608141-41-9 Usage
Uses
Used in Pharmaceutical Industry:
Apremilast is used as an oral treatment for adults with active psoriatic arthritis (PsA) and adults with moderate to severe plaque psoriasis. The inhibition of PDE4 in immune cells leads to an elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which can regulate inflammatory mediators and provide effective and well-tolerated management of these conditions.
Used in Psoriatic Arthritis Treatment:
Apremilast is used as an anti-inflammatory agent for the treatment of active psoriatic arthritis. By inhibiting the PDE4 enzyme, it helps to reduce inflammation and alleviate the symptoms associated with this autoimmune disease.
Used in Plaque Psoriasis Treatment:
Apremilast is used as a therapeutic option for adults with moderate to severe plaque psoriasis. Its mechanism of action involves the inhibition of the PDE4 enzyme, leading to an increase in cAMP levels and the regulation of inflammatory mediators, which can help improve the skin condition and reduce the severity of psoriasis symptoms.
Metabolism and Drug interaction
Oral administration of apremilast has an absolute biovailability of 73% with peak concentration at 2.5 hours (Tmax). The half-life of apremilast is 6-9 hours. Apremilast is metabolized by the both cytochrome (CYP) and non-CYP pathways. In vitro studies have demonstrated that apremilast metabolism is primarily mediated by the CYP3A4 pathway. Thus, concomitant use of apremilast with CYP450 enzyme inducers (such as rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended. There are no significant drug-drug interactions with oral contraceptives, ketoconazole, or methotrexate.
safety information
1.Apremilast may cause depression. The risk may be greater in patients who have a history of depression or suicidal thoughts or actions. Families and caregivers must closely watch patients who take apremilast. It is important to keep in close contact with the patient's doctor. Tell the doctor right away if the patient has new, worsened, or sudden symptoms, such as depression; anxiety, restlessness, or irritability; panic attacks; or any changes in behavior. Contact the doctor right away if any signs of suicidal thoughts or actions occur.
2.Apremilast may cause weight loss. You will need to have regular weight checks while you are taking apremilast.
side effects
Diarrhea; headache; nausea; weight loss.
References
1. http://www.rheumatology.org/Learning-Center/Publications-Communications/Drug-Safety/Hotline-Apremilast-for-the-Treatment-of-Psoriatic-Arthritis
2. https://www.ncbi.nlm.nih.gov/pubmed/26220911
3. https://www.drugs.com/cdi/apremilast.html
4. http://reference.medscape.com/drug/otezla-apremilast-999915
Clinical Use
Treatment of active psoriatic arthritis (PsA) and
moderate to severe chronic plaque psoriasis (PSOR)
Synthesis
Dimethyl sulfone was first subjected to n-butyllithium in
tetrahydrofuran (THF) prior to exposure to commercially available
3-ethoxy-4-methoxybenzonitrile (15) at low temperature to afford
enamine 16 in 83% yield, presumably as a single isomer enamine
possessing the E-configuration. After considerable studies conducted
by researchers at Celgene regarding the reduction of this
enamine and alternative substrates, enamine 16 was reduced
under asymmetric hydrogenation conditions consisting of [Rh
(COD)2]OTf and (S,R)-t-Bu Josiphos in trifluoroethanol (TFE) at
50 ℃ under 90 psi of hydrogen pressure. Immediate exposure of
the product to N-acetyl-L-leucine in methanol afforded the corresponding
benzylamine salt 18 in 80% yield and more than 99%
enantiomeric excess (ee). Finally, compound 18 was condensed
with commercially available N-(phthalimid-3-yl)acetamide (19)
in refluxing acetic acid to provide apremilast (III) in 83% yield
and 99.4% ee.
Overdosage
Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg twice daily) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised.
Enzyme inhibitor
This thalidomide-like psoriasis drug (FW = 460.50 g/mol; CAS 608141-41-9; Solubility: 90 mg/mL DMSO; <1 mg/mL H2O), also known as CC-10004, Otezla? and N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl-sulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, is a potent, orally active phosphodiesterase inhibitor that targets phosphodiesterase PDE4 (IC50 = 74 nM), itself a proinflammatory mediator, and TNF-α, IC50 = 77 nM. Apremilast inhibits PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-γ and tumor necrosis factor-α (TNF-α), and interleukins IL-2, IL-12 and IL- 23 from human rheumatoid synovial membrane cultures. Apremilast significantly reduces clinical scores in both murine models of arthritis over a ten-day treatment period and maintains healthy joint architecture in a dose-dependent manner. Unlike rolipram, however, apremilast demonstrated no adverse behavioral effects in na?ve mice. Otezla is specifically indicated by the Food & Drug Administration for the treatment of patients with moderate to severe plaque psoriasis who are typically candidates for phototherapy or systemic therapy. That said, the specific mechanism(s) for therapeutic action in psoriatic arthritis patients and psoriasis patients is unclear.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Metabolism
Apremilast is extensively metabolised by both CYP
and non-CYP mediated pathways including oxidation,
hydrolysis, and conjugation, suggesting inhibition of a
single clearance pathway.
After oral administration of radiolabelled apremilast,
about 3% and 7% of the radioactive dose is recovered as
apremilast in urine and faeces, respectively.
Mode of action
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis.
Check Digit Verification of cas no
The CAS Registry Mumber 608141-41-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,0,8,1,4 and 1 respectively; the second part has 2 digits, 4 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 608141-41:
(8*6)+(7*0)+(6*8)+(5*1)+(4*4)+(3*1)+(2*4)+(1*1)=129
129 % 10 = 9
So 608141-41-9 is a valid CAS Registry Number.
InChI:N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
608141-41-9Relevant articles and documents
Directed evolution of an amine transaminase for the synthesis of an Apremilast intermediate via kinetic resolution
Xiang, Chao,Wu, Shuke,Bornscheuer, Uwe T.
, (2021/06/26)
Apremilast is an important active pharmaceutical ingredient that relies on a resolution to produce the key chiral amine intermediate. To provide a new catalytic and enzymatic process for Apremilast, we performed the directed evolution of the amine transaminase from Vibrio fluvialis. Six rounds of evolution resulted in the VF-8M-E variant with > 400-fold increase specific activity over the wildtype enzyme. A homology model of VF-8M-E was built and a molecular docking study was performed to explain the increase in activity. The purified VF-8M-E was successfully applied to produce the key chiral amine intermediate in enantiopure form and 49% conversion via a kinetic resolution, representing a new enzymatic access towards Apremilast.
Methods for preparation of apremilast
-
, (2021/05/19)
The present invention discloses a method for preparation of Apremilast. β-phthalimino vinylsulfones are reacted through the asymmetric addition reaction to form an addition product, and the drug of Apremilast can be obtained from the addition product through simple reactions. The method is a process for synthesizing Apremilast in a more efficient way.
Chemoenzymatic synthesis of apremilast: A study using ketoreductases and lipases
Vega, Kimberly B.,Cruz, Daniel M. V.,Oliveira, Artur R. T.,Da Silva, Marcos R.,De Lemos, Telma L. G.,Oliveira, Maria C. F.,Bernardo, Ricardo D. S.,De Sousa, Jackson R.,Zanatta, Geancarlo,Nasário, Fábio D.,Marsaioli, Anita J.,De Mattos, Marcos C.
, p. 1100 - 1110 (2021/05/19)
The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED.P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.
AN IMPROVED PROCESS FOR THE PREPARATION OF APREMILAST AND ITS INTERMEDIATE
-
Page/Page column 17; 20, (2019/05/02)
The present invention provides an improved process for preparation of pure N-(2-(l-(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-l,3-dioxoisoindolin-4-yl)acetamide (1) (commonly known as Apremilast); wherein the content of des-acetyl apremilast (la) is less than 1% w/w and having total amount of genotoxic substances less than 25 ppm; comprising the steps of reacting the compound l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan- 1-amine (A) or its chiral acid salt with N-(l,3-dioxo-l,3-dihydroisobenzofuran-4-yl)-acetamide (B) in presence of ether or amide solvent and optionally, in presence of an acid; followed by the treatment with an acetylating agent.
Synthesis of Substituted β-Functionalised Styrenes by Microwave-Assisted Olefin Cross-Metathesis and Scalable Synthesis of Apremilast
Jana, Anupam,Zieliński, Grzegorz Krzysztof,Czarnocka-?niada?a, Sylwia,Grudzień, Krzysztof,Podwysocka, Dominika,Szulc, Marcin,Kajetanowicz, Anna,Grela, Karol
, p. 5808 - 5813 (2019/11/03)
Preparation of diversely substituted β-functionalised styrenes by microwave-assisted olefin cross-metathesis (CM) is described. This method can be also employed in the synthesis of β-deuterated α,β-unsaturated sulfones from inexpensive allylbenzenes, though unprecedented one-pot isomerisation/deuteration/cross-metathesis sequence. One of such obtained CM products has been utilised in a new scalable synthesis of Apremilast (6), a potent and orally active phosphodiesterase 4 and tumour necrosis factor-α inhibitor. The same strategy was used in synthesis of an optical antipode of 6, ent-Apremilast.
APREMILAST FOR THE TREATMENT OF A LIVER DISEASE OR A LIVER FUNCTION ABNORMALITY
-
Paragraph 0097, (2019/09/15)
Methods of treating, managing or preventing liver disease are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with additional active agents or treatment regimens.
METHODS FOR THE TREATMENT OF OBESITY USING APREMILAST
-
Paragraph 0082, (2019/05/22)
Methods of treating, managing or preventing obesity and overweight are disclosed. Specific methods encompass the administration of apremilast, alone or in combination with additional active agents or treatment regimens.
A NOVEL PROCESS FOR THE PREPARATION OF APREMILAST IN AMORPHOUS FORM
-
Page/Page column 26; 28-34, (2019/02/13)
The present invention is directed to a novel process for the preparation of Apremilast in amorphous form directly from the crude reaction mixture comprising the final stage condensation of a 3- acetamidophthalic anhydride and a chiral amino acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1- (methylsulfonyl)-eth-2-ylamine, isolated in amorphous form using a solvent-antisolvent mixture comprising acetonitrile-water, dimethylformamide-water, dimethylsulfoxide-water, acetonitrile- dimethylformamide-water or mixtures thereof.
Apremilast three-component one-pot-boiling synthesis method
-
Paragraph 0031-0039; 0044, (2019/11/29)
The invention provides an apremilast three-component one-pot-boiling synthesis method. According to the apremilast three-component one-pot-boiling synthesis method, 3-aminophthalic acid, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine N-acetyl-L-leucine salt, and acetic anhydride are taken as raw materials to prepare apremilast through one-pot-boiling method. The apremilast three-component one-pot-boiling synthesis method is simple and convenient in operation, high in yield, low in pollution, and is suitable for large scale preparation.
Asymmetric Synthesis of β-Aryl β-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast
Syu, Jin-Fong,Gopula, Balraj,Jian, Jia-Hong,Li, Wei-Sian,Kuo, Ting-Shen,Wu, Ping-Yu,Henschke, Julian P.,Hsieh, Meng-Chi,Tsai, Ming-Kang,Wu, Hsyueh-Liang
, p. 4614 - 4618 (2019/06/27)
A chiral rhodium(I)-diene catalyst enabled the one-step synthesis of β-aryl β-imido sulfones under mild reaction conditions. By selection of the chiral diene ligand L1a or L2, each enantiomer of the chiral β-aryl β-imido sulfone target can be accessed with high stereoselectivity. Demonstration of the scope of the reaction, which includes the synthesis of an N-protected chiral β-amino β-phenyl sulfone, culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.
