Elevated intraocular pressure (IOP) is the major risk factor associated with the etiology of glaucoma, a progressive optic neuropathy that can ultimately cause blindness. Prostaglandin (PG) analogs represent the most potent therapeutic agents in the clinical management of ocular hypertension and glaucoma today. The marketed PG analogs used to reduce IOP include    Travatan™ ((9S,11R,15R)-9,11,15-trihydroxy-16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor-5Z,13E-prostadienoic acid, isopropyl ester)
travoprost;    Xalatan™ ((9S,11R,15R)-9,11,15-trihydroxy-17-phenyl-18,19,20-trinor-5Z-prostenoic acid, isopropyl ester)
latanoprost;    Rescula™ ((9S,11R)-9,11-dihydroxy-15-keto-20-ethyl-5Z-prostenoic acid, isopropyl ester)
unoprostone isopropyl ester;    Lumigan™ ((9S, 11R, 15S)-9,11,15-trihydroxy-17-phenyl-18,19,20-trinor-5Z,13E-prostadienoic acid, ethylamide)
bimatoprost(J. Ocular Pharmacol. Therap., 2003, v. 19, 501). The conventional numbering of prostaglandins and like structures is indicated in connection with the formula of bimatoprost. It should be noted that bimatoprost may be easily prepared by reaction of methyl (9S,11R,15R)-9,11,15-trihydroxy-17-phenyl-18,19,20-trinor-5Z,13E-prostadienoate
with ethylamine.
Newly synthesized PGF2α analogue (9S,11R)-9,11-dihydroxy-16-phenoxy-15,15-difluoro-17,18,19,20-tetranor-5Z,13E-prostadienoic acid, isopropyl ester
tafluprostis under development as an ocular hypotensive drug in the USA, Europe, and Japan (Exp. Eye Res., 2004, v. 78, 767).
The known methods for the synthesis of alkyl 5Z-prostenoates of formula [1]
wherein
R is 3-CF3C6H4O—, 3-ClC6H4O—, PhO—, Bn—, Bu—, Me(CH2)5—; A is —CH2CH2— or —CH═CH—; X is X1, O or (α-OH, H); X1 is (α-OR3, H); —OCH2CH2O— or (F, F); R1 is C1–C10 alkyl group; R3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl group; α is down;    (see U.S. Pat. Nos. 3,931,279; 5,223,537; 5,698,733; and 5,688,819; WO95/26729, Prostaglandins, v. 9, 5 1975, J. Med. Chem., 1993, 36, 243) are shown in Scheme 1 below and include the stages of phosphonate Horner-Emmons-Wadsworth reaction with Corey aldehyde in anhydrous condition using BuLi, NaH or Et3N/LiCl as base to yield enone, reducing lactone to lactol with diisobutylaluminum hydride at temperature −70 to −80° C. and alkylation of acid [3] in the presence of DBU or K2CO3 to the desired compound [1].
wherein    R is 3-CF3C6H4O—, 3-ClC6H4O—, PhO—, Bn—, Bu—, Me(CH2)5—; A is —CH2CH2— or —CH═CH—; X is X1, O or (α-OH, H); X1 is (α-OR3, H); —OCH2CH2O— or (F, F); R1 is C1–C10 alkyl group; R2 is arylcarbonyl group; R3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl group; R4 is C1-C4 alkyl, Ph or Bn; Y is a leaving group; α is down;
The described Horner-Emmons-Wadsworth and alkylation reactions give low yield of desired products. On the other hand it is difficult to scale-up the highly exothermic reduction with diisobutylaluminum hydride at such low temperature conditions.
USPTO Backgrounds
USPTO Backgrounds