313348-27-5

Usage

Uses

Used in Myocardial Perfusion Imaging:
Regadenoson is used as a pharmacologic stress agent for myocardial perfusion imaging (MPI) studies in patients unable to undergo adequate exercise-induced stress. It increases coronary blood flow 3.4to 3.8-fold with a half-time to reversal of 1.9-2.6 minutes in open-chest anesthetized pigs.
Used in Cardiovascular Applications:
In the cardiovascular industry, Regadenoson is used as a selective and potent A2A adenosine receptor agonist. It is a G-protein-coupled receptor and a key therapeutic target for various cardiovascular diseases.
Used in Oncologic Applications:
In the oncologic industry, Regadenoson is used to induce hyperemia (increased blood flow), particularly in the context of myocardial perfusion imaging. It has been shown to increase the delivery of compounds to the central nervous system through the blood-brain barrier in animals. In rodent studies, co-administration of Regadenoson with Temozolomide (T017775) can increase Temozolomide concentration in the brain.

Synthesis

The synthesis of regadenoson has been reported in several papers and patents and a scalable procedure is detailed in the scheme. The synthesis was initiated with the reaction of 2- chloroadenosine hemihydrate (94) and hydrazine monohydrate at 40-50 °C to provide 95 in 81% yield with 99.3% purity. Hydrazine 95 was condensed with ethyl-2-formyl-3- oxopropionate (96) under refluxing IPA to furnish the pyrazole 97 in 77% yield which was collected by filtration and used in next step without further purification. Pyrazole 97 was then reacted with methyl amine at room temperature to provide regadenoson (XV). Although the yield was not reported, the product was collected by simple filtration.

in vitro

regadenoson was selective for the a2a adenosine receptor versus the a1, a2b, and a3 receptors in binding and functional studies. regadenoson was also found to be a full and potent agonist to cause coronary vasodilation, a response that has a very large a2a receptor reserve [1].

in vivo

in a study of 10 conscious dogs, authors compared intravenously injected regadenoson to that of adenosine. regadenoson caused a dose-dependent increase of coronary blood flow (cbf), whereas adenosine was less potent but produced equivalent hyperemia. thus, authors concluded that regadenoson is a potent coronary vasodilator with a short duration of action, minimal and transient systemic hemodynamic effects, and ease of administration [1].

references

[1] cerqueira md. the future of pharmacologic stress: selective a2a adenosine receptor agonists. am j cardiol. 2004 jul 22;94(2a):33d-40d; discussion 40d-42d.

InChI:InChI=1/C15H18N8O5/c1-17-13(27)6-2-19-23(3-6)15-20-11(16)8-12(21-15)22(5-18-8)14-10(26)9(25)7(4-24)28-14/h2-3,5,7,9-10,14,24-26H,4H2,1H3,(H,17,27)(H2,16,20,21)/t7-,9-,10-,14-/m1/s1

Upstream product

• 74-89-5 methylamine 
• 313348-16-2 CVT 3127 
• 1423073-21-5 2-(4-methoxycarbonylpyrazol-1-yl)adenosine 
• 146-77-0 2-Chloroadenosine 
• 35109-88-7 2-iodoadenosine 
• 1154383-52-4 N-methyl-1H-pyrazole-4-carboxamide 
• 24639-06-3 ((3aR,4R,6R,6aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol 
• 146-78-1 2-fluoroadenosine 
• 15763-11-8 2-hydrazinoadenosine 

Relevant academic research and scientific papers

Preparation method of A2A adenosine receptor agonist

The invention discloses a preparation method of an A2A adenosine receptor agonist. The preparation method comprises the following steps of: (1) reacting 2-chloroadenosine with acetic anhydride by taking sodium acetate as a catalyst to prepare a compound shown in a formula (1); (2) reacting the compound shown in the formula (1) with hydrazine hydrate by taking methanol as a reaction medium to prepare a compound shown in a formula (2); (3) reacting the compound shown in the formula (2) with 2-formyl-3-oxoethyl propionate to prepare a compound shown in a formula (3); and (4) reacting the compound shown in the formula (3) with a methylamine water solution to prepare the A2A adenosine receptor agonist. According to the preparation method, the 2-chloroadenosine is taken as a starting raw material, and hydroxyl and amino are protected by using an AC protecting group, so that formation of relevant impurities is avoided effectively; and the dosage of a genotoxic reagent hydrazine hydrate is reduced greatly, excessive 2-formyl-3-oxoethyl propionate reacts with the compound shown in the genotoxic warning structural formula (2), the residue of the compound shown in the formula (2) is controlled at a very low level, and a relatively high-purity Regabardine product is obtained finally.

Preparation method of regadenoson

The invention discloses a preparation method of regadenoson. The method comprises the following steps that 1, amino-2-chloropurine riboside and hydrazine hydrate react with each other by adopting potassium carbonate as a catalyst to prepare 2-hydrazino adenosine; 2, the 2-hydrazino adenosine and 2-formyl-3-oxo-ethyl propionate react with each other by adopting PEG and water as reaction media to obtain a compound of a formula (3); 3, the compound of the formula (3) and a 25-30% methyl amine water solution react with each other by adopting PEG as a reaction medium to obtain regadenoson. The amino-2-chloropurine riboside is adopted as a starting raw material, by adopting inorganic base potassium carbonate, the selectivity of the first-step reaction is improved, and the consumption of toxic substances hydrazine hydrates is lowered to the minimum. In the synthesis process, polyethylene glycol is adopted as the reaction medium, the reaction needed time is effectively shortened, and the reaction temperature is lowered; meanwhile, the good yield and purity are obtained.

NOVEL POLYMORPH OF REGADENOSON AND PROCESS FOR PREPARATION THEREOF

Processes are provided for the preparation of a stable polymorphic form C of regadenoson, the process involving steps of a) obtaining a solution of regadenoson in benzyl alcohol solvent, b) maintaining the reaction mixture of step a) to about 10° C. to about 90° C., and c) isolating the stable polymorphic form C of regadenoson. Polymorphic form C may be characterized by an x-ray powder diffraction pattern with peaks at about 6.1, 10.2, 10.6, 19.0 and 25.4.±0.2 degrees 2-theta.

ADENOSINE ANALOG AND ITS USE IN REGULATING THE CIRCADIAN CLOCK

Provided are a kind of nucleoside analogue compounds, and compositions comprising these compounds and pentostatin, their use for modulating circadian rhythm, preferably, for shifting circadian phase, and methods for modulating circadian rhythm, preferably, for shifting circadian phase via these compounds or the compositions.

Sweden deshong new intermediate and its preparation method and application

The invention relates to new regadenoson intermediates, a preparation method and an application thereof, and a preparation method for preparing regadenoson with the intermediates. The invention discloses the new regadenoson intermediate represented as the general formula I, a method for preparing the intermediate with hydrazinoadenine, and also a method for preparing regadenoson, wherein the method for preparing regadenoson includes steps of preparing a compound represented as the formula III with the intermediate represented as the general formula I and a compound represented as the general formula II under a catalyst, and then converting the compound represented as the formula III into the regadenoson. The method is simple in operations, is high in yield, is low in cost and is very suitable for industrialized production.

PROCESS OF MAKING REGADENOSON AND NOVEL POLYMORPH THEREOF

Novel processes for making the N-pyrrazole substituted 2-adenosine derivative regadenoson and a novel polymorph thereof. The novel polymorph of regadenoson designated form H and drug substances and pharmaceutical compositions including the novel polymorph H are disclosed.

Novel Polymorph of Regadenoson

The invention provides a novel polymorph of Regadenoson. More particularly, the invention provides propylene glycol solvate of Regadenoson. The invention also provides a process for the preparation of propylene glycol solvate of Regadenoson.

A PROCESS FOR THE PREPARATION OF REGADENOSON

The present invention provides novel processes for the preparation of regadenoson having the formula (I). In some embodiments, the intermediates for the synthesis of regadenoson are also provided.

Novel Process for the Preparation of (1-pyrazole-4-yl)-N-methylcarboxamide

The present invention relates to a novel process for the preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.

STABLE SOLID FORMS OF REGADENOSON

A process for the preparation of the amorphous form of Regadenoson of formula (I) is disclosed together with new crystalline polymorphic forms E, F and G and methods for their preparation. Regadenoson amorphous form can be prepared in mild reaction conditions with high chemical purity (>99.6%) and high stability to the heating. A particularly thermodynamically stable anhydrous crystalline form of Regadenoson (form G) is also disclosed, provided with high stability not when exposed to 90% RH at 25°C for 96 hour, but also to the heating up to 200°C.