The U.S. Food and Drug Administration today approved Belsomra (suvorexant) tablets for use as needed to treat difficulty in falling and staying asleep (insomnia).

Belsomra is an orexin receptor antagonist and is the first approved drug of this type. Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake. Belsomra alters the signaling (action) of orexin in the brain.

Insomnia is a common condition in which a person has trouble falling or staying asleep. It can range from mild to severe, depending on how often it occurs and for how long. Insomnia can cause daytime sleepiness and lack of energy. It also can make a person feel anxious, depressed, or irritable. People with insomnia may have trouble with attentiveness, learning, and memory.

“To assist health care professionals and patients in finding the best dose to treat each individual patient’s sleeplessness, the FDA has approved Belsomra in four different strengths – 5, 10, 15, and 20 milligrams,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research. “Using the lowest effective dose can reduce the risk of side effects, such as next-morning drowsiness.”

Belsomra should be taken no more than once per night, within 30 minutes of going to bed, with at least seven hours remaining before the planned time of waking. The total dose should not exceed 20 mg once daily.

The most commonly reported adverse reaction reported by clinical trial participants taking Belsomra was drowsiness. Medications that treat insomnia can cause next-day drowsiness and impair driving and other activities that require alertness. People can be impaired even when they feel fully awake.

The FDA asked the drug manufacturer, Merck, Sharpe & Dohme Corp., to study next-day driving performance in people who had taken Belsomra. The testing showed impaired driving performance in both male and female participants when the 20 mg strength was taken.  Patients using the 20 mg strength should be cautioned against next-day driving or activities requiring full mental alertness. Patients taking lower doses should also be made aware of the potential for next-day driving impairment, because there is individual variation in sensitivity to the drug.

The effectiveness of Belsomra was studied in three clinical trials involving more than 500 participants. In the studies, patients taking the drug fell asleep faster and spent less time awake during the remainder of the night compared to people taking an inactive pill (placebo). Belsomra was not compared to other drugs approved to treat insomnia, so it is not known if there are differences in safety or effectiveness between Belsomra and other insomnia medications.

Like other sleep medicines, there is a risk from Belsomra of sleep-driving and other complex behaviors while not being fully awake, such as preparing and eating food, making phone calls, or having sex. Chances of such activity increase if a person has consumed alcohol or taken other medicines that make them sleepy. Patients or their families should call the prescribing health care professional if this type of activity occurs.

Belsomra will be dispensed with an FDA-approved patient Medication Guide that provides instructions for its use and important safety information. Belsomra is a controlled substance (Schedule-IV) because it can be abused or lead to dependence.

Belsomra is made by Merck, Sharpe & Dohme Corp. of Whitehouse Station, N.J.

old article

[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone

Suvorexant

may23,2013

A panel of experts at the US Food and Drug Administration has recommended Merck & Co’s insomnia drug suvorexant when given in lower dosages but rejected the higher dose that the company was seeking.———read more at

http://www.pharmatimes.com/Article/13-05-23/FDA_panel_backs_Merck_Co_sleep_drug_but_at_low_doses.aspx

Suvorexant (MK-4305) is a dual orexin receptor antagonist in development by Merck & Co.^[1][2][3] Suvorexant works by turning off wakefulness rather than by inducing sleep.^[4] It is not currently approved for commercial use, but it has completed three Phase III trials.^[5]The recent FDA review showed that the drug is associated with increased somnolence the next day and users of higher doses had an increased rate of suicidal ideation. ^[6] It is one of two such compounds currently in development, the other being GlaxoSmithKline‘s SB-649,868.

OREXINS A AND B ARE EXCITATORY NEUROPEPTIDES THAT STIMULATE WAKEFULNESS. SUVOREXANT IS A DUAL OREXIN RECEPTOR ANTAGONIST THAT IS IN PHASE III CLINICAL TRIALS FOR THE TREATMENT OF INSOMNIA. THE KEY STEP IN THE ASYMMETRIC SYNTHESIS ­DEPICTED IS A TANDEM ENZYMATIC TRANSAMINATION–ANNULATION SEQUENCE (F → G → H).

A previous synthesis of suvorexant (N. A. Strotman et al. J. Am. Chem. Soc. 2011, 133, 8362) involved an asymmetric Ru-catalyzed reductive amination in the construction of the diazepane ring. The present route benefits from the circumvention of transition-metal catalysis and dichloromethane as solvent.

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http://www.google.co.in/patents/US7951797

benzyl (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane-1-carboxylate (G-1)

To a solution of 22.3 g (78 mmol) of the hydrochloride salt of F-1, 15.9 g (78 mmol) A-2, 12.8 g (94 mmol) 1-hydroxy-7-azabenzotriazole, and 43.1 mL (392 mmol) N-methylmorpholine in 300 mL of DMF was added 22.5 g (118 mmol) EDC and the reaction was stirred overnight at room temperature. The reaction was partitioned between EtOAc and saturated aqueous NaHCO₃, washed with water, brine, dried over MgSO₄, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc/hexanes) to provide G-1 as a colorless gum. Data for G-1: LC/MS: rt=2.22 min; m/z (M+H)=434.2 found; 434.2 required.

(7R)-7-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane (G-2)

A round bottom flask containing a solution of 29.6 g (68.3 mmol) G-1 in 300 mL EtOAc and 200 ml MeOH was evacuated under reduced pressure and purged three times with an atmosphere of N₂. To the flask was then added 2.4 g of 20% Pd(OH)₂on carbon. The flask was again evacuated under reduced pressure and purged three times with an atmosphere of N₂, and then three times with H₂. The reaction was stirred under an atmosphere of H₂ for three days, then filtered through a pad of celite, rinsing with EtOAc followed by MeOH. The filtrate was concentrated to provide G-2 as a white foam. Data for G-2: LC/MS: rt=0.96 & 1.13 min (see two conformers under these conditions); m/z (M+H)=300.0 found; 300.2 required.

5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole (G-3)

To 21.0 g (70.1 mmol) G-2 in 250 mL DMF was added 29.3 mL (210 mmol) triethylamine and 13.2 g (70.1 mmol) D-1 and the mixture was heated in an oil bath at 75° C. for 2 h. After cooling to room temperature, the reaction was diluted with EtOAc, washed with saturated aqueous NaHCO₃, water, brine and dried over MgSO₄. Following concentration by rotary evaporation, the residue was purified by flash column chromatography (hexanes/EtOAc) to provide a gum. The gum was stirred in a mixture of 150 ml EtOAc and 300 ml hexanes overnight. Filtration provided G-3 as a white solid. Data for G-3: LC/MS: rt=2.29 min; m/z (M+H)=451.1 found; 451.2 required; HRMS (APCI) m/z (M+H) 451.1631 found; 451.1644 required.