320345-91-3

Upstream product

• 320347-97-5 hydroxydithien-2-ylacetic acid 1-aza-bicyclo[2.2.2]oct-3(R)-yl ester 
• 13633-25-5 1-Bromo-4-phenylbutane 

Relevant academic research and scientific papers

NOVEL QUINUCLIDINE DERIVATIVES AND MEDICINAL COMPOSITIONS CONTAINING THE SAME

A compound according to formula (I) wherein z? is a phenyl ring, a C4 to C9 heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, —OR4, —SR4, —NR4R5, —NHCOR4, —CONR4R5, —CN, —NO2, —COOR4 or —CF3 group, or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alcoxy group, wherein R4 and R5 each independently represent a hydrogen atom, straight or branched lower alkyl group, or together form an alicyclic ring; or R1 and R2 together form an aromatic, alicyclic or heterocyclic ring; n is an integer from 0 to 4; A represents a —CH2—, —CH═CR6, —CR6═CH—, —CR6122—, —CO—, —O—, —S—, —S(O)—, SO2 or NR6— group, wherein R6 and R2 each independently represent a hydrogen atom, straight or branched lower alkyl group, or R6 and 122 together form an alicyclic ring; m is an integer from 0 to 8; provided that when m=0, A is not —CH2—; p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2,3 or 4 position including all possible configurations of the asymmetric carbons; B represents a group of formula (i) or (ii), wherein R10 represents a hydrogen atom, a hydroxy or methyl group; and R8 and R9 each independently represents formulae (a), (b), (c), (d) and wherein R11 represents a hydrogen or halogen atom, or a straight or branched lower alkyl group and Q represents a single bond, —CH2—, —CH2—CH2, —O—, —O—CH2—, —S—, —S—CH2— or —CH═CH—, and when (i) or (ii) contain a chiral centre they may represent either configuration; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, which shows high affinity for muscarinic M3 receptors (Hm3).

Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: Identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2. 2.2]octane bromide (aclidinium bromide)

The objective of this work was to discover a novel, long-acting muscarinicM3 antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl) acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidiniumbromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.