475086-01-2

Usage

Uses

Used in Pharmaceutical Industry:
NS-304 is used as a drug for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization.
Used in Vascular Disorders Treatment:
NS-304 is used as a potential drug for the treatment of various vascular disorders such as pulmonary arterial hypertension and arteriosclerosis obliterans.

Biological Activity

Prostaglandin I2 (PGI2) is a potent vasorelaxant and inhibitor of human platelet aggregation that mediates its actions by binding to a specific G protein- coupled receptor, the IP receptor, on the surface of endothelial cells and platelets. The IP receptor also participates in signal transduction of the pain response, cardioprotection, and inflammation. Selexipag(NS-304) is a prodrug of the active form of MRE-269, which is a potent and selective agonist for the human IP receptor with a Ki value of 20 nM. In contrast to prostaglandin I2, which has a half-life of 30 seconds to a few minutes in vivo, NS-304 is long-acting. Plasma concentrations of MRE-269 remain near peak levels for more than eight hours in rats and dogs after NS-304 was administered orally.

Clinical Use

Selexipag was approved by the United States FDA on December 22, 2015 for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization.Selective IP receptor agonist:Treatment of pulmonary arterial hypertension.

Synthesis

The synthesis of selexipag began with condensation of commercially available benzil (51) and glycinamide hydrochloride in the presence of concentrated sodium hydroxide in refluxing MeOH to yield hydroxypyrazine 52. NS-304 was subsequently converted to 5-chloro-2,3-diphenylpyrazine (53) upon treatment with refluxing POCl3 in the presence of a catalytic amount of H2SO4. Chloride 53 was then subjected to neat 4-(isopropylamino)-1-butanol (54, prepared by the reductive alkylation of 4-amino-1-butanol and acetone with hydrogen over PtO2 in EtOH) at 190 °C to give aminopyrazinyl alcohol 55 in 56% yield as colorless crystals. Alcohol 55 was alkylated with tert-butyl bromoacetate using Bu4NHSO4 as a phase-transfer catalyst and 40% aqueous KOH in benzene to give ester 56. Although it is particularly unusual to employ benzene on a production scale, these are the only reported conditions for this transformation. The crude ester 56 was then saponified using methanolic sodium hydroxide to yield the corresponding carboxylic acid 57 in 62% as pale-yellow crystals in two steps from compound 55. Finally, the carboxylic acid 57 was coupled with methanesulfonamide in the presence of CDI and DBU in THF to give selexipag (VI) in 77% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly reduced by rifampicin - consider increasing selexipag dose Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - consider increasing selexipag dose. Clopidogrel: concentration of selexipag possibly increased - consider reducing dose of selexipag. Deferasirox: concentration of selexipag possibly increased - consider reducing dose of selexipag. Lipid-lowering drugs: concentration possibly increased by gemfibrozil - avoid. Teriflunomide: concentration of selexipag possibly increased - consider reducing dose of selexipag

Metabolism

Selexipag is rapidly absorbed and is hydrolysed by CES1 in the liver to its active metabolite. Oxidative metabolism catalysed by CYP3A4 and CYP2C8 leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Excretion is mainly via the faeces (93%) and 12% via the urine.

Upstream product

• 475085-57-5 MRE-269 
• 3144-09-0 methanesulfonamide 
• 475086-75-0 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol 
• 59504-75-5 N-(bromoacetyl)methanesulfonamide 
• 124-63-0 methanesulfonyl chloride 
• 41270-66-0 2-chloro-5,6-diphenylpyrazine 
• 18591-57-6 5,6-diphenyl-2-hydroxypyrazine 
• 243472-70-0 2-bromo-5,6-diphenylpyrazine 
• 39099-23-5 N-isopropyl-N-butylamine 
• 134-81-6 benzil 

Relevant academic research and scientific papers

Synthesis method of diphenyl pyrazine derivative

The invention discloses a synthesis method of a diphenyl pyrazine derivative. The method is characterized in that benzil and glycinamide are used as raw materials, and a target product is prepared through five-step reaction. The obtained target product is high in purity, subsequent production of high-quality drugs is facilitated, and the synthesis method is reasonable in route design, mild in reaction condition, free of high-temperature reaction, good in safety and high in feasibility.

Preparation method of medical intermediate

The invention provides a preparation method of a medical intermediate 2 - {4 - [(5, 6 - diphenylpyrazine -2 -yl) (propane -2 -yl) amino] butoxy} acetate. The crystallization method uses a mixed solvent composed of a hydrocarbon and an alcohol, the hydroca

Preparation method for Selexipag intermediate

The invention provides a method for preparing a Selexipag intermediate 4-((5,6-diphenyl-2-pyrazinyl)(1-methylethyl)amino)-1-butanol. The method includes protecting 4-isopropylamino n-butyl alcohol byusing a hydroxy protecting group reagent, performs addition with 5,6-diphenyl-2-pyrazinyl trifluoromethanesulfonate, and obtains a target compound by removing protecting groups. The preparation methodis high in yield, low in production cost, mild in condition, simple in operation and suitable for industrial production.

METHOD FOR PREPARING PROSTACYCLIN RECEPTOR AGONIST

The present invention relates to preparation methods of a prostacyclin receptor agonist of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and its intermediates. These methods are simple and convenient to operate, environment-friendly and suitable for industrial production to obtain the product with good yield and high purity.

POLYMORPHIC FORMS AND AMORPHOUS SOLID DISPERSION OF SELEXIPAG

The present disclosure relates to crystalline forms of selexipag and their processes for preparation. The present disclosure also relates to an amorphous solid dispersion of selexipag and its processes for their preparation as well as premix of crystalline selexipag and their process.

Match le xipa intermediate and match le xipa preparation method (by machine translation)

The invention discloses a match le xipa intermediate and match le xipa preparation method, the midbody is compound And compounds The present invention provides a preparation method of match le xipa of reasonable process design, is suitable for industrial scale production. (by machine translation)

Preparation method of selexipag

The invention discloses a preparation method of selexipag. The method comprises the following steps that a compound II and 2-halogenated acetamide are subjected to condensation reaction in an alkalinecondition, so as to obtain a compound I, and then the c

CRYSTALLINE FORM VI OF SELEXIPAG

The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof and pharmaceutical compositions thereof.

PROCESS FOR THE PREPARATION OF DIPHENYLPYRAZINE DERIVATIVES

The present invention relates to a process for the preparation of amorphous Selexipag from Selexipag crystalline salts using a solvent.

High-purity match le xipa (by machine translation)

The invention discloses a high-purity match le xipa. By the match le xipa key intermediate 2 - (4 - ((5, 6 - diphenyl pyrazine - 2 - yl) isopropyl amino) butoxy) acetic acid in the organic solvent with the CDI, a sulfonamide in the organic base under the conditions of the reaction. The reaction operation is simple, low cost, environment-friendly, yield>95%, it is suitable for industrial production, the purity of the prepared match le xipa ≥ 99.9%, can better meet the requirements of drug production. The invention prepared match le xipa high purity, thereby facilitating the subsequent more high-quality drugs. (by machine translation)