960203-27-4 Usage
Uses
Used in Pharmaceutical Industry:
Vortioxetine hydrobromide is used as an antidepressant for the treatment of major depressive disorder. It modulates the serotonergic system by inhibiting 5-HT1A, 5-HT1B, 5-HT3A, 5-HT7 receptors, and the serotonin transporter (SERT), leading to an improvement in mood and reduction in depressive symptoms.
Additionally, it may be used as an anxiolytic drug for the treatment of anxiety disorders, due to its serotonergic agonist and antagonist properties, which can help regulate mood and reduce anxiety levels.
Antidepressant
Vortioxetine HBr is a new type of diaryl sulfanyl amine antidepressants developed by Japan Takeda and Denmark Lundbeck for the treatment of depression and anxiety. FDA was admitted to be on American market in September 2013 with trade name Brintellix used for the treatment of severe depression in adults and in October of the same year, the admittance application of Vortioxetine to be listed (MAA) received positive comments from European Medicines Agency (EMA) Human Medicines Products Committee (CHMP). CHMP advised to approve of Brintellix being used for the treatment of adult patients with severe depression (MDD). The EMA European Commission granted Vortioxetine the right to be sold throughout the EU in December 2013 with four dose forms,5 mg, 10 mg, 15 mg and 20 mg. Vortioxetine hydrobromide now has applied to be listed in a number of countries except in China.
Vortioxetine HBr is considered to be a new type of multi-model antidepressant. Vitro researches show that it can antagonize 5-HT3,5-HT7and 5-HT1D receptor, activate 5-HT1A receptor, partly activate 5-HT1B receptor and inhibit 5-HT from operation.
Vortioxetine is another kind of antidepressant made by Lundbeck aiming at replace Citalopram which is expired patent drug.
The pharmacological effect, indication, drug interaction, synthetic method and so on are edited by lookchem's Yao Yao.
Vortioxetine
Vortioxetine is an oral immediate release tablet whose main active ingredient is Vortioxetine hydrobromide, which is a kind of antidepressant. Vortioxetine hydrobromide is a slightly yellowish white powder and slightly soluble in water. It is a kind of tablet with different dose forms with each piece containing Vortioxetine hydrobromide 6.335mg,12.71mg,19.065mg or 25.42mg equivalent to 5mg, 10mg, 15mg and 20mg Vortioxetine respectively. The non-active ingredients in Vortioxetine tablet include mnnitol, microcrystalline cellulose, hydroxypropylcellulose, sodium carboxymethyl starch, magnesium stearate and thin film cover made up of hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol 400, ferric oxide and iron oxide yellow.
Clinical evaluation??? 1. Vortioxetine has a high affinity for 5-HT. Compared with duloxetine, oxetine, it can act on 5-HT3, 5-HT1A, 5-HT7,5-HT1D and 5-HT1B receptors with high selectivity. When used to regulate emotions , the dose is small, with simple medication once a day improving patient’s compliance. The drug has less drug interactions, high selectivity and less side effects.
Vortioxetine is a new antidepressant and is considered as the most successful drug in the study of single-phase emotional disorder. The results show that Vortioxetine is a more effective antidepressant compared with placebo and can significantly increase 5-HTT possession rate. It is safer with safety? similar to venlafaxine and the incidence of adverse reactions is lower than duloxetine. Another clinical study shows that Vortioxetine can effectively reduce the probability of recurrence after treatment.
Animal experiments show that Vortioxetine has a significant effect on behavioral analysis of antidepressant activity. In a number of rat anti-anxiety models, Vortioxetine has higher anti-anxiety activity compared to other known antidepressants and still has effect on the anxiety state on which paroxetine and duloxetine. cannot work.
In summary, compared with other antidepressants, Vortioxetine has high efficacy, less adverse reactions and obvious clinical advantages.
Biological activity
Vortioxetine (Lu AA21004) HBr is a 5-hydroxytryptamine inhibitor that inhibits 5-HT1A, 5-HT1B, 5-HT3A, 5-HT7 receptors and SERT with IC50 being 15nM,33nM, 3.7nM,19nM and1.6nM.
Approval
Vortioxetine hydrobromide is an atypical antidepressant made by Lundbeck and Takeda. It was approved by the United States Federal Drug Agency and the Committee for Medicinal Products for Human Use (CHMP) on September 30, 2013 and December 27, 2013 respectively, for the treatment of major depressive disorder in adults. Vortioxetine has also been investigated as a treatment for generalized anxiety disorder.
In vitro
Lu-AA21004 inhibits recombine human CYP1A2, CYP2C9, CYP2D6 and CYP3A4 with IC50 being 40μM, 39μM, 9.8μM and 10μM respectively. Lu AA21004 is a h5-HT1B receptor agonist with EC50 being 460nM and in the whole cell detection the intrinsic activity is 22%. In vitro full-cell cAMP assay, Lu AA21004 is a functional antagonist against r5-HT7 receptor with Ki being 200nM. Lu AA21004 is a functional antagonist of r5-HT7 receptor with IC50 being 2μM.
In vivo
The clearance on rat liver and oral bioavailability of Lu-AA21004 are 7.1(L/h)/kg and 16% respectively. Lu-AA21004 is injected subcutaneously into the hippocampus of the conscious rats at 2.5mg/kg, 5mg/kg or 10 mg/ kg to increase extracellular 5-HT levels. Lu-AA21004 significantly increases the basal level of 5-HT after being injected into medial prefrontal cortex (mPFC) at the dose of 5mg/kg or 10mg/kg for 3 days.
LuAA21004 affects the Bezold-Jarisch reflection of rats, which is dose-dependent and inhibits transient bradycardia with ED50 being 0.11mg /kg. LuAA21004 is injected subcutaneously into the medial prefrontal cortex and ventral hippocampus of the rats at the dose of 2.5-10.0mg/kg to increase the levels of extracellular 5-HT, DA, and NA. LuAA21004 is injected subcutaneously into the ventral hippocampus of rats at dose of??? 5mg/kg to increase extracellular 5-HT levels (200%). Lu AA21004 (10mg/kg) significantly reduces pain in rats. Lu AA21004 increases the level of ACh to 224% and 204% at dose of 5 and 10mg/kg after 20min.
Biological Activity
vortioxetine (lu aa21004) hbr (vortioxetine) is an antidepressant, [1] [2] and a serotonin (5-ht) receptor modulator [1] [3] with ki values of 3.7 nm, 19 nm, 200 nm, 33 nm, 15 nm, and 1.6 nm, to human (h) 5-ht3a receptor, h5-ht7 receptor, rat (r) 5-ht7 receptor, h5-ht1b receptor, h5-ht1a receptor and h5-ht transporter (hsert), respectively, with an ic50 value of 2080 nm to r5-ht7 receptor, and with an ec50 value of 460 nm to h5-ht1b receptor [3].5-ht is important in brain, acting as a neurotransmitter in neuromodulation [4].in hela cells expressing h5-ht1b receptors stably, lu aa21004 displayed a partial agonistic response with an ec50 value of 460±110 nm and an ia of 22%. in a polyclonal hek-293 cell line expressing the r5-ht7 receptor, lu aa21004 bound to the r5-ht7 receptor with a ki value of 200±27 nm and was a functional antagonist at the r5-ht7 receptor with an ic50 value of 2080±18 nm [3].in rats, subcutaneous (sc) administration of lu aa21004 resulted in ed50 values of 0.4 mg/kg and 3.2 mg/kg to the rsert and the r5-ht1b receptor, respectively. lu aa21004 acted as an antagonist of 5-ht3 receptor with an ed50 value of 0.11 mg/kg sc [3]. treatment with vortioxetine at doses of 2.5 and 5 mg/kg prior to the acquisition of novel objects made rats show 29 and 33 s, respectively, as average exploration values [5].
Synthesis
As the picture 2 showed, we have developed a new and practical synthetic route to vortioxetine hydrobromide on a hectogram scale. Adopting commercially available materials, through simple and traditional steps, including nucleophilic substitution, catalytic hydrogenation, and cyclization of the piperazine ring, gave the final product in 63.2% yield over three steps and with 99.3% purity (HPLC). Purification methods for the intermediates involved in the route are also given.
Pic.3 A new synthetic route to vortioxetine hydrobromide
Mode of action
Vortioxetine Hydrobromide is a hydrobromide salt form of vortioxetine, a serotonin (5-HT) modulator and stimulator (SMS), with antidepressant activity. Vortioxetine inhibits the reuptake of serotonin and norepinephrine from the synaptic cleft and acts variably as a serotonin receptor agonist (5-HT1A), partial agonist (5-HT1B) or antagonist (5-HT3, 5-HT1D and 5-HT7). It is not clear how this agent's purported multimodal mechanism of action contributes to its antidepressant effect; however, it is presumed to increase the synaptic availability of serotonin and norepinephrine.
references
[1]. connie sanchez, karen e. asin, francesc artigas, et al. vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. pharmacology & therapeutics, 2015, 145:43-57.[2]. er-min gu, chengke huang, bingqing liang, et al. an uplc–ms/ms method for the quantitation of vortioxetine in rat plasma: application to a pharmacokinetic study. j. chromatogr. b, 2015, 997:70-74.[3]. a. m?rk, a. pehrson, l.t. brennum, s. m?ller nielsen, et al. pharmacological effects of lu aa21004: a novel multimodal compound for the treatment of major depressive disorder. j. pharmacol. exp. ther., 2012, 340:666-675.[4]. david m. lovinger. serotonin’s role in alcohol’s effects on the brain. alcohol health & research world, 1997, 21(2):114-120.[5]. arne m?rk, liliana p. montezinho, silke miller, et al. vortioxetine (lu aa21004), a novel multimodal antidepressant, enhances memory in rats. pharmacology, biochemistry and behavior, 2013, 105:41-50.
Check Digit Verification of cas no
The CAS Registry Mumber 960203-27-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,6,0,2,0 and 3 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 960203-27:
(8*9)+(7*6)+(6*0)+(5*2)+(4*0)+(3*3)+(2*2)+(1*7)=144
144 % 10 = 4
So 960203-27-4 is a valid CAS Registry Number.
960203-27-4Relevant articles and documents
Preparation method of novel severe depression treatment drug
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, (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.
Preparation method of high-purity vortioxetine hydrobromide
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, (2021/05/08)
The invention belongs to the field of chemistry, and particularly relates to a preparation method of high-purity vortioxetine hydrobromide. According to the preparation method for preparing the high-purity vortioxetine hydrobromide, the o-fluoronitrobenzene and the piperazine are used as starting raw materials, the vortioxetine hydrobromide is further prepared in the organic solvent, the raw materials used in the method are low in price and cost and easy to operate, and the prepared vortioxetine hydrobromide is high in purity and few in impurity.
Manufacturing method of vortioxetine hydrobromide
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Paragraph 0056; 0073-0077, (2021/11/30)
Is a process for preparing fluoxetine hydrobromide used as an antidepressant. Provided is 1 [(2 dimethylphenyl) sulfanyl] aniline represented by chemical formula 4 - and bis (-chloroethyl) amine hydrochloride and hydrobromic acid represented by the following chemical formula - 2 - are reacted with benzothiazole represented 2,4- by the following general formula 4 or 3 and 2 - 2- [(2,4-dimethylphenyl) sulfanyl] aniline. The method according to claim 6, wherein the thioxanthine hydrobromide is represented by the following formula. Chemical Formula 1. Chemical Formula 2. Chemical Formula 3. Chemical Formula 4. Chemical Formula 6.
Preparation method of novel severe depression treatment drug
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Paragraph 0025-0028; 0031-0036, (2021/10/30)
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.
Preparation method of diaryl sulfide amine compound
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, (2020/03/12)
The invention relates to a preparation method for a diaryl thioether amine compound. Specifically, the invention relates to a preparation method for 1-[2-(2,4-dimethylphenylsulfalkyl)phenyl]piperazine derivative as shown in a formula I which is described in the specification. The preparation method comprises the following steps: subjecting a compound as shown in a formula V and a compound as shown in a formula IV to cyclization, condensation or introduction of an amino protective group; carrying out further condensation; etc. Thus, the target compound is obtained. Compared with other methods, the preparation method provided by the invention has the advantages of good process reproducibility and easy operation and the characteristics of high yield, low cost and high product purity, is more suitable for industrial production and has higher economic benefits.
THERAPEUTIC USES OF COMPOUNDS HAVING COMBINED SERT, 5-HT3 AND 5-HT1A ACTIVITY
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, (2020/08/09)
New pharmaceutical uses of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof are provided.
Preparation method of vortioxetine hydrobromide alpha-type crystal
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Paragraph 0043-0061, (2020/03/06)
The invention relates to the field of medicines, and discloses a preparation method of a vortioxetine hydrobromide alpha-type crystal. The method comprises the following steps: heating and dissolvingfree vortioxetine into isopropyl acetate, dropwise adding the obtained solution into an isopropyl acetate solution of hydrobromic acid, stirring, performing filtration, and drying to obtain the vortioxetine hydrobromide alpha-type crystal. The method has the advantages of good stability, good reproducibility, high yield, high purity, short time consumption, simplicity and convenience in operation,low solvent consumption, high safety, good environmental friendliness and the like, and is particularly suitable for the requirement of large-scale production in the pharmaceutical and chemical industries.
PROCESS AND NOVEL POLYMORPHIC FORM OF VORTIOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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, (2019/01/15)
Processes are disclosed for making vortioxetine and pharmaceutically acceptable salts thereof. A propylene glycol solvate of vortioxetine hydrobromide is disclosed. A novel crystalline form of vortioxetine hydrobromide propylene glycol solvate, designated form AC1, is disclosed along with a method for making same. Form AC1 may be characterized by an x-ray powder diffraction pattern with peaks at about 19.64, 22.85, 25.51, 29.57, 30.18±0.2 degrees 2-theta.
Robust Buchwald-Hartwig amination enabled by ball-milling
Cao, Qun,Nicholson, William I.,Jones, Andrew C.,Browne, Duncan L.
, p. 1722 - 1726 (2019/02/20)
An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.
AN IMPROVED PROCESS FOR THE PREPARATION OF VORTIOXETINE AND SALTS THEREOF
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Page/Page column 13-14, (2019/08/29)
The present invention relates to a novel crystalline polymorphic form of 1-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrochloride; commonly known as vortioxetine hydrochloride (hereafter referred to as the compound (Ia) and process for its preparation comprising of treating the compound (Ia) (as described herein) with a ketone solvent or mixture of ketone solvent with other solvents. The present invention also relates to an improved process for the preparation of vortioxetine hydrobromide (Ia), comprising reacting the compound (I) (as described herein) with hydrogen bromide solution in acetic acid.
