ETRIPAMIL

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

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).

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.

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. 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]

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