Melatonin agonists

The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. These include glutamate antagonists, melatonin agonists, and glucocorticoid-specific agents. Thus, monoamine function appears to be an important but not exclusive factor in the pathophysiology of depression. 

It seems very likely that there are important advances to be made in the application of melatonin agonists to the modification of sleep states and circadian rhythms. See also MELATONIN RECEPTOR ANTAGONISTS. 

Garratc. P.J. etai (1995) Mapping the melatonin receptor. 3. Design and synthesis of melatonin agonists and antagonists derived from 2-phenyltryptamines. 

He P, Ouyang X, Zhou S, Yin W, Tang C, Laudon M et al (2013) A novel melatonin agonist Neu-Pll facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer disease. Horm Behav 64 1-7... 

Factors influencing the application of literature methods toward the preparation of a chiral trans-cyclopropane carboxylic add intermediate during development of a melatonin agonist... 

Factors Influencing the Application of Literature Methods Toward the Preparation of a Chiral trans-Cyclopropane Carboxylic Acid Intermediate During Development of a Melatonin Agonist... 

Fig. 1 Retrosynthetic pathways to melatonin agonist drug candidate 1.

In the course of developing the melatonin agonist 1 (Fig. 1), potentially indicated for the treatment of sleep disorders, we evaluated approaches to the chiral cyclopropane intermediates 2 a and 2 b based on both classical resolution and asymmetric induction. Conceptually, these intermediates could be derived from di-hydrobenzofurans 3, 4 and 5 each of these was used at one stage or another during our research and development work. 

In the case of the melatonin agonist 1 a classical resolution was employed to prepare intermediate 2b, as shown in Fig. 3 (Route B). The remaining steps were then safely scaled up to prepare 1.1 kg of 1 in our kilo-lab. Route B began with re-... 

With the direct cyclopropanation step in hand, the free acid 2 b was liberated from 14 and taken through the amidation, reduction, and acylation steps (as described in Route C, Fig. 8) to afford the melatonin agonist 1 in 28% overall yield in 12 steps from dihydronaphthol 15 (Route D, Fig. 10). This sequence of procedures formed the basis of a manufacturing process. A comparison of key features relative to those from prior routes is given in Tab. 2. 

Faust, R., Garrat, P.J., Yeh, L.-K., Tsotinis, A., Panoussopoulou, M., et at- (2000) Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroin-dolo[2,l-a]isoquinolines, and 6,7-dihydro-5f/-benzo[c]azepino[2,l-ajindoles. J. Med. Chem. 43 1050-1061. 

Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms rationale for development of specific melatonin agonists. Sleep Med 2004 5 523-532. 

Prasad et al. [79] at BMS reported catalytic asymmetric synthesis of melatonin agonist 163 (Seheme 9.43), in, which the chirality of the molecule was introdueed by SAD reaetion on dihydrobenzofuran derivative 160. Catalytic Sharpless dihydroxylation of 160 gave the diol 161 in 84-94% yield (98-99% ee). One-pot conversion of the diol 161 to epoxide 162 was developed using modified Sharpless-Kolb procedure. The two-step process was demonstrated on multi kilogram scale. 

Prasad and co-workers at Bristol-Myers Squibb investigated the process-scale preparation of enantioenriched dihydrobenzofuran epoxide in support of their melatonin agonist programme (Scheme 14.56). The authors hoped to access kilogram quantities of 146 using the Jacobsen epoxidation as the key step. " Thus, the process was developed for the epoxidation of alkene 147 to afford 148. The researchers were able to carry this reaction out on kilo-scale successfully and enantioselectivities obtained were consistently 70-79%. While the Jacobsen epoxidation was able to perform where other catalysts could not (SAE), the investigators ultimately opted to use an alternative two-step process for the preparation of this epoxide on production-scale, utilising dihydrojylation and base-promoted 8 2 displacement to afford epoxide 148. 

---