AL-12182, a novel 11-oxa prostaglandin analog with topical ocular hypotensive activity in the monkey

A Convergent Synthesis of the 11-Oxa Prostaglandin Analogue AL-12182

“…Isopropyl [2 R (1 E ,3 R ), 3 S (4 Z ), 4 R )]-7-{tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl}-4-h eptenoate (AL-12182) (1). The silyl protected prostaglandin analogue 27 (2.40 g, 3.52 mmol) was dissolved in tetrahydrofuran (15 mL) (internal temperature 18 °C). Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 10.5 mL) was added (temperature rose to 20 °C over 3 min) and the mixture was stirred at room temperature under nitrogen for 4 h (TLC ethyl acetate/heptane 3:1 indicated complete reaction).…”

“…11-Oxa prostaglandin analogues have been found to be effective agents for lowering intra-ocular pressure in the treatment of glaucoma . These compounds exhibit mechanisms similar to PGD 2 2 and PGF 2 α 3 (Figure ).…”

“…An efficient synthesis of a compound of this class, AL-12182 1 , was required with the potential for development to produce kilogram quantities as a pharmaceutical product . Previous syntheses of 11-oxa prostaglandin analogues , have utilized (3a R ,4 S ,6a R )-4-hydroxymethyl-hexahydrofuro[3,4-b]furan-2-one 4 , the oxa-analogue of the Corey lactone alcohol, or functionally equivalent compounds as a key intermediate. The racemic synthesis of this core tetrahydrofuran unit by reaction of methyl 4,4-diethoxycrotonate and methylsodium glycolate has been described,3a but the reported syntheses of enantiomerically pure compounds of this type 3b-f use carbohydrate starting materials to provide the four carbon atoms of the tetrahydrofuran ring and C13 of the ω-chain.…”

“…The racemic synthesis of this core tetrahydrofuran unit by reaction of methyl 4,4-diethoxycrotonate and methylsodium glycolate has been described,3a but the reported syntheses of enantiomerically pure compounds of this type 3b-f use carbohydrate starting materials to provide the four carbon atoms of the tetrahydrofuran ring and C13 of the ω-chain. Thus, in the original patent route to AL-12182 1 (Scheme ),1a the Corey lactone alcohol equivalent 4 was synthesized from d -glucose, after which chemistry analogous to the latter stages of the Corey lactone route to carbocyclic prostanoids 4 was used. A later and more efficient, but conceptually similar, synthesis of AL-12182 1b was based on the route developed by Hanessian 3d starting with d -sorbitol.…”

Discovery to Launch of Anti-allergy (Emadine; Patanol/Pataday/Pazeo) and Anti-glaucoma (Travatan; Simbrinza) Ocular Drugs, and Generation of Novel Pharmacological Tools Such as AL-8810

“…Such FP-class-PG-directed research also helped identify and characterize other useful FP-receptor class PG analogues that met in vitro and in vivo potency/efficacy parameters and were qualified as clinical candidate ocular hypotensive drugs. These included compounds such as AL-12128 , and several other novel FP-receptor agonists that were potent and efficacious ocular hypotensive agents as demonstrated in the OHT eyes of conscious cynomolgus monkeys in multiple studies. ,, …”