A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost.

Małgorzata Krupa,Iwona Dams,Piotr Cmoch,Michał Chodyński,Anna Ostaszewska

doi:10.3390/molecules22020217

Abstract

Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia–Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde ω-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2–5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

Highlights

The discovery of potent and efficacious intraocular pressure (IOP) lowering prostaglandin F2α (PGF2α) analogs 1–5(Figure 1) has revolutionized the treatment of ocular hypertension, a major risk factor for progression of the irreversible blinding disease glaucoma [1,2]
Free isopropyl ester prodrugs, i.e., unoprostone (1, Rescula), latanoprost (2, Xalatan) and travoprost (3, Travatan), and one amide prodrug bimatoprost (4, Lumigan) of ω-chain modified PGF2α analogs have been used as first line therapy for the treatment of open angle glaucoma and ocular hypertension due to their potent IOP-lowering efficacy, low likelihood of systemic adverse effects, once-daily dosing and good patient adherence [3,4,5,6]
Tafluprost (5) is the newest 15-deoxy-15,15-difluorinated PGF2α receptor agonist possessing effective IOP-reducing effects, and the first hypotensive drug released in a preservative-free formulation under trade names Taflotan or Saflutan in Europe and Zioptan in USA [8,9,10,11,12]

Summary

Introduction

The discovery of potent and efficacious intraocular pressure (IOP) lowering PGF2α analogs 1–5(Figure 1) has revolutionized the treatment of ocular hypertension, a major risk factor for progression of the irreversible blinding disease glaucoma [1,2]. The discovery of potent and efficacious intraocular pressure (IOP) lowering PGF2α analogs 1–5. Free isopropyl ester prodrugs, i.e., unoprostone (1, Rescula), latanoprost (2, Xalatan) and travoprost (3, Travatan), and one amide prodrug bimatoprost (4, Lumigan) of ω-chain modified PGF2α analogs have been used as first line therapy for the treatment of open angle glaucoma and ocular hypertension due to their potent IOP-lowering efficacy, low likelihood of systemic adverse effects, once-daily dosing and good patient adherence [3,4,5,6]. All the available commercial preparations of 1–4 contain preservatives to maintain the sterility of the solutions, which may impair topical tolerance of these IOP-lowering agents during long-term use [7]. New preservative-free agents with greater IOP-lowering efficacy and milder local side effects are still needed. Tafluprost (5) is the newest 15-deoxy-15,15-difluorinated PGF2α receptor agonist possessing effective IOP-reducing effects, and the first hypotensive drug released in a preservative-free formulation under trade names Taflotan or Saflutan in Europe and Zioptan in USA [8,9,10,11,12].

Methods

Discussion

Conclusion