione hydrochloride

A suspension of (\R)- 1 -[(4-amino- 1 -piperidinyl)methyl]- 1 ,2-dihydro-4Η,9Η- imidazo[l,2,3-ij]-l,8-naphthyridine-4,9-dione (for a preparation see Example 5(j)) (51 mg, 0.14 mmol) in chloroform:methanol (9:1, 3 ml) at rt under argon was treated with triethylamine (0.06ml) and stirred at rt for 10 min. The solution was then treated with 1,3- dihydrofuro[3,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144,

Example 126(e)) (21mg, 0.133mmol) and stirred for a further 2h. The solution was then treated with NaBH(OAc)₃ (87mg) and stirred at rt for 2h. The reaction was then treated with saturated aqueous NaHCO (10ml) and extracted with 20% methanol/DCM (3 x 50ml). The combined organic extracts were dried (MgSO ), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (20mg, 32%) MS (ES+) m/z 448 (MH⁺). δH (CDCl₃, 400MHz) 1.15-1.49 (2H, m), 1.61-1.95 (2H, m), 1.99-2.09 (2H, m) 2.20-2.38 (IH, m), 2.45-2.85 (6H, m), 2.92-3.02(1H, m), 3.05-3.15 (IH, m), 3.78 (2H, s), 4.20 (2H, t), 4.30-4.42 (IH, m), 4.52-4.61 (IH, m), 4.95-5.05 (IH, m), 6.23-6.32 (2H, m), 7.00 (IH, s), 7.47-7.50 (2H, m), 8.07 (IH, s).

The free base in DCM was treated with one equivalent IM HCl in diethyl ether and then evaporated to give the title monohydrochloride salt.

WO2016027249A1

PATENT

WO2004058144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004058144&_cid=P20-M9AS9E-95245-1

Medical uses

Gepotidacin is indicated for the treatment of females aged twelve years of age and older weighing at least 40 kilograms (88 lb) with uncomplicated urinary tract infections (uUTI) caused by Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus, and Enterococcus faecalis.^[1]

Society and culture

Legal status

In October 2024, gepotidacin was granted priority review by the US Food and Drug Administration (FDA) for the treatment of uncomplicated urinary tract infections.^[4]

Gepotidacin was approved for medical use in the United States in March 2025.^[1]^[5]

Names

Gepotidacin is the international nonproprietary name.^[6]

Gepotidacin is sold under the brand name Blujepa.^[1]^[5]

Research

Gepotidacin is being studied for the treatment of Neisseria gonorrhoeae (gonorrhea) infection, including multidrug resistant strains.^[7]^[8]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Blujepa- gepotidacin tablet, film coated”. DailyMed. 25 March 2025. Retrieved 2 April 2025.
^ Biedenbach DJ, Bouchillon SK, Hackel M, Miller LA, Scangarella-Oman NE, Jakielaszek C, et al. (January 2016). “In Vitro Activity of Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, against a Broad Spectrum of Bacterial Pathogens”. Antimicrobial Agents and Chemotherapy. 60 (3): 1918–1923. doi:10.1128/aac.02820-15. PMC 4776004. PMID 26729499.
^ Fick M, Sneha SK, Sunny ME (2025). “FDA approval”. Reuters.
^ “GSK’s investigational antibiotic granted FDA priority review for urinary tract infections”. PMLiVE. 18 October 2024. Retrieved 21 October 2024.
^ Jump up to:^a ^b “Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and pediatric patients 12 years of age and older”. GSK (Press release). 25 March 2025. Retrieved 28 March 2025.
^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 74”. WHO Drug Information. 29 (3). hdl:10665/331070.
^ Scangarella-Oman NE, Hossain M, Dixon PB, Ingraham K, Min S, Tiffany CA, et al. (December 2018). “Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae“. Antimicrobial Agents and Chemotherapy. 62 (12). doi:10.1128/AAC.01221-18. PMC 6256812. PMID 30249694.
^ Jacobsson S, Golparian D, Scangarella-Oman N, Unemo M (August 2018). “In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae“. The Journal of Antimicrobial Chemotherapy. 73 (8): 2072–2077. doi:10.1093/jac/dky162. PMC 6927889. PMID 29796611.

External links

Clinical trial number NCT04020341 for “A Study to Evaluate Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (UTI)” at ClinicalTrials.gov
Clinical trial number NCT04187144 for “Comparative Study to Evaluate Efficacy and Safety of Gepotidacin to Nitrofurantoin in Treatment of Uncomplicated Urinary Tract Infection (UTI)” at ClinicalTrials.gov

Ross JE, Scangarella-Oman NE, Flamm RK, Jones RN: Determination of disk diffusion and MIC quality control guidelines for GSK2140944, a novel bacterial type II topoisomerase inhibitor antimicrobial agent. J Clin Microbiol. 2014 Jul;52(7):2629-32. doi: 10.1128/JCM.00656-14. Epub 2014 Apr 23. [Article]
Oviatt AA, Gibson EG, Huang J, Mattern K, Neuman KC, Chan PF, Osheroff N: Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting. ACS Infect Dis. 2024 Apr 12;10(4):1137-1151. doi: 10.1021/acsinfecdis.3c00346. Epub 2024 Mar 5. [Article]
GSK Press Release: Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and paediatric patients 12 years of age and older [Link]
FDA Approved Drug Products: Blujepa (gepotidacin) tablets for oral use (March 2025) [Link]

Clinical data

Trade names	Blujepa
Other names	GSK2140944
AHFS/Drugs.com	Blujepa
License data	US DailyMed: Gepotidacin
Routes of administration	By mouth
ATC code	J01XX13 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1075236-89-3
DrugBank	DB12134
ChemSpider	34982930
UNII	DVF0PR037D 5P7X0H2O6B
KEGG	D10878 D10879
ECHA InfoCard	100.249.088
Chemical and physical data
Formula	C₂₄H₂₈N₆O₃
Molar mass	448.527 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

///////Gepotidacin, FDA 2025, APPROVALS 2025, Blujepa, GSK-2140944, GSK2140944

Vimseltinib

April 8, 2025 1:39 pm / Leave a comment

Vimseltinib

1628606-05-2

DCC-3014

2/14/2025 FDA APPROVED, Romvimza

3-methyl-5-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-(propan-2-ylamino)pyrimidin-4-one

C₂₃H₂₅N₇O₂, 431.5

To treat symptomatic tenosynovial giant cell tumor for which surgical resection will potentially cause worsening functional limitation or severe morbidity

Vimseltinib is an orally bioavailable inhibitor of the tyrosine kinase receptor colony stimulating factor 1 receptor (CSF1R; CSF-1R; C-FMS; CD115; M-CSFR), with potential antineoplastic, macrophage checkpoint-inhibitory and immunomodulating activities. Upon administration, vimseltinib targets and binds to CSF1R expressed on monocytes, macrophages, and osteoclasts and inhibits the binding of the CSF1R ligands colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells. This blocks the production of inflammatory mediators by macrophages and monocytes and reduces inflammation. By blocking the recruitment to the tumor microenvironment (TME) and activity of CSF1R-dependent tumor-associated macrophages (TAMs), vimseltinib inhibits the immunomodulating activity by macrophages and enhances T-cell infiltration and anti-tumor T-cell immune responses, which inhibits the proliferation of tumor cells. TAMs play key roles in the TME and allow for immune suppression; TAMs promote inflammation, tumor cell proliferation, angiogenesis, invasiveness and survival.

Vimseltinib, sold under the brand name Romvimza, is an anti-cancer medication used for the treatment of tenosynovial giant cell tumor.^[1]^[2] Vimseltinib is a kinase inhibitor.^[1]^[2] Vimseltinib is a macrophage colony-stimulating factor receptor antagonist.^[3]

The most common adverse reactions, including laboratory abnormalities, include increased aspartate aminotransferase, periorbital edema, fatigue, rash, increased cholesterol, peripheral edema, face edema, decreased neutrophils, decreased leukocytes, pruritus, and increased alanine aminotransferase.^[2]

Vimseltinib was approved for medical use in the United States in February 2025.^[2]^[4]

PATENT

vimseltinib is a c-FMS (CSF-IR) and c-KIT dual inhibitor with anticancer and antiproliferative activities, can excite tyrosine protein kinase activity, influence protooncogene transcription, and is widely applied to research of anticancer drugs as an active molecule.

CN105120864B discloses heating the reaction mixture in a sealed tube at 100 ℃ for 2 days. The mixture was then cooled to room temperature, the solids were removed by filtration and the filtrate was concentrated to dryness and purified by silica gel chromatography to give 2- (isopropylamino) -3-methyl-5- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) pyrimidin-4 (3H) -one, amorphous form described.

CN113880812a reports another preparation method of Vimseltinib, and a small amount of target product meeting the requirement is finally obtained through a column chromatography purification process. The preparation method has complicated process and is not beneficial to industrialized mass production. There is no mention in this patent of reports on solid or crystalline forms of the compound of formula (I), and the purification process of column chromatography (EA/meoh=120:1 to 100:1) was repeated to give form a.

CN116283919A

https://patents.google.com/patent/CN116283919A/en

PATENT

example 10 [WO2014145025A2]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014145025&_cid=P21-M98JKR-94364-1

Example 2: A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with TEA (0.5 mL) and Ν,Ν-dimethylamine HCl salt (500 mg) and stirred at RT for 2 h. The mixture was treated with satd. NaHCO₃, extracted with DCM (2x) and the combined organics were dried over Na₂SO₄, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (60 mg, 47%). MS (ESI) m/z: 418.2 (M+H⁺).

[0199] A solution of 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.060 g, 0.144 mmol) in acetic acid (5 mL) was treated with HBr (0.065 mL, 0.575 mmol), heated at 90°C for 6 h, cooled to RT and quenched with ice water. The solution was treated with NaHCO₃ and NaCl, extracted with 1 : 1 THF/EtOAc (3x) and the combined organics were dried over Na₂SO₄ and concentrated to dryness. The material was treated with MeCN (1 mL), allowed to stand at RT and the

resulting solid was collected via filtration to afford 2-(dimethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (43 mg, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.23 (s, 1 H), 8.73 (s, 1 H), 8.36 (d, J = 5.7 Hz, 1 H), 8.30 (m, 1H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.51 (m, 1H), 7.23 (d, J = 2.4 Hz, 1 H), 6.62 (br s, 1 H), 3.85 (s, 3 H), 3.12 (s, 6 H), 2.35 (s, 3 H); MS (ESI) m/z: 404.2 (M+H⁺).

Example 3: A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with isopropyl amine (0.5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO₃, extracted with DCM (2x) and the combined organics were dried over Na₂SO₄, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-isopropyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (63 mg, 47%). MS (ESI) m/z: 432.2 (M+H⁺).

PAPER

Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT)

https://www.sciencedirect.com/science/article/pii/S0960894X22004048

Medical uses

Vimseltinib is indicated for the treatment of adults with symptomatic tenosynovial giant cell tumor for which surgical resection will potentially cause worsening functional limitation or severe morbidity.^[1]^[2]

History

The efficacy of vimseltinib was evaluated in MOTION (NCT05059262), a double-blind, multicenter, randomized (2:1), placebo-controlled trial in participants with tenosynovial giant cell tumor for whom surgical resection may cause worsening functional limitation or severe morbidity.^[2] Eligible participants had a confirmed diagnosis of tenosynovial giant cell tumor with measurable disease (RECIST v1.1) with at least one lesion having a minimum size of 2 cm.^[2] Pp[-[p;articipants were randomized to placebo or vimseltinib, 30 mg twice weekly administered for 24 weeks, during the double-blind period (part 1).^[2] During the open-label period (part 2), patients could continue vimseltinib and those receiving placebos could crossover to vimseltinib.^[2] Randomization was stratified by tumor location (lower limb versus all other) and region (United States versus Non-US).^[2] A total of 123 participants were randomized: 83 to the vimseltinib arm and 40 to placebo during part 1.^[2]

The US. Food and Drug Administration (FDA) granted the application for vimseltinib priority review designation.^[2]

Society and culture

Legal status

Vimseltinib was approved for medical use in the United States in February 2025.^[2]^[5]

Names

Vimseltinib is the international nonproprietary name.^[6]

Vimseltinib is sold under the brand name Romvimza.^[1]^[2]

References

^ Jump up to:^a ^b ^c ^d ^e “Romvimza- vimseltinib capsule”. DailyMed. 18 February 2025. Retrieved 3 March 2025.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA approves vimseltinib for symptomatic tenosynovial giant cell tumor”. U.S. Food and Drug Administration (FDA). 14 February 2025. Retrieved 16 February 2025. This article incorporates text from this source, which is in the public domain.
^ Caldwell TM, Ahn YM, Bulfer SL, Leary CB, Hood MM, Lu WP, et al. (October 2022). “Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT)”. Bioorganic & Medicinal Chemistry Letters. 74: 128928. doi:10.1016/j.bmcl.2022.128928. PMID 35961460.
^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 21 February 2025. Retrieved 9 March 2025.
^ “U.S. FDA Grants Full Approval of Deciphera’s Romvimza (vimseltinib) for the Treatment of Symptomatic Tenosynovial Giant Cell Tumor (TGCT)” (Press release). Deciphera Pharmaceuticals. 14 February 2025. Retrieved 16 February 2025 – via Business Wire.
^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.

External links

Clinical trial number NCT05059262 for “Study of Vimseltinib for Tenosynovial Giant Cell Tumor (MOTION)” at ClinicalTrials.gov

Caldwell TM, Ahn YM, Bulfer SL, Leary CB, Hood MM, Lu WP, Vogeti L, Vogeti S, Kaufman MD, Wise SC, Le Bourdonnec B, Smith BD, Flynn DL: Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT). Bioorg Med Chem Lett. 2022 Oct 15;74:128928. doi: 10.1016/j.bmcl.2022.128928. Epub 2022 Aug 10. [Article]
Smith BD, Kaufman MD, Wise SC, Ahn YM, Caldwell TM, Leary CB, Lu WP, Tan G, Vogeti L, Vogeti S, Wilky BA, Davis LE, Sharma M, Ruiz-Soto R, Flynn DL: Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages. Mol Cancer Ther. 2021 Nov;20(11):2098-2109. doi: 10.1158/1535-7163.MCT-21-0361. Epub 2021 Aug 25. [Article]
FDA Approved Drug Products: Romvimza (vimseltinib) capsules for oral use (February 2025) [Link]
FDA News Release: FDA approves vimseltinib for symptomatic tenosynovial giant cell tumor [Link]

Clinical data

Trade names	Romvimza
License data	US DailyMed: Vimseltinib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1628606-05-2
PubChem CID	86267612
IUPHAR/BPS	11190
DrugBank	DB17520
ChemSpider	95499700
UNII	PX9FTM69BF
KEGG	D12238
ChEMBL	ChEMBL5095202
Chemical and physical data
Formula	C₂₃H₂₅N₇O₂
Molar mass	431.500 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

//////Vimseltinib, FDA 2025, APPROVALS 2025, Romvimza, DCC-3014, DCC 3014, DP-6865, PX9FTM69BF, C3014, WHO 11443, DCC-3014, DP-6865,

UNII-PX9FTM69BF

TREOSULFAN

April 6, 2025 3:01 am / Leave a comment

TREOSULFAN

C₆H₁₄O₈S₂ MW 278.29

FDA APPROVED 1/21/2025 Grafapex

CAS

299-75-2

Treosulfan
299-75-2
Treosulphan
Ovastat
Treosulfano

NSC-39069

Dihydroxybusulfan
L-threitol-1,4-dimethanesulfonate

[(2S,3S)-2,3-dihydroxy-4-methylsulfonyloxybutyl] methanesulfonate

Trecondi, Treosulfan was authorized for medical use in the European Union in June 2019

For use in combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome

Treosulfan, sold under the brand name Trecondi among others, is an alkylating medication given to people before they have a bone marrow transplant from a donor known as allogeneic hematopoietic stem cell transplantation. It is used as a ‘conditioning’ treatment to clear the bone marrow and make room for the transplanted bone marrow cells, which can then produce healthy blood cells.^[9]^[10] It is used together with another medicine called fludarabine in adults and children from one month of age with blood cancers as well as in adults with other severe disorders requiring a bone marrow transplant.^[9] It belongs to the family of drugs called alkylating agents.^[9] In the body, treosulfan is converted into other compounds called epoxides which kill cells, especially cells that develop rapidly such as bone marrow cells, by attaching to their DNA while they are dividing.^[9]

The most common side effects include infections, nausea (feeling sick), stomatitis (inflammation of the lining of the mouth), vomiting, diarrhea, and abdominal pain (belly ache).^[9] Tiredness, febrile neutropenia (low white blood cell counts with fever) and high blood levels of bilirubin (a breakdown product of red blood cells) are also seen in more than 1 in 10 adults, and rash also affects more than 1 in 10 children.^[9] The most common adverse reactions include musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting.^[7] Selected grade 3 or 4 nonhematological laboratory abnormalities include increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine.^[7]

Treosulfan was authorized for medical use in the European Union in June 2019,^[9] and approved for medical use in the United States in January 2025.^[7]^[11]

Medical Uses

Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation in adults with malignant and non malignant diseases, and in children older than one month with malignant diseases.^[7]^[9]

History

Two main studies showed that treosulfan is at least as effective as busulfan, another medicine used to prepare people for haematopoietic stem cell transplantation.^[9]

In one of the studies, involving 570 adults with acute myeloid leukaemia (a blood cancer) or myelodysplastic syndromes (conditions in which large numbers of abnormal blood cells are produced), 64% of patients given treosulfan (with fludarabine) had a successful transplant and were alive and disease-free after 2 years, compared with 51% of patients given busulfan (with fludarabine).^[9]

In an additional study in 70 children with blood cancers, 99% of children given treosulfan (with fludarabine) were alive three months after their transplant.^[9]

Efficacy was evaluated in MC-FludT.14/L Trial II (NCT00822393), a randomized active-controlled trial comparing treosulfan to busulfan with fludarabine as a preparative regimen for allogeneic transplantation. Eligible patients included adults 18 to 70 years old with AML or MDS, Karnofsky performance status ≥ 60%, and age ≥ 50 years or hematopoietic cell transplantation comorbidity index [HCTCI] score > 2. There were 570 patients randomized to treosulfan (n=280) or busulfan (n=290).

Society and culture

Legal status

Treosulfan was authorized for medical use in the European Union in June 2019,^[9] and approved for medical use in the United States in January 2025.^[11]^[12]^[13]

The US Food and Drug Administration granted orphan drug designation to treosulfan in 1994, for the treatment of ovarian cancer;^[14] and in 2015, for conditioning treatment prior to hematopoietic stem cell transplantation in malignant and non-malignant diseases in adults and pediatric patients.^[15]

In February 2004, orphan designation (EU/3/04/186) was granted by the European Commission to medac Gesellschaft fuer klinische Spezialpräparate mbH, Germany, for treosulfan for the conditioning treatment prior to haematopoietic progenitor cell transplantation.^[16]

Names

Treosulfan is the international nonproprietary name.^[17]

Treosulfan is sold under the brand names Trecondi^[9] and Grafapex.^[7]

SYN

Treosulfan is an active ingredient of the drug Ovastat . Treosulfan is indicated for the treatment of ovarian cancer and belongs to the class of alkylating agents, which prevents the growth and division of cancerous cells.

US3155702 discloses the preparation of Treosulfan by methanesulphonation of (2S,3S)- l,4-dibromobutane-2,3-diol with excess amount of silver methanesulphonate. The presence of free 2,3-diol in the starting material leads to side reactions and formation of undesired by-products which necessitates an additional purification step and thereby results in lower yields. Further, an additional filtration operation is also required to remove silver bromide salt generated during the process and un-reacted silver methanesulphonate, which makes the process less attractive for commercial manufacturing.

US3246012 discloses the preparation of Treosulfan by protection of hydroxyl group of dialkyl tartrates with corresponding aldehyde, ketone or a reactive derivatives to form corresponding cyclic 2,3-O-acetals and 2,3-O-ketals of butanetetrol esters followed by reduction using lithium aluminium hydride to obtain 2,3-O-acetal or ketal protected butanetetrol, which is further methanesulphonated and treated with acid. The use of highly pyrophoric and hazardous reducing agent renders the above process not ideal for industrial production. Organic Syntheses, Coll. Vol. 10, p. 297, 2004 discloses a similar reaction sequence followed by the final de-protection of methanesulphonated 2,3-O-diisopropylidene-L- threitol in methanesulfonic acid at reflux temperature, which leads to a sluggish reaction mixture and a higher number of impurities due to maintaining the reaction mixture for longer time at higher temperature.

IN 1568/MUM/2012 also discloses similar reaction sequence involving reduction of dimethyl-2,3-0-isopropylidene-L-tartrate by sodium-bis(2-methoxyethoxy) aluminium hydride followed by methanesulphonation and final deprotection with formic acid to yield Treosulfan.

KR101367641 describes reduction using lithium borohydride, which requires about 14 hours to complete the reaction and is further extended due to involvement of column chromatography purification. Tetrahedron, vol. 49, no. 30, p. 6645, 1993 describes reduction using sodium borohydride and lithium chloride, followed by flash chromatography purification. Reduction conditions as per Chem. Pharm. Bull. Vol. 42, No. 3, p. 68, 1994, are again not commercially feasible because of lithium aluminium hydride as reducing agent.

Haberland, M., Weber, S., Sharma, A. K., Upadhyay, S., Dua, H., Musmade, S., Singh, G., Lahiri, S., & Cabri, W. (2019). A process for the preparation of Treosulfan (Patent No. WO2019043587A2).

WO2019043587A2

EXAMPLES Detailed experimental parameters suitable for the preparation of Treosulfan or intermediates according to the present invention are provided by the following examples, which are intended to be illustrative and not limiting.

Reference Example 1 (repetition of Tetrahedron, vol. 46, No. 12, p. 4165, 1990):

A reaction mixture of dimethyl-L-tartrate (10. Og), p-toluene sulfonic acid (0.013g) and p- anisaldehydedimethylacetal (l l.Og) in toluene (150ml) was refluxed and the azeotropical mixture of toluene-methanol was continuously removed from the reaction mixture for 3-5 hours. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50ml) and neutralised by addition of potassium carbonate (5.0g) followed by stirring for an hour . The reaction mixture was filtered and filtrate was evaporated to give yellow crude compound, which was further dissolved in dichloromethane (25ml) followed by addition of petroleum ether (100ml) and stirred for an hour at ambient temperature. The solid was filtered, washed with petroleum ether (20ml) and dried under vacuum at 35-40°C for 15-20 hours to obtain 16.63g (72.15%) of dimethyl (4R,5R)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5-dicarboxylate having purity 98.4% by HPLC.

Reference Example 2 (repetition of Synthesis, No. 15, p. 2488-90, 2008):

A reaction mixture of dimethyl-L-tartrate (5.0g), p-toluene sulfonic acid (0.0064g) and p- anisaldehyde dimethylacetal (5.35g) in toluene (25ml) was refluxed and the azeotropical mixture of toluene-methanol was continuously removed from the reaction mixture for 3-5 hours. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (25ml) and neutralised by addition of potassium carbonate (5.0g) followed by stirring for an hour. The reaction mixture was filtered and filtrate was evaporated to give yellow crude residues. The crude was further re-crystallized in petroleum ether (25ml), filtered the solid and washed with petroleum ether (15ml) followed by drying under vacuum at 35-40°C for 15-20 hours to obtain 7.4g (89.15%) of dimethyl (4R,5R)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5-dicarboxylate having purity 98.8% by HPLC. Example-1: Preparation of dimethyl (4R,5R)-2-(4-methoxyphenyl)-l,3-dioxolane- 4,5-dicarboxylate

A reaction mixture of dimethyl-L-tartrate (500g), p-toluene sulfonic acid (5.38g) and p- anisaldehyde dimethylacetal (665g) in toluene (2250ml) was refluxed to 110-115°C. The azeotropical mixture of toluene-methanol was continuously removed from the reaction mixture till the completion of the reaction. The reaction mixture was cooled to ambient temperature and quenched with aq. saturated sodium bicarbonate solution (2500ml), layers were separated. Resulting organic layer was washed with water (2500ml x 2) followed by evaporation of organic layer. Isopropyl alcohol (3500ml) was charged to the residue and heated to 60-70°C followed by cooling at ambient temperature. Reaction mixture was stirred at 0-5°C for 1-2 hours and filtered. The solid thus obtained was washed with pre- cooled isopropyl alcohol and dried under vacuum at 35-40°C for 15-20 hours to obtain 767.0g (92.93%) of dimethyl (4R,5R)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- dicarboxylate having purity 99.97% by HPLC.

Example-2: Preparation of (4S,5S)-2-(4-methoxyphenyl)-l ₅3-dioxo!ane-4,5- diyifdimethanol

Method-l :To a mixture of dimethyl (4R,5R)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- dicarboxylate (765g), Iodine (13. lg) in tetrahydrofuran (3750ml) and water (76ml), sodium borohydride (146.52g) was added at 0-15°C and stirred for 1 -2 hours at ambient temperature. The reaction was quenched with 30% aq. ammonium chloride (6100ml) solution and dichloromethane (7650ml). The layers were separated and the aqueous layer was extracted by dichloromethane (3800ml x 3) followed by washing of combined organic layers with water (3800ml), The resulting organic layer was evaporated at 35-65°C to obtain 525.0g (83.9%) of (4S,5S)-2-(4-methoxyphenyl)-l,3- dioxolane-4,5-diyl]dimethanol having purity 99.72% by HPLC. Method-2: To a mixture of dimethyl (4R,5R)-2-(4-methoxyphenyl)-l,3-dioxolane- 4,5-dicarboxylate (765g), Iodine (13.10g) in tetrahydrofuran (3750ml) and water (76.5ml), sodium borohydride (146.52g) was added at 0-10°C and stirred for Ihours at 0-5°C and stirred for 3-4 hours at ambient temperature. The reaction was quenched with 30% aq. ammonium chloride (6120ml) solution and dichloromethane (7650ml) at ambient temperature. The layers were separated and the aqueous layer was extracted by dichloromethane (3825m! x 3) followed by washing of combined organic layers with water (3825ml). The resulting organic layer was evaporated at 50-60°C to obtain 525 g (84.7%) of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5-diyl]dirnethaiiol having purity 99.72% by HPLC. Example-3: Preparation of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- diyl]bis(methylene) dimethanesulfonate

Method-l:To a solution of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- diyl]dimethanol (145g) in dichloromethane (2175ml), pyridine (191g) and methanesulphonyl chloride (190. l g) was added at 0-5 ^°C. The reaction mixture was stirred for 2-3 hours at ambient temperature followed by quenching with water (1450ml). The organic layer was washed with water (1450ml x 4) and evaporated. The resulting residue was added to isopropanol (725ml) and stirred for 1-2 hours at ambient temperature and further for 1-2 hours at 0-5 C. The solid was filtered and washed with pre-cooled isopropanol (145ml). The resulting product was dissolved in acetone (1300ml) followed by addition of isopropanol (2610ml). Resulting reaction mixture was stirred for 1-2 hours at ambient temperature and then cooled at 0-5 ^°C. The solid thus obtained was filtered and washed with pre-cooled isopropanol (145ml x 2) and dried under vacuum at 30-35°C for 15-20 hours to give 190.8g (79.4%)of (4S,5S)-2-(4- methoxyphenyl)-l,3-dioxolane-4,5-diyl]bis(methylene) dimethanesulfonate. Method-2: To a solution of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- diyl]dimethanol (525, Og) in dichloromethane (7350ml), di-isopropylamine (663. Og) was added at ambient temperature followed by addition of methanesulphonyl chloride solution (624. Og in 525ml dichloromethane) at 0-10°C. The reaction mixture was stirred for 1-2 hours at 0-10 ^°C followed by stirring for 3-4 hours at ambient temperature. The organic layer was washed with water (2 x 5250ml) and evaporated. The residues were dissolved in acetone (4725ml) followed by addition of isopropanol (9450ml), stirred for about 1-2 hour at ambient temperature and then at 0-5 ^°C for 1-2 hours. The resulting solid was filtered, washed with pre-cooled isopropanol (525 x 2 ml)and dried under vacuum at 35-45°C for 15-20 hours to give 705.0g (81.45%) of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5-diyl]bis(methylene)

dimethanesulfonate having purity 99.92% by HPLC.

Example-4: Preparation of Treosulfan

Method-1: To a solution of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- diyl]bis(methylene) dimethanesulfonate (745. Og) in methanol (7450ml), concentrated hydrochloric acid (260ml) was added at 15-25°C followed by stirring for 10-15 hours at ambient temperature. The reaction mixture was cooled to 0-5°C and further stirred for 1-2 hours at 0-5°C followed by filtration and washing the solid with pre-cooled methanol (745ml). The solid thus obtained was dissolved in acetone (3725ml) followed by microne filtration. Di-isopropyl ether (7450ml) was added to the filtrate and stirred for 1-2 hours at ambient temperature and then cooled at 0-5°C. The solid thus obtained was filtered and washed with di-isopropyl ether (745ml x 2) followed by drying at 30-35°C for 15-20 hours to obtain 96.5g of Treosulfan having purity 99.9% by HPLC.

XRPD of Treosulfan obtained by above process is shown in Fig. 1. Method-2:To a solution of (4S,5S)-2-(4-methoxyphenyl)-l,3-dioxolane-4,5- diyl]bis(methylene)dimethanesulfonate (650. Og) in methanol (6500ml), 9N hydrochloric acid (227.5ml) was added at 0-10°C followed by stirring for 6-8 hours at ambient temperature. The reaction mixture was cooled to 0-5°C and further stirred for 1-2 hours followed by filtration and washing the solid with pre-cooled methanol (2 x 650ml). The solid thus obtained was dissolved in acetone (3250ml). Di-isopropyl ether (6500ml) was added to the resulting solution, stirred for 1-2 hours at ambient temperature and then cooled at 0-5°C. The solid thus obtained was filtered and washed with di- isopropyl ether (650ml x 2) followed by drying at 30-35°C for 15-20 hours to obtain 312g (68.4) of Treosulfan having purity 99.81% by HPLC.

PATENT

https://patents.google.com/patent/WO2020064815A1/en

Example 1 – Preparation of form B using water/isopropanol

99.8 mg treosulfan were weighed in a vial (volume 4.0 ml) which was equipped with a PTFE (Polytetrafluoroethylene) sealing and a stirrer. 1.5 ml of a mixture of 80 % by weight water and 20 % by weight isopropanol preheated to 65°C were then added. The resulting solution was completely taken up with a syringe (volume 5 ml) and filtered using a 0.2 pm filter into a second vial (volume 4.0 ml) . The syringe, second vial and filter had been tempered at 65°C before use. The solvents were allowed to evaporate from the open vial at room temperature to dryness which resulted in formation of crystals.

The XRPD pattern of the obtained crystals of form B according to the invention is shown in Figure 1.

PATENT

1568/MUM/2012

Abstract

Abstract: The present invention provides a convenient and cost-effective process for preparation of Treosulfan. The process comprises reduction of dimethyl 2,3-O-isopropylidene-L-tartrate with sodium-bis(2-methoxyethoxy)aluminum hydride to give the alcohol 2,3-O-isopropylidene-L-threitol (III), which on reaction with methanesulfonyl chloride led to 2,3-O-isopropylidene-L-threitol 1,4-bismethanesulfonate of formula (IV) and further treatment of compound (IV) with formic acid gave Treosulfan (I) having desired purity.

Treosulfan (I), chemically known as (2S,3S)-2,3-Dihydroxy-4-memylsidfonyIoxybutylj methanesulfonate is a drug commonly used for treating ovarian cancer. It belongs to the family of anti-cancer medicines called the alkylating agents, which prevent the growth and division of cancerous cells. Treosulfan has been used for bone-marrow ablation before stem-cell transplantation and in the treatment of malignant melanoma and breast cancer.

US 3,155,702 discloses synthesis of Treosulfan by replacement of the halogen function in L-Threitol-l,4-dibromobutane-2,3-diol, by treating with a large excess of an expensive reagent like silver methanesulfonate. Further, the presence of unprotected hydroxyl groups in the starting material inevitably leads to the formation of undesired impurities, which requires additional purification steps for removal of impurities as well for lowering the level of free silver in the active ingredient as per ICH guidelines, which results in lower yields and increases the costs substantially.
Another method reported in US 3,246,012 involves acetal formation of diethyl-L-tartrate with acetone to obtain 2,3-O-isopropylidene-diethyl-L-tartrate, which, when reduced with lithium aluminium hydride gives 2,3-0-methylene-L-threitol. The obtained alcohol was treated with methanesulfonyl chloride to yield the penultimate Treosulfan intermediate, 2,3-O-methylene-L-threitol-1,4-di-(methanesulfonate).

A similar approach which employs tartrate esters in the synthesis of Treosulfan, is disclosed in Organic Syntheses, (1993), Vol.8, p. 155 and Organic .Syntheses, (2004), Coll.Vol.10, p.297. L-tartaric acid is reacted with 2,2-dimethoxypropane in presence of methanol. The resulting methyl ester, dimethyl 2,3-O-isopropylidene-L-tartrate is reduced with lithium aluminium hydride to obtain 2,3-di-O-isopropylidene-L-threitol, which, upon reaction with methanesulfonyl chloride, followed by treatment with methanesulfonic acid yields Treosulfan.
Although these routes involve protection of the diol group and avoid impurities arising out of substitution at those alcohol functionalities, use of a highly pyrophoric, hazardous reagent such as lithium aluminium hydride severely limits their synthetic applicability, especially on commercial scale. Further, the final step involves reaction of 2,3-di-O-isopropylidene-L-threitol with methanesulfonic acid, which is quite sluggish and causes considerable rise in the total number of impurities due to long reaction time.
Thus, there is a need for a convenient, economical process for a commercial scale synthesis of Treosulfan (I), which overcomes the shortcomings of the prior art, does not involve use of hazardous, pyrophoric reagents and yields Treosulfan conforming to regulatory specifications.
The present inventors have developed a novel process for preparation of (2S,3S)-2,3-Dihydroxy-4-methylsulfonyloxybutyl] methanesulfonate (I). The scheme for synthesis comprises reaction of dimethyl 2,3-O-isopropylidene-L-tartrate of formula (II) with sodium-bis(2-methoxyethoxy) aluminum hydride to give the protected diol, 2,3-0-isopropylidene-L-threitoI (III), which on further treatment with methanesulfonyl chloride, followed by reaction of the resultant ester, 2,3-O-isopropyliden-L-threitol 1,4 bismethanesulfonate (IV) with formic acid, yields Treosulfan (I) having desired purity and with impurity levels conforming to ICH guidelines.

Scheme 1; Method embodied in the present invention for the preparation of Treosulfan (I)
In an embodiment, dimethyl 2,3 -O-isopropylidene-L-tartrate of formula (II) was treated with sodium-bis-(2-methoxyethoxy) aluminium hydride in presence of an organic solvent, and in the temperature range of 25 to 80°C, but preferably 60 to 75°C.
The organic solvent was selected from the group of toluene, xylenes, nitrobenzene, hexane, cyclohexane, heptane, N-methyl-2-pyrroIidone, ethers etc.
Upon completion of the reaction, as monitored by TLC, water was carefully added to the reaction mass and the mixture was extracted with a water immiscible organic solvent.
The organic solvent was selected from the group comprising of n-hexane, cyclohexane, heptane, methyl isobutyl ketone, 2-methyl tetrahydrofuran, cyclopentyl methyl ether etc.
The organic layer was separated and concentrated under reduced pressure to give 2,3-0-isopropylidene-L-threitol of formula (III) of desired purity.
It is pertinent to mention that the reaction was quite facile and the desired product was obtained with minimal formation of associated impurities and did not require any subsequent purification.

Further reaction of compound (III) with methanesulfonyl chloride was carried out at 25 to 35°C, in an organic solvent, in presence of an organic base.
The organic solvent was selected from the group comprising of chloroform, ethylene dichloride, dichloromethane, carbon tetrachloride etc., but preferably dichloromethane.
The organic base was selected from triethyl amine, tributyl amine and pyridine.
The reaction mixture was stirred at 25-35°C and after completion of the reaction as monitored by TLC, aqueous solution of sodium bicarbonate was added slowly to the reaction mass. The organic layer was separated, concentrated under reduced pressure and stirred with isopropyl alcohol to obtain the desired compound, 2,3-O-isopropylidene-L-threitol-l,4-bis(methanesulfonate) of formula (IV).
In a further embodiment, compound (TV) was hydrolyzed by treating with formic acid at 25 to 35°C based on TLC. After completion of the reaction, the reaction mass was concentrated and the product Treosulfan (I) was isolated by addition of isopropyl alcohol to the concentrated mass.
It is pertinent to mention that Organic Syntheses (2004), Coll.Vol. 10, p.297 discloses the hydrolysis reaction using methanesulfonic acid in ethanol at reflux temperature. However, the time taken for completion is about ten hours and the procedure is applicable only for laboratory scale reaction. The hydrolysis step disclosed in the present invention is easily scalable and so facile that it takes place at room temperature and within one to two hours. This reduces the time cycle for each batch run and also reduces the possibility of formation of undesired side products.
Dimethyl 2,3-O-isopropylidene-L-tartrate of formula (II) was prepared by the reaction of dimethyl -L-tartrate with acetone by following known synthetic procedures.

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES
Example 1: Synthesis of 2,3-O-isopropylidene-L-threitol (HI)
A solution of dimethyl-2,3-0-isopropylidene-L-tartrate (50.3 g) in toluene (50 ml) was gradually added to the stirred mixture of sodium-bis(2-methoxyethoxy) aluminum hydride (122.8 g) in toluene (50 ml) at 20-40°C. The reaction mixture was heated to 60-80°C, and the reaction was continued till completion, as monitored by TLC. When the reaction was complete, the mass was cooled to 25-3 5°C, quenched with careful addition of water (10ml) and concentrated. Treatment of the resulting residue with methyl tertiary butyl ether, followed by evaporation of the organic layer under reduced pressure afforded 2,3-0-isopropyliden -L-threitol ( III) as pale yellow oil. Yield: 29.8 g (81.2%) [α]D20 + 4.6.°(CHC13, c 5)
Example 2: Synthesis of 2,3-0-isopropylidene-L-threitol-l,4-bis(methanesulfonate)
(IV)
A stirred solution of 2,3-O-isopropylidene-L-threitol (100.2 g), methylene chloride (1250
ml) and pyridine (146.3 g) was cooled to 0-5°C and methanesulfonyl chloride (176.6 g)
was slowly added to it. Temperature of the reaction mixture was raised to 25-35°C and the
reaction was continued at the same temperature till completion of the reaction, as
monitored by HPLC. After completion of the reaction, aqueous sodium bicarbonate
solution was slowly added to the reaction mass and the organic layer was separated.
Aqueous layer from the reaction mixture was extracted with methylene chloride and the
organic layers were combined. Distillation of the organic solvent, optionally followed by
addition of isopropyl alcohol gave the product, 2,3-0-isopropylidene-L-threitol-l,4-
bis(methanesulfonate).
Yield: 160.7 g (79.7%)
[α]D20-21.6°(acetone,c2)

Example 3: Synthesis of Treosulfan (I)
A mixture of formic acid (98%, 1000 ml) and 2,3-0-isopropylidene-L-threitol-l,4-bis(methanesulfonate) (100.5 g) was stirred at room temperature until completion of the desired reaction, as monitored by TLC, When the reaction was complete, the reaction mass was concentrated under reduced pressure..
Treatment of the residue after evaporation with isopropanol yielded the final product Treosulfan, which was optionally subjected to further treatment with acetone and nexanes or petroleum ether, Yield: 74.3 g (85.0%) [α]D20 – 5.3°(acetone, c 2) Purity: > 99 %.

References

^ Jump up to:^a ^b “Trecondi APMDS”. Therapeutic Goods Administration (TGA). 11 October 2022. Retrieved 25 January 2025.
^ “Updates to the Prescribing Medicines in Pregnancy database”. Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
^ “Trecondi (Link Medical Products Pty Ltd T/A Link Pharmaceuticals)”. Therapeutic Goods Administration (TGA). 14 January 2025. Retrieved 25 January 2025.
^ “AusPAR: Trecondi”. Therapeutic Goods Administration (TGA). 4 July 2023. Retrieved 25 January 2025.
^ “Health product highlights 2021: Annexes of products approved in 2021”. Health Canada. 3 August 2022. Retrieved 25 March 2024.
^ “Treosulfan 5g Powder for Solution for Infusion – Summary of Product Characteristics (SmPC)”. (emc). Archived from the original on 20 May 2022. Retrieved 21 April 2020.
^ Jump up to:^a ^b ^c ^d ^e ^f “Grafapex- treosulfan injection, powder, lyophilized, for solution”. DailyMed. 31 January 2025. Retrieved 2 April 2025.
^ “Trecondi Product Information” (PDF). European Medicines Agency (EMA). 21 April 2020.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “Trecondi EPAR”. European Medicines Agency (EMA). 11 December 2018. Archived from the original on 16 March 2023. Retrieved 21 April 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Romański M, Wachowiak J, Główka FK (October 2018). “Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives”. Clinical Pharmacokinetics. 57 (10): 1255–1265. doi:10.1007/s40262-018-0647-4. PMC 6132445. PMID 29557088.
^ Jump up to:^a ^b “FDA approves treosulfan with fludarabine as a preparative regimen for alloHSCT in adult and pediatric patients with AML or MDS”. U.S. Food and Drug Administration (FDA). 6 February 2025. Retrieved 8 March 2025. This article incorporates text from this source, which is in the public domain.
^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 21 February 2025. Retrieved 9 March 2025.
^ “Medexus Announces FDA Approval of Grafapex (treosulfan) for Injection and Provides Business Update” (Press release). Medexus Pharmaceuticals. 22 January 2025. Retrieved 25 January 2025 – via Newsfile.
^ “Treosulfan Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 16 May 1994. Retrieved 9 March 2025.
^ “Treosulfan Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 8 April 2015. Retrieved 9 March 2025.
^ “EU/3/04/186”. European Medicines Agency (EMA). 17 September 2018. Archived from the original on 16 October 2019. Retrieved 21 April 2020. This article incorporates text from this source, which is in the public domain.
^ World Health Organization (1972). “International nonproprietary names for pharmaceutical substances (INN). recommended INN: list 12”. WHO Chronicle. 26 (10).

External links

“Treosulfan”. National Cancer Institute.
^[1]
Clinical trial number NCT00822393 for “Clinical Phase III Trial Treosulfan-based Conditioning Versus Reduced-intensity Conditioning (RIC)” at ClinicalTrials.gov

Clinical data

Trade names	Trecondi, others
Other names	1,2,3,4-Butanetetrol, 1,4-dimethanesulfonate, Threitol 1,4-dimethanesulfonate, Threitol 1,4-bismethanesulfonate; L-Threitol 1,4-bis(methanesulfonate); Threosulphan; Treosulphan; Tresulfan
AHFS/Drugs.com	International Drug Names
License data	US DailyMed: Treosulfan
Pregnancy category	AU: D^[1]^[2]
Routes of administration	By mouth, intravenous
ATC code	L01AB02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)^[1]^[3]<^[4]CA: ℞-only^[5]UK: POM (Prescription only)^[6]US: ℞-only^[7]EU: Rx-only^[8]In general: ℞ (Prescription only)
Identifiers
showIUPAC name
CAS Number	299-75-2
PubChem CID	9882105
DrugBank	DB11678
ChemSpider	8057780
UNII	CO61ER3EPI
KEGG	C19557 D07253
ChEBI	CHEBI:82557
CompTox Dashboard (EPA)	DTXSID0026173
ECHA InfoCard	100.005.529
Chemical and physical data
Formula	C₆H₁₄O₈S₂
Molar mass	278.29 g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	101.5 to 105 °C (214.7 to 221.0 °F)
showSMILES
showInChI

Romanski M, Baumgart J, Bohm S, Glowka FK: Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats. Drug Metab Dispos. 2015 Dec;43(12):1946-54. doi: 10.1124/dmd.115.066050. Epub 2015 Oct 1. [Article]
EMA Summary of Product Characteristics: Trecondi (treosulfan) powder for solution for infusion [Link]
FDA Approved Drug Products: GRAFAPEX (treosulfan) for injection, for intravenous use [Link]
EMC Summary of Product Characteristics: Treosulfan 5g Powder for Solution for Infusion [Link]
NIH LiverTox: Alkylating Agents [Link]
FDA News Release: FDA approves treosulfan with fludarabine as a preparative regimen for alloHSCT in adult and pediatric patients with AML or MDS [Link]

////////TREOSULFAN, Treosulphan, Ovastat, Treosulfano, Grafapex, acute myeloid leukemia, myelodysplastic syndrome, NSC-39069, Dihydroxybusulfan, L-threitol-1,4-dimethanesulfonate, Trecondi, FSA 2025, APPROVALS 2025, EMA 2019, EU 2019

CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O

Suzetrigine

April 3, 2025 3:11 am / Leave a comment

Suzetrigine

CAS

2649467-58-1

Weight
Average: 473.4
Monoisotopic: 473.137396951
Chemical Formula
C₂₁H₂₀F₅N₃O₄

FDA 1/30/2025, Journavx

To treat moderate to severe acute pain
Press Release

2-Pyridinecarboxamide, 4-[[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)tetrahydro-4,5-dimethyl-5-(trifluoromethyl)-2-furanyl]carbonyl]amino]-
4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)oxolane-2- carboxamido]pyridine-2-carboxamide
4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-amido]pyridine2-carboxamide
4-[[[(2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)tetrahydro-4,5-dimethyl-5-(trifluoromethyl)-2-furanyl]carbonyl]amino]-2-pyridinecarboxamide

CS-0641183
HY-148800
VX 548
VX-548
VX548
Management of
Acute, moderate pain

Suzetrigine, sold under the brand name Journavx, is a medication used for the management of pain.^[1]^[2] It is a non-opioid, small-molecule analgesic that works as a selective inhibitor of Na_v1.8-dependent pain-signaling pathways in the peripheral nervous system,^[3]^[4] avoiding the addictive potential of opioids. Suzetrigine is taken by mouth.^[1]

The most common adverse reactions include itching, muscle spasms, increased blood level of creatine kinase, and rash.^[1]^[2]

It was developed by Vertex Pharmaceuticals,^[5] and was approved for medical use in the United States in January 2025.^[2]^[6] Suzetrigine is the first medication to be approved by the US Food and Drug Administration (FDA) in this new class of pain management medicines.^[2]

Medical uses

Suzetrigine is indicated for the treatment of moderate to severe acute pain in adults.^[1]^[2]

FDA Approves Novel Non-Opioid Treatment for Moderate to Severe Acute Pain

First Drug Approved in New Class of Non-Opioid Pain Medicines; Agency Continues to Take Steps to Support New Approaches for Pain Management

For Immediate Release:January 30, 2025

Today, the U.S. Food and Drug Administration approved Journavx (suzetrigine) 50 milligram oral tablets, a first-in-class non-opioid analgesic, to treat moderate to severe acute pain in adults. Journavx reduces pain by targeting a pain-signaling pathway involving sodium channels in the peripheral nervous system, before pain signals reach the brain.

Journavx is the first drug to be approved in this new class of pain management medicines.

Pain is a common medical problem and relief of pain is an important therapeutic goal. Acute pain is short-term pain that is typically in response to some form of tissue injury, such as trauma or surgery. Acute pain is often treated with analgesics that may or may not contain opioids.

The FDA has long supported development of non-opioid pain treatment. As part of the FDA Overdose Prevention Framework, the agency has issued draft guidance aimed at encouraging development of non-opioid analgesics for acute pain and awarded cooperative grants to support the development and dissemination of clinical practice guidelines for the management of acute pain conditions.

“Today’s approval is an important public health milestone in acute pain management,” said Jacqueline Corrigan-Curay, J.D., M.D., acting director of the FDA’s Center for Drug Evaluation and Research. “A new non-opioid analgesic therapeutic class for acute pain offers an opportunity to mitigate certain risks associated with using an opioid for pain and provides patients with another treatment option. This action and the agency’s designations to expedite the drug’s development and review underscore FDA’s commitment to approving safe and effective alternatives to opioids for pain management.”

The efficacy of Journavx was evaluated in two randomized, double-blind, placebo- and active-controlled trials of acute surgical pain, one following abdominoplasty and the other following bunionectomy. In addition to receiving the randomized treatment, all participants in the trials with inadequate pain control were permitted to use ibuprofen as needed for “rescue” pain medication. Both trials demonstrated a statistically significant superior reduction in pain with Journavx compared to placebo.

The safety profile of Journavx is primarily based on data from the pooled, double-blind, placebo- and active-controlled trials in 874 participants with moderate to severe acute pain following abdominoplasty and bunionectomy, with supportive safety data from one single-arm, open-label study in 256 participants with moderate to severe acute pain in a range of acute pain conditions.

The most common adverse reactions in study participants who received Journavx were itching, muscle spasms, increased blood level of creatine phosphokinase, and rash. Journavx is contraindicated for concomitant use with strong CYP3A inhibitors. Additionally, patients should avoid food or drink containing grapefruit when taking Journavx.

The application received Breakthrough Therapy, Fast Track and Priority Review designations by the FDA.

The FDA granted approval of Journavx to Vertex Pharmaceuticals Incorporated.

PATENTS

US11919887, Compound 7

https://patentimages.storage.googleapis.com/08/4f/6e/4f104b27a3772f/US11919887.pdf

https://patentscope.wipo.int/search/en/detail.jsf?docId=US407339565&_cid=P22-M90R90-47554-1

Step 1:
NEt₂ (7.7 mL, 55.2 mmol) was added to a solution of
ethyl 2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in
DCM (80 mL) with stirring at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (8.5 mL, 47.0 mmol)
was added dropwise over 5 mins and the mixture was stirred
for a further 30 mins at 0° C. The reaction mixture was
diluted with pentane (100 mL), the layers separated and the
organic phase washed with dilute aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was
dried (MgSO4), and concentrated in vacuo to give ethyl
(Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (9.4 g, 99%)
as a red oil. H NMR (500 MHz, Chloroform-d) 8 5.33 (q,
J=7.0 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.67 (d, J=7.0 Hz,
3H), 1.29 (t, J=7.1 Hz, 3H), 0.22 (s, 9H) ppm.

Step 2:
To a solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4
mmol) in DCM (80 mL) stirring at -78° C. was added TiCl
(70 mL of 1 M in DCM, 70.00 mmol) via cannula. To the
resulting solution, a solution of ethyl (Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (36.1 g of 31.3% w/w, 46.6 mmol)
in 40 mL of DCM was added dropwise over 15 mins. After
100 mins the reaction was carefully quenched with water,
allowing the temperature to rise slowly, and then extracted
with DCM. The combined organic layers were dried
(MgSO), filtered, and concentrated in vacuo. Purification
by flash chromatography (330 g SiO₂, 0 to 20% EtOAc in
heptane) gave ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-
dimethyl-3-oxo-hexanoate (8.82 g, 67%), which was stored
as a solution in toluene. H NMR (500 MHz, Chloroform-d)

8 4.33 (q, J=7.1 Hz, 2H), 4.14 (q, J=7.0 Hz, 1H), 3.98 (s,
1H), 1.43 (q, J=1.2 Hz, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.31 (dq.
J=7.0, 1.4 Hz, 3H) ppm. ESI-MS m/z calc. 282.08273, found
283.1 (M+1)*; 281.0 (M-1)-.

Step 3:
A solution of rhodium tetraacetate (245 mg, 0.55 mmol)
in benzene (32 mL) was heated at reflux for 10 min before
a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-
dimethyl-3-oxo-hexanoate (10 g, 35.4 mmol) in benzene (13
mL) was added slowly via addition funnel while refluxing
for 60 mins. The mixture was then concentrated in vacuo to
give ethyl rac-(4R, 5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (9.0 g, 100%) as a
green coloured residue containing residual catalyst, and as a
mixture of epimers at the position next to the ester. This
material was used without further purification. H NMR
(500 MHz, Chloroform-d) 8 4.83-4.57 (m, 1H), 4.38-4.16

(m, 2H), 2.60 (dddd, J=9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73-1.63
(m, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.24 (ddq, J=6.4, 4.1, 1.9
Hz, 3H) ppm.
Step 4:
To a stirred solution of ethyl rac-(4R,5R)-4,5-dimethyl- 5
3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (48
g, 188.83 mmol) in DCM (400 mL) stirring at -78° C. was
added DIPEA (29.680 g, 40 mL, 229.64 mmol). A solution
of trifluoromethylsulfonyl trifluoromethanesulfonate
(53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL) was 10
added to the reaction mixture at the same temperature over
1 h. The reaction mixture was stirred for 30 mins at 0° С.
before being quenched with 100 mL saturated aqueous
NaHCO3 solution. The organic layer was separated and
aqueous layer extracted with DCM (160 mL). The combined 15
organic layers were dried (MgSO) and concentrated in
vacuo to give ethyl rac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (71 g, 97%). H NMR (400 MHz, Chloroform-d) 8
4.38-4.32 (m, 2H), 3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37- 20
1.33 (m, 6H) ppm.

STEP 5

To stirred a solution of ethyl rac-(4R,5R)-2,3-dimethyl2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3Hfuran-5-carboxylate (26 g, 67.311 mmol) in toluene (130.00
mL) was added (3,4-difluoro-2-methoxy-phenyl)boronic
acid (14 g, 74.5 mmol) followed by K3PO4 (100 mL of 2 M,
200.00 mmol) under an argon atmosphere. The reaction was
degassed before tetrakis(triphenylphosphine)palladium(0)
(4 g, 3.46 mmol) was added. After further degassing, the
reaction was heated at 100° C. for 2 hours. The reaction was
diluted in water and the aqueous layer extracted with EtOAc
(2×100 mL). The combined organic layers were concentrated in vacuo. Purification by flash chromatography (SiO.
0 to 10% EtOAc in heptane) gave ethyl 4-(3,4-difluoro-2- 35
methoxy-pheny1)-2,3-dimethyl-2-(trifluoromethyl)-3Hfuran-5-carboxylate (24.4 g, 93%) as a 6:1 diastereomeric
mixture, with the major isomer believed to be ethyl rac-(4R,
5R)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-
(trifluoromethyl)-3H-furan-5-carboxylate. Major isomer: H 40
NMR (400 MHz, Chloroform-d) 8 6.88-6.79 (m, 2H), 4.17-
4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J=7.4 Hz, 1H), 1.67 (s,
3H), 1.12 (t, J=7.4 Hz, 3H), 1.06 (dd, J=5.4, 2.7 Hz, 3Н)
ppm. Minor isomer ¹H NMR (400 MHz, Chloroform-d) 8
6.88-6.79 (m, 2H), 4.17-4.09 (m, 2H), 3.88 (s, 3H), 3.76- 45
3.71 (m, 1H), 1.51 (s, 3H), 1.12 (t, J=7.4 Hz, 3H), 0.99 (dd,
J=5.4, 2.7 Hz, 3H) ppm. ESI-MS m/z calc. 380.1047, found
381.02 (M+1)+.

Step 6:
To an ice-cooled solution of ethyl 4-(3,4-difluoro-2- 50
methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3Hfuran-5-carboxylate (110 g, 243.0 mmol) in DCM (360 mL)
was added BBr, (370 mL of 1 M, 370.0 mmol) dropwise.
Upon completion the mixture was quenched by addition of
water and aqueous sodium bicarbonate solution, the aqueous 55
layer extracted with DCM and the combined organic layers
dried (MgSO) and concentrated in vacuo. The residue was
dissolved in DCM (430 mL) at ambient temperature and
TFA (40 mL, 519.2 mmol) was added, then the reaction was
heated to 45° C. Upon completion, the mixture was
quenched by addition of aqueous sodium bicarbonate solution and the aqueous layer extracted with DCM, dried
(MgSO) and concentrated in vacuo to give the desired
product in a 5:1 mixture of diastereomers. Recrystallization
was carried out by solubilizing the crude in the smallest
possible amount of DCM and adding a layer of heptane on
top of this solution (liquid-liquid diffusion). After approx. 1

Compound 7 [WO2021113627A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021113627&_cid=P22-M90RUB-70989-1

Example 6

rel-(2S,3R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (20), (2S,3R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)- 5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (21), rel- (2R,3S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2- carbonyl]amino]pyridine-2-carboxamide (22), and (2R,3S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy- phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (23)

[00676] Step 7:

[00677] (4-[[3-(3-Chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (420 mg, 0.8827 mmol) was separated by chiral SFC [(R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies, MeOH, 20 mM NH₃], followed by further purification of one or more of the fractions by chiral SFC using a Chiralpak IC column, 5 µm particle size, 25 cm x 20 mm from Daicel or a Chiralpak ID column, 5 µum particle size, 25 cm x 20 mm from Daicel to give:

[00678] First Eluting Isomer: rel-(2S,3R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (20, 30 mg, 7.1%) (further purified by chiral SFC using Chiralpak IC column). ¹H NMR (500 MHz, Chloroform-d) δ 8.92 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.21 (dd, J = 5.6, 2.1 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 4.1 Hz, 1H), 7.26 (dd, J = 8.8, 5.8 Hz, 1H), 7.03 (t, J = 8.4 Hz, 1H), 5.87 – 5.82 (m, 1H), 4.77 (d, J = 10.6 Hz, 1H), 3.98 (td, J = 11.2, 8.3 Hz, 1H), 3.88 (s, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42 (dd, J = 13.2, 8.3 Hz, 1H), 1.69 (s, 3H) ppm. ESI-MS m/z calc.475.0922, found 476.4 (M+1)⁺; 474.4 (M-1)-.

[00679] Second Eluting Isomer: (2S,3R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (21, 29 mg, 6.7%) (further purified by chiral SFC using Chiralpak ID column). ¹H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.08 (dd, J = 5.5, 2.2 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.23 (dd, J = 8.8, 5.8 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H), 5.86 (d, J = 4.2 Hz, 1H), 4.80 (d, J = 9.7 Hz, 1H), 4.10 – 4.00 (m, 1H), 3.93 (s, 3H), 3.52 – 3.48 (m, 1H), 2.86 (dd, J = 13.9, 8.4 Hz, 1H), 2.16 -2.07 (m, 1H), 1.64 (s, 2H) ppm. ESI-MS m/z calc.475.0922, found 476.4 (M+1)⁺; 474.4 (M-1)-.

[00680] Third Eluting Isomer: rel-(2R,3S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (22, 42 mg, 9.5%).

¹H NMR (500 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.08 (dd, J = 5.6, 2.2 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 4.5 Hz, 1H), 7.12 (dd, J = 8.8, 5.8 Hz, 1H), 6.89 (t, J = 8.4 Hz, 1H), 5.79 (d, J = 4.5 Hz, 1H), 4.63 (d, J = 10.7 Hz, 1H), 3.85 (td, J = 11.2, 8.4 Hz, 1H), 3.74 (s, 3H), 2.37 (dd, J = 13.2, 11.7 Hz, 1H), 2.28 (dd, J = 13.1, 8.4 Hz, 1H), 1.55 (s, 3H) ppm. ESI-MS m/z calc.

475.0922, found 476.4 (M+1)⁺; 474.4 (M-1)-.

[00681] Fourth Eluting Isomer: (2R,3S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (23, 40 mg, 8.8%).

¹H NMR (500 MHz, Chloroform-d) δ 8.43 (s, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.95 (dd, J = 5.5, 2.2 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 4.3 Hz, 1H), 7.10 (dd, J = 8.8, 5.9 Hz, 1H), 6.87 (t, J = 8.4 Hz, 1H), 5.76 – 5.71 (m, 1H), 4.67 (d, J = 9.7 Hz, 1H), 3.97 – 3.87 (m, 1H), 3.80 (s, 3H), 2.73 (dd, J = 13.9, 8.4 Hz, 1H), 1.98 (dd, J = 13.9, 11.6 Hz, 1H), 1.51 (s, 3H) ppm. ESI-MS m/z calc.475.0922, found 476.4 (M+1)⁺; 474.4 (M-1)-.

[00682] Compound 22 – Solid Form A

Efficacy

When people used suzetrigine in clinical studies conducted through 2024, there was a reduction in pain typically from seven to four on the standard numerical scale used to rate pain.^[7]^[8] Suzetrigine provided pain relief equal to a combination of hydrocodone and paracetamol (acetaminophen) (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen).^[8]^[9]

Suzetrigine suppresses pain at the same level as an opioid, but without the risks of addiction, sedation, or overdose.^[10] An alternative to opioids, it is the first pain medication to be approved by the Food and Drug Administration in two decades.^[10]

The efficacy of suzetrigine was evaluated in two randomized, double-blind, placebo- and active-controlled trials of acute surgical pain, one following abdominoplasty and the other following bunionectomy.^[2] Both trials found that suzetrigine reduced pain more effectively than a placebo.^[2]

Contraindications

Concomitant use of suzetrigine with strong CYP3A inhibitors is contraindicated.^[1]^[2]

Adverse effects

Common adverse effects of suzetrigine may include itching, rash, muscle spasms, and increased levels of creatine kinase.^[2] Mild side effects may include nausea, constipation, headache, and dizziness.^[7]^[8] As of 2024, long-term safety and side effects remain undetermined.^[8]

In preliminary research, suzetrigine had no serious neurological, behavioral, or cardiovascular effects.^[3]

Interactions

Consuming grapefruit while using suzetrigine may cause an adverse grapefruit–drug interaction.^[1]^[2]

Mechanism of action

Suzetrigine operates on peripheral nerves, avoiding the addictive potential of opioids which affect the central nervous system.^[3]^[4]^[7] Unlike opioid medications, which reduce pain signals in the brain, suzetrigine works by closing sodium channels in peripheral nerves, inhibiting pain-signaling nerves from transmitting painful sensations to the brain.^[3]^[4]^[7]

In pharmacological studies, suzetrigine selectively inhibited Na_v1.8 channels, but not other voltage-gated sodium channels, and bound to a unique site on these sodium channels with a novel allosteric mechanism, by binding to the channel’s second voltage sensing domain, thereby stabilizing the closed state, causing tonic inhibition. It exerts its action on dorsal root ganglion.^[3]

History

Vertex Pharmaceuticals announced in January 2024 that suzetrigine had successfully met several endpoints in its Phase III clinical trials.^[5] The company announced in July 2024 that the FDA had accepted a new drug application for suzetrigine.^[11] The FDA granted the application for suzetrigine priority review, fast track, and breakthrough therapy designations.^[2]^[11] In January 2025, the FDA granted approval of Journavx to Vertex Pharmaceuticals.^[2]

Society and culture

Legal status

Suzetrigine was approved for medical use in the United States in January 2025.^[2]

Names

Suzetrigine is the international nonproprietary name.^[12]

Suzetrigine is sold under the brand name Journavx.^[1]^[2]

References

a) WO2021113627A1 (Vertex, 10.06.2021; USA-prior. 06.12.2019).

US11834441B2 (Vertex, 05.12.2023; USA-prior. 06.12.2019).

b) WO2022256660A1 (Vertex, 08.12.2022; USA-prior. 04.06.2021).

WO2024123815A1 (Vertex, 13.06.2024; USA-prior. 06.12.2022).

Formulation:

WO2022256708A1 (Vertex, 08.12.2022; USA-prior. 04.06.2021, 02.12.2021).

Source:

Suzetrigine, in Kleemann A., Kutscher B., Reichert D., Bossart M., Pharmaceutical Substances, Thieme. https://pharmaceutical-substances.thieme.com/lexicon/KD-19-0151, accessed: 05-29-2025

Clinical data


Pronunciation	/suˈzɛtrɪdʒiːn/ soo-ZE-tri-jeen
Trade names	Journavx
Other names	VX-548
AHFS/Drugs.com	Journavx
License data	US DailyMed: Suzetrigine
Routes of administration	By mouth
Drug class	Na_v1.8 sodium channel blocker; Analgesic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	2649467-58-1
PubChem CID	156445116
DrugBank	DB18927
ChemSpider	128942439
UNII	LOG73M21H5
KEGG	D12860
ChEMBL	ChEMBL5314487
Chemical and physical data
Formula	C₂₁H₂₀F₅N₃O₄
Molar mass	473.400 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Journavx- suzetrigine tablet, film coated”. DailyMed. 6 February 2025. Retrieved 2 April 2025.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA Approves Novel Non-Opioid Treatment for Moderate to Severe Acute Pain” (Press release). U.S. Food and Drug Administration (FDA). 30 January 2025. Archived from the original on 7 February 2025. Retrieved 30 January 2025. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e Osteen, Jeremiah D.; Immani, Swapna; Tapley, Tim L.; Indersmitten, Tim; Hurst, Nicole W.; Healey, Tiffany; et al. (January 2025). “Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain”. Pain and Therapy. doi:10.1007/s40122-024-00697-0. PMID 39775738.
^ Jump up to:^a ^b ^c Jones, Jim; Correll, Darin J.; Lechner, Sandra M; Jazic, Ina; Miao, Xiaopeng; Shaw, David; et al. (August 2023). “Selective Inhibition of NaV1.8 with VX-548 for Acute Pain”. The New England Journal of Medicine. 389 (5): 393–405. doi:10.1056/NEJMoa2209870. PMID 37530822. S2CID 260377748.
^ Jump up to:^a ^b “Vertex Announces Positive Results From the VX-548 Phase 3 Program for the Treatment of Moderate-to-Severe Acute Pain” (Press release). Vertex. 30 January 2024. Archived from the original on 25 December 2024. Retrieved 31 January 2025 – via Business Wire.
^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 21 February 2025. Retrieved 9 March 2025.
^ Jump up to:^a ^b ^c ^d Broadfoot, Marla (20 August 2024). “New Painkiller Could Bring Relief to Millions — without Addiction Risk”. Scientific American. Archived from the original on 30 December 2024. Retrieved 31 January 2025.
^ Jump up to:^a ^b ^c ^d Hang Kong, Aaron Yik; Tan, Hon Sen; Habib, Ashraf S. (September 2024). “VX-548 in the Treatment of Acute Pain”. Pain Management. 14 (9): 477–486. doi:10.1080/17581869.2024.2421749. PMC 11721852. PMID 39552600.
^ Kingwell, Katie (December 2024). “Na_V1.8 inhibitor poised to provide opioid-free pain relief”. Nature Reviews. Drug Discovery. 24 (1): 3–5. doi:10.1038/d41573-024-00203-3. PMID 39668193.
^ Jump up to:^a ^b Dolgin, Elie (January 2025). “US drug agency approves potent painkiller – the first non-opioid in decades”. Nature. 638 (8050): 304–305. doi:10.1038/d41586-025-00274-1. PMID 39885357.
^ Jump up to:^a ^b “Vertex Announces FDA Acceptance of New Drug Application for Suzetrigine for the Treatment of Moderate-to-Severe Acute Pain” (Press release). Vertex. 30 July 2024. Retrieved 31 January 2025 – via Business Wire.
^ World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90”. WHO Drug Information. 37 (3). hdl:10665/373341.

External links

“Suzetrigine (Code C199115)”. NCI Thesaurus.
Clinical trial number NCT05661734 for “A Single-arm Study to Evaluate Safety and Effectiveness of VX-548 for Acute Pain” at ClinicalTrials.gov
Clinical trial number NCT05558410 for “Evaluation of Efficacy and Safety of VX-548 for Acute Pain After an Abdominoplasty” at ClinicalTrials.gov

//////////Suzetrigine, Journavx, FDA 2025, APPROVALS 2025, CS-0641183, HY-148800, VX 548, VX-548, VX548, Breakthrough Therapy, Fast Track, Priority Review

MIRDAMETINIB

July 31, 2021 2:46 am / Leave a comment

MIRDAMETINIB

391210-10-9
Chemical Formula: C16H14F3IN2O4
Molecular Weight: 482.19

PD0325901; PD 0325901; PD-325901; mirdametinib

FDA APPROVED 2/11/2025, Gomekli, To treat neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection

IUPAC/Chemical Name: (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

SpringWorks Therapeutics (a spin out of Pfizer ) is developing mirdametinib, a second-generation, non-ATP competitive, allosteric MEK1 and MEK2 inhibitor derived from CI-1040, for treating type 1 neurofibromatosis (NF1) and advanced solid tumors. In June 2021, a phase I/II trial was initiated in patients with low grade glioma.

OriginatorPfizer
DeveloperAstraZeneca; BeiGene; BIOENSIS; Pfizer; SpringWorks Therapeutics; St. Jude Childrens Research Hospital; University of Oxford
ClassAniline compounds; Anti-inflammatories; Antineoplastics; Benzamides; Immunotherapies; Small molecules
Mechanism of ActionMAP kinase kinase 1 inhibitors; MAP kinase kinase 2 inhibitors
Orphan Drug StatusYes – Neurofibromatosis 1

Phase IINeurofibromatosis 1
Phase I/IIGlioma
Phase ISolid tumours
PreclinicalChronic obstructive pulmonary disease
No development reportedCervical cancer
DiscontinuedBreast cancer; Cancer; Colorectal cancer; Malignant melanoma; Non-small cell lung cancer

22 Jul 2021SpringWorks Therapeutics receives patent allowance for mirdametinib from the US Patent and Trademark Office for the treatment of Neurofibromatosis type 1-associated plexiform neurofibromas
16 Jun 2021SpringWorks Therapeutics and St. Jude Children’s Research Hospital agree to develop mirdametinib in USA for glioma
15 Jun 2021Efficacy and safety data from the phase IIb RENEU trial for Neurofibromatosis type 1-associated plexiform neurofibromas released by SpringWorks Therapeutics

Mirdametinib, sold under the brand name Gomekli, is a medication used for the treatment of people with neurofibromatosis type 1.^[1] Mirdametinib is a kinase inhibitor.^[1]^[2] It is taken by mouth.^[1]

The most common adverse reactions in adults include rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.^[3] The most common grade 3 or 4 laboratory abnormalities include increased creatine phosphokinase.^[3] The most common adverse reactions in children include rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.^[3] The most common grade 3 or 4 laboratory abnormalities include decreased neutrophil count and increased creatine phosphokinase.^[3]

Mirdametinib was approved for medical use in the United States in February 2025.^[1]^[3]

SCHEME

SIDE CHAIN

MAIN

Medical uses

Mirdametinib is indicated for the treatment of people with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection.^[1]

Adverse effects

Mirdametinib can cause left ventricular dysfunction and ocular toxicity including retinal vein occlusion, retinal pigment epithelial detachment, and blurred vision.^[3]

History

The efficacy of mirdametinib was evaluated in ReNeu (NCT03962543), a multicenter, single-arm trial in 114 participants aged two years of age and older (58 adults, 56 pediatric participants) with symptomatic, inoperable NF1-associated plexiform neurofibromas causing significant morbidity.^[3] An inoperable plexiform neurofibromas was defined as a plexiform neurofibromas that could not be completely surgically removed without risk for substantial morbidity due to encasement or close proximity to vital structures, invasiveness, or high vascularity.^[3]

The US Food and Drug Administration (FDA) granted the application for mirdametinib priority review, fast track, and orphan drug designations along with a priority review voucher.^[3]

Society and culture

Legal status

Mirdametinib was approved for medical use in the United States in February 2025.^[3]^[4]^[5]

PATENT

US-11066358

https://patentscope.wipo.int/search/en/detail.jsf?docId=US330982129&tab=PCTDESCRIPTION&_cid=P11-KRR5IB-89620-1

On July 20, 2021, SpringWorks Therapeutics announced that the United States Patent and Trademark Office (USPTO) has issued US11066358 , directed to mirdametinib , the Company’s product candidate in development for several oncology indications, including as a monotherapy for patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and was assigned to Warner-Lambert Company (a subsidiary of Pfizer ).This patent was granted on July 20, 2021, and expires on Feb 17, 2041. Novel crystalline forms of mirdametinib and compositions comprising them are claimed.

N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (“mirdametinib”, or “PD-0325901”) is a small molecule drug which has been designed to inhibit mitogen-activated protein kinase kinase 1 (“MEK1”) and mitogen-activated protein kinase kinase 2 (“MEK2”). MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase (“MAPK”) signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2. By virtue of its mechanism of action, mirdametinib leads to significantly inhibited phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby leading to impaired growth of tumor cells both in vitro and in vivo. In addition, evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

Crystal forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide have been described previously. WO2002/006213 describes crystalline Forms I and II. U.S. Pat. No. 7,060,856 (“the ‘856 patent”) describes a method of producing Form IV. The ‘856 patent indicates that the material produced by this method was greater than 90% Form IV (The ‘856 patent, Example 1). The ‘856 patent also states that the differential scanning calorimetry (“DSC”) of the material produced shows an onset of melting at 110° C., as well as a small peak with an onset at 117° C., consistent with the material being a mixture of two forms.

WO 2006/134469 (“the ‘469 PCT publication”) also describes a method of synthesizing N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The ‘469 PCT publication reports the method yields a product conforming to the polymorphic Form IV disclosed in U.S. patent application Ser. No. 10/969,681 which issued as the ‘856 patent.

Compositions containing more than one polymorphic form are generally undesirable because of the potential of interconversion of one polymorphic form to another. Polymorphic interconversion can lead to differences in the effective dose or physical properties affecting processability of a drug, caused by differences in solubility or bioavailability. Thus, there is a need for a composition containing essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, for use in treatment of a tumor, a cancer, or a Rasopathy disorder.

Example 1: Production of Essentially Pure Form IV

Lab Scale Production of Essentially Pure Form IV

2 kg PD-0325901 has been prepared using the below convergent synthesis scheme starting from commercially available 2,3,4-Trifluorobenzoic Acid (TFBA), 2-Fluoro-4-Iodoaniline (FIA) and chiral S-Glycerol Acetonide (SGA)

All reactions were performed in toluene other than otherwise stated. Triflic anhydride gave the best yield.

[TABLE-US-00002]TABLE 1 Coupling Agents for Step 1Entry No.Coupling AgentYieldNotes 1Mesyl Chloridedid not react 2Benzyl chloride27Had to heat 70° C. for 166 hr34-fluorobenzensulfonylchloride27Ran 93 hrs. at 70° C.44-chlorobenzensulfonylchloride35Complete after 68 hrs. 50° C.5Tosyl Chloride36Had to heat to 70° C. for 164 hrs6Benzyl chloride52study solvent effects: DMF, DMSO, NMP – all similar DMSO fastest all complete after 110 hrs., heated to 70° C. after 66 hrs.7Triflic anhydride91Cooled to −74° C.

Recognizing that triflate gave the highest yield, the possibility of eliminating the cryogenic conditions was investigated, set possibly due to stability concerns of the “methanesulfonate” intermediate. The following experiments suggest no significant yield loss for experiments run at −20° C.

[TABLE-US-00003]TABLE 2 Yield of Coupling ReactionExperimentalHold time afterYield (Alcohol toDescription*TFMSA addn.IPGAP) 1.07 equiv. NHP15min.85%1.07 equiv. NHP2hours86%1.77 equiv. NHP2hours72%1.07 equiv. NHP (reverse1hours91%addition) * 2 g (1 eq.) SGA in 16 ml toluene was treated with triflic anhydride, trifluoromethanesulfonic acid (TFMSA) (4.2 g, 1.002 equiv.) at −20° C. and then stirred for a prescribed time prior to solid N-hydroxyphthalimide (NIP) addition or transfer to a flask containing solid NHP.

The data presented above suggest no detrimental effect was observed after prolonged stirring of the “trifluoromethane sulfonate” intermediate prior to the N-hydroxyphthalimide addition. Reverse addition of intermediate mixture to solid NHP appears to give the highest yield.

An additional advantage of the triflate usage was easy removal of the Et ₃N triflate salts side product simply by water wash. This resulted in highly pure N-hydroxyphthalimide-protected alcohol, IPGAP (PD-0333760) in Toluene, which can be isolated as crystals or carried through to the final deprotection reaction.

Both aqueous and anhydrous ammonia base were examined as deprotecting agents. The results were both successful. The phthalimide side product was simply filtered out from solution of product (PD-0337792) in toluene when anhydrous ammonia was used. Similarly, it was filtered out from the solution after performing azeotropic water removal from toluene when aqueous ammonia (28% solution) was used. Anhydrous ammonia however, requires the reaction to be performed at high-pressure containment. Experiments conducted by sparging the ammonia gas gave acceptable yields; however, they required large volumes and use of a cryogenic condenser (to avoid gas from escaping the reactor headspace).

[TABLE-US-00004]TABLE 3 Yields for base deprotection ReagentYield* Methyl hydrazine85-95% Anhydrous NH₃(sparged)78-90% Anhydrous NH₃(50 psi)80-92% Aqueous NH₃90-97% *from PD-0333760

Step 2: Fluoride Displacement

Examination of the reaction in an automated reactor reveals that the reaction is essentially dosed-controlled after the initiation period. Increasing the amount of lithium amide and increased agitation rate appear to shorten the induction time. The addition of water was shown to prolong the induction time. However, it is not clear whether it is due to lithium hydroxide formation.

Induction time is increased when 0.1 equivalent H ₂O was added. The trend was reversed however when 0.1 equivalent lithium hydroxide was added. Induction times were decreased upon increasing lithium amide equivalents and agitation.

CDI-assisted coupling of PD-0315209 acid and sidechain reagent followed by the acid (with aqueous HCl) hydrolysis consistently yielded good results in the laboratory. The development focus of this step was to ensure that impurity levels are within the specification limit. The known impurities in the final isolated diol product are excess PD-0315209 acid, dimeric impurities and chiral impurities. The chiral impurities are controlled by limiting the R-enantiomer in the starting s-glycerol acetonide. Elevated levels of dimeric impurity (d) has been known to cause difficulties in the polymorph transformation step. The dimeric impurity is formed initially by the reaction of imidazole (CDI-activated acid) in the presence of excess acid PD-0315209 forming dimer (a) and possibly (b) which are then carried through in the subsequent IPGA coupling and acid hydrolysis steps forming dimer (c) and (d), respectively. Impurity d is referred to as PF-00191189.

The reaction can be easily carried out in the laboratory either by charging both solids, FIPFA and CDI, followed by solvent (acetonitrile) or charging solids CDI into a slurry of FIPFA in acetonitrile. None of the solids is initially soluble in acetonitrile. The acid activation reaction was fast (almost instantaneous), forming highly soluble imidazolide product that turned the slurry into a clear homogenous solution while CO ₂gas evolution occurs.

Lab experiments generally resulted in impurity levels under 3%, which can be completely removed by the subsequent recrystallization from a 3-5% ethanol-toluene system. An additional recrystallization was performed in the few instances where the impurity level was above 0.3%. Table 4 shows selected results of lab experiments where elevated levels of impurities were observed and how they were removed in the subsequent recrystallization. The crude PD-0325901 was obtained using the acetonitrile/toluene system and the purified product was recrystallized from a 5% ethanol/toluene system. Entries no. 4 and 5 used additional solvent to ensure impurity removal with entry 5 requiring two recrystallizations in order to achieve a level of “ND” in the polymorph transformation. The 8-10 ml/g crude crystallization volume was chosen to limit product loss while maintaining a filterable slurry and ensuring removal of impurities.

[TABLE-US-00005]TABLE 4 Purification of PD-0325901 Tot. Imp. In Final Tot.isolated Tot. Imp.assay (after Imp. InCrude PurifiedpolymorphEntryreactionPD-RecrystallizationPD-trans-Nomixture0325901Vol (ml/g crude)0325901formation) 1 2.4%ND8ND99.8%210.5% 2%8ND99.6%3 6% 1%8ND99.4%4 10%3.2%15ND98.6%5 20%12%130.6%98.4%*

A scale up procedure that would give tolerable levels of impurities prior to the polymorph transformation (<0.3%), without losing too much product in the recrystallization was developed considering the solid CDI addition rate. Fast addition is preferred to minimize impurity formation; however, the addition needs to be performed at a rate that ensures safely venting of the evolved CO ₂.

A half portion of solid CDI was initially added to the PD-0325901 acid, followed by solvent addition. The remaining CDI was added then through a hopper in less than 30 minutes to ensure that the impurity levels were below 3%.

Pilot Plant Preparation of Essentially Pure Form IV

Step 1: Preparation of “Side Chain”, PD-0337792

14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6% enantiomeric excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA) solution in toluene (overall yield ˜60%). The triflate activation was performed in the 200 L reactor by maintaining temperatures under −20° C. during triflic anhydride addition. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxypthalimide (NHP) and the reaction was allowed to occur at ambient temperature to completion. The final base de-protection was performed by adding aqueous ammonia (˜28% soln, 5 equiv., 34 kg). After reaction completion, water was removed by distillation from toluene, and the resulting solid side product was filtered out to yield the product solution.

Step 2: Preparation of PD-0315209

The process yielded 21.4 kg (99.4% w/w assay), which is 80% of theoretical from starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 eq.) with lithium amide base (5 kg, 3.2 eq.). The reaction was initiated by adding 5% of total solution of TFBA and FIA into lithium amide slurry at 50° C. This reaction demonstrated a minimal initiation period of ˜10 minutes, which was observed by color change and slight exotherm. The remaining TFBA/FIA solution in THE was slowly added through a pressure can in an hour while maintaining the reaction temperatures within 45-55° C. There was no appreciable pressure rise (due to ammonia gas release) observed during the entire operation.

Step 3: Preparation of PD-0325901

A modification was made to the CDI charging to mitigate potential gas generation. Two equal portions of CDI were added into solid FIPFA before and after solvent addition (through a shot loader). The timing between the two solid CDI additions (4.6 kg each) should not exceed 30 minutes. Then two intermediate filter cakes were dissolved with ethanol. The excess ethanol was distilled and replaced with toluene to approximately 5% v/v ethanol prior to PD-0325901 recrystallization. Lab studies suggested that the crystallization from toluene and acetonitrile and recrystallization from ethanol in toluene would not be able to reduce impurities which is essential for the polymorph transformation. The presence of a dimeric impurity (PF-00191189) at a level greater than 0.2% has been known to result in the formation of undesired polymorph.

The crude crystallization from the final reaction mixture reduced dimeric impurity PF-00191189 to approximately 1.9% and the subsequent recrystallization further reduced it to approximately 0.4%. As a consequence, undesired polymorphs were produced. The DSC patterns indicated two different melting points ˜80° C. (low melt Form II) and ˜117° C. (Form I). Also during the processing, the solids crystallized at a much lower temperature than expected (actual ˜10° C., expected ˜40° C.). It is suspected that the unsuccessful recrystallization is due to a change in the solvent composition as a result of incomplete drying of the crude. Drying of the crude wet cake prior to ethanol dissolution was stopped after about 36 hours when the crude product was ˜28 kg (26 kg theoretical).

Polymorph Transformation

Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the final EtOH/Water crystallization and precipitated materials from the earlier EtOH/Toluene filtrate were taken forward to the polymorph transformation. Both crops were separately dried in the filter until constant weights and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC and resulted in an estimated amount of 16.4 kg PD-0325901. The recrystallization was started after removing EtOH via vacuum distillation and adjusting the solvent composition to about 5% EtOH in Toluene at 65° C. (i.e., EtOH is added dropwise at 65° C. until complete solids dissolution).

A slow 4-hour cooling ramp to 5° C. followed by 12 h stirring was performed to ensure satisfactory results. The resulting slurry was filtered and again it was completely dried in the filter until constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 with not detected level of dimeric impurity PF-00191189.

The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes of EtOH (62 L) off of the filter, transferred to the reactor and precipitated by a slow (˜3 h) water addition (308 L) at 30-35° C., cooled to 20° C. and stirred for 12 h. The DSC analysis of a slurry sample taken at 2 h shows the solids to be completely Form IV (desired polymorph).

21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of 9.7% PD-0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg of PD-0325901 (assay 99.4%, 100% Form IV, Yield 48%).

PATENT

WO2006134469 , claiming methods of preparing MEK inhibitor, assigned to Warner-Lambert Co .

https://patents.google.com/patent/WO2006134469A1/enThe compound Λ/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide represented by formula 1

i is a highly specific non-ATP-competitive inhibitor of MEK1 and MEK2. The compound of formula ± (Compound I) is also known as the compound PD 0325901. Compound I is disclosed in WO 02/06213; WO 04/045617; WO 2005/040098; EP 1262176; U.S. Patent Application Pub. No. 2003/0055095 A1 ; U.S. Patent Application Pub. No. 2004/0054172 A1; U.S. Patent Application Pub. No. 2004/0147478 A1 ; and U.S. Patent Application No. 10/969,681, the disclosures of which are incorporated herein by reference in their entireties.Numerous mitogen-activated protein kinase (MAPK) signaling cascades are involved in controlling cellular processes including proliferation, differentiation, apoptosis, and stress responses. Each MAPK module consists of 3 cytoplasmic kinases: a mitogen-activated protein kinase (MAPK), a mitogen-activated protein kinase kinase (MAPKK), and a mitogen-activated protein kinase kinase kinase (MAPKKK). MEK occupies a strategic downstream position in this intracellular signaling cascade catalyzing the phosphorylation of its MAP kinase substrates, ERK1 and ERK2. Anderson et al. “Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase.” Nature 1990, v.343, pp. 651-653. In the ERK pathway, MAPKK corresponds with MEK (MAP kinase ERK Kinase) and the MAPK corresponds with ERK (Extracellular Regulated Kinase). No substrates for MEK have been identified other than ERK1 and ERK2. Seger et al. “Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells.” J. Biol. Chem., 1992, v. 267, pp. 14373-14381. This tight selectivity in addition to the unique ability to act as a dual-specificity kinase is consistent with MEK’s central role in integration of signals into the MAPK pathway. The RAF-MEK-ERK pathway mediates proliferative and anti-apoptotic signaling from growth factors and oncogenic factors such as Ras and Raf mutant phenotypes that promote tumor growth, progression, and metastasis. By virtue of its central role in mediating the transmission of growth- promoting signals from multiple growth factor receptors, the Ras-MAP kinase cascade provides molecular targets with potentially broad therapeutic applications.One method of synthesizing Compound I is disclosed in the above-referenced WO 02/06213 andU.S. Patent Application Pub. No. 2004/0054172 A1. This method begins with the reaction of 2-fluoro-4- iodo-phenylamine and 2,3,4-trifluoro-benzoic acid in the presence of an organic base, such as lithium diisopropylamide, to form 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid, which is then reacted with (R)-0-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of a peptide coupling agent (e.g., diphenylphosphinic chloride) and a tertiary amine base (e.g., diisopropylethylamine). The resulting product is hydrolyzed under standard acidic hydrolysis conditions (e.g., p-TsOH in MeOH) to provide Compound 1. (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine is prepared by reaction of [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol with N-hydroxyphthalimide in the presence of Ph₃P and diethyl azodicarboxylate.Another method of synthesizing Compound I, which is disclosed in the above-referenced U.S.Patent Application No. 10/969,681, comprises reaction of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzoic acid with (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of N₁N¹– carbonyldiimidazole. The resulting product is hydrolyzed with aqueous acid and crystallized to provide polymorphic form IV of Compound I.Although the described methods are effective synthetic routes for small-scale synthesis of Compound I, there remains a need in the art for new synthetic routes that are safe, efficient and cost effective when carried out on a commercial scale.The present invention provides a new synthetic route including Steps I through Step III to the MEK inhibitor Λ/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I).Step I: Preparation of 0-{r(4RV2.2-dimethyl-1.3-dioxolan-4-ynmethyl}hydroxylanπine (6) The method of the present invention comprises a novel Step I of preparing of 0-{[(4R)-2,2- dimethyl-1 ,3-dioxolan-4-yl]methyl}hydroxylamine (6) from [(4S)-2,2-dimethyl-1 ,3-dioxoIan-4-yl]methanol (1) through the formation of [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl trifluoromethanesulfonate (3) and its coupling with N-hydroxyphthalimide (4) to afford 2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-1 H- isoindole-1 ,3(2H)-dione (5), which is subsequently de-protected to give 6 as shown in Scheme 1.Scheme 1

The reaction of compound (1) with trifluoromethanesulfonic anhydride (2) is carried out in the presence of a non-nucleophilic base, such as, for example, a tertiary organic amine, in an aprotic solvent at a temperature of from -5O⁰C to 5⁰C, preferably, at a temperature less than -15⁰C, to form triflate (3). A preferred tertiary organic amine is triethylamine, and a preferred solvent is toluene. Treatment of triflate (3) with N-hydroxyphthalimide (4) furnishes phthalimide (5), which can be isolated if desired. However, in order to minimize processing time and increase overall yield, 0-{[(4R)- 2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) can be prepared in a one-pot process with no phthalimide (S) isolation. Cleavage of the phthalimide function could be achieved by methods known in the art, for example, by hydrazinolysis. However, the use of less hazardous aqueous or anhydrous ammonia instead of methyl hydrazine (CH₃NHNH₂) is preferred.Step II: Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) As shown in Scheme 2, Step Il of the method of the present invention provides 3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-benzoic acid (9).Scheme 2

Preparation of compound (9) can be carried out by reacting compound (7), wherein X is halogen, or O-SC^R^ or 0-P(³O)(OR^, wherein R^ is alkyl or aryl, with compound (8) optionally in a solvent, and in the presence of from about 1 mol equivalent to about 10 mol equivalents of at least one base, wherein the base is selected from: a Group I metal cation hydride or a Group 2 metal cation hydride, including lithium hydride, sodium hydride, potassium hydride, and calcium hydride, a Group I metal cation dialkylamide or a Group 2 metal cation dialkylamide, including lithium diisopropylamide, a Group I metal cation amide or a Group 2 metal cation amide, including lithium amide, sodium amide, potassium amide, a Group I metal cation alkoxide or a Group 2 metal cation alkoxide, including sodium ethoxide, potassium terf-butoxide, and magnesium ethoxide, and a Group I metal cation hexamethyldisilazide, including lithium hexamethyldisilazide; for a time, and at a temperature, sufficient to yield compound (9).Preferably, preparation of compound (9) is carried out by reacting compound (7), wherein X is halogen, more preferably, X is fluorine, in an aprotic solvent with compound (8) in the presence of from about 3 mol equivalents to about 5 mol equivalents of a Group I metal cation amide at a temperature of from 2O C to 55^°C, more preferably, at a temperature from 45^°C to 55^°C. A catalytic amount of Group I metal cation dialkylamide can be added if necessary. A preferred Group I metal cation amide is lithium amide, a preferred Group I metal cation dialkylamide is lithium diisopropylamide, and a preferred solvent is tetrahydrofuran. Preferably, the reaction is performed by adding a small amount of compound (7) and compound (8) to lithium amide in tetrahydrofuran followed by slow continuous addition of the remaining portion. This procedure minimizes the risk of reactor over-pressurization due to gas side product (ammonia) generation.Step III: Preparation of N-((RV2.3-dihydroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I)Compound I can be obtained by coupling 0-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl}hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using a carboxylic acid activating reagent such as, for example, COCI2, S(O)C^, S(O)2Cl2, P(O)Cl3, triphenylphosphine/diethylazodicarboxylate, diphenylphosphinic chloride, N, N’-dicyclohexylcarbodiimide, (benzotriazol-1 -yloxy)tripyrolidinophosphonium hexafluorophosphate, (benzotriazol-1 – yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide hydrochloride, or 1,1′-carbonyldiimidazole (CDI).A preferred carboxylic acid activating reagent is 1,1′-carbonyldimidazole (CDI) shown in Scheme 3. Preparation of the desirable polymorphic Form IV of Compound I using CDI is described in the above- referenced U.S. Patent Application No. 10/969,681.Scheme 3

10 11 Compound IIn according to the present invention, the method was modified to include the advantageous procedure for product purification and isolation, which procedure is performed in single-phase systems such as, for example, toluene/acetonitrile for the first isolation/crystallization and ethanol/toluene for the second recrystallization. Water addition, implemented in the previous procedure, was omitted to avoid the two-phase crystallization from the immiscible water-toluene system that caused inconsistent product purity. The one-phase procedure of the present invention provides consistent control and removal of un- reacted starting material and side products. Alternatively, Compound I can be obtained by coupling 0-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl}hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using thionyl chloride (SOCI₂) as shown in Scheme 4.Scheme 4

Compound IExamplesThe reagents and conditions of the reactions described herein are merely illustrative of the wide variety of starting materials, their amounts and conditions which may be suitably employed in the present invention as would be appreciated by those skilled in the art, and are not intended to be limiting in any way.HPLC (Conditions A): 10 μL injection volume onto Agilent Zorbax RX-C18 150 mm x 4.6 mm x 3.5 μm column at 30^°C column temperature, 1.0 mL/min flow rate and detection at 246 nm. Mobile phase A (v/v): 25 mM Acetate Buffer, pH 6.0; Mobile phase B (v/v): Acetonitrile, and Linear Gradient Table:

Sample Preparation: Dilute 100 μL reaction mixture to 10 mL with acetonitrile. Mix in a vial 200 μL of this sample solution with 300 μL carbonate buffer pH 10.0 and 300 μL solution of 2-mercaptopyridine in acetonitrile (18 mM), heat the vial for 10 minutes at 50⁰C and dilute to 1:1 ratio in mobile phase A.GC (Conditions B): 1 μL injection onto an RTX-5 column (30 m x 0.25 mm x 0.25 μm) with initial oven temperature of 120^°C for 2 min. to final temperature of 250^°C in 15^°C/minute ramping and a final time of 2.33 min; Flow rate: 1 mL/min.HPLC (Conditions C): 5 μL injection onto Phenomenex Luna C18(2) 150 mm x 4.6 mm x 3μm column ; flow rate : 1.0 mL/min; detection at 225 nm; mobile phase A: 95/5 v/v Water/Acetonitrile with 0.1% Trifluoroacetic acid (TFA), mobile phase B: 5/95 v/v Water/Acetonitriie with 0.1% TFA; Linear Gradient Table:

Sample preparation: Dilute 1 ml_ reaction mixture to 100 mL with acetonitrile and dilute 1 mL of this solution to 10 mL with 50:50 Water/Acetonitrile.HPLC (Conditions D): 5 μL injection onto Waters SymmetryShield RP 18, 150 mm x 4.6 mm x 3.5 μm column; flow rate: 1.0 mL/min; detection at 235 nm; mobile phase A: 25 mM Acetate Buffer adjusted to pH 5.5, mobile phase B: Acetonitrile; Linear Gradient Table:

Sample preparation: Dilute 40 μL of reaction mixture in 20 mL acetonitrile.HPLC (Conditions E): 10 μL sample injection onto YMC ODS-AQ 5 μm, 250 mm x 4.6 mm column; flow rate: 1.0 ml_/min; detection at 280 nm; temperature 30^°C; mobile phase : 75/25 v/v Acetonitrile/Water with 0.1% Formic acid.Sample preparation: Quench reaction mixture sample with dipropylamine and stir for about 5 minutes before further dilution with mobile phase.DSC measurement was performed using a Mettler-Toledo DSC 822, temperature range 25^° to 150^°C with 5^°C/min heating rate in a 40 μL aluminum pan. Experimental Conditions for Powder X-Rav Diffraction (XRD):A Rigaku Miniflex+ X-ray diffractometer was used for the acquisition of the powder XRD patterns. The instrument operates using the Cu Ka₁ emission with a nickel filter at 1.50451 units. The major instrumental parameters are set or fixed at:X-ray: Cu / 30 kV (fixed) / 15 mA (fixed)Divergence Slit: Variable Scattering Slit: 4.2° (fixed) Receiving Slit: 0.3 mm (fixed) Scan Mode: FT Preset Time: 2.0 s Scan Width: 0.050° Scan Axis: 2Theta/Theta Scan Range: 3.000° to 40.000°Jade Software Version: 5.0.36(SP1) 01/05/01 (Materials Data, Inc.) Rigaku Software: Rigaku Standard Measurement for Windows 3.1 Version 3.6(1994-1995) Example 1. Preparation of 0-ffl4R)-2.2-dimethyl-1.3-dioxolan-4-vπmethyl}hvdroxylamine (6)A solution containing [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (1) (13.54 ml_, 0.109 mol) (DAISO Co., Ltd., CAS# 22323-82-6) and triethylamine (18.2 ml_, 0.131 mol) in 115 mL toluene was cooled to -15 C, then trifluoromethanesulfonic anhydride (2) (18.34 mL, 30.75 g, 0.109 mol) (Aldrich, Catalog # 17,617-6 ) was added drop wise while maintaining the temperature at less than -15^°C. The mixture was then stirred for 2 hours, and transferred to a separate flask containing a mixture (slurry) of N- hydroxyphthalimide (4) (18.99 g, 0.116 mol) (Aldrich, Catalog # H5.370-4) and 18.2 mL (0.13 mol) triethylamine in 95 mL toluene. The resulting mixture was warmed to 20-25^°C and stirred for at least 5 hours or until reaction completion (determined by HPLC (Conditions A)). Water (93 mL) was then added to quench the reaction mixture, the phases were separated, and the bottom aqueous layer was discarded. The water quench was repeated two more times resulting in a pale yellow organic layer. The organic layer was heated to 35 C and treated with 36.7 mL ammonium hydroxide solution (contains about 28-29% wt/wt ammonia). The mixture was stirred for at least 12 hours or until the reaction was deemed complete as determined by GC (Conditions B). The water was then removed under reduced pressure by co- distilling it with toluene to about half of the original volume at temperatures around 35-45 C. Toluene (170 mL) was added to the concentrated solution and the distillation was repeated. A sample was drawn for water content determination by Karl Fisher method (using EM Science Aquastar AQV-2000 Titrator with a sample injected to a pot containing methanol and salicylic acid). The distillation was repeated ifl water content was more than 0.1%. The concentrated solution was filtered to remove the white solid side product, and the filtrate was stored as 112mL (98 g) product solution containing 9.7% w/w compound 6 in toluene. This solution was ready for use in the final coupling step (Example 3). Overall chemical yield was 59%. A small sample was evaporated to yield a sample for NMR identification.¹H NMR (400 MHz, CDCI₃): δ 5.5 (bs, 2H), 4.35 (m, 1H), 4.07 (dd, 1H), 3.77 (m, 2H), 3.69 (dd, 1H), 1.44 (s, 3H), 1.37 (s, 3H).Example 2. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9)A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog # 30,660-6) and 2,3,4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat # 33,382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5%) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55^°C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25^°C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50% sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50^°C, stirred, and added with 25 mL warm (40-50^°C) water and cooled to 25-30^°C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5^°C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55^°C. Overall chemical yield was 21.4 g, 80%. ¹H NMR (400 MHz, (CD₃)₂SO): δ 13.74 (bs, 1H), 9.15 (m, 1 H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 7.10 (q, 1H), 6.81 (m, 1H).Example 2B. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide methodTo a stirring solution of 2,3,4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N₂ atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH₂CI₂ (30 mL) for 1h, filtered and dried in a vacuum oven at 45^°C for 14 hours to give 8.Og (72%) of compound (9) as an off-white solid, mp 201.5-203 ^°C.Example 3. Preparation of N-((R)-2.3-dihvdroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound \)3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (20 g, 0.051 mol) in 100 mL acetonitrile was treated with 1,1′-carbonyldiimidazole (CDI) (8.66 g, 0.053 mol) (Aldrich, Cat # 11,553-3) and stirred for about 2 hours at 20-25^°C until the reaction was deemed complete by HPLC (Conditions D). 94 mL (84.9 g) of 9.7% w/w solution of O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) in toluene was then added and stirred for about 4 hours or until the reaction was deemed complete by HPLC (Conditions D). To this mixture was added 66 mL of 5.6 % hydrochloric acid solution, and after stirring, the bottom aqueous phase was discarded. Again 66 mL of 5.6 % hydrochloric acid solution was added to the organic phase and stirred at 20-25^°C for 12-18 hours or until the reaction was deemed complete by HPLC (Conditions D). The bottom layer was then discarded and the remaining organic layer was concentrated under reduced pressure to remove about 10-20% solvent, and the volume was adjusted to about 9-11 mL/g with toluene (80 mL). Crude product was then crystallized at 10-15^°C. The slurry was allowed to stir for about 2 hours and the crude solid product was filtered, and dried. The dried crude product was recharged to the reactor and dissolved into 150 mL of 5% v/v ethanol/toluene mixture at 55- 67^°C. The solution was then clarified at this temperature through filter (line filter) to remove any remaining particulate matter. The solution was then cooled slowly to 5^°C to crystallize and stirred for at least 2 h, filtered and dried. The dried solid product was redissolved in EtOH (60 mL) at 35^°C, and product was precipitated out by adding water (300 mL) at 35^°C followed by cooling to 20⁰C. The slurry was stirred for at least 2 hours to transform the crystals to the desired polymorphic Form IV as determined by DSC and Powder X-ray Diffraction pattern (PXRD). The slurry was filtered and dried under vacuum oven at 70- 90^°C to yield the final N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I) product. Overall chemical yield was 13 g, 53%. Melting point (DSC): 112+1^° C. Appearance: White to off-white crystals.Shown in Figure 1, PXRD conforms to polymorphic crystal Form IV disclosed in the above mentioned U.S. Patent Application No. 10/969,681 ¹H NMR (400 MHz, (CD₃)₂SO): δ 11.89 (bs, 1H), 8.71 (bs, 1H), 7.57 (d, 1H), 7.37 (m, 2H), 7.20 (q, 1H), 6.67 (m, 1H), 4.84 (bs, 1H), 4.60 (m, 1H), 3.87 (m, 1 H), 3.7 (m, 2H), 3.34 (m, 2H).Example 4. Preparation of N-((R)-2.3-dihydroxypropoxyV3.4-difluoro-2-(2-fluoro-4-iodo-phenylanrιinoV benzamide (Compound \)To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (120 g, 0.30 mol) in a mixture of 1 mL N,N-dimethylformamide and 1000 mL toluene was added thionyl chloride (55 g, 0.462 mol). The mixture was heated to 50-65 C and stirred for 2 hours or until reaction completion as determined by HPLC (Conditions E). The final reaction mixture was then cooled and concentrated under reduced pressure to a slurry keeping the temperature below 35^°C. Toluene (600 mL) was added to dissolve the slurry and vacuum distillation was repeated. Additional toluene (600 mL) was added to the slurry dissolving all solids and the solution was then cooled to 5^° -10^°C. The solution was then treated with O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) (63 g, 0.43 mol) solution in 207 mL toluene followed by potassium carbonate (65 g) and water (200 mL), stirred for at least 2 hours at 20- 25^°C. The stirring was stopped to allow phase separation and the bottom phase was discarded. The remaining organic layer was treated with hydrochloric acid solution (7.4%, 240 mL) until pH was less than 1 and stirred for 2 hours. The final reaction mixture was slightly concentrated under vacuum collecting about 100 mL distillate and the resulting organic solution was cooled to 5^°C to crystallize the product and filtered. The filter cake was washed with toluene (1000 mL) followed by water (100 mL) and the wet cake (crude product Compound I) was charged back to the flask. Toluene (100 mL), ethanol (100 mL) and water (100 mL) are then added, stirred at 30-35^°C for about 15 min, and the bottom aqueous phase was discarded. Water (200 mL) was then added to the organic solution and the mixture was stirred at about 3O C to allow for crystallization. The stirring was continued for 2 hours after product crystallized, then it was further cooled to about 0^°C and stirred for at least 2 hours. The slurry was filtered and wet cake was dried under reduced pressure at 55-85^°C to yield the final product N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I) product. Overall chemical yield was 86 g, 58%.

PATENT

WO2002/006213 describes crystalline Forms I and II. U.S. Pat. No. 7,060,856 (“the ‘856 patent”)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2002006213

Clinical data

Trade names	Gomekli
Other names	PD-0325901
AHFS/Drugs.com	Gomekli
License data	US DailyMed: Mirdametinib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	L01EE05 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	391210-10-9
PubChem CID	9826528
IUPHAR/BPS	7935
DrugBank	DB07101
ChemSpider	10814340
UNII	86K0J5AK6M
KEGG	D11675
ChEBI	CHEBI:9826528
ChEMBL	ChEMBL507361
PDB ligand	4BM (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₆H₁₄F₃IN₂O₄
Molar mass	482.198 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Gomekli- mirdametinib capsule; Gomekli- mirdametinib tablet, for suspension”. DailyMed. 27 February 2025. Retrieved 2 April 2025.
^ Armstrong AE, Belzberg AJ, Crawford JR, Hirbe AC, Wang ZJ (June 2023). “Treatment decisions and the use of MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas”. BMC Cancer. 23 (1): 553. doi:10.1186/s12885-023-10996-y. PMC 10273716. PMID 37328781.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection”. U.S. Food and Drug Administration (FDA). 11 February 2025. Archived from the original on 13 February 2025. Retrieved 16 February 2025. This article incorporates text from this source, which is in the public domain.
^ “UPDATE: SpringWorks Therapeutics Announces FDA Approval of Gomekli (mirdametinib) for the Treatment of Adult and Pediatric Patients with NF1-PN” (Press release). SpringWorks Therapeutics. 12 February 2025. Archived from the original on 13 February 2025. Retrieved 16 February 2025 – via GlobeNewswire News Room.
^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 14 February 2025. Retrieved 16 February 2025.

External links

“Mirdametinib (Code C52195)”. NCI Thesaurus.
Clinical trial number NCT03962543 for “MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas (ReNeu)” at ClinicalTrials.gov

Moertel CL, Hirbe AC, Shuhaiber HH, Bielamowicz K, Sidhu A, Viskochil D, Weber MD, Lokku A, Smith LM, Foreman NK, Hajjar FM, McNall-Knapp RY, Weintraub L, Antony R, Franson AT, Meade J, Schiff D, Walbert T, Ambady P, Bota DA, Campen CJ, Kaur G, Klesse LJ, Maraka S, Moots PL, Nevel K, Bornhorst M, Aguilar-Bonilla A, Chagnon S, Dalvi N, Gupta P, Khatib Z, Metrock LK, Nghiemphu PL, Roberts RD, Robison NJ, Sadighi Z, Stapleton S, Babovic-Vuksanovic D, Gershon TR: ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma. J Clin Oncol. 2025 Feb 20;43(6):716-729. doi: 10.1200/JCO.24.01034. Epub 2024 Nov 8. [Article]
Weiss BD, Wolters PL, Plotkin SR, Widemann BC, Tonsgard JH, Blakeley J, Allen JC, Schorry E, Korf B, Robison NJ, Goldman S, Vinks AA, Emoto C, Fukuda T, Robinson CT, Cutter G, Edwards L, Dombi E, Ratner N, Packer R, Fisher MJ: NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. J Clin Oncol. 2021 Mar 1;39(7):797-806. doi: 10.1200/JCO.20.02220. Epub 2021 Jan 28. [Article]
Ioannou M, Lalwani K, Ayanlaja AA, Chinnasamy V, Pratilas CA, Schreck KC: MEK Inhibition Enhances the Antitumor Effect of Radiotherapy in NF1-Deficient Glioblastoma. Mol Cancer Ther. 2024 Sep 4;23(9):1261-1272. doi: 10.1158/1535-7163.MCT-23-0510. [Article]
FDA Approved Drug Products: GOMEKLI (mirdametinib) capsules and tablets for oral and oral suspension use (Feb 2024) [Link]
FDA News: FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection [Link]

////////MIRDAMETINIB, Orphan Drug Status, Neurofibromatosis 1, PHASE 2, PD0325901, PD 0325901, PD-325901, FDA 2025, GOMEKLI, APPROVALS 2025

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