320345-99-1 Usage
Description
Aclidinium bromide, a quaternary ammonium salt, is the bromide salt of aclidinium. It is a muscarinic acetylcholine M3 receptor antagonist, specifically designed for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). Aclidinium bromide is characterized by its high potency, long duration of action, low oral absorption, and rapid plasma degradation.
Uses
Used in Pharmaceutical Industry:
Aclidinium bromide is used as a selective muscarinic antagonist for the treatment of chronic obstructive pulmonary disorder (COPD). It acts as a bronchodilator by inhibiting the muscarinic AChR M1, M2, M3, M4, and M5 receptors with Ki values of 0.1 nM, 0.14 nM, 0.14 nM, 0.21 nM, and 0.16 nM, respectively. This selective action on the muscarinic M3 receptor, which is primarily responsible for bronchial and tracheal smooth muscle contraction, makes it an effective treatment for COPD.
Additionally, aclidinium bromide is used as a long-acting antimuscarinic bronchodilator in phase II clinical trials for the treatment of chronic obstructive pulmonary disease. Its rapid hydrolysis in human plasma and inhaled administration help limit systemic exposure and reduce the potential for systemic side effects.
Brand Names:
In the United States, aclidinium bromide is marketed under the brand name Tudorza Pressair, while in the European Union, it is known as Eklira, Bretaris, and Genuair.
Originator
Almirall (Spain)
Clinical Use
Aclidinium bromide was approved by the U. S. Food and Drug Administration (FDA) in July 2012
for the treatment of chronic obstructive pulmonary disease (COPD). Marketed by Forest
Pharmaceuticals, aclidinium bromide selectively binds to five human muscarinic receptors (M1-M5), and
posesses a subnanomolar binding affinity for these particular targets. Administered by inhalation, this
medicine has demonstrated favorable onset and duration of action, and its safety profile is an
improvement over competitor therapies.
Synthesis
No manufacturing route has been disclosed to date, the most scalable published synthesis is described in the scheme. Dimethyl oxalate (1) was initially
treated with two equivalents of Grignard 2 to give bis-thiophenoate 3 in 36% yield. Subsequent
transesterification with (R)-quinuclidinol (4) gave rise to the quinuclidine-containing ester 5 in 50%
yield. Aclidinium bromide (I) could be accessed by two different methods involving bromoalkyl phenyl
ether 6—an excess of bromide in the presence of an acetonitrile/chloroform mixture gave the drug in 89% isolated yield, or with fewer equivalents of electrophile (1.25 eq) during exposure to refluxing
acetophenone has reportedly delivered (I) quantitatively on multi-gram scale.17 From commercial 2, the multi-gram synthesis of Aclidinium bromide (I) was completed in 17.8% over three steps.
references
[1] gavaldà a1, ramos i2, carcasona c3, calama e4, otal r5, montero jl6, sentellas s7, aparici m8, vilella d9, alberti j10, beleta j11, miralpeix m12. the in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide. pulm pharmacol ther. 2014 aug;28(2):114-21.
Check Digit Verification of cas no
The CAS Registry Mumber 320345-99-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,2,0,3,4 and 5 respectively; the second part has 2 digits, 9 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 320345-99:
(8*3)+(7*2)+(6*0)+(5*3)+(4*4)+(3*5)+(2*9)+(1*9)=111
111 % 10 = 1
So 320345-99-1 is a valid CAS Registry Number.
InChI:InChI=1/C13H9N.BrH/c1-3-7-12-10(5-1)9-11-6-2-4-8-13(11)14-12;/h1-9H;1H
320345-99-1Relevant articles and documents
A PROCESS FOR PREPARING ACLIDINIUM BROMIDE AND INTERMEDIATES THEREOF
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, (2018/09/12)
Provided herein is a process for synthesis of aclidinium bromide and intermediates thereof, wherein the process for the preparation of aclidinium bromide increases the % yield of aclidinium bromide by about 70% to 90%.
Novel method for synthesis and purification of aclidinium bromide
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Page/Page column 6-9, (2018/12/05)
The invention discloses a novel method for synthesis and purification of aclidinium bromide. According to the method, tetrahydrofuran is used, haloalkane is used as an initiator, and a finished product is obtained through solvent extraction and recrystall
Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists
Xiang, Zuojuan,Liu, Jun,Sun, Hongbin,Wen, Xiaoan
, p. 1173 - 1182 (2017/08/15)
The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki=0.16 nm, IC50=0.38 nm, t1/2=9.34 min; 1 b: Ki=0.32 nm, IC50=1.01 nm, t1/2=19.2 min) with proper plasma stability were identified, which (particularly 1 a) hold great promise as clinical drug candidates to overcome the drawbacks caused by the inappropriate stability of the currently marketed M3 antagonists. In addition, structure–activity relationship studies revealed that the R configuration of the pyrrolidinyl C3 atom was clearly better than the S configuration.