1030377-33-3 Usage
description
Suvorexant (Belsomra? ) is a novel sedative hypnotic drug that is prescribed to promote sleep in patients with insomnia. It is the first of a new class of drugs classified as dual orexin receptor antagonists (DORAs) and is currently approved for the treatment of insomnia in the United States and Japan. It is a CNS depressant and blocks the binding of wake-promoting neuropeptides orexin A and orexin B to the two orexin receptors (OX1R and OX2R) thus, altering the signaling (action) of orexin in the brain and suppressing the sleep-wake drive.
Suvorexant is a central nervous system (CNS) depressant and can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam. CNS depressant effects may persist in some patients for up to several days after discontinuing Suvorexant.
Belsomra (Suvorexant) can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. Caution patients taking Belsomra 20 mg against next-day driving and other activities requiring full mental alertness. Caution patients taking lower doses of Belsomra as well, because there is individual variation in sensitivity to Belsomra.
Pharmacokinetics
In fasting conditions, the median time to maximum plasma concentration of suvorexant is 2 h. For suvorexant 10 mg, the mean absolute bioavailability is 82 %. Administration of suvorexant with a high-fat meal had no clinically significant on systemic drug exposure, but delayed tmax by 1.5 h. Steady state is achieved within 3 days. The mean volume of distribution of suvorexant is 49 L. Suvorexant is extensively bound to plasma proteins, including albumin and a1-acid glycoprotein, and does not preferentially distribute into the red blood cells.?
Suvorexant is primarily metabolized by CYP3A, with a minor contribution by CYP2C19. The main circulating compounds are the unchanged drug and a hydroxyl metabolite, which is not expected to be pharmacologically active. Suvorexant is primarily eliminated in the faeces.
Hypnotic drugs
Suvorexant is a new hypnotic drug developed by the US pharmaceutical giant Merck. Unlike other hypnotics, instead of being administrated on demand like general hypnotics (that is, they are taken only when needed), Merck's Suvorexant is a therapeutic drug, should be subject to long-term administration.
The drug can block Orexins (neuropeptides) to send messages. Orexins (neuropeptides) usually transduces a variety of sobering messages for the human body, being the culprit leading to insomnia.
Professor Andrew Krystal from the Center for Medical Research at Duke University said Merck's drug would become a new drug favored by patients.
Darryle Schoepp, the head of neurology and ophthalmology at Merck, says the drug is especially suitable for patients who have been unable to sleep all night and have received little benefit from existing medications.
?“More than 2,000 patients with insomnia that not caused by other medical problems have participated in the two post-trials of Suvorexant,”Said by Merck. The most common side effects of the drug are fatigue and headache.
On August 13, 2014, the US Food and Drug Administration (FDA) approved the release of Belsomra (Suvorexant) from Merck for the treatment of patients who fall asleep and have difficulty sleeping (insomnia). Belsomra is an orexin receptor antagonist and is the first approved drug in this class of drugs. Orexin is a kind of chemical substances that participate into the regulation of sleep wake-up period, playing an important role in maintaining human awakening. Belsomra can alter the information behavior of orexins in the brain.
Figure 1 structure of the Suvorexant.
Mechanism of action
Suvorexant is a dual antagonist of orexin receptors OX1R and OX2R. It exerts its pharmacological effect by inhibiting binding of neuropeptides orexin A and B, also known as hypocretin 1 and 2, that are produced by neurons in the lateral hypothalamus. These neurons control the wake-promoting centers of the brain and are active during wakefulness, especially during motor activities, and stop firing during sleep. By inhibiting the reinforcement of arousal systems, suvorexant use causes a decrease in arousal and wakefulness, rather than having a direct sleep-promoting effect. References https://www.drugbank.ca/drugs/DB09034
Clinical evaluation
The US Food and Drug Administration (FDA) have approved a new remedy for the treatment of insomnia, suvorexant (Belsomra), which is an orexin receptor antagonist.
Suvorexant is the first approved orexin receptor antagonist that inhibits the neuronal activation of the wake-up system by blocking the binding of the neuropeptides, orelectins A and B, to the orexin receptors.
According to suvorexant producer Merck, the FDA recommended its inclusion in the control substance, to which DEA proposed earlier this year that it should be classified as a Category IV control substance under the Controlled Substances law.
At the end of 2012, Merck submitted its listing application to the US Food and Drug Administration (FDA). In May 2013, FDA's Peripheral and CNS Drugs Committee questioned the safety of the initial dose proposed by the company. A few months later, the FDA recommended that the initial dose for most patients should be set at 10 mg.
The company had not prepared the formulation of this dosage, thus have redesigned and produced of several new formulations.
"The FDA has approved four specifications-5, 10, 15, and 20 mg of Belsomra," said by Dr. Ellis Unger who is the director of the FDA's Center for Drug Evaluation and Evaluation. Dr. Unger said in a statement, "using the smallest effective doses can reduce the risk of side effects, such as drowsiness in the morning.”
FDA and Merck said that: it is only needed to administrate 1 tablet of Suvorexant at a time of between half an hour before sleeping every night to at least 7 hours before getting up at least 7 hours, no more than 20 mg per day.
Drowsiness is the most common side effect. In the next day driving behavior study, which was required by the FDA, the capability of the patients who have administrated 20 mg were impaired. The FDA warned that patients subjecting to a 20 mg dosage should be warned not to engage in driving or any other activity requiring vigilance the next day.
The drug may also lead to what the FDA calls "complex behaviors upon sleepy driving and other non-complete arousal state", including cooking and eating, phone calls, or sexual activity. If this behavior occurs, the patient and his family should inform the doctor.
Suvorexant is distributed together with a patient medication guide, which contains detailed safety information.
The FDA said that although three trials were conducted on the drug, none were compared with other approved hypnotic drugs, so the comparative effectiveness of the drug remains unknown.
Information on the indications, dosage and pharmacological effects of new hypnotic drug suvorexant (Belsomra) are edited by Tongtong from the lookchem.
side effects
Suvorexant (BELSOMRA) has possible side effects. Before you begin treatment, it’s important to know what these side effects are and to discuss the risks and benefits of taking BELSOMRA with your doctor.
Below is a list of the most commonly reported adverse events that occurred in 3-month clinical trials:
placebo (n=767) BELSOMRA 15 mg or 20 mg (n=493)
Diarrhea (placebo 1%, BELSOMRA 2%)
Dry mouth (placebo 1%, BELSOMRA 2%)
Upper respiratory tract infection (placebo 1%, BELSOMRA 2%)
Headache (placebo 6%, BELSOMRA 7%)
Next-day drowsiness (placebo 3%, BELSOMRA 7%)
Dizziness (placebo 2%, BELSOMRA 3%)
Abnormal dreams (placebo 1%, BELSOMRA 2%)
Cough (placebo 1%, BELSOMRA 2%)
Side effects that you should report to your doctor or health care professional as soon as possible:
allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
confusion
depressed mood
feeling faint or lightheaded, falls
hallucinations
inability to move or speak for up to several minutes while you are going to sleep or waking up
memory loss
periods of leg weakness lasting from seconds to a few minutes
problems with balance, speaking, walking
restlessness, excitability, or feelings of agitation
unusual activities while asleep like driving, eating, making phone calls
Side effects that usually do not require medical attention (Report these to your doctor or health care professional if they continue or are bothersome.):
abnormal dreams
daytime drowsiness
diarrhea
dizziness
headache
Dosage
The recommended dosage is 10 mg, to be taken orally no more than once per night, within 30 min of going to bed and with at least 7 h remaining until the planned awaken time. If this dosage is well tolerated but not effective, the dosage can be increased up to a maximum of 20 mg once daily; the lowest effective dosage should be used. Patients taking concomitant moderate cytochrome P450 (CYP) 3A4 inhibitors should receive a reduced dose of 5 mg.
Biological activity
Suvorexant (MK-4305) is a potent OX receptor antagonist, acting on the OX1 receptor and the OX2 receptor with a Ki being 0.55 nM and 0.35 nM, respectively. Phase III.
In vivo studies
In rats, Suvorexant has excellent passive permeability and oral bioavailability, and is conducive to sleep. In addition, suvorexant significantly and dose-dependently decreased the motor activity of rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and monkeys (10 mg/kg), while promoting their sleep.
Feature
The regulation of dual OX antagonist on sleep is currently in phase III clinical trials.
Description
Different sources of media describe the Description of 1030377-33-3 differently. You can refer to the following data:
1. Suvorexant, a dual orexin receptor antagonist marketed under
the trade name Belsomra?, discovered and developed by Merck
for the treatment of insomnia, was approved by the US FDA in
August 2014 and became available in Japan in November of the
same year. The drug’s mechanism of action operates through
the competitive blockade of wake-promoting neuropeptides orexin
A and orexin B toward receptors orexin receptor type 1 and orexin
receptor type 2, which are believed to modulate sleep-wake
cycles.
2. Suvorexant (Item No. 22911) is an analytical reference standard categorized as a diazepane sedative. Formulations containing suvorexant show abuse potential similar to zolpidem in recreational polydrug users with a history of sedative and psychedelic drug use. Suvorexant is regulated as a Schedule IV compound in the United States. This product is intended for use in analytical forensic applications. This product is also available as a general research tool .
3. Suvorexant is a dual orexin receptor (OXR) antagonist that blocks both OX1R and OX2R (Kis = 1.2 and 0.60 nM, respectively). It reduces locomotor activity and promotes sleep by inhibiting the binding of orexin A and B. In rats, suvorexant decreases self-administration of, and conditioned place preference for, cocaine ( | 16186 | ISO60176). It also decreases dopamine levels in the rat ventral striatum following a cocaine-induced increase. Formulations containing suvorexant are used in the treatment of insomnia. This compound is also available as an analytical reference standard .
Uses
Suvorexant (MK-4305) is a dual (non-selective) orexin receptor antagonist in development by Merck & Co. for the treatment of insomnia. It works by turning off wakefulness rather than by inducing sleep. Users of higher doses had an increased rate of suicidal ideation.
Definition
ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with the secondary amino group of 5-chloro-2-[(5R)-5-methyl-1,4-diazepan-1-yl]-1,3-benzoxazole. An
rexin receptor antagonist used for the management of insomnia.
Synthesis
Commercially available acid 240 was first
subjected to a copper-assisted substitution reaction involving
1,2,3-triazole in DMF at elevated temperatures. Although these
conditions resulted in an excellent yield of a triazole-substituted
product, an approximate 4:1 ratio of the desired 2-arylated triazole
241 and the undesired 1-arylated triazole byproduct were recovered
from the reaction. The mixture was then treated with N,Ndimethylethylenediamine
in acid to sequester copper. Next, the
mixture of arylated triazoles was carefully subjected to sodium tbutoxide
in DMF and ethyl acetate to form the corresponding
sodium salts, and interestingly it was found that the desired
sodium salt of 241 could be isolated based on its solubility profile
under these conditions. Acidification of the desired carboxylate salt
using dilute HCl gave rise to acid 241 in 60% yield across the fourstep
sequence. Next, subjection of this acid to oxalyl chloride in
chilled DMF generated the acid chloride 242 in excellent yield. This
crude acid chloride was used immediately in the next step of the
synthetic sequence.
For the preparation of the diazepine-containing portion of
suvorexant, the synthesis commenced with the condensation of
commercial 2-amino-4-chlorophenol (243) with thiophosgene
(244) to furnish benzoxazole 245. Next, thiol 245
was converted to the corresponding chloride prior to exposure to
Boc-protected ethylenediamine 246 under basic conditions. This
was followed by a Michael addition of the resulting aminobenzoxazole
and methyl vinyl ketone (MVK). The result of this sequence of
reactions delivered aminobenzoxazole ketone 247 in 75% yield
over the three steps. Next, subjection of the carbamate to methanesulfonic acid removed the Boc functionality and this was
followed by an intramolecular reductive amination sequence to
construct the diazaepine ring. Acid–base workup ultimately provided
the racemic diazepine 248 in 92% yield from 247. Next, salt
formation with a benzoyl tartaric acid and subsequent recrystallization
upgrade using isopropyl acetate and methanol at ambient
temperature was used to resolve racemic 248 into the tartrate salt
249 in 27% yield and excellent enantiomeric excess. Finally, salt
249 was freebased using sodium hydroxide prior to exposure to
the crude acid chloride 242 under basic conditions to ultimately
deliver suvorexant (XXX) in 95% yield and 99% ee across the twostep
sequence.
Check Digit Verification of cas no
The CAS Registry Mumber 1030377-33-3 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,3,0,3,7 and 7 respectively; the second part has 2 digits, 3 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1030377-33:
(9*1)+(8*0)+(7*3)+(6*0)+(5*3)+(4*7)+(3*7)+(2*3)+(1*3)=103
103 % 10 = 3
So 1030377-33-3 is a valid CAS Registry Number.
1030377-33-3Relevant articles and documents
Rhodium-Catalyzed ortho-Cyanation of 2-Aryl-1,2,3-triazole: An Alternative Approach to Suvorexant
Zhang, Hailong,Jing, Li,Zheng, Yang,Sang, Rui,Zhao, Yi,Wang, Qiantao,Wu, Yong
, p. 723 - 729 (2018)
A rhodium-catalyzed ortho-cyanation protocol for 2-aryl-1,2,3-triazole has been developed by using N-cyano-N-phenyl-p-toluensulfonamide (NCTS) as an environmentally friendly cyanide source. This simple cyanation reaction provides a new protocol for the diversification of benzonitriles in moderate to good yields and tolerates useful functional groups. In addition, the method was used to synthesize 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, which is the key intermediate of suvorexant.
Preparation method and application of suvorexant intermediate
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Paragraph 0183-0185, (2021/03/31)
The invention provides a preparation method and application of a suvorexant intermediate, and relates to the technical field of chemical synthesis. The preparation method of the suvorexant intermediate comprises the following step: (e) reacting a compound as shown in a formula IV under the action of a Grubbs catalyst to obtain a compound as shown in a formula V. The Grubbs catalyst (Grubbs second-generation catalyst) is creatively used for construction of the suvorexant intermediate seven-membered nitrogen-containing chiral heterocycle, an inflammable and highly toxic compound methyl vinyl ketone is not needed, inflammable and explosive toxic gas is not needed, reaction is not needed under the conditions of strong acid, strong alkali and high temperature, generation of a large amount of acid liquor and alkali liquor and high-temperature operation can be avoided, the method is mild in reaction condition, environment-friendly, high in safety coefficient and easy to industrialize.
SUVOREXANT INTERMEDIATE AND PREPARATION METHOD THEREOF
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Paragraph 0087-0091, (2019/02/19)
The present invention relates to a synthesis process of suvorexant, novel compounds represented by formulas II, III, IV or V, or salts thereof for preparing suvorexant, and a method for preparing the intermediates. The preparation method uses a chiral starting material to synthesize chiral compounds represented by formulas II, III, IV or V, the compounds obtained being used for synthesizing the suvorexant. The preparation method has the advantages of simple operation, low cost, mild reaction conditions, simple post-treatment, easy to purify, high yield, high ee value for the product, and easy to industrialize. In the reaction route shown, R represents benzyl, allyl or 1-phenethyl, or optionally substituted benzyl at the 2 position to 6 position, such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl.
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