508233-74-7 Usage
Curative for Major Depression Disorder
Vortioxetine is a new drug for treating depression, jointly developed and researched by the Danish Lundbeck (Lundbeck) and Japanese Takeda. ?In September 30, 2013, It is approved by the U.S. Food and Drug Administration (FDA) to enter into market with the brand name of Brintellix, for Major Depression Disorder (MDD) treatment.
In October 2013, the European Medicines Agency (EMA)’s subordinate agency: Committee for Medicinal Products for Human Use (CHMP) recommended that vortioxetine for the treatment of severe depression should be licensed in the European market and be launched into ?the ?European market in January 2014.
MDD features mood changes and a series of other symptoms, which have a great impact on the patient's ability to work, sleep, study, eat and enjoy the current happiness. Depressive symptoms can recur many times in life, but some patients may experience only once.
Vortioxetine, mainly by increasing the concentration of serotonin (5-HT) in the central nervous system (CNS), exerts antidepressant effects. Compared with other selective serotonin reuptake inhibitors (SSRIS) or serotonin-norepinephrine reuptake inhibitors (SNRIS), vortioxetine almost has no effect on norepinephrine and dopamine neurons. A number of clinical trials have demonstrated the efficacy, safety and tolerability of vortioxetine in the treatment of MDD.
Figure 1 shows the structure of vortioxetine.
Mechanism of Action
Vortioxetine is a small molecule piperazine sulfide. WHO w classifies it as antidepressants (N06A). The drug classification system of European Pharmaceutical Market Research Association (EPhMRA) classifies it as hypnotic / sedative drugs (N5B), antidepressants and mood stabilizers (N6A). Currently, depression is thought to be associated with a decrease in 5-HT activity, and decreased activity of norepinephrine (NE) and dopamine (DA) is thought to be associated with depression.
Vortioxetine is a potent serotonin reuptake inhibitor. In human body it has high affinity with serotonin trans-porter (Ki=1.6 nmol - L - 1). But it almost has no affinity with norepinephrine transporter (Ki=113nmol - L-1) and dopamine transporter (Ki= 1000nmol - L - 1). At the same time, it is also a 5-HT1A receptor agonist and 5-HT1B receptor partial agonist, 5-HT1D, 5-HT3 and 5-HT7 receptor antagonist and 5-HT uptake inhibitor. Animal studies have shown that in rats, vinpocetine through interaction on these receptors, will increase depression related brain regions -- the level of the ventral hippocampus, prefrontal cortex extracellular serotonin , dopamine, norepinephrine, acetylcholine and histamine, at the same time it is also regulating the function of ?y -GABA (γ-aminobutyric acid) and glutamatergic neuron, thus exerting the effect of antidepressant.
Pharmacokinetics
The relative molecular weight of vortioxetine is small, and the plasma protein binding rate is 98 percent, which is not related to plasma concentration. It is widely distributed outside the cell and the apparent distribution volume is about 2600 L. Daily oral administration is 2.5 ~ 60mg, showing the linear pharmacokinetic characteristics in proportion to dosage of administration. Bioavailability is 75 percent and generally after 2 weeks of taking vortioxetine, its concentration will be stable in blood. Cmax is 7 to 11 hours. Vortioxetine is metabolized mainly by oxidation and glucuronidation . After a single oral administration of the radioisotope labeled vortioxetine, about 59 percent of it is excreted through the urine, and about 26 percent were excreted through the feces. There was almost no original vortioxetine 48 hours after administration of the drug. The complete metabolism in body requires about 66 hours. The oxidation is mainly completed through cytochrome P450 enzyme (CYP). The involved CYP includes CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6 and CYP2D6. Among them, CYP2D6 is the key enzyme which catalyzes and produces the main metabolite of duloxetine carboxylic acid. The drug concentration of CYP2D6 in the plasma with slow metabolism is twice higher than that of CYP2D6 in the plasma with the fast metabolism.
Drug Interaction
In the different experiment and researches using healthy volunteers as subjects, vortioxetine will be co-administered respectively with CYP2D6 inhibitor bupropion, CYP2C9/CYP2C19/CYP3A inhibitor fluconazole or CYP3A/ permeability glycoprotein (P-gp) inhibitor ketoconazole. The vortioxetine’s bioavailability will increase. Therefore when vortioxetine and strong CYP2D6 inhibitors (such as bupropion, fluoxetine, paroxetine and quinidine) are co-administered, the dosage should be halved.
When vortioxetine and strong CYP inducers (rifampicin) are co-administered, its bioavailability will be reduced. Therefore when vortioxetine is co-administered with rifampicin or other strong CYP inducers (such as carbamazepine, Phenytoin sodium), the dosage should be increased, but the maximum dosage should not be three times higher than the normal dose.
In addition, the use of 5-HT drugs itself is a risk factors of incurring abnormal bleeding. Therefore when vortioxetine is co-administered with aspirin, nonsteroidal anti-inflammatory drugs or other drugs affecting blood coagulation, special attention should be drawn to the abnormal bleeding of patients.
Considering the functional mechanism of vortioxetine and potential toxicity of serotonin, so when it is co-administered with other drugs affecting 5-HT neurotransmitter systems (such as SSRIs, SNRIs, and triptans, buspirone, tramadol and tryptophan products), lt is likely to occur 5-HT syndrome. Therefore, close attention should be paid to the risk of 5-HT syndrome when it is used in combination with such drug. Once the 5-HT syndrome occurs, all such drugs should be discontinued immediately.
Similar to the above reasons, monoamine oxidase inhibitors (MAOIs) are prohibited from being used in combination with MAOIs. MAOIs can not be administered within 21d after discontinuation of vortioxetine, and vortioxetine can not be administered within 14d after discontinuation of MAOIs. Because the combination of both will increase the risk of 5-HT syndrome in patients.
Synthesis
Different sources of media describe the Synthesis of 508233-74-7 differently. You can refer to the following data:
1. 2,4-dimethyl-1- iodo-benzene reacts with 2- bromophenyl thiophenol and Bis(dibenzylidene acetone)palladium, under sodium tert-butoxide’s catalysis ?to generate vortioxetine
2,4- dimethyl thiophenol and 2- bromo benzene and piperazine(1-BOC-piperazine) react under the catalysis of Bis(dibenzylidene acetone)palladium , 1, 1'- linked naphthalene -2, 2'- bis diphenyl ?phosphine and sodium tert-butoxide to generate vortioxetine.
Figure 1 is a chemical reaction diagram for the synthesis of vortioxetine.
2. The sequence involves iterative palladium-catalyzed carbon–
heteroatom bond formations, the first establishing the thioethereal
bond between commercially available thiol (213) and o-iodobromobenzene
(214) employing conditions described by Schopfer
and Schlapbach. Next, Buchwald–Hartwig conditions were
employed to establish the piperazine linkage, and this was
followed by subjection to warm hydrobromic acid to furnish
vortioxetine hydrobromide (XXVI) in 75% yield across the entire
three-step sequence.
Description
In September 2013, vortioxetine (also known as Lu AA21004) was approved in the United States for the treatment of major depressive disorder (MDD). Vortioxetine was discovered from a designed multiple ligand approach to identifying an antidepressant agent that combined SERT inhibition with 5-HT1A agonism to more rapidly desensitize 5-HT1A receptors and 5-HT3A antagonism to improve mood and cognitive function. Vortioxetine has a human SERT IC50=5.4 nM, an EC50=200 nM as a human 5-HT1A receptor agonist (efficacy=96%; Ki=39 nM), and an IC50=12 nM as a human 5-HT3A receptor antagonist (Ki=3.7 nM). It has weak inhibition of the dopamine and norepinephrine transporters, but high affinity for the human β1-noradrenergic receptor (Ki=46 nM), human 5-HT1B receptor (Ki=33 nM, partial agonist), and the human 5-HT-7 receptor (Ki=19 nM, antagonist).
Uses
Vortioxetine can be used in biological study of effectiveness of long term vortioxetine treatment of patients with major depressive disorder.
Definition
ChEBI: An N-arylpiperazine in which the aryl group is specified as 2-[(2,4-dimethylphenyl)sulfanyl]phenyl. Used (as its hydrobromide salt) for treatment of major depressive disorder.
Brand name
Brintellix
in vitro
vortioxetine (lu aa21004) was the lead compound, displaying high affinity for recombinant human 5-ht1a (ki = 15 nm), 5-ht1b (ki = 33 nm), 5-ht3a (ki = 3.7 nm), 5-ht7 (ki = 19 nm), and noradrenergic β1 (ki = 46 nm) receptors, and sert (ki = 1.6 nm). vortioxetine displayed antagonistic properties at 5-ht3a and 5-ht7 receptors, partial agonist properties at 5-ht1b receptors, agonistic properties at 5-ht1a receptors, and potent inhibition of sert [1].
in vivo
in conscious rats, vortioxetine significantly increased extracellular 5-ht levels in the brain after acute and 3 days of treatment. following the 3-day treatment (5 or 10 mg/kg/day) sert occupancies were only 43% and 57%, respectively [1].
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: avoid with linezolid; concentration
reduced by rifampicin - consider increasing
vortioxetine dose.
Antidepressants: possible increased risk of
convulsions with SSRIs and, tricyclics; avoid with
moclobemide; increased risk of hypertension and
CNS excitation with MAOIs - avoid.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin and phenytoin -
consider increasing vortioxetine dose.
Antimalarials: possible increased risk of convulsions
with mefloquine; avoid with artemether with
lumefantrine and artenimol with piperaquine.
Antipsychotics: possible increased risk of convulsions
with butyrophenones, phenothiazines and
thioxanthenes.
Dopaminergics: risk of CNS excitation and
hypertension with rasagiline and selegiline.
Metabolism
Vortioxetine is extensively metabolised in the liver, mainly
by oxidation catalysed by CYP2D6 and to a minor extent
CYP3A4/5 and CYP2C9, and subsequent glucuronic
acid conjugation. The major metabolite of vortioxetine is
pharmacologically inactive.
Approximately two thirds of the inactive vortioxetine
metabolites are excreted in the urine and approximately
one third in the faeces. Only negligible amounts of
vortioxetine are excreted in the faeces.
references
[1] bang-andersen b, ruhland t, j?rgensen m, smith g, frederiksen k, jensen kg, zhong h, nielsen sm, hogg s, m?rk a, stensb?l tb. discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (lu aa21004): a novel multimodal compound for the treatment of major depressive disorder. j med chem. 2011;54(9):3206-21. [2] theunissen el, street d, h?jer am, vermeeren a, van oers a, ramaekers jg. a randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (lu aa21004), on actual driving and cognition. clin pharmacol ther. 2013;93(6):493-501.
Check Digit Verification of cas no
The CAS Registry Mumber 508233-74-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 5,0,8,2,3 and 3 respectively; the second part has 2 digits, 7 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 508233-74:
(8*5)+(7*0)+(6*8)+(5*2)+(4*3)+(3*3)+(2*7)+(1*4)=137
137 % 10 = 7
So 508233-74-7 is a valid CAS Registry Number.
InChI:InChI=1S/C18H22N2S/c1-14-7-8-17(15(2)13-14)21-18-6-4-3-5-16(18)20-11-9-19-10-12-20/h3-8,13,19H,9-12H2,1-2H3
508233-74-7Relevant articles and documents
Preparation method of novel severe depression treatment drug
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Paragraph 0033-0036; 0040-0043; 0045-0048; 0050-0053; ..., (2021/10/16)
The invention provides a preparation method of novel medicament for treating severe depression, and belongs to the field of drug synthesis. A specific scheme of the invention is as follows: 2,4 - dimethyl thiophenol is used. 2 - Bromoiodobenzene, piperazine is a starting material, cuprous iodide is used as a catalyst, one-pot method is used for preparing the, and an organic base is added in the reaction system. To the preparation process, the reaction can be effectively carried out in a homogeneous phase, so that the reaction speed is obviously increased, and the product yield is greatly improved. The problem that in the prior art, homogeneous phase cannot be formed in a reaction system, the reaction time is over 40 hours, and the cost is not greatly reduced in industrial production is solved. Due to the adoption of triethylamine, N, N - diisopropylethylamine and other organic amines, the reaction can be carried out in a homogeneous phase, so that the secondary reaction is reduced, the yield and the purity are greatly improved. The piperazine does not need to be simultaneously added with the starting materials, the feeding step is optimized, the side reaction is reduced, the processes such as filtering are not increased, the procedures in industrialization are not increased, and the investment of equipment and the like is increased.
Redox-active benzimidazolium sulfonamides as cationic thiolating reagents for reductive cross-coupling of organic halides
Zhang, Weigang,Huang, Mengjun,Zou, Zhenlei,Wu, Zhengguang,Ni, Shengyang,Kong, Lingyu,Zheng, Youxuan,Wang, Yi,Pan, Yi
, p. 2509 - 2514 (2021/03/01)
Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C-S bond coupling. The IMDN-SO2R reagent provides a bench-stable cationic precursor to generate a portfolio of highly active N-S intermediates, which can be successfully applied in cross-electrophilic coupling with various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and excellent tolerance.
Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS2 fingerprinting from collision-induced decomposition of protonated ions
Wang, Shaolan,Lin, Jinsheng,Li, Dan,Huang, Tianpei,Zhu, Wenquan,Chen, Wenbin,Li, Min,Shen, Weiyang
, (2021/04/14)
Rationale: The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS2) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. Methods: Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2. Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. Results: The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2H3O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. Conclusions: The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.
