119356-77-3

Premature ejaculation (PE) is the most common male sexual dysfunction. Dapoxetine hydrochloride,marketed as Priligy and Westoxetin, is a class of PE treatment drugs known as selective serotonin reuptake inhibitors (SSRI) , was the first drug originally approved for the on-demand treatment of men 18–64 years old with PE.Premature ejaculation (PE) is a common problem worldwide and has significant impact not only on the sufferer but on the partner in terms of self-esteem, interpersonal distress and sexual satisfaction. Tricyclic antidepressants and clomipramine are the most widely used drugs for the treatment of premature ejaculation . Randomized, double blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for the treatment of PE. Different dosage has different impacts on different type of PE. Dapoxetine 60 mg significantly improves the mean intravaginal ejaculation latency time (IELT) compared to that of dapoxetine 30 mg in men with lifelong PE, but there is no difference in men with acquired PE. Dapoxetine, giving 1–3 hours before sexual episode, prolongs IELT, increases the sense of control and sexual satisfaction in men of 18 to 64 years of age with PE. Since PE is associated with personal distress, interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition. Because lack of specific approval treatment for PE in the US and some other countries, other SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram have been used as off label drugs to treat PE. Waldinger's meta analysis shows that the use of these conventional antidepressants increasing IELT from two to ninefold above base line in comparison of three to eightfold when dapoxetine is used. However, these SSRIs must be taken daily in order to achieve meaningful efficacy, and the long half-life increases the risk of the drug accumulation and as a consequence increased of adverse effects such as decreasing sexual libido and causing erectile dysfunction. Dapoxetine, on the other hand, is a fast-acting SSRI. It is rapidly absorbed and eliminated from the body within a few hours. This favorable pharmacokinetics minimizes the risk of the drug's accumulation in the body, and therefore reducing side effects.

Mechanism of Actions

The mechanism through which dapoxetine affects premature ejaculation is still unclear. However, it is presumed that dapoxetine works by inhibiting serotonin transporter and subsequently increasing serotonin's action at pre and postsynaptic receptors. Human ejaculation is regulated by various areas in the central nervous system (CNS). The ejaculatory pathway originates from spinal reflex at the thoracolumbar and lumbosacral level of spinal cord activated by stimuli from male genital. These signals are relayed to the brain stem, which then is influenced by a number of nuclei in the brain such as medial preoptic and paraventricular nulcei. Clement's study performed on anaesthetized male rats showed that acute administration of dapoxetine inhibits ejaculatory expulsion reflex at supraspinal level by modulating activity of lateral paragigantocellular nucleus (LPGi) neurons. These effects cause an increase in pudendal motoneuron reflex discharge (PMRD) latency. However, it is unclear whether dapoxetine acts directly on LPGi or on the descending pathway in which LPGi located.

Development in Marketing internationally

Originally developed by Eli Lilly pharmaceutical company, dapoxetine was sold to Johnson & Johnson in 2003 and submitted as a New Drug Application to the Food and Drug Administration (FDA) for the treatment of PE in 2004.Dapoxetine is sold in some European and Asian countries, and in Mexico. In the US, dapoxetine has been in phase III development since 2003. However, it was rejected by FDA last year. In 2012, Menarini acquired the rights to sell Dapoxetine in Europe, most of Asia, Africa, Latin America and the Middle East.

Synthesis

Several synthetic routes for the preparation of dapoxetine have been disclosed, all on gram scale. Based on the routes and yields, the most likely process route is described in the scheme 4. Commercially available (R)-(+)-3-chloro-1-phenyl- 1-propanol (19) was reacted with 1-naphthol in the presence of 50% aqueous sodium hydroxide in DMF to give ether 20 in 90% yield. Activation of the secondary alcohol was accomplished through treatment of 20 with methane sulfonyl chloride and triethylamine with catalytic DMAP. Upon complete conversion to the corresponding mesylate, dimethylamine was added to the reaction mixture. The addition of hydrochloric acid in ethyl acetate to the resultant crude product gave dapoxetine hydrochloride (IV) in 67% yield. Purification of this material by re-crystallization from isopropanol provided IV in 86% yield and in 99.6% ee.

InChI:InChI=1/C21H23NO/c1-22(2)21(18-9-4-3-5-10-18)14-15-23-20-13-12-17-8-6-7-11-19(17)16-20/h3-13,16,21H,14-15H2,1-2H3