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EVEROLIMUS

March 4, 2021 10:16 am / Leave a comment

Everolimus

159351-69-6[RN]
23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone, 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-(2-hydr oxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-, (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,26R,27R,34aS)-
23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone, 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-, (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-
42-O-(2-Hydroxyethyl)rapamycin

Synonyms:RAD-001, SDZ-RAD, Afinitor
ATC:L04AA18

Use:immunosuppressantChemical name:42-O-(2-hydroxyethyl)rapamycinFormula:C₅₃H₈₃NO₁₄

MW:958.24 g/mol
CAS-RN:159351-69-6

EverolimusCAS Registry Number: 159351-69-6CAS Name: 42-O-(2-Hydroxyethyl)rapamycinAdditional Names: 40-O-(2-hydroxyethyl)rapamycinManufacturers’ Codes: RAD-001; SDZ RADTrademarks: Certican (Novartis)Molecular Formula: C53H83NO14Molecular Weight: 958.22Percent Composition: C 66.43%, H 8.73%, N 1.46%, O 23.38%Literature References: Macrolide immunosuppressant; derivative of rapamycin, q.v. Inhibits cytokine-mediated lymphocyte proliferation. Prepn: S. Cottens, R. Sedrani, WO9409010; eidem, US5665772 (1994, 1997 both to Sandoz). Pharmacology: W. Schuler et al., Transplantation64, 36 (1997). Whole blood determn by LC/MS: N. Brignol et al., Rapid Commun. Mass Spectrom.15, 898 (2001); by HPLC: S. Baldelli et al., J. Chromatogr. B816, 99 (2005). Clinical pharmacokinetics in combination with cyclosporine: J. M. Kovarik et al., Clin. Pharmacol. Ther.69, 48 (2001). Clinical study in prevention of cardiac-allograft vasculopathy: H. J. Eisen et al.,N. Engl. J. Med.349, 847 (2003). Review: F. J. Dumont et al., Curr. Opin. Invest. Drugs2, 1220-1234 (2001); B. Nashan, Ther. Drug Monit.24, 53-58 (2002).Therap-Cat: Immunosuppressant.Keywords: Immunosuppressant.эверолимус[Russian][INN]إيفيروليموس[Arabic][INN]依维莫司[Chinese][INN]Trade Name：Certican^® / Zortress^® / Afinitor^®MOA：mTOR inhibitorIndication：Rejection of organ transplantation; Renal cell carcinoma; Advanced renal cell carcinoma (RCC); Advanced breast cancer; Pancreatic cancer; Renal angiomyolipoma; Tuberous sclerosis complex (TSC); Rejection in heart transplantation; Rejection of suppression renal transplantation; Subependymal giant cell astrocytoma; neuroendocrine tumors (NET); Advanced gastrointestinal tumorsStatus：ApprovedCompany：Novartis (Originator)Sales：$1,942 Million (Y2015);
$1,902 Million (Y2014);
$1,558 Million (Y2013);
$1,007 Million (Y2012);
$630 Million (Y2011);ATC Code：L04AA18Approved Countries or Area

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2012-08-29	New dosage form	Afinitor Disperz	Renal cell carcinoma , Advanced breast cancer, Pancreatic cancer, Renal angiomyolipoma, Tuberous sclerosis complex (TSC)	Tablet, For suspension	2 mg/3 mg/5 mg	Novartis	Priority
2010-04-20	New strength	Zortress	Advanced renal cell carcinoma (RCC)	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis
2009-03-30	Marketing approval	Afinitor	Advanced renal cell carcinoma (RCC)	Tablet	2.5 mg/5 mg/7.5 mg/10 mg	Novartis	Priority

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2016-06-02	New indication	Afinitor	neuroendocrine tumors (NET), Advanced gastrointestinal tumors	Tablet		Novartis
2011-09-02	Marketing approval	Votubia	Advanced breast cancer, Renal cell carcinoma , Pancreatic cancer	Tablet	2.5 mg/5 mg/10 mg	Novartis	Orphan; Conditional Approval
2011-09-02	Marketing approval	Votubia	Advanced breast cancer, Renal cell carcinoma , Pancreatic cancer	Tablet, Orally disintegrating	2 mg/3 mg/5 mg	Novartis	Orphan; Conditional Approval
2009-08-03	Marketing approval	Afinitor	Advanced breast cancer, Renal cell carcinoma , Pancreatic cancer	Tablet	2.5 mg/5 mg/10 mg	Novartis

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2011-12-22	New indication	Certican	Rejection of suppression renal transplantation	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis
2007-01-26	Marketing approval	Certican	Rejection in heart transplantation	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company
2014-02-13	Marketing approval	飞尼妥/Afinitor	Advanced renal cell carcinoma (RCC), Subependymal giant cell astrocytoma	Tablet	2.5 mg	Novartis
2013-01-22	Marketing approval	飞尼妥/Afinitor	Advanced renal cell carcinoma (RCC), Subependymal giant cell astrocytoma	Tablet	10 mg	Novartis
2013-01-22	Marketing approval	飞尼妥/Afinitor	Advanced renal cell carcinoma (RCC), Subependymal giant cell astrocytoma	Tablet	5 mg	Novartis

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2003-07-18	Marketing approval	Certican	Rejection of organ transplantation, Renal cell carcinoma	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis

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Click to access afinitor-epar-public-assessment-report_en.pdf

Active Substance The active substance Everolimus is a hydroxyethyl derivative of rapamycin, which is a macrolide, isolated from the micro-organism Streptomyces hygroscopicus. The guideline, impurities in new active substances ICHQ 3A (R), does not apply to active substance of fermented origin. Everolimus (INN) or 42-O-(2-hydroxyethyl)-rapamycin (chemical name) or C5 3H8 3N O1 4 has been fully described. The molecule is amorphous and is stabilised with an antioxidant. Its physico-chemical properties including parameters such as solubility, pH, specific rotation, potential polymorphism and potential isomerism have been fully characterised. Everolimus is a white to faintly yellow amorphous powder. It is almost insoluble in water, is unstable at temperatures above 25 °C and is sensitive to light. In addition, possible isomerism has been investigated. Everolimus contains 15 asymmetric carbon atoms and 4 substituted double bonds. The configuration of the asymmetric carbon atoms and the double bonds is guaranteed by the microbial origin of Rapamycin. The configuration is not affected by the chemical synthesis. Polymorphism has been comprehensively discussed and it was demonstrated that the molecule domain remains amorphous.

Synthesis of Everolimus The manufacturing process consists of four main steps, (1) fermentation, (2) extraction of rapamycin from the fermentation broth, (3) chemical modification of rapamycin starting material, (4) purification of crude everolimus and stabilisation with BHT. The choice of the stabilizer has been sufficiently explained and justified by experimental results. Interactions products of Everolimus and the antioxidant were not detected, or were below detection limit. Rapamycin, obtained by a fermentation process, was used as the starting material. Reaction conditions and the necessary in-process controls are described in detail. Adequate specifications for starting materials and isolated intermediates and descriptions of the test procedures have been submitted. Control of the quality of solvents, reagents and auxiliary materials used in the synthesis has been adequately documented. It is stated by the manufacturer of rapamycin solution that no starting material of animal or human origin is used in the fermentation. Elucidation of structure and other characteristics The structure of Everolimus has been fully elucidated using several spectroscopic techniques such as ultraviolet absorption spectroscopy (UV), Infra-red spectroscopy (FT-IR), proton and carbon nuclear magnetic resonance spectroscopy (1 H and 13C NMR), mass spectroscopy, diffractometry (X-ray) and elemental analysis. Related substances An extensive discussion was presented on the related substances. The complex structure of Everolimus allows several possible degradation pathways to occur at various positions of the molecule. Everolimus alone is extremely sensitive to oxidation. By the addition of an antioxidant, the sensitivity to oxidation is significantly reduced (the antioxidant is known to react as a scavenger of peroxide radicals). It is assumed that oxidation of Everolimus proceeds via a radical mechanism. All the requirements set in the current testing instruction valid for Everolimus are justified on the basis of the results obtained during development and manufactured at the production scale.

fda

Click to access 022334s000_ChemR.pdf

Everolimus was first approved by Swiss Agency for therapeutic products，Swissmedic on July 18, 2003, then approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on April 23, 2004, and approved by the U.S. Food and Drug Administration (FDA) on Mar 30, 2009, approved by European Medicine Agency (EMA) on Aug 3, 2009. It was developed and marketed as Certican^® by Novartis in SE.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR). It is indicated for the treatment of renal cell cancer and other tumours and currently used as an immunosuppressant to prevent rejection of organ transplants.

Certican^® is available as tablet for oral use, containing 0.25, 0.5 or 0.75 mg of free Everolimus. The recommended dose is 10 mg once daily with or without food for advanced HR+ breast cancer, advanced progressive neuroendocrine tumors, advanced renal cell carcinoma or renal angiomyolipoma with tuberous sclerosis complex.
Everolimus, also known as RAD001, is a derivative of the natural macrocyclic lactone sirolimus with immunosuppressant and anti-angiogenic properties. In cells, everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production.

Everolimus is a medication used as an immunosuppressant to prevent rejection of organ transplants and in the treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors as targeted therapy for use in a number of cancers.^{[medical citation needed]}

It is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

It is marketed by Novartis under the trade names Zortress (USA) and Certican (European Union and other countries) in transplantation medicine, and as Afinitor (general tumours) and Votubia (tumours as a result of TSC) in oncology. Everolimus is also available from Biocon, with the brand name Evertor.

Medical uses

Everolimus is approved for various conditions:

Advanced kidney cancer (US FDA approved in March 2009)^[3]
Prevention of organ rejection after renal transplant(US FDA April 2010)^[4]
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (US FDA October 2010)^[5]
Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)^[6]
Breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (US FDA July 2012)^[7]
Prevention of organ rejection after liver transplant(Feb 2013)
Progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease (US FDA February 2016).^[8]
Tuberous sclerosis complex-associated partial-onset seizures for adult and pediatric patients aged 2 years and older. (US FDA April 2018).^[9]

UK National Health Service

NHS England has been criticised for delays in deciding on a policy for the prescription of everolimus in the treatment of Tuberous Sclerosis. 20 doctors addressed a letter to the board in support of the charity Tuberous Scelerosis Association saying ” around 32 patients with critical need, whose doctors believe everolimus treatment is their best or only option, have no hope of access to funding. Most have been waiting many months. Approximately half of these patients are at imminent risk of a catastrophic event (renal bleed or kidney failure) with a high risk of preventable death.”^[10] In May 2015 it was reported that Luke Henry and Stephanie Rudwick, the parents of a child suffering from Tuberous Sclerosis were trying to sell their home in Brighton to raise £30,000 to pay for treatment for their daughter Bethany who has tumours on her brain, kidneys and liver and suffers from up to 50 epileptic fits a day.^[11]

Clinical trials

As of October 2010, Phase III trials are under way in gastric cancer, hepatocellular carcinoma, and lymphoma.^[12] The experimental use of everolimus in refractory chronic graft-versus-host disease was reported in 2012.^[13]

Interim phase III trial results in 2011 showed that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.^[14]

A study published in 2012, shows that everolimus sensitivity varies between patients depending on their tumor genomes.^[15] A group of patients with advanced metastasic bladder carcinoma (NCT00805129) ^[16] treated with everolimus revealed a single patient who had a complete response to everolimus treatment for 26 months. The researchers sequenced the genome of this patient and compared it to different reference genomes and to other patients’ genomes. They found that mutations in TSC1 led to a lengthened duration of response to everolimus and to an increase in the time to cancer recurrence. The mutated TSC1 apparently had made these tumors vulnerable to treatment with everolimus.^{[medical citation needed]}

A phase 2a randomized, placebo-controlled everolimus clinical trial published in 2014 showed that everolimus improved the response to an influenza vaccine by 20% in healthy elderly volunteers.^[17] A phase 2a randomized, placebo-controlled clinical trial published in 2018 showed that everolimus in combination with dactolisib decreased the rate of reported infections in an elderly population.^[17]

Mechanism

Compared with the parent compound rapamycin, everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex.^[18] This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop, while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.^{[medical citation needed]} Thus, everolimus has important effects on cell growth, cell proliferation and cell survival.

mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase tumor-infiltrating lymphocytes, and to improve adoptive cell transfer therapy.^[19]

Additionally, mTORC2 is believed to play an important role in glucose metabolism and the immune system, suggesting that selective inhibition of mTORC1 by drugs such as everolimus could achieve many of the benefits of rapamycin without the associated glucose intolerance and immunosuppression.^[18]

TSC1 and TSC2, the genes involved in tuberous sclerosis, act as tumor suppressor genes by regulating mTORC1 activity. Thus, either the loss or inactivation of one of these genes lead to the activation of mTORC1.^[20]

Everolimus binds to its protein receptor FKBP12, which directly interacts with mTORC1, inhibiting its downstream signaling. As a consequence, mRNAs that code for proteins implicated in the cell cycle and in the glycolysis process are impaired or altered, and tumor growth is inhibited.^[20]

Adverse reactions

A trial using 10 mg/day in patients with NETs of GI or lung origin reported “Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash. The most common blood abnormalities found (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase (AST) and fasting hyperglycemia.”.^[8]

Role in heart transplantation

Everolimus may have a role in heart transplantation, as it has been shown to reduce chronic allograft vasculopathy in such transplants. It also may have a similar role to sirolimus in kidney and other transplants.^[21]

Role in liver transplantation

Although, sirolimus had generated fears over use of m-TOR inhibitors in liver transplantation recipients, due to possible early hepatic artery thrombosis and graft loss, use of everolimus in the setting of liver transplantation is promising. Jeng et al.,^[22] in their study of 43 patients, concluded the safety of everolimus in the early phase after living donor liver transplantation. In their study, no hepatic artery thrombosis or wound infection was noted. Also, a possible role of everolimus in reducing the recurrence of hepatocellular carcinoma after liver transplantation was correlated. A target trough level of 3 ng/mL at 3 months was shown to be beneficial in recipients with pre-transplant renal dysfunction. In their study, 6 of 9 renal failure patients showed significant recovery of renal function, whereas 3 showed further deterioration, one of whom required hemodialysis.^[23] Recently published report by Thorat et al. showed a positive impact on hepatocellular carcinoma (HCC) when everolimus was used as primary immunosuppression starting as early as first week after living donor liver transplantation (LDLT) surgery.^[24] In their retrospective and prospective analysis at China Medical University Hospital in Taiwan, the study cohort (n=66) was divided in two groups depending upon the postoperative immunosuppression. Group A: HCC patients that received Everolimus + Tacrolimus based immunosuppressive regimen (n=37). Group B: HCC patients that received standard Tacrolimus based immunosuppressive regimen without everolimus (n=29). The target trough level for EVR was 3 to 5 ng/ml while for TAC it was 8–10 ng/ml. The 1-year, 3-year and 4-year overall survival achieved for Group A patients (Everolimus group) was 94.95%, 86.48% and 86.48%, respectively while for Group B patients it was 82.75%, 68.96%, and 62.06%, respectively (p=0.0217). The first 12-month report of ongoing Everolimus multicenter prospective trial in LDLT (H2307 trial), Jeng LB et al. have shown a 0% recurrence of HCC in everolimus group at 12 months.^[25] Jeng LB concluded that an early introduction of everolimus + reduced tacrolimus was non-inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with HCC recurrence only in tacrolimus control patients.

Use in vascular stents

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produce an everolimus-eluting stent (EES) called Xience Alpine. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis’ everolimus. The product is widely available globally including the US, the European Union, and Asia-Pacific (APAC) countries. Boston Scientific also market EESes, recent offerings being Promus Elite and Synergy.^{[citation needed]}

Use in aging

Inhibition of mTOR, the molecular target of everolimus, extends the lifespan of model organisms including mice,^[26] and mTOR inhibition has been suggested as an anti-aging therapy. Everolimus was used in a clinical trial by Novartis, and short-term treatment was shown to enhance the response to the influenza vaccine in the elderly, possible by reversing immunosenescence.^[27] Everolimus treatment of mice results in reduced metabolic side effects compared to sirolimus.^[18]Route 1

Reference：1. US5665772A.

2. Drug. Future 1999, 24, 22-29.Route 2

Reference：1. WO2014203185A1.Route 3

Reference：1. WO2012103959A1.Route 4

Reference：1. CN102731527A.

SYN

Synthetic Reference

Wang, Feng. Everolimus intermediate and preparation method thereof. Assignee Shanghai Institute of Pharmaceutical Industry, Peop. Rep. China; China State Institute of Pharmaceutical Industry. CN 109776570. (2019).

SYN 2

Synthetic Reference

Polymer compositions containing a macrocyclic triene compound; Shulze, John E.; Betts, Ronald E.; Savage, Douglas R.; Assignee Sun Bow Co., Ltd., Bermuda; Sun Biomedical Ltd. 2003; Patent Information; Nov 06, 2003; WO 2003090684 A2

SYN 3

Synthetic Reference

SYN 4

Synthetic Reference

Zabudkin, Oleksandr; Schickaneder, Christian; Matviienko, Iaroslav; Sypchenko, Volodymyr. Method for the synthesis of rapamycin derivatives. Assignee Synbias Pharma AG, Switz. EP 3109250. (2016).

SYN 5

Synthetic Reference

Lu, Shiyong; Zhang, Xiaotian; Chen, Haohan; Ye, Weidong. Preparation of sirolimus 40-ether derivative. Assignee Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory, Peop. Rep. China. CN 105237549. (2016).

SYN 6

Synthetic Reference

Seo, Jeong U.; Ham, Yun Beom; Kang, Heung Mo; Lee, Gwang Mu; Kim, In Gyu; Kim, Jeong Jin; Park, Ji Su. Preparation of everolimus and synthetic intermediate thereof. Assignee CKD Bio Corp., S. Korea. KR 1529963 (2015).

SYN

EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010

SYN

J Label Compd Radiopharm 1999,42(1),29

The compound has been obtained biosynthetically by an optimized fermentation process using Streptomyces hygroscopicus mutant RSH 1701 with a complex culture medium were [14C]-labeled (1R,3R,4R)-2,3-dichydroxycyclo-hexanecarboxylic acid (I) and [14C]-labeled (S)-pipecolic acid (II) have been added. This fermentation process yielded [14C]-labeled rapamycin (III), which was finally selectively O-alkylated at the C-40 position with monosilylated ethylene glycol triflate in DMSO/dimethoxyethane.

SYN

The reaction of the labeled acylated (+)-bornane-10,2-sultam (IV) with triethyl phosphite gives the phosphonate (V), which is treated with paraformaldehyde, galvinoxyl and K2CO3 yielding the acrylate derivative (VI). The cyclization of (VI) with butadiene (VII) by means of diethylaluminum chloride and galvinoxyl (as radical scavenger) affords the cyclohexene-carboxamide derivative (VIII), which is hydrolyzed with LiOH in THF/water giving the (1R)-3-cyclohexenecarboxylic acid (IX). The oxidation of (IX) with m-chloroperbenzoic acid and triethylamine in CCl4 yielded regioselectively the hydroxylactone (X), which is finally hydrolyzed with HCl to the labeled intermediate (I).

SYN

The reaction of the labeled acylated (-)-bornane-10,2-sultam (XI) with benzophenone imine (XII) gives the glycylsultam derivative (XIII), which is alkylated with 4-iodobutyl chloride (XIV) by means of butyllithium and DMPU in THF yielding intermediate (XV). The selective hydrolysis of (XV) with HCl affords the omega-chloro-L-norleucine derivative (XVI), which is cyclized by means of tetrabutylammonium fluoride and DIEA in hot acetonitrile giving the (2S)-piperidyl derivative (XVII). Finally, this compound is hydrolyzed with LiOH in THF/water to the labeled intermediate (II).

clipRapamycin is a known macrolide antibiotic produced by Streptomvces hvgroscopicus. having the structure depicted in Formula A:

See, e.g., McAlpine, J.B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am. Chem. Soc. (1991) J_13: ⁷⁴³³‘- US Patent No. 3 929 992. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailabiiity as well as its high toxicity. Moreover, rapamycin is highly insoluble, making it difficult to formulate stable galenic compositions.

Everolimus, 40-O-(2-hydroxyethyl)-rapamycin of formula (1) is a synthetic derivative of rapamycin (sirolimus) of formula (2), which is produced by a certain bacteria strain and is also pharmaceutically active.

(1) (2)

Everolimus is marketed under the brand name Certican for the prevention of rejection episodes following heart and kidney transplantation, and under the brand name Afinitor for treatment of advanced kidney cancer.

Due to its complicated macrolide chemical structure, everolimus is, similarly as the parent rapamycin, an extremely unstable compound. It is sensitive, in particular, towards oxidation, including aerial oxidation. It is also unstable at temperatures higher than 25°C and at alkaline pH.

Everolimus and a process of making it have been disclosed in WO 94/09010

Synthesis

Alkylation of rapamycin (I) with 2-(tert-butyldimethylsilyloxy)ethyl triflate (II) by means of 2,6-lutidine in hot toluene gives the silylated target compound (III), which is deprotected by means of 1N HCl in methanol (1). (Scheme 21042401a) Manufacturer Novartis AG (CH). References 1. Cottens, S., Sedrani, R. (Sandoz-Refindungen VmbH; Sandoz-Patent GmbH; Sandoz Ltd.). O-Alkylated rapamycin derivatives and their use, particularly as immunosuppressants. EP 663916, EP 867438, JP 96502266, US 5665772, WO 9409010.EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010

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SYNTHESIS

https://www.google.com/patents/WO2012103960A1

(US 5,665,772, EP 663916). The process principle is shown in the scheme below, wherein the abbreviation RAP-OH has been used as an abbreviation for the rapamycin structure of formula (2) above, L is a leaving group and P is a trisubstituted silyl group serving as a OH- protective group.

RAP-OH + L-CH₂-CH₂-0-P — –> RAP-O-CH2-CH2-O-P — – > RAP-O-CH2-CH2-OH

(2) (4) (1)

Specifically, the L- group is a trifluoromethanesulfonate (triflate) group and the protective group P- is typically a tert-butyldimethylsilyloxy- group. Accordingly, the known useful reagent within the above general formula (3) for making everolimus from rapamycin is 2-(tert-butyldimethylsilyloxy)ethyl triflate of formula (3 A):

According to a known synthetic procedure disclosed in Example 8 of WO 94/09010 and in Example 1 of US application 2003/0125800, rapamycin (2) reacts in hot toluene and in the presence of 2,6-lutidine with a molar excess of the compound (3 A), which is charged in several portions, to form the t-butyldimethylsilyl-protected everolimus (4A). This compound is isolated and deprotected by means of IN aqueous HC1 in methanol. Crude everolimus is then purified by column chromatography. Yields were not reported.

(2) (3A) (4A) (1)

In an article of Moenius et al. (J. Labelled Cpd. Radiopharm. 43, 113-120 (2000)), which used the above process for making C14-labelled and tritiated everolimus, a diphenyl- tert.butylsilyloxy -protective group was used as the alkylation agent of formula (3B).

Only 8% yield of the corresponding compound (4B)

and 21% yield of the compound (1) have been reported.

Little is known about the compounds of the general formula (3) and methods of their preparation. The synthesis of the compound (3 A) was disclosed in Example 1 of US application 2003/0125800. It should be noted that specification of the reaction solvent in the key step B of this synthesis was omitted in the disclosure; however, the data about isolation of the product allow for estimation that such solvent is dichloromethane. Similarly also a second article of Moenius et al. (J. Labelled Cpd. Radiopharm.42, 29-41 (1999)) teaches that dichloromethane is the solvent in the reaction.

It appears that the compounds of formula (3) are very reactive, and thus also very unstable compounds. This is reflected by the fact that the yields of the reaction with rapamycine are very low and the compound (3) is charged in high molar extent. Methods how to monitor the reactivity and/or improve the stability of compounds of general formula (3), however, do not exist.

Thus, it would be useful to improve both processes of making compounds of formula (3) and, as well, processes of their application in chemical synthesis.

xample 6: 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin

In a 100 mL flask, Rapamycin (6 g, 6.56 mmol) was dissolved in dimethoxyethane (4.2 ml) and toluene (24 ml) to give a white suspension and the temperature was raised to 70°C. After 20 min, N,N-diisopropylethylamine (4.56 ml, 27.6 mmol) and 2-((2,3-dimethylbutan-2- yl)dimethylsilyloxy)ethyl trifluoromethanesulfonate (8.83 g, 26.3 mmol) were added in 2 portions with a 2 hr interval at 70°C. The mixture was stirred overnight at room temperature, then diluted with EtOAc (40 ml) and washed with sat. NaHC0₃ (30 ml) and brine (30 ml). The organic layer was dried with Na₂S0₄, filtered and concentrated. The cmde product was chromatographed on a silica gel column (EtOAc/heptane 1/1 ; yield 4.47 g).

Example 7: 40-O-(2-hydroxyethyl)-rapamycin [everolimus]

In a 100 mL flask, 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin (4.47 g, 4.06 mmol) was dissolved in methanol (20 ml) to give a colorless solution. At 0°C, IN aqueous hydrochloric acid (2.0 ml, 2.0 mmol) was added and the mixture was stirred for 90 min. The reaction was followed by TLC (ethyl acetate/n-heptane 3 :2) and HPLC. Then 20 ml of saturated aqueous NaHC03 were added, followed by 20 ml of brine and 80 ml of ethyl acetate. The phases were separated and the organic layer was washed with saturated aqueous NaCl until pH 6/7. The organic layer was dried by Na₂S0₄, filtered and concentrated to yield 3.3 g of the product.

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SYNTHESIS

https://www.google.co.in/patents/WO1994009010A1

Example 8: 40-O-(2-Hydroxy)ethyl-rapamycin

a) 40-O-[2-(t-Butyldimethylsilyl)oxy]ethyl-rapamycin

A solution of 9.14 g (10 mmol) of rapamycin and 4.70 mL (40 mmol) of 2,6-lutidine in 30 mL of toluene is warmed to 60°C and a solution of 6.17 g (20 mmol) of 2-(t-butyldimethylsilyl)oxyethyl triflate and 2.35 mL (20 mmol) of 2,6-lutidine in 20 mL of toluene is added. This mixture is stirred for 1.5h. Then two batches of a solution of 3.08 g (10 mmol) of triflate and 1.2 mL (10 mmol) of 2,6-lutidine in 10 mL of toluene are added in a 1.5h interval. After addition of the last batch, stirring is continued at 60°C for 2h and the resulting brown suspension is filtered. The filtrate is diluted with ethyl acetate and washed with aq. sodium bicarbonate and brine. The organic solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (40:60 hexane-ethyl acetate) to afford 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin as a white solid: ¹H NMR (CDCl₃) δ 0.06 (6H, s), 0.72 (1H, dd), 0.90 (9H, s), 1.65 (3H, s), 1.75 (3H, s), 3.02 (1H, m), 3.63 (3H, m), 3.72 (3H, m); MS (FAB) m/z 1094 ([M+Na]⁺), 1022 ([M-(OCH₃+H₂O)]⁺).

b) 40-O-(2-Hydroxy)ethyl-rapamycin

To a stirred, cooled (0°C) solution of 4.5 g (4.2 mmol) of 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin in 20 mL of methanol is added 2 mL of IN HCl. This solution is stirred for 2h and neutralized with aq. sodium bicarbonate. The mixture is extracted with three portions of ethyl acetate. The organic solution is washed with aq.

sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and

concentrated. Purification by column chromatography on silica gel (ethyl acetate) gave the title compound as a white solid:¹H NMR (CDCl₃) δ 0.72 (1H, dd), 1.65 (3H, s), 1.75 (3H, s), 3.13 (5H, s and m), 3.52-3.91 (8H, m); MS (FAB) m/z 980 ([M+Na]⁺), 926 ([M-OCH₃]⁺), 908 ([M-(OCH₃+H₂O)]⁺), 890 ([M-(OCH₃+2H₂O)]⁺), 876 ([M-(2CH₃OH+OH)]⁺), 858 ([M-(OCH₃+CH₃OH+2H₂O)]⁺).

MBA (rel. IC50) 2.2

IL-6 dep. prol. (rel. IC50) 2.8

MLR (rel. IC50) 3.4

…………………..

synthesis

Everolimus (Everolimus) was synthesized by the Sirolimus (sirolimus, also known as rapamycin Rapamycin) ether from. Sirolimus is from the soil bacterium Streptomyces hygroscopicus isolated metabolites. Activation end sirolimus (triflate, Tf) the other end of the protection (t-butyldimethylsilyl, TBS) of ethylene glycol 1 reaction of 2 , because the hydroxyl group 42 hydroxyl site over the 31-bit resistance is small, so the reaction only occurs in 42. Compound 2under acidic conditions TBS protection is removed everolimus.

PATENT

https://patents.google.com/patent/WO2016020664A1/en

Everolimus (RAD-001) is the 40-O- 2-hydroxyethyl)-rapamycin of formula (I),

It is a derivative of sirolimus of formula III),

and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR). Everolimus is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. It is marketed by Novartis under the tradenames Zortress™ (USA) and Certican™ (Europe and other countries) in transplantation medicine, and Afinitor™ in oncology.

Trisubstituted silyloxyethyltrifluoromethane sulfonates (triflates) of the general formula (IV),

wherein R₂, R₃ are independently a straight or branched alkyl group, for example C^-Cw alkyl, and/or an aryl group, for example a phenyl group, are important intermediates useful in the synthesis of everolimus.

Everolimus and its process for manufacture using the intermediate 2-(t-butyldimethyl silyl) oxyethyl triflate of formula (IVA),

was first described in US Patent Number 5,665,772. The overall reaction is depicted in Scheme I.

Sche

Everolimus (I)

For the synthesis, firstly sirolimus of formula (III) and 2-(t-butyldimethylsilyl)oxyethyl triflate of formula (IVA) are reacted in the presence of 2,6-Lutidine in toluene at around 60°C to obtain the corresponding 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin of formula (I la), which is then deprotected in aqueous hydrochloric acid and converted into crude everolimus [40-O-(2- Hydroxy)ethyl rapamycin] of formula (I). However, this process results in the formation of impure everolimus, which requires purification by column chromatography. The process results in very poor overall yield and purity and thereby the process is not suitable for the commercial scale production of everolimus.

Moenius et al. (I. Labelled Cpd. Radiopharm. 43, 1 13-120 (2000) have disclosed a process to prepare C-14 labelled everolimus using the diphenyltert-butylsilyloxy-protective group of formula (IV B),

as the alkylation agent. The overall yield reported was 25%. International patent application, publication number WO 2012/103960 discloses the preparation of everolimus using the alkylating agent 2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl triflate of formula (IVC),

wherein the overall yield reported is 52.54%. The process involves a derivatization method based on the reaction of the triflate (IV) with a derivatization agent, which preferably is a secondary aromatic amine, typically N-methylaniline.

International patent application, publication number WO 2012/103959 also discloses the preparation of everolimus using the alkylating agent of formula (IVC). The process is based on a reaction of rapamycin with the compound of formula (IVC) in the presence of a base (such as an aliphatic tertiary amine) to form 40-O-2-(t-hexyldimethylsiloxy)ethylrapamycin, which is subsequently deprotected under acidic conditions to obtain everolimus. European Patent Number 1518517B discloses a process for the preparation of everolimus which employs the triflate compound of formula (IVA), 2-(t-butyldimethyl silyl) oxyethyl triflate. The disclosed process for preparing the compound of formula (IVA) involves a flash chromatography purification step. The compounds of formula (IV) are key intermediates in the synthesis of everolimus. However, they are highly reactive and also very unstable, and their use often results in decomposition during reaction with sirolimus. This is reflected by the fact that the yields of the reaction with sirolimus are very low and the compounds of formula (IV) are charged in high molar extent. Thus it is desirable to develop a process to stabilize compounds of formula (IV) without loss of reactivity

Example 1 :

Step 1 : Preparation of protected everolimus (TBS-everoismus) of formula (Ma) using metal salt, wherein “Pg” is t-butyldimethylsilyl t-butyldimethylsilyloxy ethanol, of formula (VA) (2.8g, 0.016mol) was dissolved in dichloromethane (DCM) (3 vol) and to this 2,6-Lutidine (3.50 g, 0.0327 mol) was added and the mixture was cooled to -40°C. Thereafter, trifluoromethane sulfonic anhydride (3.59ml, 0.021 mol) was added drop-wise. The mixture was maintained at -40°C for 30 minutes. Sirolimus (0.5g, 0.00054mol) was taken in another flask and dissolved in DCM (1 ml). To this sirolimus solution, silver acetate (0.018g, 0.000109mol) was added and cooled to -40°C. The earlier cooled triflate solution was transferred in 3 lots to the sirolimus solution maintaining temperature at -40°C. The reaction mixture was stirred at -40°C further for 15min before which it was slowly warmed to 0°C and further to RT. The reaction mixture was then warmed to 40°C and maintained at this temperature for 3 hours. The reaction was monitored by TLC. On completion of reaction, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and solvent was removed by vacuum distillation to obtain the title compound, which was directly used in the next step. HPLC product purity: 60%-85%.

Step 2: Preparation of everolimus of formula (I) Protected everolimus of formula (I la) obtained in step 1 was dissolved in methanol (10 volumes) and chilled to 0-5° C. To this solution was added drop wise, a solution of 1 N HCI. The pH of the reaction was maintained between 1-3. The temperature of the reaction mixture was raised to 25° C and stirred for 1 hour. After completion of reaction, the reaction mixture was diluted with water (15 volumes) and extracted in ethyl acetate (2X20 volumes). The organic layers were combined and washed with brine, dried over sodium sulphate. The organic layer was distilled off under reduced pressure at 30-35° C, to obtain a crude everolimus (0.8 g). The crude everolimus was further purified by preparative HPLC to yield everolimus of purity >99%.

Example 2:

Step 1 : Preparation of TBS-everoiimus of formula (Ma) without using metal salt, wherein “Pg” is t-butyldimethylsilyl t-butyldimethylsilyloxy ethanol, of formula (VA) (2.8g, 0.016mol) was dissolved in DCM (3 vol) and to this 2,6-Lutidine (3.50 g, 0.0327 mol) was added and the mixture was cooled to -40°C. Thereafter, trifluoromethane sulfonic anhydride (3.59ml, 0.021 mol) was added drop-wise. The mixture was maintained at -40°C for 30 minutes. Sirolimus (0.5g, 0.00054mol) was taken in another flask and dissolved in DCM (1 ml). The solution was cooled to -40°C. The earlier cooled triflate solution was transferred in 3 lots to the sirolimus solution maintaining temperature at -40°C. The reaction mixture was stirred at -40°C further for 15min before which it was slowly warmed to 0°C and further to RT. The reaction mixture was then warmed to 40°C and maintained at this temperature for 3 hours. On completion of reaction, the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and solvent was removed by vacuum distillation to obtain the title compound, which was directly used in next step. HPLC purity: 10%-20%.

Step 2: Preparation of everolimus of formula (I)

Protected everolimus of formula (I la) obtained in step 1 was dissolved in methanol (10 volumes) and chilled to 0-5° C. To this solution was added drop wise, a solution of 1 N HCI. The pH of the reaction was maintained between 1-3. The temperature of the reaction mixture was raised to 25° C and stirred for 1 hour. After completion of reaction, the reaction mixture was diluted with water (15 volumes) and extracted in ethyl acetate (2X20 volumes). The organic layers were combined and washed with brine, dried over sodium sulphate. The organic layer was distilled off under reduced pressure at 30-35° C, to obtain a crude everolimus which was further purified by preparative HPLC. Example 3:

Preparation of crude Everolimus

Step 1 : Preparation of TBS-ethylene glycol of formula (Va)

Ethylene glycol (1.5L, 26.58 mol) and TBDMS-CI (485g, 3.21 mol) were mixed together with stirring and cooled to 0°C. Triethyl amine (679 ml, 4.83 mol) was then added at 0°C in 30-45 minutes. After addition, the reaction was stirred for 12 hours at 25-30°C for the desired conversion. After completion of reaction, the layers were separated and the organic layer (containing TBS- ethylene glycol) was washed with water (1 L.x2) and brine solution (1 L). The organic layer was then subjected to high vacuum distillation to afford 350g of pure product.

Step 2: Preparation of TBS-glycol-Triflate of formula (IVa)

The reaction was carried out under a nitrogen atmosphere. TBS- ethylene glycol prepared as per step 1 (85.10g, 0.48 mol) and 2, 6-Lutidine (84.28ml, 0.72 mol) were stirred in n-heptane (425ml) to give a clear solution which was then cooled to -15 to – 25°C. Trif!uoromethanesulfonic anhydride (Tf₂0) (99.74 ml, 0.590 mol) was added drop-wise over a period of 45 minutes to the n-heptane solution (white precipitate starts to form immediately) while maintaining the reaction at -15 to – 25°C. The reaction mixture was kept at temperature between -15 to -25°C for 2 hours. The precipitate generated was filtered off. The filtrate was then evaporated up to ~2 volumes with respect to TBS-ethyiene glycol (~200 ml).

Step 3: Preparation of TBS-evero!imus of formula (Ha)

30g of sirolimus (0,0328 mo!) and toluene (150m!) were stirred together and the temperature was slowly raised to 60-65°C. At this temperature, a first portion of TBS-g!yco!-triflate prepared as per step 2 (100ml) and 2,6-Lutidine (1 1.45ml, 0.086 moles) were added and stirred for 40 min. Further, a second portion of TBS- glycol-triflate (50mi) and 2, 6-Lutidine (19.45ml, 0.138 mol) were added and the reaction was stirred for another 40 min. This was followed by a third portion of TBS- glycol- triflate (50m!) and 2, 6-Lutidine (19.45ml, 0.138 mol), after which the reaction was stirred for further 90 minutes. The reaction was monitored through HPLC to check the conversion of Sirolimus to TBS-everolimus after each addition of TBS-glycol-trifiate. After completion of the reaction, the reaction mixture was diluted with n-heptane (150mi), cooled to room temperature and stirred for another 60 minutes. The precipitated solids were filtered off and the filtrate was washed with deionized water (450 ml x4) followed by brine solution (450ml). The filtrate was subsequently distilled off to afford TBS-everolimus (60-65g) with 60-70% conversion from sirolimus.

Step 4: Preparation of everolimus of formula (I)

TBS-everolimus (65g) obtained in step 3 was dissolved in 300 mi methanol and cooled to 0°C. 1 N HCI was then added to the methanol solution (pH adjusted to 2-3) and stirred for 2 h. After completion of reaction, toluene (360m!) and deionized wafer (360mi) were added to the reaction mixture and the aqueous layer was separated. The organic layer was washed with brine solution (360ml). The organic layer was concentrated to obtain crude everolimus (39g) with an assay content of 30-35%, HPLC purity of 60-65%.

The crude everolimus purified by chromatography to achieve purity more than 99 %.

Patent

Publication numberPriority datePublication dateAssigneeTitleUS5665772A *1992-10-091997-09-09Sandoz Ltd.O-alkylated rapamycin derivatives and their use, particularly as immunosuppressantsEP1518517A2 *2002-04-242005-03-30Sun Biomedical, Ltd.Drug-delivery endovascular stent and method for treating restenosisWO2012103960A12011-02-042012-08-09Synthon BvProcess for making trisubstituted silyloxyethyl triflatesCN102786534A2012-05-252012-11-21上海现代制药股份有限公司Preparation method of everolimusCN103788114A *2012-10-312014-05-14江苏汉邦科技有限公司Preparation method for everolimusEP3166950A12014-08-042017-05-17Cipla LimitedProcess for the synthesis of everolimus and intermediates thereof

CN107417718A *2017-08-182017-12-01常州兰陵制药有限公司The preparation method of everolimus intermediateUS9938297B22014-08-042018-04-10Cipia LimitedProcess for the synthesis of everolimus and intermediates thereofCN108676014A *2018-06-152018-10-19国药集团川抗制药有限公司The method for purifying the method for everolimus intermediate and preparing everolimus

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References

a WO 9 409 010 (Sandoz-Erfindungen; 28.4.1994; GB-prior. 9.10.1992).
b US 6 277 983 (American Home Products; 21.8.2001; USA-prior. 27.9.2000).
US 6 384 046 (Novartis; 7.5.2002; GB-prior. 27.3.1996).
US 20 040 115 (Univ. of Pennsylvania; 15.1.2004; USA-prior. 9.7.2002).
fermentation of rapamycin (sirolimus):
- Chen, Y. et al.: Process Biochemistry (Oxford, U. K.) (PBCHE5) 34, 4, 383 (1999).
- The Merck Index, 14th Ed., 666 (3907) (Rahway 2006).
- US 3 929 992 (Ayerst McKenna & Harrison Ltd.; 30.12.1975; USA-prior. 29.9.1972).
- WO 9 418 207 (Sandoz-Erfindungen; 18.8.1994; GB-prior. 2.2.1993).
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- US 6 313 264 (American Home Products; 6.11.2001; USA-prior. 8.3.1994).

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https://doi.org/10.1039/C7MD00474E Issue 1, 2018

MedChemComm

Ascomycins and rapamycins The ascomycin tacrolimus (44, FK-506) and the two rapamycins sirolimus (45, rapamycin) and everolimus (46) are macrolides that contain 21- and 29-membered macrocyclic rings, respectively (Figure 7).[3] Their MWs range from just over 800 Da for tacrolimus (44) to >900 Da for sirolimus (45) and everolimus (46) and they have >10 HBAs. Like other natural product derived drugs in bRo5 space, they are above average complexity (SMCM 119–134) due to their 14–15 chiral centres. All three are immunosuppressants that are mainly used to prevent rejection of transplanted organs. They bind to overlapping, but slightly different parts of a shallow pocket at the surface of the immunophilin FK506 binding protein (FKBP12, Figure 8 A). Whereas tacrolimus (44) only binds in the pocket on FKBP12 (Figure 8 B),[67] sirolimus (45) and everolimus (46) promote binding of mammalian target of rapamycin (mTOR) so that they bind in a groove formed by FKBP12 and mTOR (Figure 8 C).[68] The complex between tacrolimus (44) and FKBP12 inhibits calcineurin, which results in reduced production of interleukin-2 and inactivation of T cells. Formation of the ternary complexes between FKBP12, sirolimus (45) [or everolimus (46)] and mTOR inhibits mTOR, which arrests growth of T lymphocytes by reducing their sensitivity to interleukin 2. Both tacrolimus (44) and sirolimus (45) have low (15–20 %) and variable bioavailabilities, whereas the bioavailability of everolimus (46) has been increased somewhat as compared to sirolimus (45).[3] Tacrolimus (44) was isolated from Streptomyces tsukubaensis in 1987,[69, 70] while sirolimus (45) was first identified from a Streptomycete strain found in a soil sample from Easter Island.[71] Later it was also isolated from fermentation of another Streptomycete strain.[72, 73] Both drugs are now produced through fermentation.[74, 75] Sirolimus suffers from low bioavailability as well as toxicity, and semi-synthetic derivatives were therefore prepared to minimise these issues. This led to the discovery of everolimus (46), synthesised by selective alkylation of one of the two secondary hydroxyl groups of sirolimus (45) with 2-(tert-butyldimethylsilyl)oxyethyltriflate followed by silyl ether deprotection with HCl (Scheme 8).[76, 77]

Figure 7. Structures of the ascomycin tacrolimus (44) and the rapamycins sirolimus (45) and everolimus (46) that are used mainly to prevent rejection of organ transplants.

[67] G. D. Van Duyne, R. F. Standaert, P. A. Karplus, S. L. Schreiber, J. Clardy, Science 1991, 252, 839 – 842. [68] A. M. Marz, A.-K. Fabian, C. Kozany, A. Bracher, F. Hausch, Mol. Cell. Biol. 2013, 33, 1357 – 1367.

[69] T. Kino, H. Hatanaka, M. Hashimoto, M. Nishiyama, T. Goto, M. Okuhara, M. Kohsaka, H. Aoki, H. Imanaka, J. Antibiot. 1987, 40, 1249 – 1255. [70] H. Tanaka, A. Kuroda, H. Marusawa, H. Hatanaka, T. Kino, T. Goto, M. Hashimoto, T. Taga, J. Am. Chem. Soc. 1987, 109, 5031 – 5033. [71] C. Vzina, A. Kudelski, S. N. Sehgal, J. Antibiot. 1975, 28, 721 – 726. [72] S. N. Sehgal, H. Baker, C. Vzina, J. Antibiot. 1975, 28, 727 – 732. [73] S. N. Sehgal, T. M. Blazekovic, C. Vzina, 1975, US3929992A. [74] C. Barreiro, M. Mart nez-Castro, Appl. Microbiol. Biotechnol. 2014, 98, 497 – 507. [75] S. R. Park, Y. J. Yoo, Y.-H. Ban, Y. J. Yoon, J. Antibiot. 2010, 63, 434 – 441. [76] F. Navarro, S. Petit, G. Stone, 2007, US20020032213A1. [77] S. Cottens, R. Sedrani, 1997, US5665772A.

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Ferreting out why some cancer drugs struggle to shrink tumors

Study shows how stopping one enzyme could help drugs treat an important class of cancers more effectively

by Stu Borman

JUNE 27, 2018 | APPEARED IN VOLUME 96, ISSUE 27

In several types of cancer, including most cases of breast cancer, a cell-signaling network called the PI3K pathway is overactive. Drug designers have tried to quiet this pathway to kill cancer, but they haven’t had much success and, more frustratingly, haven’t understood why the problem is so hard to solve.

“There have been more than 200 clinical trials with experimental drugs that target the PI3K pathway, and probably more than $1 billion invested,” says Sourav Bandyopadhyay of the University of California, San Francisco. Just a handful of drugs have been approved by the U.S. FDA and one, Novartis’s Afinitor (everolimus), deters cancer growth but doesn’t shrink tumors, and it prolongs patient survival only a few months.

Bandyopadhyay, his UCSF colleague John D. Gordan, and coworkers used a proteomics approach to ferret out why previous attempts to target the PI3K pathway have had limited success and, using that information, devised and tested a possible fix (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0081-9).

The stubborn pathway involves a series of kinases—enzymes that modify other proteins by adding phosphate groups—starting with one called PI3K. Overactivation of the pathway produces the transcription factor MYC, which turns on protein synthesis and can spark cancer growth.

The UCSF team used kinase-affinity beads and tandem mass spectrometry to survey all kinases active in breast cancer cells before and after treatment with a variety of cancer drugs. The team studied this so-called kinome to look for kinases associated with the cells’ tendency to resist drug treatments.

The researchers found that a kinase called AURKA undermines everolimus and other pathway-targeted drugs by reversing their effects. While the drugs try to turn off the PI3K pathway, AURKA, activated separately by other pathways, keeps the PI3K pathway turned on. To add insult to injury, MYC boosts AURKA production, maintaining a plentiful supply of the drug spoiler.

When the researchers coadministered everolimus with the AURKA inhibitor MLN8237, also called alisertib, everolimus could inhibit the PI3K pathway as it was designed to do, without interference. The combination treatment killed most types of cancer cells in culture and shrank tumors in mice with breast cancer, whereas everolimus alone permitted slow tumor growth to continue.

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^ Jeng LB, Lee SG, Soin AS, Lee WC, Suh KS, Joo DJ, Uemoto S, Joh J, Yoshizumi T, Yang HR, Song GW, Lopez P, Kochuparampil J, Sips C, Kaneko S, Levy G (December 2017). “Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study”. American Journal of Transplantation. 18 (6): 1435–1446. doi:10.1111/ajt.14623. PMID 29237235.
^ Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (July 2009). “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice”. Nature. 460 (7253): 392–5. Bibcode:2009Natur.460..392H. doi:10.1038/nature08221. PMC 2786175. PMID 19587680.
^ Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB (December 2014). “mTOR inhibition improves immune function in the elderly”. Science Translational Medicine. 6 (268): 268ra179. doi:10.1126/scitranslmed.3009892. PMID 25540326. S2CID 206685475.

External links

“Everolimus”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Pronunciation	Everolimus /ˌɛvəˈroʊləməs/
Trade names	Afinitor, Zortress
Other names	42-O-(2-hydroxyethyl)rapamycin, RAD001
AHFS/Drugs.com	Monograph
MedlinePlus	a609032
License data	EU EMA: by INNUS DailyMed: EverolimusUS FDA: Everolimus
Pregnancy category	AU: C^[1]
Routes of administration	By mouth
ATC code	L01EG02 (WHO) L04AA18 (WHO)
Legal status
Legal status	US: ℞-onlyEU: Rx-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life	~30 hours^[2]
Identifiers
show IUPAC name
CAS Number	159351-69-6
PubChem CID	6442177
DrugBank	DB01590
ChemSpider	21106307
UNII	9HW64Q8G6G
KEGG	D02714
ChEMBL	ChEMBL1908360
CompTox Dashboard (EPA)	DTXSID0040599
ECHA InfoCard	100.149.896
Chemical and physical data
Formula	C₅₃H₈₃NO₁₄
Molar mass	958.240 g·mol⁻¹
3D model (JSmol)	Interactive image
hide SMILESOCCO[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(/C)[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4
hide InChIInChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1Key:HKVAMNSJSFKALM-GKUWKFKPSA-N

//////////////// RAD-001, SDZ RAD, Certican, Novartis, Immunosuppressant, Everolimus, Afinitor, эверолимус , إيفيروليموس , 依维莫司 ,

Everolimus

Synonyms:RAD-001, SDZ-RAD, Afinitor
ATC:L04AA18

Use:immunosuppressantChemical name:42-O-(2-hydroxyethyl)rapamycinFormula:C₅₃H₈₃NO₁₄

MW:958.24 g/mol
CAS-RN:159351-69-6

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2012-08-29	New dosage form	Afinitor Disperz	Renal cell carcinoma , Advanced breast cancer, Pancreatic cancer, Renal angiomyolipoma, Tuberous sclerosis complex (TSC)	Tablet, For suspension	2 mg/3 mg/5 mg	Novartis	Priority
2010-04-20	New strength	Zortress	Advanced renal cell carcinoma (RCC)	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis
2009-03-30	Marketing approval	Afinitor	Advanced renal cell carcinoma (RCC)	Tablet	2.5 mg/5 mg/7.5 mg/10 mg	Novartis	Priority

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2016-06-02	New indication	Afinitor	neuroendocrine tumors (NET), Advanced gastrointestinal tumors	Tablet		Novartis
2011-09-02	Marketing approval	Votubia	Advanced breast cancer, Renal cell carcinoma , Pancreatic cancer	Tablet	2.5 mg/5 mg/10 mg	Novartis	Orphan; Conditional Approval
2011-09-02	Marketing approval	Votubia	Advanced breast cancer, Renal cell carcinoma , Pancreatic cancer	Tablet, Orally disintegrating	2 mg/3 mg/5 mg	Novartis	Orphan; Conditional Approval
2009-08-03	Marketing approval	Afinitor	Advanced breast cancer, Renal cell carcinoma , Pancreatic cancer	Tablet	2.5 mg/5 mg/10 mg	Novartis

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2011-12-22	New indication	Certican	Rejection of suppression renal transplantation	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis
2007-01-26	Marketing approval	Certican	Rejection in heart transplantation	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company
2014-02-13	Marketing approval	飞尼妥/Afinitor	Advanced renal cell carcinoma (RCC), Subependymal giant cell astrocytoma	Tablet	2.5 mg	Novartis
2013-01-22	Marketing approval	飞尼妥/Afinitor	Advanced renal cell carcinoma (RCC), Subependymal giant cell astrocytoma	Tablet	10 mg	Novartis
2013-01-22	Marketing approval	飞尼妥/Afinitor	Advanced renal cell carcinoma (RCC), Subependymal giant cell astrocytoma	Tablet	5 mg	Novartis

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2003-07-18	Marketing approval	Certican	Rejection of organ transplantation, Renal cell carcinoma	Tablet	0.25 mg/0.5 mg/0.75 mg	Novartis

clip

Click to access afinitor-epar-public-assessment-report_en.pdf

fda

Click to access 022334s000_ChemR.pdf

It is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

Medical uses

Everolimus is approved for various conditions:

Advanced kidney cancer (US FDA approved in March 2009)^[3]
Prevention of organ rejection after renal transplant(US FDA April 2010)^[4]
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (US FDA October 2010)^[5]
Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)^[6]
Breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (US FDA July 2012)^[7]
Prevention of organ rejection after liver transplant(Feb 2013)
Progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease (US FDA February 2016).^[8]
Tuberous sclerosis complex-associated partial-onset seizures for adult and pediatric patients aged 2 years and older. (US FDA April 2018).^[9]

UK National Health Service

Clinical trials

Mechanism

mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase tumor-infiltrating lymphocytes, and to improve adoptive cell transfer therapy.^[19]

Adverse reactions

Role in heart transplantation

Role in liver transplantation

Use in vascular stents

Use in aging

Reference：1. US5665772A.

2. Drug. Future 1999, 24, 22-29.Route 2

Reference：1. WO2014203185A1.Route 3

Reference：1. WO2012103959A1.Route 4

Reference：1. CN102731527A.

SYN

Synthetic Reference

SYN 2

Synthetic Reference

SYN 3

Synthetic Reference

SYN 4

Synthetic Reference

Zabudkin, Oleksandr; Schickaneder, Christian; Matviienko, Iaroslav; Sypchenko, Volodymyr. Method for the synthesis of rapamycin derivatives. Assignee Synbias Pharma AG, Switz. EP 3109250. (2016).

SYN 5

Synthetic Reference

SYN 6

Synthetic Reference

SYN

EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010

SYN

J Label Compd Radiopharm 1999,42(1),29

SYN

SYN

clipRapamycin is a known macrolide antibiotic produced by Streptomvces hvgroscopicus. having the structure depicted in Formula A:

(1) (2)

Everolimus and a process of making it have been disclosed in WO 94/09010

Synthesis

…………..

SYNTHESIS

https://www.google.com/patents/WO2012103960A1

RAP-OH + L-CH₂-CH₂-0-P — –> RAP-O-CH2-CH2-O-P — – > RAP-O-CH2-CH2-OH

(2) (4) (1)

(2) (3A) (4A) (1)

Only 8% yield of the corresponding compound (4B)

and 21% yield of the compound (1) have been reported.

Thus, it would be useful to improve both processes of making compounds of formula (3) and, as well, processes of their application in chemical synthesis.

xample 6: 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin

Example 7: 40-O-(2-hydroxyethyl)-rapamycin [everolimus]

……………………….

SYNTHESIS

https://www.google.co.in/patents/WO1994009010A1

Example 8: 40-O-(2-Hydroxy)ethyl-rapamycin

a) 40-O-[2-(t-Butyldimethylsilyl)oxy]ethyl-rapamycin

b) 40-O-(2-Hydroxy)ethyl-rapamycin

sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and

MBA (rel. IC50) 2.2

IL-6 dep. prol. (rel. IC50) 2.8

MLR (rel. IC50) 3.4

…………………..

synthesis

PATENT

https://patents.google.com/patent/WO2016020664A1/en

Everolimus (RAD-001) is the 40-O- 2-hydroxyethyl)-rapamycin of formula (I),

It is a derivative of sirolimus of formula III),

Trisubstituted silyloxyethyltrifluoromethane sulfonates (triflates) of the general formula (IV),

Everolimus and its process for manufacture using the intermediate 2-(t-butyldimethyl silyl) oxyethyl triflate of formula (IVA),

was first described in US Patent Number 5,665,772. The overall reaction is depicted in Scheme I.

Sche

Everolimus (I)

Moenius et al. (I. Labelled Cpd. Radiopharm. 43, 1 13-120 (2000) have disclosed a process to prepare C-14 labelled everolimus using the diphenyltert-butylsilyloxy-protective group of formula (IV B),

Example 1 :

Example 2:

Step 2: Preparation of everolimus of formula (I)

Preparation of crude Everolimus

Step 1 : Preparation of TBS-ethylene glycol of formula (Va)

Step 2: Preparation of TBS-glycol-Triflate of formula (IVa)

Step 3: Preparation of TBS-evero!imus of formula (Ha)

Step 4: Preparation of everolimus of formula (I)

The crude everolimus purified by chromatography to achieve purity more than 99 %.

Patent

Enzymes

Streptomyces hygroscopicus NRRL 5491 (ATCC 29253)

Synthesis Path

Trade Names

Country	Trade Name	Vendor
D	Certican	Novartis ,2004
F	Certican	Novartis
I	Certican	Novartis
J	Certican	Novartis

Formulations

tabl. 0.25 mg, 0.5 mg, 0.75 mg

References

a WO 9 409 010 (Sandoz-Erfindungen; 28.4.1994; GB-prior. 9.10.1992).
b US 6 277 983 (American Home Products; 21.8.2001; USA-prior. 27.9.2000).
US 6 384 046 (Novartis; 7.5.2002; GB-prior. 27.3.1996).
US 20 040 115 (Univ. of Pennsylvania; 15.1.2004; USA-prior. 9.7.2002).
fermentation of rapamycin (sirolimus):
- Chen, Y. et al.: Process Biochemistry (Oxford, U. K.) (PBCHE5) 34, 4, 383 (1999).
- The Merck Index, 14th Ed., 666 (3907) (Rahway 2006).
- US 3 929 992 (Ayerst McKenna & Harrison Ltd.; 30.12.1975; USA-prior. 29.9.1972).
- WO 9 418 207 (Sandoz-Erfindungen; 18.8.1994; GB-prior. 2.2.1993).
- EP 638 125 (Pfizer; 17.4.1996; J-prior. 27.4.1992).
- US 6 313 264 (American Home Products; 6.11.2001; USA-prior. 8.3.1994).

clip

https://doi.org/10.1039/C7MD00474E Issue 1, 2018

MedChemComm

Figure 7. Structures of the ascomycin tacrolimus (44) and the rapamycins sirolimus (45) and everolimus (46) that are used mainly to prevent rejection of organ transplants.

clip

Ferreting out why some cancer drugs struggle to shrink tumors

Study shows how stopping one enzyme could help drugs treat an important class of cancers more effectively

by Stu Borman

JUNE 27, 2018 | APPEARED IN VOLUME 96, ISSUE 27

In several types of cancer, including most cases of breast cancer, a cell-signaling network called the PI3K pathway is overactive. Drug designers have tried to quiet this pathway to kill cancer, but they haven’t had much success and, more frustratingly, haven’t understood why the problem is so hard to solve.

References

^ Jump up to:^a ^b Use During Pregnancy and Breastfeeding
^ Formica RN, Lorber KM, Friedman AL, Bia MJ, Lakkis F, Smith JD, Lorber MI (March 2004). “The evolving experience using everolimus in clinical transplantation”. Transplantation Proceedings. 36 (2 Suppl): 495S–499S. doi:10.1016/j.transproceed.2004.01.015. PMID 15041395.
^ “Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib” (Press release). Novartis. 30 March 2009. Retrieved 6 April 2009.
^ “Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients” (Press release). Novartis. 22 April 2010. Archived from the original on 25 April 2010. Retrieved 26 April 2010.
^ “Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis”. 1 November 2010.
^ https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
^ “US FDA approves Novartis drug Afinitor for breast cancer”. Reuters. 20 July 2012.
^ Jump up to:^a ^b Everolimus (Afinitor). Feb 2016
^ Everolimus (Afinitor). April 2018
^ Lintern, Shaun (14 April 2015). “Policy delays risk ‘preventable deaths’, doctors warn NHS England”. Health Service Journal. Retrieved 20 April 2015.
^ “Couple forced to sell home after NHS refuse to fund daughter’s treatment for rare illness”. Daily Express. 11 May 2015. Retrieved 12 May 2015.
^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
^ Lutz M, Kapp M, Grigoleit GU, Stuhler G, Einsele H, Mielke S (April 2012). “Salvage therapy with everolimus improves quality of life in patients with refractory chronic graft-versus-host disease” (PDF). Bone Marrow Transplant. 47 (S1): S410–S411.
^ “Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End”. 2011.
^ Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB (October 2012). “Genome sequencing identifies a basis for everolimus sensitivity”. Science. 338 (6104): 221. Bibcode:2012Sci…338..221I. doi:10.1126/science.1226344. PMC 3633467. PMID 22923433.
^ [1]
^ Jump up to:^a ^b Zhavoronkov A (2020). “Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections”. Aging. 12 (8): 6492–6510. doi:10.18632/aging.102988. PMC 7202545. PMID 32229705.
^ Jump up to:^a ^b ^c Arriola Apelo SI, Neuman JC, Baar EL, Syed FA, Cummings NE, Brar HK, Pumper CP, Kimple ME, Lamming DW (February 2016). “Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system”. Aging Cell. 15 (1): 28–38. doi:10.1111/acel.12405. PMC 4717280. PMID 26463117.
^ Wang S, Raybuck A, Shiuan E, Jin J (2020). “Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity”. JCI Insight. 5 (15): e139237. doi:10.1172/jci.insight.139237. PMC 7455083. PMID 32759497.
^ Jump up to:^a ^b “Archived copy”. Archived from the original on 8 March 2014. Retrieved 26 February 2014.
^ Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sørensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P (August 2003). “Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients”. The New England Journal of Medicine. 349 (9): 847–58. doi:10.1056/NEJMoa022171. PMID 12944570.
^ Jeng LB, Thorat A, Hsieh YW, Yang HR, Yeh CC, Chen TH, Hsu SC, Hsu CH (April 2014). “Experience of using everolimus in the early stage of living donor liver transplantation”. Transplantation Proceedings. 46 (3): 744–8. doi:10.1016/j.transproceed.2013.11.068. PMID 24767339.
^ Jeng L, Thorat A, Yang H, Yeh C-C, Chen T-H, Hsu S-C. Impact of Everolimus On the Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation When Used in Early Stage: A Single Center Prospective Study [abstract]. Am J Transplant. 2015; 15 (suppl 3). http://www.atcmeetingabstracts.com/abstract/impact-of-everolimus-on-the-hepatocellular-carcinoma-recurrence-after-living-donor-liver-transplantation-when-used-in-early-stage-a-single-center-prospective-study/. Accessed 1 September 2015.
^ Thorat A, Jeng LB, Yang HR, Yeh CC, Hsu SC, Chen TH, Poon KS (November 2017). “Assessing the role of everolimus in reducing hepatocellular carcinoma recurrence after living donor liver transplantation for patients within the UCSF criteria: re-inventing the role of mammalian target of rapamycin inhibitors”. Annals of Hepato-Biliary-Pancreatic Surgery. 21 (4): 205–211. doi:10.14701/ahbps.2017.21.4.205. PMC 5736740. PMID 29264583.
^ Jeng LB, Lee SG, Soin AS, Lee WC, Suh KS, Joo DJ, Uemoto S, Joh J, Yoshizumi T, Yang HR, Song GW, Lopez P, Kochuparampil J, Sips C, Kaneko S, Levy G (December 2017). “Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study”. American Journal of Transplantation. 18 (6): 1435–1446. doi:10.1111/ajt.14623. PMID 29237235.
^ Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (July 2009). “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice”. Nature. 460 (7253): 392–5. Bibcode:2009Natur.460..392H. doi:10.1038/nature08221. PMC 2786175. PMID 19587680.
^ Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB (December 2014). “mTOR inhibition improves immune function in the elderly”. Science Translational Medicine. 6 (268): 268ra179. doi:10.1126/scitranslmed.3009892. PMID 25540326. S2CID 206685475.

External links

“Everolimus”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Pronunciation	Everolimus /ˌɛvəˈroʊləməs/
Trade names	Afinitor, Zortress
Other names	42-O-(2-hydroxyethyl)rapamycin, RAD001
AHFS/Drugs.com	Monograph
MedlinePlus	a609032
License data	EU EMA: by INNUS DailyMed: EverolimusUS FDA: Everolimus
Pregnancy category	AU: C^[1]
Routes of administration	By mouth
ATC code	L01EG02 (WHO) L04AA18 (WHO)
Legal status
Legal status	US: ℞-onlyEU: Rx-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life	~30 hours^[2]
Identifiers
show IUPAC name
CAS Number	159351-69-6
PubChem CID	6442177
DrugBank	DB01590
ChemSpider	21106307
UNII	9HW64Q8G6G
KEGG	D02714
ChEMBL	ChEMBL1908360
CompTox Dashboard (EPA)	DTXSID0040599
ECHA InfoCard	100.149.896
Chemical and physical data
Formula	C₅₃H₈₃NO₁₄
Molar mass	958.240 g·mol⁻¹
3D model (JSmol)	Interactive image
hide SMILESOCCO[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(/C)[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4
hide InChIInChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1Key:HKVAMNSJSFKALM-GKUWKFKPSA-N

//////////////// RAD-001, SDZ RAD, Certican, Novartis, Immunosuppressant, Everolimus, Afinitor, эверолимус , إيفيروليموس , 依维莫司 ,

#RAD-001, #SDZ RAD, #Certican, #Novartis, #Immunosuppressant, #Everolimus, #Afinitor, #эверолимус , #إيفيروليموس , #依维莫司 ,

Fluvoxamine

February 28, 2021 9:09 am / 1 Comment on Fluvoxamine

Fluvoxamine

Molecular FormulaC₁₅H₂₁F₃N₂O₂
Average mass318.335 Da
54739-18-3

(E)-5-Methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone O-(2-Aminoethyl)oxime1-Pentanone, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-, O-(2-aminoethyl)oxime, (1E)-2-[({(1E)-5-Methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene}amino)oxy]ethanamine
2-{[(E)-{5-Methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene}amino]oxy}ethanamine1-Pentanone, 5-methoxy-1-(4-(trifluoromethyl)phenyl)-, O-(2-aminoethyl)oxime, (E)-
387954739-18-3[RN]5583954[Beilstein]5-Methoxy-4′-(trifluoromethyl)valerophenone (E)-O-(2-aminoethyl)oximeA selective serotonin reuptake inhibitor that is used in the treatment of DEPRESSION and a variety of ANXIETY DISORDERS.

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class^[5] which is used primarily for the treatment of obsessive–compulsive disorder (OCD).^[6] It is also used to treat depression and anxiety disorders, such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.^[7]^[8]

FLUVOXAMINE MALEATE

C₁₉H₂₅F₃N₂O₆, 434.4 g/mol

1-Pentanone, 5-methoxy-1-(4-(trifluoromethyl)phenyl)-, O-(2-aminoethyl)oxime, (E)-, (Z)-2-butenedioate (1:1)

(Z)-but-2-enedioic acid;2-[(E)-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine

Luvox

61718-82-9

CAS 54739-20-7

Fevarin, Luvox CR

Synonyms

5-Methoxy-4′-(trifluoromethyl)valerophenone (E)-O-(2-aminoethyl)oxime, maleate (1:1)
5-Methoxy-4′-trifluoromethylvalerophenone (E)-O-2-aminoethyloxime monomaleate
DU23000
- Fevarin
- Fluvoxamine maleate
- Luvox
- Luvox CR
- SME 3110
- UNII-5LGN83G74V

Originator Company	Solvay SA
Active Companies	AbbVie Inc; Abbott Laboratories; Meiji Seika Pharma Co Ltd; Solvay SA

Launched (Obsessive compulsive disorder – EU – Dec-1983)

In the EU, the product is indicated for the treatment of obsessive compulsive disorder (OCD) and for the treatment of major depressive disorder (MDD)

In Japan, Luvox is indicated for the treatment of adult or pediatric OCD, social anxiety disorder (SAD) and MDD

USFDA The drug was approved for the treatment of OCD and SAD in April 2008

CHINA

In 2000, the drug was launched in China for the treatment of OCD and MDD

Patents and Generics

FDA exclusivity expired in the US in June 2000. Generic versions have been on the market since that time. Generic fluvoxamine was still available in the US by May 2007, despite the fact the Solvay/Jazz product had not been relaunched . By October 2004, the drug was also off patent in most European countries .

Medical uses

Fluvoxamine is approved in the United States for OCD,^[9]^[6] and social anxiety disorder.^[10] In other countries (e.g., Australia,^[11]^[12] the UK,^[13] and Russia^[14]) it also has indications for major depressive disorder. In Japan it is currently^[when?] approved to treat OCD, SAD and MDD.^[15]^[16] Fluvoxamine is indicated for children and adolescents with OCD.^[17] The drug works long-term, and retains its therapeutic efficacy for at least one year.^[18] It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.^[19]^[20]^[21]

There is tentative evidence that fluvoxamine is effective for social phobia in adults.^[22] Fluvoxamine is also effective for GAD, SAD, panic disorder and separation anxiety disorder in children and adolescents.^[23] There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.^[24]^[25]

A double-blind controlled study found that fluvoxamine may prevent clinical deterioration in outpatients with symptomatic COVID-19. The study had important limitations: it was run fully remotely; it had a small sample size (150) and short follow-up duration (15 days).^[26] The accompanying editorial noted that, although this study is important enough to choose out of more than 10,000 other COVID-19 related submissions, it “presents only preliminary information” and “the findings should be interpreted as only hypothesis generating; they should not be used as the basis for current treatment decisions.”^[27] Similarly, the study authors themselves cautioned that “the trial’s results should not be treated as a measure of fluvoxamine’s effectiveness against COVID-19 but as an encouraging indicator that the drug warrants further testing.”^[28] A prospective open-labelled cohort study showed similar results.^[29]

Adverse effects

Gastrointestinal side effects are more common in those receiving fluvoxamine than with other SSRIs.^[30] Otherwise, fluvoxamine’s side-effect profile is very similar to other SSRIs.^[2]^[9]^[11]^[13]^[31]^[32]Common (1–10% incidence) adverse effects

Nausea
Vomiting
Weight loss
Yawning
Loss of appetite
Agitation
Nervousness
Anxiety
Insomnia
Somnolence (drowsiness)
Tremor
Restlessness
Headache
Dizziness
Palpitations
Tachycardia (high heart rate)
Abdominal pain
Dyspepsia (indigestion)
Diarrhea
Constipation
Hyperhidrosis (excess sweating)
Asthenia (weakness)
Malaise
Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.)
Xerostomia (dry mouth)

Uncommon (0.1–1% incidence) adverse effects

Arthralgia
Hallucination
Confusional state
Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.)
Orthostatic hypotension
Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus)

Rare (0.01–0.1% incidence) adverse effects

Mania
Seizures
Abnormal hepatic (liver) function
Photosensitivity (being abnormally sensitive to light)
Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding)

Unknown frequency adverse effects

Hyperprolactinaemia (elevated plasma prolactin levels leading to galactorrhoea, amenorrhoea [cessation of menstrual cycles], etc.)
Bone fractures
Glaucoma
Mydriasis
Urinary incontinence
Urinary retention
Bed-wetting
Serotonin syndrome — a potentially fatal condition characterised by abrupt onset muscle rigidity, hyperthermia (elevated body temperature), rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.
Neuroleptic malignant syndrome — practically identical presentation to serotonin syndrome except with a more prolonged onset
Akathisia — a sense of inner restlessness that presents itself with the inability to stay still
Paraesthesia
Dysgeusia
Haemorrhage
Withdrawal symptoms
Weight changes
Suicidal ideation and behaviour
Violence towards others^[33]
Hyponatraemia
Syndrome of inappropriate antidiuretic hormone secretion
Ecchymoses

Interactions[edit]

Luvox (fluvoxamine) 100 mg film-coated scored tablets

Fluvoxamine inhibits the following cytochrome P450 enzymes:^[34]^[35]^[36]^[37]^[38]^[39]^[40]^[41]^[42]

CYP1A2 (strongly) which metabolizes agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
CYP3A4 (moderately) which metabolizes alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.^[43]
CYP2D6 (weakly) which metabolizes aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.^[44]
CYP2C9 (moderately) which metabolizes nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
CYP2C19 (strongly) which metabolizes clonazepam, diazepam, phenytoin, etc.
CYP2B6 (weakly) which metabolizes bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.^[34]

The plasma levels of oxidatively metabolized benzodiazepines (e.g., triazolam, midazolam, alprazolam and diazepam) are likely to be increased when co-administered with fluvoxamine. However the clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam)^[45]^[46] is unlikely to be affected by fluvoxamine.^[47] It appears that benzodiazepines metabolized by nitro-reduction (clonazepam, nitrazepam) are unlikely to be affected by fluvoxamine.^[48] Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations.^[49] If alprazolam is coadministered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.^[50]^[51]

Fluvoxamine and ramelteon coadministration is not indicated.^[52]^[53]

Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolized by CYP1A2, CYP2D6, and CYP3A4, by 3- to 4-fold in humans.^[54] Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.^[54]

Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.^[55]

Fluvoxamine’s interaction with St John’s wort can lead to increased serotonin levels and potentially lead to serotonin syndrome.^{[citation needed]}

Pharmacology

Site	K_i (nM)
SERT	2.5
NET	1,427
5-HT_2C	5,786
α₁-adrenergic	1,288
σ₁	36

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter.^[35] It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ₁ receptor.^[59]^[60] It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so.^[59] This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression.^[61] Unlike fluoxetine, fluvoxamine’s metabolites are inactive, without a significant effect on serotonin or norepinephrine uptake.^[62]

History

Fluvoxamine was developed by Kali-Duphar,^[63] part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983.^[63] It was approved by the U.S. Food and Drug Administration (FDA) in 1994, and introduced as Luvox in the US.^[64] In India, it is available, among several other brands, as Uvox by Abbott.^[65] It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression.^[66] It was the first SSRI, a non-TCA drug, approved by the U.S. FDA specifically for the treatment of OCD.^[67] At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine.^[68]^{[failed verification]} Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997.^[69] In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999^[70]^[71] and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder.^[72] Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.^[73]

Society and culture

Manufacturers include BayPharma, Synthon, and Teva, among others.^[74]

SYN

File:Fluvoxamine synthesis.png - Wikimedia Commons

SYN

J. Zhejiang Univ. (Medical Sci.) (2003), 32 (5), 441-442

PATENT

WO 2014178064

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9506B104B5D45A1607976196D81EFEEB.wapp2nC?docId=WO2014178064&tab=PCTDESCRIPTION

The present invention relates to an improved and industrially applicable process for the preparation of fluvoxamine maleate of formula I,

Fluvoxamine or (E)-5-methoxy-1 -[4-(trifluoromethyl)phenyl]pentan- 1 -one-O-2-aminoethyl oxime is an antidepressant which functions as a selective serotonin reuptake inhibitor (SSRI). Fluvoxamine is used for the treatment of major depressive disorder (MDD), obsessive compulsive disorder (OCD), and anxiety disorders such as panic disorder and post-traumatic stress disorder (PTSD). Fluvoxamine CR (controlled release) is approved to treat social anxiety disorder.

Fluvoxamine maleate and compounds were first disclosed in US patent 4,085,225. According to said patent, Fluvoxamine maleate prepared by alkylation reaction of 5-methoxy-4′-trifluoromethylvalerophenone oxime, compound of formula III with 2-chloroethylamine hydrochloride in dimethylformamide in the presence of a base such as potassium hydroxide powder for two days at 25°C.

Subsequently the solvent is removed under vacuum then the residue is acidified and extracted with ether to remove the unreacted oxime followed by basification. The obtained fluvoxamine base in ether extract is washed with sodium bicarbonate solution. The fluvoxamine base is then treated with maleic acid in absolute ethanbl and the residue obtained by concentration under vacuum is recrystallized from acetonitrile to obtain fluvoxamine maleate. The process is very much tedious, time consuming as it requires two days for the reaction completion. Operations like removal of dimethylformamide, ether, ethanol makes process cumbersome at plant level. Requirement of

various solvents lead the process to be non-eco-friendly. Moreover the patent is silent about yield and purity of the product.

In an alternate route described in US patent 4,085,225, the oxime of formula III is converted to formula I in a five step process i.e. alkylation of formula III with ethylene oxide. The reaction solvent is ethanol in which lithium is already dissolved. The reaction further involves addition of acetic acid to give the hydroxyethyl compound of formula A as oil. The compound of formula A is purified chromatographically over the silica gel, which is converted to a mesylate compound of formula B by treating with methanesulfonyl chloride and triethylamine at -5 to 0°C, then aminated with ammonia in methanol at 100°C using autoclave for 16 hours followed by removal of methanol and extraction in ether to give fluvoxamine base.

The base is then converted to the maleate salt formula I, which is finally purified by recrystallization from acetonitrile.

There are lots of disadvantages involve like more unit operations, use of various solvents and handling of ethylene oxide which is also known for its carcinogen effect. More unit operations lead to long occupancy of reactors in the plant as well as man power, high energy consumption and require bigger plant. These all parameters make the process commercially unviable as wel l as environmentally non-feasible. Further, purification of the compound of formula A requires cumbersome technique i.e chromatography over silica gel as well as lengthy work-up procedure in U.S. Pat. No. 4,085,225 requires complete removal of organic solvents at various stages.

US patent 6,433,225 discloses the process for preparing fluvoxamine maleate, prepared by alkylating 5-methoxy-4′-trtfluoromethylvalerophenone oxime, compound of formula III with 2-chloroethylamine hydrochloride in toluene and PEG-400 (polyethyleneglycol-400) as facilitator in the presence of a base potassium hydroxide powder at 30-35°C to obtain fluvoxamine base in

toluene layer is then treated with maleic acid in water. The precipitated fluvoxamine maleate is filtered and washed with toluene and dried. The obtained dried cake recrystallized with water to get fluvoxamine maleate. The process disclosed in the patent is silent about actual purity of the product. As per our scientist’s observation alkylation reaction at the temperature of 30-35°C may lead to non completion of reaction and results lower yield. Additional step of purification may further lead to loss of yield.

Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of fluvoxamine maleate, which provides fluvoxamine maleate in high purity and overall good yield.

EXAMPLES:

Stage – 1 : Preparation of (1E)-N-hydroxy-5-methoxy-1-(4-trifluoromethyI pheny 1) pentan-1-imine formula III

To a stirred solution of 5-methoxy- 1 -(4-trifluoromethylphenyl) pentan-1 -one ( 150 gm) in methanol (750 ml), sodium carbonate (granule) (72 gm) and hydroxylamine hydrochloride (59.64 gm) were added at temperature 25-30°C. The reaction mass was heated 45-50°C for 10- 15 minutes followed by maintaining the reaction mass at temperature 45-50°C for 8-9 hours under stirring. The reaction mass was cooled to 25-30°C and filtered under vacuum to remove unreacted inorganic matter, then distilled out the methanol completely from the collected filtrate under vacuum at temperature below 50°C. The obtained slurry was cooled to 25-30°C and water (300 ml) was added into the residue followed by the addition of hexane (300×2 ml) and stirred for 30 minutes. The layers were separated. The collected organic layer was stirred for 5- 10 minutes at temperature 25-30°C followed by cooling the mass at temperature -5°C to – 10°C, stirred for 30-40 minutes and filtered at the same temperature. The product was suck dried at -5 to -10°C and further in vacuum at 25-30°C for 2-3 hours to give 138 – 142 gm of title compound. HPLC purity: >98.5%

Stage – 2: Preparation of crude fluvoxamine maleate formula I

To a prepared solution of dimethyl sulphoxide (575 ml), potassium hydroxide flakes ( 1 14.64 gm) and water (69 ml), stage-1 (1 15 gm) was added at temperature 40-45°C. The reaction mixture was stirred to get clear solution followed by adding 2-chloroethylamine hydrochloride (86.36 gm) drop wise into the reaction mixture at temperature 40-45°C and maintained for 1 -2 hour. Water (1 150 ml) was added in to the reaction mixture at temperature 25-30°C and stirred for 20-25 minutes. Then toluene (575 ml x 2) was added and stirred for 30 minutes and preceded for separation of layers followed by washing the toluene layer with water ( 1 1 50 x 5 ml). The solution of maleic acid (48.47 gm) dissolved in water (98 ml) was added into above obtained toluene layer and stirred at temperature 25-30°C for 2-3 hours. The reaction mixture was cooled to 0-5°C and maintained for 30-40 minutes at the same temperature. The obtained material was washed with toluene, filtered and suck dried. The wet cake was then added hexane (600 ml) and stirred for 30 minutes at temperature 25-30°C, filtered, washed with hexane and dried to get 161 gm of title compound. HPLC purity: >98.5%

Stage – 3: Preparation of pure fluvoxamine maleate formula I

In to the reaction assembly, water (600 ml) was added and heated to 40-45°C. Stage -2 ( 1 50 gm) was added into the hot water under stirring. The reaction mixture was stirred for 5- 10 minutes, filtered and cooled to 25°C. Toluene (68 ml) was added into the reaction mixture at temperature 25°C and stirred for 30 minutes. Filtered the solid, washed with 10-15°C chilled water and dried to get the pure 127.5 gm fluvoxamine maleate. HPLC purity: >99.8%

Process for isolation of 5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one formula II

To a solution of cone. HCl (600 ml) and water ( 160 ml), organic residue (250 gm) of ( 1 £)+( 1 Z) of 1 -N-hydroxy-5-methoxy- 1 -[4-(trifluoromethyl) phenyl]pentan-1 -imine and traces of 5-methoxy- 1 -[4-(trifluoromethyl)phenyl]pentan- 1-one (obtained after hexane recovery from stage-1 filtrate) was added at temperature 25-30°C under stirring. The reaction mixture was heated to 67-75°C and maintained for 13-14 hours followed by cool ing the reaction mixture at temperature 25-30°C. Then after hexane (500 x 2 ml) was added into the reaction mixture and stirred for 15 minutes at 25-30°C. The organic layers were separated and sodium bicarbonate solution (25 gm sodium bicarbonate dissolved in 250 ml water) was added into the hexane layer and stirred for 15 minutes. The layers were separated and water (250ml) was added into hexane layer and stirred for 15 minutes at temperature 25-30°C. Further the layers were separated and hexane layer was added activated charcoal ( 12.5 gm) and stirred for 20-30 minutes at temperature 30-35°C. The reaction mixture was filtered and stirred for 5-10 minutes at 25-30°C followed by cooling at 0 to -5°C and stirred for 30-40 minutes at 0 to -5°C. The reaction mixture was filtered and dried to get 150 to l 75 gm of title compound. HPLC purity: >99%.

PATENT

US 20140243544

IN 2013MU01290/WO 2014178064

WO 2014035107

PATENT

https://patents.google.com/patent/US9783492B2/en

Fluvoxamine or (E)-5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one-O-2-aminoethyl oxime is an antidepressant which functions as a selective serotonin reuptake inhibitor (SSRI). Fluvoxamine is used for the treatment of major depressive disorder (MDD), obsessive compulsive disorder (OCD), and anxiety disorders such as panic disorder and post-traumatic stress disorder (PTSD). Fluvoxamine CR (controlled release) is approved to treat social anxiety disorder.

Fluvoxamine maleate and compounds were first disclosed in U.S. Pat. No. 4,085,225. According to said patent, Fluvoxamine maleate prepared by alkylation reaction of 5-methoxy-4′-trifluoromethylvalerophenone oxime, compound of formula III with 2-chloroethylamine hydrochloride in dimethylformamide in the presence of a base such as potassium hydroxide powder for two days at 25° C.

Subsequently the solvent is removed under vacuum then the residue is acidified and extracted with ether to remove the unreacted oxime followed by basification. The obtained fluvoxamine base in ether extract is washed with sodium bicarbonate solution. The fluvoxamine base is then treated with maleic acid in absolute ethanol and the residue obtained by concentration under vacuum is recrystallized from acetonitrile to obtain fluvoxamine maleate. The process is very much tedious, time consuming as it requires two days for the reaction completion. Operations like removal of dimethylformamide, ether, ethanol makes process cumbersome at plant level. Requirement of various solvents lead the process to be non-eco-friendly. Moreover the patent is silent about yield and purity of the product.

In an alternate route described in U.S. Pat. No. 4,085,225, the mine of formula III is converted to formula I in a five step process i.e. alkylation of formula III with ethylene oxide. The reaction solvent is ethanol in which lithium is already dissolved. The reaction further involves addition of acetic acid to give the hydroxyethyl compound of formula A as oil. The compound of formula A is purified chromatographically over the silica gel, which is converted to a mesylate compound of formula B by treating with methanesulfonyl chloride and triethylamine at −5 to 0° C., then aminated with ammonia in methanol at 100° C. using autoclave for 16 hours followed by removal of methanol and extraction in ether to give fluvoxamine base.

The base is then converted to the maleate salt formula I, which is finally purified by recrystallization from acetonitrile.

There are lots of disadvantages in like more unit operations, use of various solvents and handling of ethylene oxide which is also known for its carcinogen effect. More unit operations lead to long occupancy of reactors in the plant as well as man power, high energy consumption and require bigger plant. These all parameters make the process commercially unviable as well as environmentally non-feasible. Further, purification of the compound of formula A requires cumbersome technique i.e chromatography over silica gel as well as lengthy work-up procedure in U.S. Pat. No. 4,085,225 requires complete removal of organic solvents at various stages.

U.S. Pat. No. 6,433,225 discloses the process for preparing fluvoxamine maleate, prepared by alkylating 5-methoxy-4′-trifluoromethylvalerophenone oxime compound of formula III with 2-chloroethylamine hydrochloride in toluene and PEG-400 (polyethyleneglycol-400) as facilitator in the presence of a base potassium hydroxide powder at 30-35°C. to obtain fluvoxamine base in toluene layer is then treated with maleic acid in water. The precipitated fluvoxamine maleate is filtered and washed with toluene and dried. The obtained dried cake recrystallized with water to get fluvoxamine maleate. The process disclosed in the patent is silent about actual purity of the product. As per our scientist’s observation alkylation reaction at the temperature of 30-35° C. may lead to non completion of reaction and results lower yield. Additional step of purification may further lead to loss of yield.

EXAMPLES

Stage-1: Preparation of (1 E)-N-hydroxy-5-methoxy-1-(4-trifluoromethyl phenyl)pentan-1-imine Formula III

To a stirred solution of 5-methoxy-1-(4-trifluoromethylphenyl)pentan-1one (150 gm) in methanol (750 ml), sodium carbonate (granule) (72 gm) and hydroxylamine hydrochloride (59.64 gm) were added at temperature 25-30° C. The reaction mass was heated 45-50° C. for 10-15 minutes followed by maintaining the reaction mass at temperature 45-50° C. for 8-9 hours under stirring. The reaction mass was cooled to 25-30° C. and filtered under vacuum to remove unreacted inorganic matter, then distilled out the methanol completely from the collected filtrate under vacuum at temperature below 50° C. The obtained slurry was cooled to 25-30° C. and water (300 ml) was added into the residue followed by the addition of hexane (300×2 ml) and stirred for 30 minutes. The layers were separated. The collected organic layer was stirred for 5-10 minutes at temperature 25-30° C. followed by cooling the mass at temperature −5° C. to −10° C., stirred for 30-40 minutes and filtered at the same temperature. The product was suck dried at −5 to −10° C. and further in vacuum at 25-30° C. for 2-3 hours to give 138-142 gm of title compound. HPLC purity: >98.5%

Stage-2: Preparation of Crude Fluvoxamine Maleate Formula I

To a prepared solution of dimethyl sulphoxide (575 ml), potassium hydroxide flakes (114.64 gm) and water (69 ml), stage-1 (115 gm) was added at temperature 40-45° C. The reaction mixture was stirred to get clear solution followed by adding 2-chloroethylamine hydrochloride (8636 gm) drop wise into the reaction mixture at temperature 40-45° C. and maintained for 1-2 hour. Water (1150 ml) was added in to the reaction mixture at temperature 25-30° C. and stirred for 20-25 minutes. Then toluene (575 ml×2) was added and stirred for 30 minutes and preceded for separation of layers followed by washing the toluene layer with water (1150×5 ml). The solution of maleic acid (48.47 gm) dissolved in water (98 ml) was added into above obtained toluene layer and stirred at temperature 25-30° C. for 2-3 hours. The reaction mixture was cooled to 0-5° C. and maintained for 30-40 minutes at the same temperature. The obtained material was washed with toluene, filtered and such dried. The wet cake was then added hexane (600 ml) and stirred for 30 minutes at temperature 25-30° C., filtered, washed with hexane and dried to get 161 gm of title compound. HPLC purity: >98.5%

Stage-3: Preparation of Pure Fluvoxamine Maleate Formula I

In to the reaction assembly, water (600 ml) was added and heated to 40-45° C. Stage-2 (150 gm) was added into the hot water under stirring. The reaction mixture was stirred for 5-10 minutes, filtered and cooled to 25° C. Toluene (68 ml) was added into the reaction mixture at temperature 25° C. and stirred for 30 minutes. Filtered the solid, washed with 10-15° C. chilled water and dried to get the pure 127.5 gm fluvoxamine maleate. HPLC purity: >99.8%

Process for isolation of 5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one Formula II

To a solution of conc. HCl (600 ml) and water (160 organic residue (250 gm) of (1 E)+(1 Z) of 1-N-hydroxy-5-methoxy-1-[4trifluoromethyl)phenyl]pentan-1-imine and traces of 5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one (obtained after hexane recovery from stage-1 filtrate) was added at temperature 25-30° C. under stirring. The reaction mixture was heated to 67-75° C. and maintained for 13-14 hours followed by cooling the reaction mixture at temperature 25-30° C. Then after hexane (500×2 ml) was added into the reaction mixture and stirred for 15 minutes at 25-30° C. The organic layers were separated and sodium bicarbonate solution (25 gm sodium bicarbonate dissolved in 250 ml water) was added into the hexane layer and stirred for 15 minutes. The layers were separated and water (250 ml) was added into hexane layer and stirred for 15 minutes at temperature 25-30° C. Further the layers were separated and hexane layer was added activated charcoal (12.5 gm) and stirred for 20-30 minutes at temperature 30-35° C. The reaction mixture was filtered and stirred for 5-10 minutes at 25-30° C. followed by cooling at 0 to −5° C. and stirred for 30-40 minutes at 0 to −5° C. The reaction mixture was filtered and dried to get 150 to 175 gm of title compound. HPLC purity: >99%.
Claims (5)Hide Dependent

We claim:1. An improved process for the preparation of fluvoxamine maleate of formula I,

wherein the improvements comprises the steps of:a). condensing the compound of formula II,

with hydroxylamine hydrochloride in the presence of sodium carbonate granules at temperature 45-50° C. in suitable solvent to form a compound of formula III, wherein the compound of formula III comprises a mixture of (1E)+(1Z) isomers of 1-N-hydroxy-5-methoxy-1-[4(trifluoromethyl)phenyl]pentan-1-imine, and wherein the mixture of (1E)+(1Z) isomers of 1-N-hydroxy-5-methoxy-1-[4(trifluoromethyl)phenyl]pentan-1-imine comprises 98% of E-isomer and 2% of Z-isomer;

b). isolating compound of formula III;c). treating compound of formula III with 2-chloroethylamine hydrochloride in the presence of base in suitable solvent at 40-45° C. to form compound of formula IV;

d). extracting compound of formula IV with suitable solvent to form an organic layer;e). treating organic layer of step d) with maleic acid;f). isolating crude fluvoxamine maleate of formula I; andg). optionally purifying fluvoxamine maleate of formula I.

2. The process according to claim 1, wherein in step a), said suitable solvent is selected from the group consisting of alcohol, ketone, nitrile, and hydrocarbons in any suitable proportion or mixtures thereof;in step c), said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine and diisopropylethyamine;in step c), said solvent is selected from the group consisting of dimethylformamide (DMF), dimethylsulphoxide (DMSO) and hexamethylphosphoramide (HMPA) in any suitable proportion or mixtures thereof; andin step d) said suitable solvent is selected from the group consisting of toluene and xylene.3. A process for the isolation of 5-methoxy-1-[4-(trifluoromethyl)phenyl]pentan-1-one of formula II from mixture of (1E)+(1Z) of 1-N -hydroxy-5-methoxy-1-[4-(trifluoromethyl) phenyl]pentan-1-imine of formula III by treating compound of formula III with aqueous hydrochloric acid, wherein the mixture of (1E)+(1Z) of 1-N-hydroxy-5-methoxy-1-[4-(trifluoromethyl) phenyl]pentan-1-imine of formula III comprises 98% of E-isomer and 2% of Z-isomer.4. The process according to claim 3, wherein the reaction is performed at temperature 65-75°C.5. The process according to claim 1, wherein in step a), said suitable solvent is methanol.
Publication numberPriority datePublication dateAssigneeTitleUS4081551A *1975-03-201978-03-28U.S. Philips CorporationOxime ethers having anti-depressive activityUS4085225A1975-03-201978-04-18U.S. Philips CorporationOxime ethers having anti-depressive activityCN1079733A *1993-04-081993-12-22中国科学院成都有机化学研究所The synthetic method of a-benzoin oximeUS6433225B11999-11-122002-08-13Sun Pharamaceutical Industries, Ltd.Process for the preparation of fluvoxazmine maleateCN101654419A *2009-09-122010-02-24西北师范大学Preparation method of fluvoxamine maleate
Syn

US 6433225 SUN

https://patents.google.com/patent/US6433225B1/en

EXAMPLE 1

To a stirred mixture of toluene (1.20 lit.), PEG-400 (0.4 lit) and powdered potassium hydroxide (86.0 g on 100% basis, 1.53 mol.) at ambient temperature is added 5-methoxy-4′-trifluoromethylvalerophenone oxime (100 g, 0.363 mol.), followed by 2-chloroethyl amine hydrochloride (50.56 g, 0.435 mol.). The mixture is stirred at 30-35° C. for 2 hours. Water (1.2 lit.) is then added, stirred for 30 mins. and the aqueous layer is separated out. The organic layer is washed with water (˜3×500 ml) until the washings are neutral. To the washed organic layer is added a solution of maleic acid (14.14 g, 0.363 mol.) in water (65 ml) and the mixture is stirred at 25-30° C. temperature for 2 hours, then cooled to 5-10° C. when the maleate salt crystallizes out. The crystallized fluvoxamine maleate is filtered, washed with toluene (200 ml) and sucked to dryness. The crude fluvoxamine maleate thus obtained is dissolved in water (300 ml) at 50-55° C. to get a clear solution, then gradually cooled to 5-8° C. and then further stirred at this temperature for 2 hours. The recrystallised fluvoxamine maleate is filtered, washed with chilled water (5° C., 100 ml) and sucked dry. The product is finally dried at 50-55° C. to constant weight. The fluvoxamine maleate obtained complies with the specifications of British Pharmacopoeia, 1999.EXAMPLE 2

This process when scaled up in pilot plant on 4.0 kg scale input of 5-methoxy-4′-trifluoromethylvalerophenone oxime gave 4.5 kg (71.2%) of fluvoxamine maleate, complying to the specifications of British Pharmacopoeia, 1999.

SYN

US 4085225

https://patents.google.com/patent/US4085225A/en

EXAMPLE 15-Methoxy-4′-trifluoromethylvalerophenone O-(2-aminoethyl) oxime maleate (1:1).

20.4 Mmol (5.3 g) of 5-methoxy-4′-trifluoromethylvalerophenone (melting point 43°-44° C), 20.5 mmol (3.1 g) of 2-aminooxyethylaminedihydrochloride and 10 ml of pyridine were refluxed for 15 hours in 20 ml of absolute ethanol. After evaporating the pyridine and the ethanol in vacuo, the residue was dissolved in water. This solution was washed with petroleum ether and 10 ml of 50% sodium hydroxide solution were then added. Then three extractions with 40 ml of ether were carried out. The ether extract was washed successively with 20 ml of 5% sodium bicarbonate solution and 20 ml of water. After drying on sodium sulphate, the ether layer was evaporated in vacuo. Toluene was then evaporated another three times (to remove the pyridine) and the oil thus obtained was dissolved in 15 ml of absolute ethanol. An equimolar quantity of maleic acid was added to said solution and the solution was then heated until a clear solution was obtained. The ethanol was then removed in vacuo and the residue was crystallized from 10 ml of acetonitrile at +5° C. After sucking off and washing with cold acetonitrile, it was dried in air. The melting point of the resulting title compound was 120°-121.5° C.

SYN

GB 1535226

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External links

“Fluvoxamine”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Trade names	Luvox, Faverin, Fluvoxin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a695004
License data	EU EMA: by INNUS DailyMed: Fluvoxamine
Pregnancy category	AU: C^[1]
Routes of administration	By mouth
Drug class	Selective serotonin reuptake inhibitor (SSRI)
ATC code	N06AB08 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability	53% (90% confidence interval: 44–62%)^[2]
Protein binding	77-80%^[2]^[3]
Metabolism	Hepatic (via cytochrome P450 enzymes. Mostly via oxidative demethylation)^[2]
Elimination half-life	12–13 hours (single dose), 22 hours (repeated dosing)^[2]
Excretion	Renal (98%; 94% as metabolites, 4% as unchanged drug)^[2]
Identifiers
show IUPAC name
CAS Number	54739-18-3
PubChem CID	5324346
IUPHAR/BPS	7189
DrugBank	DB00176
ChemSpider	4481878
UNII	O4L1XPO44W
KEGG	D07984
ChEBI	CHEBI:5138
ChEMBL	ChEMBL814
CompTox Dashboard (EPA)	DTXSID2044002
ECHA InfoCard	100.125.476
Chemical and physical data
Formula	C₁₅H₂₁F₃N₂O₂
Molar mass	318.335 g·mol⁻¹
3D model (JSmol)	Interactive image
hide SMILESFC(F)(F)c1ccc(\C(=N\OCCN)CCCCOC)cc1
hide InChIInChI=1S/C15H21F3N2O2/c1-21-10-3-2-4-14(20-22-11-9-19)12-5-7-13(8-6-12)15(16,17)18/h5-8H,2-4,9-11,19H2,1H3/b20-14+Key:CJOFXWAVKWHTFT-XSFVSMFZSA-N

/////////DU23000, Fevarin, Fluvoxamine maleate, Luvox, Luvox CR, SME 3110, UNII-5LGN83G74V, Fluvoxamine, sme 3110, DU 23000

#DU23000, #Fevarin, #Fluvoxamine maleate, #Luvox, #Luvox CR, #SME 3110, #UNII-5LGN83G74V, #Fluvoxamine, #sme 3110, #DU 23000

OI 338

January 25, 2021 10:16 am / Leave a comment

OI 338

OI338GT (NN1953)

NNC0123-0000-0338

Insulin oral (NN 1953); Insulin-338-GIPET-I; LAI 338; NN 1438; NN-1953; NNC-0123-0000-0338; NNC0123-0338; OI-338GT; Oral insulin 338 C10

OriginatorNovo Nordisk
ClassAntihyperglycaemics; Insulins; Pancreatic hormones
Mechanism of ActionOrnithine decarboxylase stimulants; Phosphokinase stimulants; Protein tyrosine kinase stimulants
Phase IIType 1 diabetes mellitus; Type 2 diabetes mellitus

28 Jul 2018No recent reports of development identified for phase-I development in Type-1 diabetes mellitus in Germany (SC, Injection)
28 Jul 2018No recent reports of development identified for phase-I development in Type-2-diabetes-mellitus in Denmark (SC, Injection)
11 Sep 2017Efficacy and adverse events data from a phase II trial in Type-2 diabetes mellitus presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD-2017)

OI-338GT is a long-acting oral basal insulin analogue which had been in phase II clinical trials at Novo Nordisk for the treatment of patients with type 2 and type 1 diabetes. In 2016, the company discontinued the development of the product as the emergent product profile and required overall investments were not commercially viable in the increasingly challenging payer environment.

PAPERJ. Med. Chem. 2021, 64, 1, 616–628

Publication Date:December 28, 2020
https://doi.org/10.1021/acs.jmedchem.0c01576 https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01576

Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes to insulin glargine in a phase 2a clinical trial. Here, we report the engineering of a novel class of basal oral insulin analogues of which OI338, 10, in this publication, was successfully tested in the phase 2a clinical trial. We found that the introduction of two insulin substitutions, A14E and B25H, was needed to provide increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic acid (C20) to the lysine in position B29. Crucial for obtaining the ultralong PK profile was also a significant reduction of insulin receptor affinity. Oral bioavailability in dogs indicated that C18-based analogues were superior to C20-based analogues. These studies led to the identification of the two clinical candidates OI338 and OI320 (10 and 24, respectively).

Oral insulin 338 (I338) is a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate. We investigated the efficacy and safety of I338 versus subcutaneous insulin glargine (IGlar) in patients with type 2 diabetes. METHODS: This was a phase 2, 8-week, randomised, double-blind, double-dummy, active-controlled, parallel trial completed at two research institutes in Germany. Insulin-naive adult patients with type 2 diabetes, inadequately controlled on metformin monotherapy or combined with other oral antidiabetic drugs (HbA1c 7·0-10·0%; BMI 25·0-40·0 kg/m(2)), were randomly assigned (1:1) to receive once-daily I338 plus subcutaneous placebo (I338 group) or once-daily IGlar plus oral placebo (IGlar group). Randomisation occurred by interactive web response system stratified by baseline treatment with oral antidiabetic drugs. Patients and investigators were masked to treatment assignment. Weekly insulin dose titration aimed to achieve a self-measured fasting plasma glucose (FPG) concentration of 4·4-7·0 mmol/L. The recommended daily starting doses were 2700 nmol I338 or 10 U IGlar, and maximum allowed doses throughout the trial were 16 200 nmol I338 or 60 U IGlar. The primary endpoint was treatment difference in FPG concentration at 8 weeks for all randomly assigned patients receiving at least one dose of trial product (ie, the full analysis set). The trial has been completed and is registered at ClinicalTrials.gov, number NCT02470039. FINDINGS: Between June 1, 2015, and Oct 19, 2015, 82 patients were screened for eligibility and 50 patients were randomly assigned to the I338 group (n=25) or the IGlar group (n=25). Mean FPG concentration at baseline was 9·7 (SD 2·8) in the I338 group and 9·1 (1·7) in the IGlar group. Least square mean FPG concentration at 8 weeks was 7·1 mmol/L (95% CI 6·4-7·8) in the I338 group and 6·8 mmol/L (6·5-7·1) in the IGlar group, with no significant treatment difference (0·3 mmol/L [-0·5 to 1·1]; p=0·46). I338 and IGlar were well tolerated by patients. Adverse events were reported in 15 (60%) patients in the I338 group and 17 (68%) patients in the IGlar group. The most common adverse events were diarrhoea (three [12%] patients in each group) and nasopharyngitis (five [20%] in the I338 group and two [8%] in the IGlar group). Most adverse events were graded mild (47 of 68 events), and no severe adverse events were reported. One patient in the IGlar group had a treatment-emergent serious adverse event (urogenital haemorrhage of moderate intensity, assessed by the investigator as unlikely to be related to treatment; the patient recovered). Incidence of hypoglycaemia was low in both groups (n=7 events in the I338 group; n=11 in the IGlar group), with no severe episodes. INTERPRETATION: I338 can safely improve glycaemic control in insulin-naive patients with type 2 diabetes with no evidence of a difference compared with insulin glargine, a widely used subcutaneously administered basal insulin. Further development of this particular oral insulin project was discontinued because I338 doses were high and, therefore, production of the required quantities of I338 for wide public use was deemed not commercially viable. Improvement of technologies involved in the product’s development is the focus of ongoing research. FUNDING: Novo Nordisk…..Halberg, I. B.; Lyby, K.; Wassermann, K.; Heise, T.; Zijlstra, E.; Plum-Mörschel, L. Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial. Lancet Diabetes Endocrinol. 2019, 7, 179– 188, DOI: 10.1016/s2213-8587(18)30372-3

ral insulin 338 is a novel tablet formulation of a long-acting basal insulin. This randomised, open-label, four-period crossover trial investigated the effect of timing of food intake on the single-dose pharmacokinetic properties of oral insulin 338. Methods: After an overnight fast, 44 healthy males received single fixed doses of oral insulin 338 administered 0, 30, 60 or 360 min before consuming a standardised meal (500 kcal, 57 energy percent [E%] carbohydrate, 13 E% fat, 30 E% protein). Blood samples for pharmacokinetic assessment were taken up to 288 h post-dose. Results: Total exposure (area under the concn.-time curve from time zero to infinity [AUCIns338,0-∞]) and max. concn. (Cmax,Ins338) of insulin 338 were both significantly lower for 0 vs. 360 min post-dose fasting (ratio [95% confidence interval (CI)]: 0.36 [0.26-0.49], p < 0.001, and 0.35 [0.25-0.49], p < 0.001, resp.). There were no significant differences in AUCIns338,0-∞ and Cmax,Ins338 for 30 or 60 vs. 360 min post-dose fasting (ratio [95% CI] 30 vs. 360 min: 0.85 [0.61-1.21], p = 0.36, and 0.86 [0.59-1.26], p = 0.42; ratio [95% CI] 60 vs. 360 min: 0.96 [0.72-1.28], p = 0.77, and 0.99 [0.75-1.31], p = 0.95). The mean half-life was ∼ 55 h independent of the post-dose fasting period. Oral insulin 338 was well-tolerated with no safety issues identified during the trial. Conclusions: Oral insulin 338 pharmacokinetics are not affected by food intake from 30 min after dosing, implying that patients with diabetes mellitus do not need to wait more than 30 min after a morning dose of oral insulin 338 before having their breakfast. This is considered important for convenience and treatment compliance. ClinicalTrials.gov identifier: NCT02304627./……Halberg, I. B.; Lyby, K.; Wassermann, K.; Heise, T.; Plum-Mörschel, L.; Zijlstra, E. The effect of food intake on the pharmacokinetics of oral basal insulin: A randomised crossover trial in healthy male subjects. Clin. Pharmacokinet. 2019, 58, 1497– 1504, DOI: 10.1007/s40262-019-00772-2

///////////////OI 338, OI338GT, NN1953, NNC0123-0000-0338, Insulin oral (NN 1953), Insulin-338-GIPET-I, LAI 338, NN 1438, NN-1953, NNC-0123-0000-0338, NNC0123-0338, OI-338GT, Oral insulin 338 C10

Esketamine

January 23, 2021 2:29 am / Leave a comment

Esketamine

Molecular FormulaC₁₃H₁₆ClNO
Average mass237.725 Da

(+)-Ketamine(2S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
(S)-Ketamine33643-46-8[RN]7884Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (2S)-Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (S)-
KetamineCAS Registry Number: 6740-88-1CAS Name: 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanoneMolecular Formula: C13H16ClNOMolecular Weight: 237.73Percent Composition: C 65.68%, H 6.78%, Cl 14.91%, N 5.89%, O 6.73%Literature References: Prepn: C. L. Stevens, BE634208; idem,US3254124 (1963, 1966 both to Parke, Davis). Isoln of optical isomers: T. W. Hudyma et al.,DE2062620 (1971 to Bristol-Myers), C.A.75, 118119x (1971). Clinical pharmacology of racemate and enantiomers: P. F. White et al.,Anesthesiology52, 231 (1980). Toxicity: E. J. Goldenthal, Toxicol. Appl. Pharmacol.18, 185 (1971). Enantioselective HPLC determn in plasma: G. Geisslinger et al.,J. Chromatogr.568, 165 (1991). Comprehensive description: W. C. Sass, S. A. Fusari, Anal. Profiles Drug Subs.6, 297-322 (1977). Review of pharmacology and use in veterinary medicine: M. Wright, J. Am. Vet. Med. Assoc.180, 1462-1471 (1982). Review of pharmacology and clinical experience: D. L. Reich, G. Silvay, Can. J. Anaesth.36, 186-197 (1989); in pediatric procedures: S. M. Green, N. E. Johnson, Ann. Emerg. Med.19, 1033-1046 (1990).Properties: Crystals from pentane-ether, mp 92-93°. uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5). pKa 7.5. pH of 10% aq soln 3.5.Melting point: mp 92-93°pKa: pKa 7.5Absorption maximum: uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5)
Derivative Type: HydrochlorideCAS Registry Number: 1867-66-9Manufacturers’ Codes: CI-581Trademarks: Ketalar (Pfizer); Ketanest (Pfizer); Ketaset (Fort Dodge); Ketavet (Gellini); Vetalar (Bioniche)Molecular Formula: C13H16ClNO.HClMolecular Weight: 274.19Percent Composition: C 56.95%, H 6.25%, Cl 25.86%, N 5.11%, O 5.84%Properties: White crystals, mp 262-263°. Soly in water: 20 g/100 ml. LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal).Melting point: mp 262-263°Toxicity data: LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal)
NOTE: This is a controlled substance (depressant): 21 CFR, 1308.13.Therap-Cat: Anesthetic (intravenous).Therap-Cat-Vet: Anesthetic (intravenous).Keywords: Anesthetic (Intravenous).Esketamine hydrochloride, S enantiomer of ketamine, is in phase III clinical trials by Johnson & Johnson for the treatment of depression.Drug Name：Esketamine HydrochlorideResearchCode：JNJ-54135419MOA：Dopamine reuptake inhibitor; NMDA receptor antagonistIndication：DepressionStatus：Phase III (Active)Company：Johnson & Johnson (Originator)

Molecular Weight	274.19
Formula	C13H16ClNO•HCl
CAS No.	33643-46-8 (Esketamine); 33643-47-9 (Esketamine Hydrochloride);

Route 1

Reference：1. US6040479.

https://patents.google.com/patent/US6040479A/en

EXAMPLE 1

50 g (0.21 mol) R,S-ketamine are dissolved in 613 ml of acetone at the boiling point and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid. In order to obtain a clear solution, 40 ml of water are added thereto at the boiling point and subsequently the clear solution is filtered off while still hot. After the addition of seed crystals obtained in a small preliminary experiment, the whole is allowed to cool to ambient temperature while stirring. After standing overnight, the crystals formed are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.).

Yield (tartrate): 64.8 g

m.p.: 161° C.

[α]_D : +26.1° (c=2/H₂ O)

Thereafter, the crystallisate is recrystallised in a mixture of 1226 ml acetone and 90 ml water. After cooling to ambient temperature and subsequently stirring for 4 hours, the crystals are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C). There are obtained 38.8 g of tartrate (95.29% of theory).

m.p.: 175.3° C.

[α]_D : +68.9° (c=2/H₂ O)

The base is liberated by taking up 38.8 g of tartrate in 420 ml of aqueous sodium hydroxide solution and stirring with 540 ml of diethyl ether. The ethereal phase is first washed with water and subsequently with a saturated solution of sodium chloride. The organic phase is dried over anhydrous sodium sulphate. After filtering, the solution is evaporated to dryness on a rotary evaporator, a crystalline, colourless product remaining behind.

Yield (crude base): 21.5 g=86.0% of theory

m.p.: 118.9° C. (literature: 120-122° C.)

[α]_D : -55.8° (c=2/EtOH) (literature: [α]_D : -56.35° ).

In order possibly to achieve a further purification, the base can be recrystallised from cyclohexane. For this purpose, 10.75 g of the crude base are dissolved in 43 ml cyclohexane at the boiling point. While stirring, the clear solution is slowly cooled to about 10° C. and then stirred at this temperature for about 1 hour. The crystallisate which precipitates out is filtered off with suction and dried to constant weight.

Yield (base): 10.3 g=82.4% of theory

m.p.: 120° C. (literature: 120-122° C.)

[α]_D : -56.8° (c=2/EtOH) (literature: [α]_D : -56.35° )

EXAMPLE 2

125 ml of water are taken and subsequently 31.5 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine added thereto. While stirring, this mixture is warmed to 50-60° C. until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is first washed with water (1-6° C.) and subsequently washed twice with, in each case, 20 ml of acetone. Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 31.79 g of tartrate (78.23%) of theory).

EXAMPLE 3

150 ml of water are taken and subsequently mixed with 39.8 g (0.27 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine. While stirring, this mixture is warmed to 50-60° C. until a clear solution results.

After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is successively washed with 8 ml of water (1-6° C.) and thereafter twice with, in each case, 20 ml acetone.

Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 32.58 g of tartrate (80.02% of theory).

EXAMPLE 4

150 ml of water and 50 ml isopropanol are taken. After the addition of 39.8 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine, the mixture is heated to reflux temperature while stirring until a solution results (possibly add water until all is dissolved).

Subsequently, while stirring, the solution is allowed to cool to ambient temperature and stirred overnight. The crystals are filtered off with suction and subsequently washed with a 1:2 mixture of 20 ml of water/isopropanol and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 24.45 g of tartrate (62.63% of theory).

EXAMPLE 5

50 g (0.21 mol) R,S-ketamine are dissolved at the boiling point in 300 ml acetone and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid and 100 ml of water. The whole is allowed to cool while stirring and possibly seeded.

After standing overnight, the crystals formed are filtered off with suction, then washed twice with, in each case, 20 ml acetone and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 30.30 g of tartrate (74.57% of theory).

EXAMPLE 6

75 ml of water and 50 ml isopropanol are taken and subsequently 39.8 g (0.27 mol) L-(+)-tartaric acid added thereto. While stirring, the mixture is heated to reflux temperature until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is washed with a 1:2 mixture of 20 ml water/isopropanol. After drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.), there are obtained 34.84 g of tartrate (85.74% of theory).

EXAMPLE 7

20 g of the S-(+)-tartrate obtained in Example 4 are dissolved in 100 ml of water at 30-40° C. With about 7 ml of 50% sodium hydroxide solution, an S-(-)-ketamine base is precipitated out up to about pH 13. It is filtered off with suction and washed neutral with water to pH 7-8. Subsequently, it is dried for about 24 hours at 50° C. in a circulating air drying cabinet. There are obtained 11.93 g S-(-)-ketamine (97.79% of theory).

EXAMPLE 8

5 g of the S-(-)-ketamine obtained in Example 7 are dissolved in 50 ml isopropanol at about 50° C. and possibly filtered off with suction over kieselguhr. Subsequently, gaseous hydrogen chloride is passed in at 50-60° C. until a pH value of 0-1 is reached. The reaction mixture is allowed to cool to ambient temperature, filtered off with suction and washed with about 5 ml isopropanol. The moist product is dried overnight at about 50° C. in a circulating air drying cabinet. There are obtained 5.09 g S-(+)-ketamine hydrochloride (88.06% of theory).

Route 2

Reference：1. J. Am. Chem. Soc. 2015, 137, 3205-3208.

https://pubs.acs.org/doi/10.1021/jacs.5b00229

Here we report the direct asymmetric amination of α-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N-containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantioenriched α-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical.

CLIP

Initial reagent: cyclopentyl Grignard Step 0: Producing cyclopentyl Grignard Reacting cyclopentyl bromide with magnesium in solvent (ether or THF) Best results: distill solvent from Grignard under vacuum and replace with hydrocarbon solvent (e.g. benzene) Step 1: processing to (o-chlorophenyl)-cyclopentyl ketone Adding o-chlorobenzonitrile to cyclopentyl Grignard in solvent, stirring for long period of time (typically three days) Hydrolyzing reaction with mixture containing crushed ice, ammonium chloride and some ammonium hydroxide Extraction with organic solvent gives (o-chlorophenyl)-cyclopentyl ketone

Step 2: processing to alpha-bromo (o-chlorophenyl)-cyclopentyl ketone ketone processed with bromine in carbon tetrachloride at low temperature (typical T = 0°C), addition of bromine dropwise forming orange suspension Suspension washed in dilute aquerous solution of sodium bisufide and evaporated giving 1-bromocyclopentyl-(o-chlorophenyl)-ketone Note: bromoketone is unstable, immeadiate usage. Bromination carried out with NBromosuccinimide result higher yield (roughly 77%) Step 3: processing to 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine Dissolving bromoketone in liquid methylamine freebase (or benzene as possible solvent) After time lapse (1h): excess methylamine evaporated, residue dissolved in pentane and filtered evaporation of solvent yields 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine Note: longer time span (4-5d) for evaporation of methylaminemay increase yield Step 4: processing to 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine) Method: Thermal rearragement (qualitative yield after 30min in 180°C) N-methylimine dissolved in 15ml decalin, refluxed for 2.5h Evaporation of solvent under reduced temperature followed by extraction of residue with dilute hydrochloric acid Treatment with decolorizing charcoal (solution: acidic => basic) Recrystallization from pentane-ether Note – alternative to use of decalin: pressure bomb

racemic compound, in pharmaceutical preparation racemic more active enantiomere esketamine (S-Ketamine) available as Ketanest S, but Arketamine (R-Ketamine) never marketed for clinical use, Optical rotation: varies between salt and free base form free base form: (S)-Ketamine dextrorotation  (S)-(+)-ketamine hydrochloridesalt: levorotation(S)-(-)-ketamine  Reason found in molecular level: different orientation of substituents: freebase: o-chlorophenyl equatorial, methylamino axia

Sources: http://creationwiki.org/Ketamine#Synthesis http://www.lycaeum.org/rhodium/chemistry/pcp/ketamine.html https://pubchem.ncbi.nlm.nih.gov/compound/ketamine https://pubchem.ncbi.nlm.nih.gov/compound/ketamine#section=Drug-Warning http://www.rsc.org/chemistryworld/2014/02/ketamine-special-k-drugs-podcast http://drugabuse.com/library/the-effects-of-ketamine-use/ http://www.drugfreeworld.org/drugfacts/prescription/ketamine.html http://onlinelibrary.wiley.com/doi/10.1002/1615-9314(20021101)25:15/17%3C1155::AID-JSSC1155%3E3.0.CO;2-M/pdf

CLIP

Process Research and Impurity Control Strategy of Esketamine Organic Process Research & Development ( IF 3.023
) Pub Date: 2020-03-18 , DOI: 10.1021/acs.oprd.9b00553
Shenghua Gao; Xuezhi Gao; Zhezhou Yang; Fuli Zhang
An improved synthesis of ( S )-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the ( S )-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity . The ICH-grade quality ( S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.

Process Research and ketamine impurity control strategy

has been developed an improved ( S ) – ketamine (esketamine) synthesis, the high cost-effective way, the undesired isomer may be recycled by racemization. Determine the key process parameters and process-related impurities for each step. First, the formation mechanism and control strategy of most impurities are discussed. In addition, ( S )-ketamine tartrate is a dihydrate, which is the first time it has been published. The feasible racemization catalyzed by aluminum chloride proceeds in a quantitative yield with a purity of 99%. ICH grade quality ( S) 5-ketamine hydrochloride can be obtained through chiral resolution and three times the mother liquor recovery rate. The total yield is 51.1% (14.0% without racemization). The robust process of ketamine can be used in Industrial promotion.

CLIP

CLIP

https://link.springer.com/article/10.1007/s13738-018-1404-1#citeas

Taghizadeh, M.J., Gohari, S.J.A., Javidan, A. et al. A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione. J IRAN CHEM SOC 15, 2175–2181 (2018). https://doi.org/10.1007/s13738-018-1404-1

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DOIhttps://doi.org/10.1007/s13738-018-1404-1

Abstract

We present a novel asymmetric synthesis route for synthesis of (S)-ketamine using a chiral reagent according to the strategy (Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional group of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-N–tert-butanesulfinyl ketamine (3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield.

Esketamine, sold under the brand name Spravato^[4] among others,^[6]^[7] is a medication used as a general anesthetic and for treatment-resistant depression.^[4]^[1] Esketamine is used as a nasal spray or by injection into a vein.^[4]^[1]

Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.^[1]^[8] It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors.^[1] The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly.^[1] It is unknown whether its antidepressant action is superior, inferior or equal to racemic ketamine and its opposite enantiomer, arketamine, which are both being investigated for the treatment of depression.

Esketamine was introduced for medical use in 1997.^[1] In 2019, it was approved for use with other antidepressants, for the treatment of depression in adults in the United States.^[9]

In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.^[10]

Medical uses

Anesthesia

Esketamine is a general anesthetic and is used for similar indications as ketamine.^[1] Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.^[1]

Depression

Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant.^[8]^[11] It received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016.^[12]^[11] The medication was studied for use in combination with an antidepressant in people with TRD who had been unresponsive to treatment;^[12]^[8]^[11] six phase III clinical trials for this indication were conducted in 2017.^[12]^[8]^[11] It is available as a nasal spray.^[12]^[8]^[11]

In February 2019, an outside panel of experts recommended that the FDA approve the nasal spray version of esketamine,^[13] provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after.^[14]

In January 2020, esketamine was rejected by the National Health Service of Great Britain. NHS questioned the benefits and claimed that it was too expensive. People who have been already using the medication were allowed to complete treatment if their doctors consider this necessary.^[15]

Side effects

Most common side effects when used in those with treatment resistant depression include dissociation, dizziness, nausea, sleepiness, anxiety, and increased blood pressure.^[16]

Pharmacology

Esketamine is approximately twice as potent as an anesthetic as racemic ketamine.^[17] It is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows its elimination.^[18]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine^{[citation needed]} but, in mice, that the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine.^[19] The usefulness of arketamine over eskatamine has been supported by other researchers.^[20]^[21]^[22]

Esketamine inhibits dopamine transporters eight times more than arketamine.^[23] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.^[24]^[25] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.^[17]^[26] This is however in contradiction with R-ketamine being devoid of psychotomimetic side effects.^[27]

Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing.^[26] However, another study found no difference between racemic and (S)-ketamine on the patient’s level of vigilance.^[24] Interpretation of this finding is complicated by the fact that racemic ketamine is 50% (S)-ketamine.

History

Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries.^[1]^[28] In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.^[8]^[12] In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States.^[8]^[12] Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on September 4, 2018;^[29] the application was endorsed by an FDA advisory panel on February 12, 2019, and on March 5, 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults.^[9]

In the 1980s and ’90s, closely associated ketamine was used as a club drug known as “Special K” for its trip-inducing side effects.^[30]^[31]

Society and culture

Names

Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM.^[28] It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine, as well as by its developmental code name JNJ-54135419.^[28]^[12]

Esketamine is marketed under the brand name Spravato for use as an antidepressant and the brand names Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.^[28]

Availability

Esketamine is marketed as an antidepressant in the United States;^[9] and as an anesthetic in the European Union.^[28]

Legal status

Esketamine is a Schedule III controlled substance in the United States.^[4]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie. 33 (12): 764–70. doi:10.1055/s-2007-994851. PMID 9893910.
^ “Spravato 28 mg nasal spray, solution – Summary of Product Characteristics (SmPC)”. (emc). Retrieved 24 November 2020.
^ “Vesierra 25 mg/ml solution for injection/infusion – Summary of Product Characteristics (SmPC)”. (emc). 21 February 2020. Retrieved 24 November2020.
^ Jump up to:^a ^b ^c ^d ^e “Spravato- esketamine hydrochloride solution”. DailyMed. 6 August 2020. Retrieved 26 September 2020.
^ “Spravato EPAR”. European Medicines Agency (EMA). 16 October 2019. Retrieved 24 November 2020.
^ “Text search results for esketamine: Martindale: The Complete Drug Reference”. MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August 2017.^{[dead link]}
^ Brayfield A, ed. (9 January 2017). “Ketamine Hydrochloride”. MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August2017.^{[dead link]}
^ Jump up to:^a ^b ^c ^d ^e ^f ^g Rakesh G, Pae CU, Masand PS (August 2017). “Beyond serotonin: newer antidepressants in the future”. Expert Review of Neurotherapeutics. 17 (8): 777–790. doi:10.1080/14737175.2017.1341310. PMID 28598698. S2CID 205823807.
^ Jump up to:^a ^b ^c “FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic”. U.S. Food and Drug Administration (FDA) (Press release). Retrieved 2019-03-06.
^ “FDA Approves A Nasal Spray To Treat Patients Who Are Suicidal”. NPR. 4 August 2020. Retrieved 27 September 2020.
^ Jump up to:^a ^b ^c ^d ^e Lener MS, Kadriu B, Zarate CA (March 2017). “Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression”. Drugs. 77 (4): 381–401. doi:10.1007/s40265-017-0702-8. PMC 5342919. PMID 28194724.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Esketamine – Johnson & Johnson – AdisInsight”. Retrieved 7 November 2017.
^ Koons C, Edney A (February 12, 2019). “First Big Depression Advance Since Prozac Nears FDA Approval”. Bloomberg News. Retrieved February 12, 2019.
^ Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee (February 12, 2019). “FDA Briefing Document” (PDF). Food and Drug Administration. Retrieved February 12, 2019. Meeting, February 12, 2019. Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceutica, for the treatment of treatment-resistant depression.
^ “Anti-depressant spray not recommended on NHS”. BBC News. 28 January 2020.
^ “Esketamine nasal spray” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 21 October 2019.
^ Jump up to:^a ^b Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie (in German). 33 (12): 764–70. doi:10.1055/s-2007-994851. PMID 9893910.
^ Ihmsen H, Geisslinger G, Schüttler J (November 2001). “Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine”. Clinical Pharmacology and Therapeutics. 70 (5): 431–8. doi:10.1067/mcp.2001.119722. PMID 11719729.
^ Zhang JC, Li SX, Hashimoto K (January 2014). “R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine”. Pharmacology, Biochemistry, and Behavior. 116: 137–41. doi:10.1016/j.pbb.2013.11.033. PMID 24316345. S2CID 140205448.
^ Muller J, Pentyala S, Dilger J, Pentyala S (June 2016). “Ketamine enantiomers in the rapid and sustained antidepressant effects”. Therapeutic Advances in Psychopharmacology. 6 (3): 185–92. doi:10.1177/2045125316631267. PMC 4910398. PMID 27354907.
^ Hashimoto K (November 2016). “Ketamine’s antidepressant action: beyond NMDA receptor inhibition”. Expert Opinion on Therapeutic Targets. 20 (11): 1389–1392. doi:10.1080/14728222.2016.1238899. PMID 27646666. S2CID 1244143.
^ Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K (October 2016). “Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression”. Psychopharmacology. 233 (19–20): 3647–57. doi:10.1007/s00213-016-4399-2. PMC 5021744. PMID 27488193.
^ Nishimura M, Sato K (October 1999). “Ketamine stereoselectively inhibits rat dopamine transporter”. Neuroscience Letters. 274 (2): 131–4. doi:10.1016/s0304-3940(99)00688-6. PMID 10553955. S2CID 10307361.
^ Jump up to:^a ^b Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P (October 1992). “[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings]”. Der Anaesthesist (in German). 41 (10): 610–8. PMID 1443509.
^ Pfenninger E, Baier C, Claus S, Hege G (November 1994). “[Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]”. Der Anaesthesist (in German). 43 Suppl 2: S68-75. PMID 7840417.
^ Jump up to:^a ^b Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). “Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)”. European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/s0924-977x(96)00042-9. PMID 9088882. S2CID 26861697.
^ Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (September 2015). “R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects”. Translational Psychiatry. 5 (9): e632. doi:10.1038/tp.2015.136. PMC 5068814. PMID 26327690.
^ Jump up to:^a ^b ^c ^d ^e “Esketamine”. Drugs.com.
^ “Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression”. Janssen Pharmaceuticals, Inc.
^ Marsa, Linda (January 2020). “A Paradigm Shift for Depression Treatment”. Discover. Kalmbach Media.
^ Hoffer, Lee (7 March 2019). “The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression”. Vice. Retrieved 11 February 2020.

External links

“Esketamine”. Drug Information Portal. U.S. National Library of Medicine.
“Esketamine hydrochloride”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Trade names	Spravato, Ketanest, Vesierra, others
Other names	Esketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419
AHFS/Drugs.com	Monograph
MedlinePlus	a619017
License data	US DailyMed: EsketamineUS FDA: Esketamine
Addiction liability	Low–moderate^{[citation needed]}
Routes of administration	Intranasal, Intravenous infusion^[1]
Drug class	NMDA receptor antagonists; Antidepressants; General anesthetics; Dissociative hallucinogens; Analgesics
ATC code	N01AX14 (WHO) N06AX27 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug)UK: POM (Prescription only) ^[2]^[3]US: Schedule III ^[4]EU: Rx-only ^[5]In general: ℞ (Prescription only)
Identifiers
IUPAC name [show]
CAS Number	33643-46-8as HCl: 33795-24-3
PubChem CID	182137
IUPHAR/BPS	9152
DrugBank	DB01221
ChemSpider	158414
UNII	50LFG02TXDas HCl: 5F91OR6H84
KEGG	D07283as HCl: D10627
ChEBI	CHEBI:6121
ChEMBL	ChEMBL742
CompTox Dashboard (EPA)	DTXSID6047810
ECHA InfoCard	100.242.065
Chemical and physical data
Formula	C₁₃H₁₆ClNO
Molar mass	237.73 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide]CN[C@](C1=C(Cl)C=CC=C1)(CCCC2)C2=O
InChI [hide]InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1Key:YQEZLKZALYSWHR-ZDUSSCGKSA-N

/////////////Esketamine, JNJ 54135419, phase 3

Inclisiran

January 21, 2021 11:53 am / Leave a comment

Inclisiran

CAS 1639324-58-5

ALN-60212
ALN-PCSsc

US FDA APPROVED

12/22/2021

To treat heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease as an add-on therapy, Leqvio

Inclisiran was first developed by Alnylam Pharmaceuticals, Inc. (Cambridge, Massachusetts, US). Development has now been assumed by The Medicines Company (Parsippany, New Jersey, US). One phase I and two phase II trials have been completed. Topline results of two phase III trials were also recently presented while other phase III trials are still ongoing as part of the ORION clinical development program. …..https://www.ncbi.nlm.nih.gov/books/NBK555477/

Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol.^1,2 Lowering circulating plasma LDL-C levels offers an additional benefit of reducing the risk of cardiovascular disease (CVD) and improving cardiovascular outcomes, as hypercholesterolemia is a major known risk factor for CVD.^1,2

On December 11, 2020, the European Commission (EC) granted authorization for marketing inclisiran as the first and only approved siRNA for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, alone or in combination with other lipid-lowering therapies. It is marketed under the trade name Leqvio ⁸ and is also currently under review by the FDA.

Inclisiran, sold under the brand name Leqvio, is a medication for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA that inhibits translation of the protein PCSK9.^[2]^[3]^[4] It is being developed by The Medicines Company which licensed the rights to inclisiran from Alnylam Pharmaceuticals.^[5]

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqvio, intended for the treatment for primary hypercholesterolaemia or mixed dyslipidaemia.^[6] Inclisiran was approved for use in the European Union in December 2020.^[1]

History

In 2019 The Medicines Company announced positive results from pivotal phase III study (all primary and secondary endpoints were met with efficacy consistent with Phase I and II studies). The company anticipates regulatory submissions in the U.S. in the fourth quarter of 2019, and in Europe in the first quarter of 2020.^[7] The Medicines Company is being acquired by Novartis.^[8]

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References

^ Jump up to:^a ^b “Leqvio EPAR”. European Medicines Agency. 13 October 2020. Retrieved 6 January 2021.
^ Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. (January 2017). “A Highly Durable RNAi Therapeutic Inhibitor of PCSK9”. The New England Journal of Medicine. 376 (1): 41–51. doi:10.1056/NEJMoa1609243. PMC 5778873. PMID 27959715.
^ Spreitzer H (11 September 2017). “Neue Wirkstoffe: Inclisiran”. Österreichische Apotheker-Zeitung (in German) (19/2017).
^ “Proposed INN: List 114” (PDF). WHO Drug Information. WHO. 29 (4): 531f. 2015.
^ Taylor NP (26 August 2019). “Medicines Company’s PCSK9 drug hits phase 3 efficacy goals”. FierceBiotech.
^ “Leqvio: Pending EC decision”. European Medicines Agency (EMA). 16 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “The Medicines Company Announces Positive Topline Results from First Pivotal Phase 3 Trial of Inclisiran”. The Medicines Company. Retrieved 29 August 2019.
^ “Novartis acquires medicines company”. Novartis. Retrieved 15 January 2020.

External links

“Inclisiran”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03399370 for “Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION-10)” at ClinicalTrials.gov
Clinical trial number NCT03400800 for “Inclisiran for Subjects With ACSVD or ACSVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION-11)” at ClinicalTrials.gov

Clinical data
Trade names	Leqvio
Other names	ALN-PCSsc, ALN-60212
Routes of administration	Subcutaneous injection
ATC code	C10AX16 (WHO)
Legal status
Legal status	EU: Rx-only ^[1]
Identifiers
CAS Number	1639324-58-5
DrugBank	DB14901
UNII	UOW2C71PG5
KEGG	D11931
Chemical and physical data
Formula	C₅₂₀H₆₇₉F₂₁N₁₇₅O₃₀₉P₄₃S₆
Molar mass	16248.27 g·mol⁻¹

General References

Kosmas CE, Munoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E: Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases. 2018 Jul 13;6(3). pii: diseases6030063. doi: 10.3390/diseases6030063. [PubMed:30011788]
German CA, Shapiro MD: Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9. BioDrugs. 2020 Feb;34(1):1-9. doi: 10.1007/s40259-019-00399-6. [PubMed:31782112]
Doggrell SA: Inclisiran, the billion-dollar drug, to lower LDL cholesterol – is it worth it? Expert Opin Pharmacother. 2020 Nov;21(16):1971-1974. doi: 10.1080/14656566.2020.1799978. Epub 2020 Aug 4. [PubMed:32749892]
Goldstein JL, Brown MS: Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987 Sep;76(3):504-7. doi: 10.1161/01.cir.76.3.504. [PubMed:3621516]
Pratt AJ, MacRae IJ: The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009 Jul 3;284(27):17897-901. doi: 10.1074/jbc.R900012200. Epub 2009 Apr 1. [PubMed:19342379]
Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, Kastelein JJP, Ray KK: Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28. [PubMed:30487231]
Cupido AJ, Kastelein JJP: Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovasc Res. 2020 Sep 1;116(11):e136-e139. doi: 10.1093/cvr/cvaa212. [PubMed:32766688]
Novartis: Novartis receives EU approval for Leqvio (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year [Link]
Summary of Product Characteristics: Leqvio (inclisiran), solution for subcutaneous injection [Link]

Summary

Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of death in Canada. Cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), is a major risk factor for cardiovascular disease (CVD) and is thereby targeted to reduce the likelihood of a cardiovascular event, such as a myocardial infarction (MI) and stroke.
Inclisiran, first developed by Alnylam Pharmaceuticals, Inc. (Cambridge, Massachusetts, US) then by The Medicines Company (Parsippany, New Jersey, US), is a small interfering ribonucleic acid (siRNA) molecule being investigated for the treatment of hypercholesterolemia.
ORION-1 was a phase II, double-blind, placebo-controlled, multi-centre, randomized controlled trial of 501 patients. Patients were included in the trial if they had a history of ASCVD or were at high risk of ASCVD. The treatment arms were administered 200 mg, 300 mg, or 500 mg of inclisiran on day 1, or 100 mg, 200 mg, or 300 mg of inclisiran on days 1 and 90. The comparator was either placebo on day 1 or placebo on days 1 and 90. The primary end point was percentage change in LDL-C at day 180 from baseline.
The ORION-1 study demonstrated that inclisiran, administered at various doses and intervals, compared with placebo, resulted in a statistically significant reduction in LDL-C levels (P < 0.001 for all comparisons versus placebo). The greatest reduction in LDL-C levels was obtained with the 300 mg dose of inclisiran given at days 1 and 90 with a 52.6% (95% confidence interval [CI]: −57.1 to −48.1) reduction at day 180 compared with baseline, and a mean absolute reduction in LDL-C levels of 1.66 (standard deviation 0.54) mmol/L. Results from the ORION-1 trial provided the necessary data to make a decision regarding the dosing regimen to be used in subsequent phase III trials, in particular the ORION-11 phase III trial.
The ORION-11 study was a phase III international, multi-centre, and double-blind trial which randomized 1,617 participants (87% with established ASCVD) to inclisiran 300 mg (n = 810) or placebo (n = 807). An initial inclisiran dose of 300 mg given subcutaneously was administered at day 1, day 90, and then every six months for two doses, that is at days 270 and 450. The mean baseline LDL-C level was 2.8 mmol/L (inclisiran) and 2.7 mmol/L (placebo); 96% of participants were on high-dose statin therapy. There was a 50% time-averaged reduction in LDL-C levels from day 90 to day 540 (P < 0.00001). Pre-specified exploratory cardiovascular composite end point (cardiac death, cardiac arrest, MI, or stroke) occurred in 7.8% of inclisiran treated patients versus 10.3% of patients on placebo; this lower rate was mainly driven by a reduction in MI and stroke. With respect to adverse effects, 4.69% of patients on inclisiran reported an injection site reaction, compared with 0.5% of patients on placebo. All reactions were transient. There was no evidence of liver, kidney, muscle, or platelet toxicity.
Inclisiran may be an option in the future as a cholesterol-lowering medication, where it would likely be used in patients who are unable to achieve their LDL-C targets despite maximally tolerated statin therapy or who are intolerant to statin therapy. However, results from the inclisiran cardiovascular outcome trial (ORION-4), are needed to confirm its efficacy in reducing CVD and its long-term safety.
Inclisiran is not yet approved by any regulatory authority, but its ORION clinical development program identifies the year 2021 as the goal to reach worldwide markets.

///////////Inclisiran, LEQVIO, ALN 60212, ALN PCSsc , NOVARTIS, Leqvio, APPROVALS 2021, FDA 2021

NEW DRUG APPROVALS

ONE TIME

$10.00

IDEBENONE

January 11, 2021 10:10 am / 2 Comments on IDEBENONE

IDEBENONE

2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone

Molecular FormulaC₁₉H₃₀O₅
Average mass338.439 Da
58186-27-9
Idebenona, Idebenonum, CV 2619

IdesolKS-5193NemocebralSNT-MC17идебенонإيديبينون艾地苯醌

Puldysa (idebenone), for the treatment of Duchenne muscular dystrophyTitle: Idebenone
CAS Registry Number: 58186-27-9
CAS Name: 2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1,4-dione
Additional Names: 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone; 2,3-dimethoxy-5-methyl-6-(10¢-hydroxydecyl)-1,4-benzoquinone; 6-(10-hydroxydecyl)ubiquinone
Manufacturers’ Codes: CV-2619
Trademarks: Avan (Takeda); Daruma (Takeda); Lucebanol (Hormona); Mnesis (Takeda)
Molecular Formula: C19H30O5Molecular Weight: 338.44
Percent Composition: C 67.43%, H 8.93%, O 23.64%
Literature References: Ubiquinone derivative with protective effects against cerebral ischemia. Prepn: H. Morimoto et al.,DE2519730; eidem,US4271083 (1975, 1981 both to Takeda); K. Okamoto et al.,Chem. Pharm. Bull.30, 2797 (1982); C.-A. Yu, L. Yu, Biochemistry21, 4096 (1982). Effect on ischemia-induced amnesia in rats: N. Yamazaki et al.,Jpn. J. Pharmacol.36, 349 (1984). Metabolism in animals: T. Kobayashi et al.,J. Pharmacobio-Dyn.8, 448 (1985). Disposition: H. Torii et al.,ibid. 457. Pharmacokinetics and tolerance in humans: M. F. Barkworth et al.,Arzneim.-Forsch.35, 1704 (1985). Series of articles on pharmacology and clinical studies: Arch. Gerontol. Geriatr.8, 193-366 (1989). Review of chemistry, toxicology and pharmacology: I. Zs-Nagy, Arch. Gerontol. Geriatr.11, 177-186 (1990).Properties: Orange needles from ligroin, mp 46-50° (Morimoto); also reported as crystals from hexane + ethyl acetate, mp 52-53° (Okamoto). Sol in organic solvents. Practically insol in water.Melting point: mp 46-50° (Morimoto); mp 52-53° (Okamoto)Therap-Cat: Nootropic.Keywords: Nootropic.

Idebenone is a member of the class of 1,4-benzoquinones which is substituted by methoxy groups at positions 2 and 3, by a methyl group at positions 5, and by a 10-hydroxydecyl group at positions 6. Initially developed for the treatment of Alzheimer’s disease, benefits were modest; it was subsequently found to be of benefit for the symptomatic treatment of Friedreich’s ataxia. It has a role as an antioxidant. It is a primary alcohol and a member of 1,4-benzoquinones.

Idebenone (pronounced eye-deb-eh-known, trade names Catena, Raxone, Sovrima, among others) is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer’s disease and other cognitive defects.^[1] This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich’s ataxia^[2] and Duchenne muscular dystrophy^[3] have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber’s hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.^[4]

Chemically, idebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analog of coenzyme Q₁₀ (CoQ₁₀).

Uses

Indications that are or were approved in some territories

Nootropic effects and Alzheimer’s disease

Idebenone improved learning and memory in experiments with mice.^[5] In humans, evaluation of Surrogate endpoints like electroretinography, auditory evoked potentials and visual analogue scales also suggested positive nootropic effects,^[6] but larger studies with hard endpoints are missing.

Research on idebenone as a potential therapy of Alzheimer’s disease have been inconsistent, but there may be a trend for a slight benefit.^[7]^[8] In May 1998, the approval for this indication was cancelled in Japan due to the lack of proven effects. In some European countries, the drug is available for the treatment of individual patients in special cases.^[1]

Friedreich’s ataxia (Sovrima)

Preliminary testing has been done in humans and found idebenone to be a safe treatment for Friedreich’s ataxia (FA), exhibiting a positive effect on cardiac hypertrophy and neurological function.^[9] The latter was only significantly improved in young patients.^[10] In a different experiment, a one-year test on eight patients, idebenone reduced the rate of deterioration of cardiac function, but without halting the progression of ataxia.^[11]

The drug was approved for FA in Canada in 2008 under conditions including proof of efficacy in further clinical trials.^[12] However, on February 27, 2013, Health Canada announced that idebenone would be voluntarily recalled as of April 30, 2013 by its Canadian manufacturer, Santhera Pharmaceuticals, due to the failure of the drug to show efficacy in the further clinical trials that were conducted.^[13] In 2008, the European Medicines Agency (EMA) refused a marketing authorisation for this indication.^[1] As of 2013 the drug was not approved for FA in Europe^[14] nor in the US, where there is no approved treatment.^[15]

Leber’s hereditary optic neuropathy (Raxone)

Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. Santhera completed a Phase III clinical trial in this indication in Europe with positive results,^[16] and submitted an application to market the drug to European regulators in July 2011.^[17] It is approved by EMA for this indication and was designated an orphan drug in 2007.^[4]

Indications being explored

Duchenne muscular dystrophy (Catena)

After experiments in mice^[18] and preliminary studies in humans, idebenone has entered Phase II clinical trials in 2005^[3] and Phase III trials in 2009.^[19]

Other neuromuscular diseases

Phase I and II clinical trials for the treatment of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)^[20] and primary progressive multiple sclerosis^[21] are ongoing as of December 2013.

Life style

Idebenone is claimed to have properties similar to CoQ₁₀ in its antioxidant properties, and has therefore been used in anti-aging on the basis of free-radical theory. Clinical evidence for this use is missing. It has been used in topical applications to treat wrinkles.^[22]

Pharmacology

In cellular and tissue models, idebenone acts as a transporter in the electron transport chain of mitochondria and thus increases the production of adenosine triphosphate (ATP) which is the main energy source for cells, and also inhibits lipoperoxide formation. Positive effects on the energy household of mitochondria has also been observed in animal models.^[1]^[23] Clinical relevance of these findings has not been established.

Pharmacokinetics

Idebenone is well absorbed from the gut but undergoes excessive first pass metabolism in the liver, so that less than 1% reach the circulation. This rate can be improved with special formulations (suspensions) of idebenone and by administering it together with fat food; but even taking these measures bioavailability still seems to be considerably less than 14% in humans. More than 99% of the circulating drug are bound to plasma proteins. Idebenone metabolites include glucuronides and sulfates, which are mainly (~80%) excreted via the urine.^[1]

SYN

https://www.sciencedirect.com/science/article/abs/pii/S0040402014014306

Single-step synthesis of idebenone from Coenzyme Q0 via free-radical alkylation under silver catalysis - ScienceDirect

SYN

https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532014001202186

The palladium-catalyzed olefination of a sp² or benzylic carbon attached to a (pseudo)halogen is known as the Heck reaction.²^,⁶³ It is a powerful tool, mainly used for the synthesis of vinylarenes, and it has also been employed for the construction of conjugated double bonds. The widespread application of this reaction can be illustrated by numerous examples in both academia small-scale⁶⁴ and industrial syntheses.⁵ As an example, in 2011, a idebenone (124) total synthesis based on a Heck reaction was described (Scheme 35).⁶⁵ This compound, initially designed for the treatment of Alzheimer’s and Parkinson’s diseases, presented a plethora of other interesting activities, such as free radical scavenging and action against some muscular illnesses. The key step in the synthesis was the coupling of 2-bromo-3,4,5-trimethoxy-1-methylbenzene (125) with dec-9-en-1-ol affording products 126. Under non-optimized conditions (Pd(OAc)₂, PPh₃, Et₃N, 120 ºC), a mixture composed of 60% linear olefins 126 and 15% of the undesired branched product 127 was obtained after three days of reaction. Therefore, the conditions were optimized, allowing the preparation of 126 in 67% yield with no detection of 127 after only 30 min of reaction employing DMF, Pd(PPh₃)₄, ⁱPr₂NEt under microwave heating. To conclude the synthesis, the Heck adducts were submitted to hydroxyl protection/deprotection, hydrogenation, and ring oxidation. After these reactions, idebenone was obtained with 20% overall yield over 6 steps.

Scheme 35 Synthesis of idebenone (124) based on Heck reaction of 2-bromo-3,4,5-trimethoxy-1-methylbenzene with dec-9-en-1-ol under microwave irradiation.

Syn

Duveau, Damien Y.; Bioorganic & Medicinal Chemistry 2010, V18(17), P6429-6441
Okada, Taiiti; EP 289223 A1 1988
Watanabe, Masazumi; EP 58057 A1 1982
Okamoto, Kayoko; Chemical & Pharmaceutical Bulletin 1982, V30(8), P2797-819
“Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)

Paper

Tsoukala, Anna; Organic Process Research & Development 2011, V15(3), P673-680

https://pubs.acs.org/doi/10.1021/op200051v

An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation, and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.

PAPER

Bioorganic & Medicinal Chemistry 2010, V18(17), P6429-6441

https://www.sciencedirect.com/science/article/abs/pii/S0968089610006322

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6–8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6–8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.

Idebenone (5)18 To a stirred solution containing 200 mg (0.467 mmol) of 2,3- dimethoxy-6-methyl-5-benzyloxydecyl-p-benzoquinone (38) in 5 mL of anhydrous methanol at 23 C was added 15 mg of 10 % Pd/C in one portion. The reaction mixture was stirred at 23 C under an atmosphere of hydrogen for 24 h. Air was then bubbled through the reaction mixture at 23 C for 24 h. The suspension was filtered through Celite and the filtrate was concentrated under diminished pressure to afford idebenone (5) as an orange solid: yield 130 mg (82%); mp: 46–47 C; 1 H NMR (400 MHz, CDCl3) d 1.34 (m, 14H), 1.60 (quint, 2H, J = 7.6 Hz), 2.04 (s, 3H), 2.44 (t, 2H, J = 8.0 Hz), 3.63 (t, 2H, J = 6.8 Hz), and 3.99 (s, 6H); 13C NMR (100 MHz, CDCl3) d 11.9, 25.7, 26.4, 28.7, 29.3, 29.3, 29.4, 29.5, 29.8, 32.7

References

^ Jump up to:^a ^b ^c ^d ^e “CHMP Assessment Report for Sovrima” (PDF). European Medicines Agency. 20 November 2008: 6, 9–11, 67f.
^ Clinical trial number NCT00229632 for “Idebenone to Treat Friedreich’s Ataxia” at ClinicalTrials.gov
^ Jump up to:^a ^b Clinical trial number NCT00654784 for “Efficacy and Tolerability of Idebenone in Boys With Cardiac Dysfunction Associated With Duchenne Muscular Dystrophy (DELPHI)” at ClinicalTrials.gov
^ Jump up to:^a ^b “Raxone”. http://www.ema.europa.eu. Retrieved 12 July 2019.
^ Liu, XJ; Wu, WT (1999). “Effects of ligustrazine, tanshinone II A, ubiquinone, and idebenone on mouse water maze performance”. Zhongguo Yao Li Xue Bao. 20 (11): 987–90. PMID 11270979.
^ Schaffler, K; Hadler, D; Stark, M (1998). “Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug”. Arzneimittel-Forschung. 48 (7): 720–6. PMID 9706371.
^ Gutzmann, H; Kühl, KP; Hadler, D; Rapp, MA (2002). “Safety and efficacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study”. Pharmacopsychiatry. 35 (1): 12–8. doi:10.1055/s-2002-19833. PMID 11819153.
^ Parnetti, L; Senin, U; Mecocci, P (1997). “Cognitive enhancement therapy for Alzheimer’s disease. The way forward”. Drugs. 53 (5): 752–68. doi:10.2165/00003495-199753050-00003. PMID 9129864. S2CID 46987059.
^ Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (October 2007). “Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial”. Lancet Neurol. 6 (10): 878–86. doi:10.1016/S1474-4422(07)70220-X. PMID 17826341. S2CID 24749816.
^ Tonon C, Lodi R (September 2008). “Idebenone in Friedreich’s ataxia”. Expert Opin Pharmacother. 9 (13): 2327–37. doi:10.1517/14656566.9.13.2327. PMID 18710357. S2CID 73285881.
^ Buyse G, Mertens L, Di Salvo G, et al. (May 2003). “Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring”. Neurology. 60 (10): 1679–81. doi:10.1212/01.wnl.0000068549.52812.0f. PMID 12771265. S2CID 36556782.
^ “Heath Canada Fact Sheet – Catena”. Archived from the original on 19 June 2014.
^ Voluntary Withdrawal of Catena from the Canadian Market
^ Margaret Wahl for Quest Magazine, MAY 28, 2010. FA Research: Idebenone Strikes Out Again
^ NINDS Fact Sheet
^ Klopstock, T; et al. (2011). “A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy”. Brain. 134 (9): 2677–86. doi:10.1093/brain/awr170. PMC 3170530. PMID 21788663.
^ Staff (26 July 2011). “Santhera publishes pivotal trial results of idebenone and goes for EU approval”. European Biotechnology News. Archived from the original on 2013-02-17.
^ Buyse, GM; Van Der Mieren, G; Erb, M; D’hooge, J; Herijgers, P; Verbeken, E; Jara, A; Van Den Bergh, A; et al. (2009). “Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance”. European Heart Journal. 30 (1): 116–24. doi:10.1093/eurheartj/ehn406. PMC 2639086. PMID 18784063.
^ Clinical trial number NCT01027884 for “Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)” at ClinicalTrials.gov
^ Clinical trial number NCT00887562 for “Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis & Stroke-like Episodes (MELAS)” at ClinicalTrials.gov
^ Clinical trial number NCT00950248 for “Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)” at ClinicalTrials.gov
^ McDaniel D, Neudecker B, Dinardo J, Lewis J, Maibach H (September 2005). “Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone”. J Cosmet Dermatol. 4 (3): 167–73. doi:10.1111/j.1473-2165.2005.00305.x. PMID 17129261. S2CID 2394666.
^ Suno M, Nagaoka A (May 1988). “[Effect of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate in the presence of succinate]”. Nippon Yakurigaku Zasshi (in Japanese). 91 (5): 295–9. doi:10.1254/fpj.91.295. PMID 3410376.

Clinical data

Trade names	Catena, Raxone, Sovrima
AHFS/Drugs.com	International Drug Names
License data	EU EMA: by INN
ATC code	N06BX13 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	<1% (high first pass effect)
Protein binding	>99%
Elimination half-life	18 hours
Excretion	Urine (80%) and feces
Identifiers
IUPAC name [show]
CAS Number	58186-27-9
PubChem CID	3686
ChemSpider	3558
UNII	HB6PN45W4J
KEGG	D01750
ChEMBL	ChEMBL252556
CompTox Dashboard (EPA)	DTXSID0040678
Chemical and physical data
Formula	C₁₉H₃₀O₅
Molar mass	338.444 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide]O=C1/C(=C(\C(=O)C(\OC)=C1\OC)C)CCCCCCCCCCO
InChI [hide]InChI=1S/C19H30O5/c1-14-15(12-10-8-6-4-5-7-9-11-13-20)17(22)19(24-3)18(23-2)16(14)21/h20H,4-13H2,1-3H3Key:JGPMMRGNQUBGND-UHFFFAOYSA-N

////////////IDEBENONE, Puldysa, Duchenne muscular dystrophy, Idesol, KS 5193, Nemocebral, SNT MC17, идебенон, إيديبينون , 艾地苯醌 , CV 2619

CC1=C(C(=O)C(=C(C1=O)OC)OC)CCCCCCCCCCO

PF 3635659

January 10, 2021 3:00 am / 2 Comments on PF 3635659

PF-3635659

CAS 931409-24-4 FREE FORM

Molecular Formula, C28-H32-N2-O3, Molecular Weight, 444.5718

1-Azetidinepentanamide, 3-(3-hydroxyphenoxy)-delta,delta-dimethyl-alpha,alpha-diphenyl-

5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide;hydrochloride

Molecular Formula	C₂₈H₃₃ClN₂O₃
Synonyms	PF-3635659 (hydrochloride)1079781-31-95-[3-(3-Hydroxy-phenoxy)-azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanoic acid amide hydrochloride
Molecular Weight	481 g/mol

READwww.soci.org › David_Price_Presentation_0945_1030

PDFDiscovery of PF–3635659. An Inhaled Once. An Inhaled Once-daily M3. A t. i t. A t. i t f A th & COPD f A th & COPD. Antagonist. Antagonist for Asthma & COPD.file:///C:/Users/Inspiron/Downloads/David_Price_Presentation_0945_1030.pdf

Pf03635659 has been used in trials studying the treatment of Chronic Obstructive Pulmonary Disease.

Inhaled long-acting muscarinic antagonists in chronic obstructive pulmonary disease | Future Medicinal Chemistry

Synthetic Route

Previous 1/4 Next

5-[3-(3-hydroxy… 931409-66-4~65%PF-3635659931409-24-4

Literature: PFIZER LIMITED Patent: WO2008/135819 A1, 2008 ; Location in patent: Page/Page column 14; 15 ; WO 2008/135819 A1

N/A 1374308-52-7~%PF-3635659931409-24-4

Literature: Dillon, Barry R.; Roberts, Dannielle F.; Entwistle, David A.; Glossop, Paul A.; Knight, Craig J.; Laity, Daniel A.; James, Kim; Praquin, Celine F.; Strang, Ross S.; Watson, Christine A. L. Organic Process Research and Development, 2012 , vol. 16, # 2 p. 195 – 203

N/A 521267-13-0~%PF-3635659931409-24-4

Literature: Glossop, Paul A.; Watson, Christine A. L.; Price, David A.; Bunnage, Mark E.; Middleton, Donald S.; Wood, Anthony; James, Kim; Roberts, Dannielle; Strang, Ross S.; Yeadon, Michael; Perros-Huguet, Christelle; Clarke, Nicholas P.; Trevethick, Michael A.; MacHin, Ian; Stuart, Emilio F.; Evans, Steven M.; Harrison, Anthony C.; Fairman, David A.; Agoram, Balaji; Burrows, Jane L.; Feeder, Neil; Fulton, Craig K.; Dillon, Barry R.; Entwistle, David A.; Spence, Fiona J. Journal of Medicinal Chemistry, 2011 , vol. 54, # 19 p. 6888 – 6904

PAPER

Organic Process Research & Development (2012), 16(2), 195-203.

https://pubs.acs.org/doi/10.1021/op200233r

An efficient and scalable process for the synthesis of muscarinic antagonist, PF-3635659 1, is described, illustrating redesign of an analogue-targeted synthesis which contained a scale-limiting rhodium-activated C–H amination step. The final route includes a reproducible modified Bouveault reaction which has not previously been reported on a substrate of this complexity, or on such a scale with over 5 kg of the requisite gem-dimethylamine prepared via this methodology.

5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide (1).

First Discovery Route.

To a solution of 5-methyl-2,2-diphenyl-5-{3-[3-(prop-2-en-1-yloxy)phenoxy]azetidin1-yl}hexane nitrile 9 (2.8 g, 6.01 mmol) in 3-methyl-pentan-3-ol (30 mL) was added potassium hydroxide (6.7 g, 120 mmol) and the resulting solution was stirred at 120 ºC for 22 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous layer was re-extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo to yield 5-methyl-2,2-diphenyl-5-(3-{3- (propenyl)oxy-phenoxy}-azetidin-1-yl)-hexanamide 10 as a yellow oil (3 g, 6.01 mmol, 100%) which was taken on crude to the next step. To a solution of 5-methyl-2,2-diphenyl-5-(3-{3-(propenyl)oxy-phenoxy}-azetidin-1-yl)- hexanoic acid amide 10 (3.0 g, 6.01 mmol) in methanol (100 mL) was added a 2M aqueous hydrochloric acid solution (30 mL, 15 mmol) and the resulting solution was stirred at 60 ºC for 40 minutes. The volatile solvents were removed in vacuo and the remaining aqueous residue was basified with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried with magnesium sulphate and concentrated in vacuo.

The crude residue was purified by flash chromatography eluting in ethyl acetate:methanol:ammonia (90:10:1) / pentane (50/50) to yield the title compound 1 as a colourless foam (1.5 g, 3.37 mmol, 54.5%).

Second Discovery Route.

To a solution of 5-[3-(3-methoxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide 19 (9.0 g, 19.6 mmol) in dichloromethane (1.25 L) at 0 ºC was dropwise added a solution of boron tribromide (1M in dichloromethane, 58.9 mL, 58.9 mmol) and the mixture stirred for 2 hours at 0 ºC to 20 oC. The mixture was cooled to 0 ºC and quenched with 1M aqueous sodium hydroxide solution (200 mL). The reaction mixture was allowed to warm to 20 oC and stirred as such for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried with sodium sulphate and concentrated in vacuo. The crude residue was purified by column chromatography eluting in ethyl acetate:methanol:ammonia (90:10:1) / pentane (50/50) to yield the title compound 1 as a white foam (3.4 g, 7.64 mmol, 39%)

1H NMR (MeOD): δ=0.93 (s, 6H), 1.09-1.14 (m, 2H), 2.38-2.42 (m, 2H), 3.11-3.15 (m, 2H), 3.43-3.47 (m, 2H), 4.57-4.62 (m, 1H), 6.19-6.23 (m, 2H), 6.36 (d, 1H), 7.02 (t, 1H), 7.23-7.38 (m, 10H); MS: m/z 445 [M+H]+.

PAPER

Journal of Medicinal Chemistry (2011), 54(19), 6888-6904.

https://pubs.acs.org/doi/10.1021/jm200884j

A novel tertiary amine series of potent muscarinic M₃ receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M₃ receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug–drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Patent

WO 2007034325

WO 2008135819

US 8263583

Patent

WO-2020261160

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020261160

Methods and intermediates for preparing the hydrochloride salt of PF-3635659 ,

Cholinergic muscarinic receptors are members of the G-protein coupled receptor super-family and are further divided into 5 subtypes, M to Ms. Muscarinic receptor sub-types are widely and differentially expressed in the body. Genes have been cloned for all 5 sub-types and of these, Mi, M>, and Ms receptors have been extensively pharmacologically characterized in animal and human tissue. Mi receptors are expressed in the brain (cortex and hippocampus), glands and in the ganglia of sympathetic and parasympathetic nerves. M2 receptors are expressed in the heart, hindbrain, smooth muscle and in the synapses of the autonomi c nervous system. Ms receptors are expressed m the brain, glands and smooth muscle. In the airways, stimulation of Ms receptors evokes contraction of airway smooth muscle leading to bronchoeonstnction, while in the salivary-gland Ms receptor stimulation increases fluid and mucus secretion leading to increased salivation. M2 receptors expressed on smooth muscle are understood to be pro-contractile while pre-synaptic M2 receptors modulate acetylcholine release from parasympathetic nerves. Stimulation of M2 receptors expressed in the heart produces bradycardia.

[0003] Short and long-acting muscarinic antagonists are used in the management of asthma and chronic obstructive pulmonary disease (COPD); these include the short acting agents Atrovent® (ipratropium bromide) and Oxivent® (oxitropium bromide) and the long acting agent Spiriva® (tiotropium bromide). These compounds produce bronchodilation following inhaled administration. In addition to improvements in spirometric values, anti-muscarinic use in COPD is associated with improvements m health status and quality of life scores. As a consequence of the wide distribution of muscarinic receptors in the body, significant systemic exposure to muscarinic antagonists is associated with effects such as dry mouth, constipation, mydriasis, urinary retention (all predominantly mediated via blockade of M3 receptors) and tachycardia (mediated by blockade of M2 receptors).

[0004] A newer M3 receptor antagonist that is in the carboxamide family is 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride. This carboxamide compound exhibits the following structure (formula II):

[0005] To date, it has not been appreciated that 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride can be synthesized from the benzoate salt of 5-[3-(3-hydroxyphenoxy)azetidin~l~y!]-5-methyl-2,2-diphenylhexanenitrile Therefore, there is a need for methods and intermediates used to efficiently prepare 5-[3-(3-hydroxyphenoxy)azetidin~l~y!]-5-methyl-2,2-diphenylhexanamide hydrochloride of good quality from the benzoate salt of 5~[3~ (3~hydroxyphenoxy)azetidin-l-yl]-5-rn ethyl-2, 2-diphenylhexanenitrile.

Reaction Scheme 1 -Preparation of Crude Carboxamide Hydrochloride

formula I formula II

[0061] The coupled benzoate compound of formula 1 can be reacted with KOH, 2-methyl-2-butano!, water, then HC1 aqueous, HC1, and TBME to obtain the crude carboxamide hydrochloride of formula II. The benzoate salt of the nitrile provides for easier purification of the nitrile.

[0062] The reagents useful in the preparation of 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-metiiyl-2,2-diphenyl-hexanamide hydrochloride include a base and an alcohol In some embodiments, a useful base includes potassium hydroxide, while a useful alcohol includes tertiary amyl alcohol also known as 2-methyl-2-butanol. The reaction of the benzoate compound of formula II in tertiary amyl alcohol and potassium hydroxide can be carried in a temperature range from about 85 ± 5°C to about 103 ± 2°C. In a later stage, the temperature of 103 ± 2°C can be maintained in that range for from about 30 hours to about 65 hours. A cooling period to about room temperature is followed by adjusting the pH to a range from about 6.5 to about 8.0. Hydrochloric acid is added to the product of this initial reaction to form a crude carboxamide hydrochloride compound of formula II. The initially isolated crude carboxamide hydrochloride compound of formula II can be washed with an alcohol and then washed with, or slurried in an ether. In some embodiments, the alcohol can be tertiary amyl alcohol and the ether can be methyl tertiary butyl ether.

[0063] In various embodiments, the crude 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride can be further purified by treating this carboxamide hydrochloride compound with a slurry of activated charcoal, for example, commercially available ENQPC, PF133 or PF511 SPL (A) carbon, in isopropyl alcohol and water at 85 ± 5°C and filtering as illustrated m the Reaction Scheme 2 below:

Reaction Scheme 2 – Purification of Carboxamide Hydrochloride

Reaction Scheme 3 – Preparation of the Coupled Compound Benzoate

[0065] In some embodiments, the benzyl coupled compound of formula III is prepared by reacting an azetidine mesyl HC1 1 -(5-cyano-2-methyl-5,5-diphenylpentan-2-yl)azetidin-3-yl methanes ulfonate hydrochloride with a reagent comprising benzyl resorcinol as illustrated in the Reaction Scheme 4 below:

Reaction Scheme 4 – Preparation of the Benzyl Coupled Compound

In Reaction Scheme 4, the azetidine mesyl hydrochloride of formula IV

is reacted with benzyl resorcinol of formula V

The reagent can comprise benzyl resorcinol and, in some aspects, acetonitrile, a carbonate salt of either cesium or potassium, sodium hydroxide, water, ethyl acetate, hexanes or a mixture thereof. The order of addition of reagents in this step overcomes the need for specific equipment (e.g., a bespoke/unusual agitator) and allows the step to be run in a general purpose reactor.

[0066] Benzyl resorcinol is commercially available and can be obtained commercially, for example, from Sigma Aldrich Corp. In various embodiments, benzyl resorcinol of formula V can be prepared by reacting resorcinol with benzyl chloride to form benzyl resorcinol according to the Reaction Scheme 5 below:

Reaction Scheme 5 — Preparation of Benzyl Resorcinol

Resorcinol DMF/Hexane

Toluene Benzyl Resorcinol

3-{benzyioxy) phenol

[0067] In certain aspects, the benzyl resorcinol is prepared by reacting resorcinol with benzyl chloride m a reagent which can include potassium carbonate, dimethylformamide, water, sodium hydroxide, toluene, hydrochloric acid, hexanes or a combination thereof. In some instances, benzyl resorcinol seeding material may also be added. For the conversion of the resorcinol to the benzyl resorcinol (V), the developed chemistry’- allows effective removal of remaining resorcinol starting material and dibenzyl impurity to give the benzyl resorcinol product in good yield and quality.

Reaction Scheme 6 – Preparation of Azetidine Mesyl Hydrochloride

Azetidine alcohol Azetidine mesyl

VI hydrochloride

Reaction Scheme 7 – Preparation of Azetidine Alcohol

Scheme 8 – Preparation of Diphenyl Amine

Reaction Scheme 9 Preparation of Diphenyl Chloro Amide

Reaction Scheme 10 – Preparation of Diphenyl Alkene

3-methyl-3-buien-t-ol Mesyi Alkene Diphenyl Alkene

PATENT

WO2007034325

https://patents.google.com/patent/WO2007034325A1/en

The compound was originally claimed without an action as example 108 in WO2007034325 , for the treatment of chronic obstructive pulmonary disease, and this is the first filing from Pfizer relating to the compound since the program was presumed discontinued in 2011.

Example 108 5-r3-(3-Hvdroxyphenoxy)azetidin-1-vπ-5-methyl-2,2-diphenylhexanamide

Boron tribromide (1M in dichloromethane, 1.75mL, 1.75mmol) was added to an ice-cooled solution of the product of example 100 (200mg, 0.44mmol) in dichloromethane (5mL) and the mixture was stirred at O⁰C for 1 hour. Further boron tribromide (1M in dichloromethane, 0.5mL, O.δmmol) was added and the mixture was stirred at O⁰C for 30 minutes. The reaction was then quenched with 1M sodium hydroxide solution (5mL), diluted with dichloromethane (2OmL) and stirred at room temperature for 40 minutes. The aqueous layer was separated, extracted with ethyl acetate (2x25mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate/methanol/0.88 ammonia (90/10/1), 75:25 to 50:50, afforded the title compound as a colourless foam in 91% yield, 176mg.

¹HNMR(400MHz, CDCI₃) δ: 1.10(s, 6H), 1.22-1.34(m, 2H), 2.42-2.55(m, 2H), 3.28-3.40(m, 2H), 3.65-3.88(m, 2H), 4.70-4.80(m, 1H), 5.55-5.70(brs, 2H), 6.23-6.36(m, 2H), 6.45-6.53(m, 1H), 7.03-7.12(m, 1H), 7.19-7.39(m, 10H); LRMS ESI m/z 445 [M+H]⁺ E

PATENT

WO2018167804

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018167804

It does however, follow on from WO2018167804 , assigned solely to Mylan , claiming amorphous and crystalline forms designated as Forms I-XI, for treating allergy, and this seems to confirm the potential of the candidate is being revisited, and possibly licensed.

(5-[3-(3-Hydroxyphenoxy)azetidin-l-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride has a structure depicted below as Compound-A.

Compound-A

Compound-A is a muscarinic antagonist useful for treating allergy or respiratory chronic obstructive pulmonary disease.

Compound-A and pharmaceutically acceptable salts are claimed in U.S. Pat. No. 7,772,223 B2 and one of its non-solvated crystalline forms is claimed in U.S. Pat. No. 8,263,583 B2.

Examples:

Example 1: Processes for the preparation of amorphous form of Compound-A.

Compound-A (5 g) was dissolved in methanol (150 ml) at 60-65°C. The solution was filtered at 60-65°C to remove undissolved particulate and then cooled to 25-30°C. The clear solution of Compound-A was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a 5 ml/min feed rate of the solution and inlet temperature at 75°C with 100% aspiration to yield an amorphous form of Compound-A.

///////////// PF-3635659, PF 3635659

CC(C)(CCC(C1=CC=CC=C1)(C2=CC=CC=C2)C(=O)N)N3CC(C3)OC4=CC=CC(=C4)O.Cl

Ansuvimab-zykl

December 25, 2020 4:18 am / Leave a comment

Ebola Virus Treatment Ebanga Gets FDA Approval - MPR

Ansuvimab-zykl

FDA APPROVED, 12/21/2020, EBANGA

To treat ebola

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-treatment-ebola-virus

The U.S. Food and Drug Administration approved Ebanga (Ansuvimab-zykl), a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga blocks binding of the virus to the cell receptor, preventing its entry into the cell.

Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease. It is transmitted through blood, body fluids, and tissues of infected people or wild animals, and through surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who care for people with the disease, including health care workers who do not use correct infection control precautions, are at the highest risk for infection.

During an Ebola outbreak in the Democratic Republic of the Congo (DRC) in 2018-2019, Ebanga was evaluated in a clinical trial (the PALM trial). The PALM trial was led by the U.S. National Institutes of Health and the DRC’s Institut National de Recherche Biomédicale with contributions from several other international organizations and agencies.

In the PALM trial, the safety and efficacy of Ebanga was evaluated in a multi-center, open-label, randomized controlled trial. 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all patients who were randomized and concurrently eligible to receive either Ebanga or the investigational control during the same time period of the trial. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

The most common symptoms experienced while receiving Ebanga include: fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.

Patients who receive Ebanga should avoid the concurrent administration of a live virus vaccine against Ebolavirus. There is the potential for Ebanga to inhibit replication of a live vaccine virus and possibly reduce the efficacy of this vaccine.

Ebanga was granted an Orphan Drug designation, which provides incentives to assist and encourage drug development for rare diseases. Additionally, the agency granted Ebanga a Breakthrough Therapy designation.

FDA granted the approval to Ridgeback Biotherapeutics, LP.

Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.^[1]^[2]

The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.^[1]

Ansuvimab was approved for medical use in the United States in December 2020.^[1]^[2]

Chemistry

The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo.^[3] In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune.^[4]^[5]

Mechanism of action

Neutralization

Ansuvimab is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. Ansuvimab is a neutralizing antibody,^[3] meaning it binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with virus’s cell receptor protein, Niemann-Pick C1 (NPC1).^[6]^[7]^[8] This “competition” by ansuvimab prevents Ebola virus from binding to NPC1 and “neutralizes” the virus’s ability to infect the targeted cell.^[6]

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to “kill” virus particles directly and/or kill infected cells using antibody-mediated “effector functions” such as opsonization, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity.^[3] Other functional killing tests have not been performed.

History

Ansuvimab is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease.^[9] Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.^[3]^[10] Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo roughly ten years later.^[3]

In 2018, a Phase 1 clinical trial of ansuvimab was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood.^[5]^[4]^[11] Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak.^[12]

Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.^[13]^[14]

Discovery

A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts lead by Dr. Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo.^[3]^[10] This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.^[3]^[10] A survivor from the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered.^[3] Memory B cells isolated from the survivor’s blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. Ansuvimab was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells.^[3] These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells.^[3]

Ansuvimab and mAb100 combination

In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.^[3]

Ansuvimab monotherapy

In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived.^[3] Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.^[5]^[4]

Development

Ansuvimab was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans.^[4]^[5]

Human safety testing

In early 2018,^[9] a Phase 1 clinical trial of ansuvimab’s safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood.^[5]^[4]^[11] The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a half-life of 24 days.^[5]^[4]

Ridgeback Biotherapeutics

A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the National Institutes of Health–National Institute of Allergy and Infectious Diseases.^[15] Ansuvimab was given orphan drug status in May 2019 and March 2020.^[16]^[17]^[18]

Experimental use in the Democratic Republic of Congo

During the 2018 Équateur province Ebola outbreak, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites.^[19]^[20]^[11] However, the outbreak came to a conclusion before any therapeutic agents were given to patients.^[11]

Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols.^[11] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.^[21]^[22]^[13]^[12]

In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus.^[23]

FDA approves ansuvimab-zykl for Ebola virus infection

DECEMBER 21, 2020 BY JANICE REICHERT https://www.antibodysociety.org/antibody-therapeutic/fda-approves-ansuvimab-zykl-for-ebola-virus-infection/embed/#?secret=zWW0Sr0BdW

On December 21, 2020, the US Food and Drug Administration approved Ebanga (ansuvimab-zykl) for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga had been granted US Orphan Drug designation and Breakthrough Therapy designations. Ansuvimab is a human IgG1 monoclonal antibody that binds and neutralizes the virus.

The safety and efficacy of Ebanga were evaluated in the multi-center, open-label, randomized controlled PALM trial. In this study, 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

Ebanga is the 12th antibody therapeutic to be granted a first approval in the US or EU during 2020.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

References

^ Jump up to:^a ^b ^c ^d “FDA Approves Treatment for Ebola Virus”. U.S. Food and Drug Administration. 21 December 2020. Retrieved 23 December 2020. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b “Ridgeback Biotherapeutics LP Announces the Approval of Ebanga for Ebola” (Press release). Ridgeback Biotherapeutics LP. 22 December 2020. Retrieved 23 December 2020– via Business Wire.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. (March 2016). “Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody”. Science. 351 (6279): 1339–42. Bibcode:2016Sci…351.1339C. doi:10.1126/science.aad5224. PMID 26917593.
^ Jump up to:^a ^b ^c ^d ^e ^f Clinical trial number NCT03478891 for “Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults” at ClinicalTrials.gov
^ Jump up to:^a ^b ^c ^d ^e ^f Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, et al. (March 2019). “Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody ansuvimab targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study”. Lancet. 393 (10174): 889–898. doi:10.1016/S0140-6736(19)30036-4. PMC 6436835. PMID 30686586.
^ Jump up to:^a ^b Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, et al. (March 2016). “Structural and molecular basis for Ebola virus neutralization by protective human antibodies”. Science. 351 (6279): 1343–6. Bibcode:2016Sci…351.1343M. doi:10.1126/science.aad6117. PMC 5241105. PMID 26917592.
^ Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. (August 2011). “Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection”. Nature. 477 (7364): 344–8. Bibcode:2011Natur.477..344C. doi:10.1038/nature10380. PMC 3230319. PMID 21866101.
^ Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (August 2011). “Ebola virus entry requires the cholesterol transporter Niemann-Pick C1”. Nature. 477 (7364): 340–3. Bibcode:2011Natur.477..340C. doi:10.1038/nature10348. PMC 3175325. PMID 21866103.
^ Jump up to:^a ^b “NIH begins testing Ebola treatment in early-stage trial”. National Institutes of Health (NIH). 2018-05-23. Retrieved 2018-10-15.
^ Jump up to:^a ^b ^c Hayden EC (2016-02-26). “Ebola survivor’s blood holds promise of new treatment”. Nature. doi:10.1038/nature.2016.19440. ISSN 1476-4687.
^ Jump up to:^a ^b ^c ^d ^e “NIH VideoCast – CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development”. videocast.nih.gov. Retrieved 2019-08-09.
^ Jump up to:^a ^b Kingsley-Hall A. “Congo’s experimental mAb114 Ebola treatment appears successful: authorities | Central Africa”. http://www.theafricareport.com. Retrieved 2018-10-15.
^ Jump up to:^a ^b McNeil DG (12 August 2019). “A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo”. The New York Times. Retrieved 13 August 2019.
^ Molteni M (12 August 2019). “Ebola is Now Curable. Here’s How The New Treatments Work”. Wired. Retrieved 13 August 2019.
^ “Ridgeback Biotherapeutics LP announces licensing of mAb114, an experimental Ebola treatment, from the National Institute of Allergy and Infectious Diseases” (Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
^ “Ansuvimab Orphan Drug Designations and Approvals”. accessdata.fda.gov. 8 May 2019. Retrieved 24 December 2020.
^ “Ansuvimab Orphan Drug Designations and Approvals”. accessdata.fda.gov. 30 March 2020. Retrieved 24 December 2020.
^ “Ridgeback Biotherapeutics LP Announces Orphan Drug Designation for mAb114”(Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
^ Check Hayden, Erika (May 2018). “Experimental drugs poised for use in Ebola outbreak”. Nature. 557 (7706): 475–476. Bibcode:2018Natur.557..475C. doi:10.1038/d41586-018-05205-x. ISSN 0028-0836. PMID 29789732.
^ WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
^ Mole B (2019-08-13). “Two Ebola drugs boost survival rates, according to early trial data”. Ars Technica. Retrieved 2019-08-17.
^ “Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates”. National Institutes of Health (NIH). 2019-08-12. Retrieved 2019-08-17.
^ “FDA Approves First Treatment for Ebola Virus”. U.S. Food and Drug Administration(FDA) (Press release). 14 October 2020. Retrieved 14 October 2020. This article incorporates text from this source, which is in the public domain.

External links

“Ansuvimab”. Drug Information Portal. U.S. National Library of Medicine.

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Zaire ebolavirus
Clinical data
Trade names	Ebanga
Other names	Ansuvimab-zykl, mAb114
License data	US DailyMed: Ansuvimab
Routes of administration	Intravenous
Drug class	Monoclonal antibody
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
CAS Number	2375952-29-5
DrugBank	DB16385
UNII	TG8IQ19NG2
KEGG	D11875
Chemical and physical data
Formula	C₆₃₆₈H₉₉₂₄N₁₇₂₄O₁₉₉₄S₄₄
Molar mass	143950.15 g·mol⁻¹

//////////Ansuvimab-zykl , EBANGA, FDA 2020, 2020 APPROVALS, MONOCLONAL ANTIBODY, Orphan Drug designation, , Breakthrough Therapy designation , Ridgeback Biotherapeutics,

CITRULLINE

December 20, 2020 1:15 pm / Leave a comment

CITRULLINE

CAS 372-75-8

L-Citrulline
瓜氨酸

Used for nutritional supplementation, also for treating dietary shortage or imbalance.

L-Citrulline

Molecular FormulaC₆H₁₃N₃O₃
Average mass175.186 Da

SYN

Hua Bai, Peijie Yang, Zhengjie Chen, Chongyan Xu, Zhaorul Li, Zigang Zhao, Luyan Jiang, Zongyi Yang, Jiang Li, “PROCESSES FOR THE PRODUCTION OF L-CITRULLINE.” U.S. Patent US20090142813, issued June 04, 2009.

US20090142813(S)-2-Amino-5-ureidopentanoic acid1725416[Beilstein]206-759-6[EINECS]372-75-8[RN]a-Amino-d-ureidovaleric Acid

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Citrulline malate	PAB4036KHO	70796-17-7	DROVUXYZTXCEBX-WCCKRBBISA-N

CitrullineCAS Registry Number: 372-75-8
CAS Name:N5-(Aminocarbonyl)-L-ornithine
Additional Names: d-ureidonorvaline; a-amino-d-ureidovaleric acid; Nd-carbamylornithine
Molecular Formula: C6H13N3O3Molecular Weight: 175.19
Percent Composition: C 41.13%, H 7.48%, N 23.99%, O 27.40%Line Formula: H2NCONH(CH2)3CH(NH2)COOH
Literature References: An amino acid, first isolated from the juice of watermelon, Citrullus vulgaris Schrad., Cucurbitaceae: Wada, Biochem. Z.224, 420 (1930); isoln from casein: Wada, ibid.257, 1 (1933). Synthesis from ornithine through copper complexes: Kurtz, J. Biol. Chem.122, 477 (1938); by alkaline hydrolysis of arginine: Fox, ibid.123, 687 (1938); from cyclopentanone oxime: Fox et al.,J. Org. Chem.6, 410 (1941). Crystallization: Matsuda et al.,JP71 174 (1971 to Ajinomoto), C.A.74, 126056u (1971). Crystal and molecular structure: Naganathan, Venkatesan, Acta Crystallogr.27B, 1079 (1971); Ashida et al.,ibid.28B, 1367 (1972). Use in asthenia and hepatic insufficiency: FR2198739 (1974 to Hublot & Vallet), C.A.82, 144952c (1975). Clinical trial in treatment of lysinuric protein intolerance: J. Rajantie et al.,J. Pediatr.97, 927 (1980); T. O. Carpenter et al.,N. Engl. J. Med.312, 290 (1985).Properties: Prisms from methanol + water, mp 222°. [a]D20 +3.7° (c = 2). pK1 2.43; pK2 9.41. Sol in water. Insol in methanol, ethanol.Melting point: mp 222°pKa: pK1 2.43; pK2 9.41Optical Rotation: [a]D20 +3.7° (c = 2) Derivative Type: HydrochlorideCAS Registry Number: 34312-10-2Molecular Formula: C6H13N3O3.HClMolecular Weight: 211.65Percent Composition: C 34.05%, H 6.67%, N 19.85%, O 22.68%, Cl 16.75%Properties: Crystals, dec 185°. [a]D22 +17.9° (c = 2).Optical Rotation: [a]D22 +17.9° (c = 2) Derivative Type: Malate (salt)CAS Registry Number: 54940-97-5Trademarks: Stimol (Biocodex)Molecular Formula: C6H13N3O3.C4H6O5Molecular Weight: 309.27Percent Composition: C 38.84%, H 6.19%, N 13.59%, O 41.39% Therap-Cat: Treatment of asthenia.

Asklepion is developing an iv formulation of citrulline, Citrupress, for the potential treatment of pulmonary hypertension and for the potential prevention of clinical sequelae of acute lung injury complicating congenital heart repair surgery in pediatric patients, and also investigating the drug for the potential treatment of acute sickle cell crisis. In August 2016, a phase III study was initiated for preventing clinical sequelae of acute lung injury?in pediatric patients undergoing cardiopulmonary bypass (CPB) for heart defects; in July 2019, results were expected in October 2019.

Citrulline is an amino acid. It is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by NOS family. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated.

The organic compound citrulline is an α-amino acid.^[2] Its name is derived from citrullus, the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in 1914 by Japanese researchers Yotaro Koga and Ryo Odake^[3]^{[note 1]} and further codified by Mitsunori Wada of Tokyo Imperial University in 1930.^[4] It has the formula H₂NC(O)NH(CH₂)₃CH(NH₂)CO₂H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia by converting it into urea. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase.^[5]

Biosynthesis

Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a byproduct of the reaction catalyzed by NOS family (NOS; EC 1.14.13.39).^[6] It is made from arginine by the enzyme trichohyalin at the inner root sheath and medulla of hair follicles.^[7] Arginine is first oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide.

Citrulline is also made by enterocytes of the small intestine.^[2]^[8]

Function

Several proteins contain citrulline as a result of a posttranslational modification. These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert arginine into citrulline in a process called citrullination or deimination with the help of calcium ion. Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation.

Circulating citrulline concentration is a biomarker of intestinal functionality.^[9]^[10

PAPER

Biochemistry, 53(41), 6511-6519; 2014

PAPER

Journal of the Chemical Society of Pakistan, 34(2), 451-454; 2012

PAPER

Journal of Agricultural and Food Chemistry, 66(33), 8841-8850; 2018

https://pubs.acs.org/doi/10.1021/acs.jafc.8b02858

l-Citrulline is a nonessential amino acid with a variety of physiological functions and can be enzymatically produced by arginine deiminase (ADI, EC 3.5.3.6). The enzymatic-production approach is of immense interest because of its mild conditions, high yield, low cost, and environmental benignity. However, the major hindrances of l-citrulline industrialization are the poor thermostability and enzyme activity of ADI. Hence, in this work, directed evolution and site-directed mutagenesis aided with in silico screening, including the use of b-factor values and HoTMuSiC, were applied to a previously identified ADI from Enterococcus faecalis SK23.001 (EfADI), and a triple-site variant R15K–F269Y–G292P was obtained. The triple-site variant displays a 2.5-fold higher specific enzyme activity (333 U mg^–1), a lower K_m value of 6.4 mM, and a 6.1-fold longer half-life (t_1/2,45°C = 86.7 min) than wild-type EfADI. This work provides a protein-engineering strategy to improve enzyme activity and thermostability, which might be transferrable to other ADIs and enzymes.

PAPER

ACS Sustainable Chemistry & Engineering, 7(9), 8522-8529; 2019

https://pubs.acs.org/doi/10.1021/acssuschemeng.9b00301

Biocatalytic transformation of carbamate formed readily from CO₂ and NH₃ provides attractive green routes for mitigation of these important environmental pollutants. Accordingly, a coupled-enzyme system was developed for the one-pot production of citrulline through carbamoylation of ornithine in aqueous solutions of CO₂ and NH₃. Hyperthermophilic ornithine carbamoyltransferases are produced recombinantly in E. coli with carbamate kinases known to have a propensity for carbamoyl phosphate synthesis. Importantly, in vitro biocatalysis is carried out by E. coli cell lysate prepared through coexpression of the required recombinant enzymes in a single bacterial culture, greatly reducing limitations normally associated with protein production and purification. Acetate kinase that is endogenous in the lysate also recycles the required ATP cofactor, which would otherwise have been required in costly stoichiometric amounts. Recombinant lysates catalyze the production of carbamoyl phosphate with substoichiometric ATP (>300 turnovers) as well as its in situ reaction with ornithine to give citrulline in high yield (>95%) and g L^–1 h^–1 titers. The system is active over a wide range of NH₃ concentrations (2.5 mM – 2 M), and >90% conversions of NH₃ may be reached within 1.5 h. Aqueous NH₃ used to sequester CO₂ gas (10% v/v) may be directly used as the biocatalyst feedstock. In preliminary studies, citrulline is found to be an effective organic nitrogen fertilizer of the wheat grass Brachypodium distachyon. Therefore, lysates described here constitute a cost-effective biocatalytic platform for one-pot production of a promising organic nitrogen fertilizer, under mild reaction conditions, from environmental pollutants as feedstock.

PATENT

WO 2015050276

https://patents.google.com/patent/WO2015050276A1/en

PATENT

WO2018125999 claiming method for maintaining the coupling of endothelial nitric oxide synthase.

PATENT

WO-2020247853

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020247853&tab=PCTDESCRIPTION&_cid=P11-KIWJPR-87833-1

Process for preparing citrulline from a transition metal complex of ornithine using cyanate useful to reduce the incidence or severity of cardiopulmonary bypass-induced pulmonary injury due to free radical formation in a patient during cardiopulmonary bypass.

Ornithine is an alpha amino acid with a terminal amino group opposite the alpha carbon.

Citrulline is an alpha amino acid with a terminal carbamido group in the same position as the terminal amino group of ornithine. Dr. A. Kurtz described synthesis of racemic citrulline from racemic ornithine in 1938 (J. Biol. Chem., 122:477-484), and that disclosure was followed up by synthesis of optically active /-citrulline from /-ornithine in 1949 (J. Biol. Chem., 180: 1253-1267). Optical activity was preserved by complexing the starting material (/-ornithine) in a transition metal complex via the alpha amino and carboxyl groups, then reacting the terminal amino group with urea to from a carbamido derivative (see Figure 1). Kurth 1949 describes numerous other syntheses, all depending on the transition metal complex to preserve the alpha amino acid character of the starting compound while derivatizing other parts of the molecule. An example of this synthesis is described in Example 1 below.

Details of various steps in the improved processes developed by the present inventors for producing pharmaceutical grade citrulline are discussed below.

Synthesis of Citrulline from Ornithine

[00014] The present inventors preserved the stereochemical structure around the alpha carbon of the alpha amino acid during reaction of amino groups elsewhere on the compound by complexing the alpha end of the molecule with a transition metal atom, as reported by

Kurth 1938 and 1949. The initial production of the /-ornithine-copper complex is carried out as described by Kurtz. Kurtz describes a variety of transition metals as the complexing metal in the 1949 paper, but the preferred metal is copper (II), based on the ease of forming stable complexes and the ease with which copper (II) may subsequently be removed from the product. The copper is typically supplied as cupric sulfate, although complex formation from copper (II) acetate, cupric carbonate, or cupric oxide have also been reported.

[00015] The present inventors have discovered an alternative method of derivatizing the terminal amino group of the complexed alpha amino acid using cyanate rather than the urea reaction reported by Kurth. An example of this improved synthesis is shown in Figure 2A and described in Example 3 below. Use of cyanate as the derivatizing agent has been found to produce fewer distinct product compounds, which simplifies purification of the desired citrulline product. Kurth carried out urea derivatization by refluxing the copper complex in the presence of excess urea. Cyanate derivatization may be carried out at lower temperatures (e.g. 55°C-65°C) which may contribute to higher yield of citrulline, based on the initial amount of ornithine. Cyanate is preferably provided in excess, and the reaction is driven by precipitation of the citrulline: copper complex. The precipitated complex is washed with water to remove unreacted copper (e.g., wash until no blue coloration persists in the filtrate). The precipitated copper complex of citrulline may be recovered and dried.

Enriching Citrulline as a Copper Complex

[00016] The inventors have discovered that the relative citrulline content of the reaction

product(s) can be enhanced by reprecipitation of the citrulline: copper complex. Precipitated copper complex of citrulline (produced, for example, by reaction of a ornithine: copper complex with urea or cyanate in water) may be dried. The

citrulline: copper complex may be redissolved by suspending the precipitate in water and acidifying the suspension until the complex dissolves. Acidification may be

accomplished by adding concentrated acid, preferably hydrogen chloride, to the suspension while stirring. Once the copper: citrulline complex solution is clear, base (typically sodium hydroxide) is added to bring the pH up to 7-10. Both the acidification and subsequent neutralization steps are actively cooled (temperature not more than 45°C) to protect the citrulline product from hydrolysis or reaction to produce side products. The precipitate is washed with water (e.g., until the filtrate is free of chloride by checking the filtrate for turbidity with silver nitrate), and then the precipitate is dried. Reprecipitation under these conditions is selective for citrulline: copper complex over ornithine: copper complex, because the ornithine complex is more soluble in water. If the dried complex contains higher than the desired level of ornithine contamination (e.g., greater than 10 mole% ornithine – as measured by NMR, for example), the complex may be redissolved and reprecipitated as necessary to further lower the relative amount of ornithine.

Recovering Citrulline from Its Copper Complex

[00017] Once the ornithine content in the copper: citrulline complex precipitate is sufficiently low

(preferably less than 10 mole% ornithine), the precipitate is resuspended in water and citrulline is freed from the complex by removing the copper as an inorganic precipitate, typically copper sulfide (See Figure 2B). Sulfide may be introduced in a variety of salt forms, but the inventors have found it preferable to use hydrogen sulfide gas as the sulfide source. In a preferred mode, the aqueous suspension is placed in a stirred, pressure vessel. The air is then pumped out of the reactor’s head space to form an under pressure. The reactor is then repressurized with hydrogen sulfide gas over the aqueous suspension (preferably at low temperature, e.g., 0°C-5°C, to maximize the solubility of hydrogen sulfide). Hydrogen sulfide is continuously added to the reactor to maintain parity with ambient pressure during consumption of this gas. Copper salts will precipitate, leaving citrulline in solution. As hydrogen sulfide is consumed, the pressure in the vessel decreases; the reaction is complete when the pressure stabilizes. Reaction of hydrogen sulfide with residual copper salts (for example chloride or sulfate) will lower the pH; typically the pH will be below 4, preferably pH~3. Copper salts typically include copper (II) sulfide, but may also include copper (I) sulfide and copper oxide. The solution temperature is elevated for filtration, typically to about 30°C, to promote solubility of the citrulline and drive off excess hydrogen sulfide gas, while precipitated copper salts are removed by filtration.

Purifying Citrulline

[00018] For pharmaceutical use, the active compound must be substantially free of contaminants, and further purification steps are necessary to produce a pharmaceutical grade product. For the purposes of this invention, substantially free of contaminants is considered to include: ornithine not more than (NMT) 0.8%, individual specified impurities NMT 0.15%, individual unspecified (unknown) impurities NMT 0.1%; total related substances NMT 1.3%, and Cu not more than lOppm. For citrulline manufactured from ornithine using copper complex to protect the alpha amino acid functions, the inventors have found that desired purification after citrulline is released from the copper complex can be achieved by activated carbon adsorption of contaminants and solvent/anti- solvent crystallization of the active pharmaceutical component.

[00019] The citrulline-containing aqueous solution remaining after removal of precipitated copper salts is neutralized to stabilize the citrulline against hydrolysis, to enhance adsorption of residual copper to activated carbon, and to facilitate solvent/anti-solvent precipitation of citrulline; pH is preferably adjusted to 5.9 ± 0.2, the isoelectric point of citrulline. The neutralized citrulline solution may be passed through a nano-filter to remove any bacteria and/or bacterial cell wall fragments that contaminate the solution. The nano-filtered solution may be held in a semi-sterile reservoir for staging purposes between the subsequent purification steps. The neutralized citrulline solution is treated with activated carbon, either by mixing with carbon dust or passing the solution through an activated carbon adsorber bed. The aqueous citrulline-containing effluent from the activated carbon is mixed with an anti-solvent to induce anti-solvent crystallization. Suitable anti solvents are miscible with water, including aliphatic alcohols, such as 2-propanol, ethanol or methanol, as well as acetone. A preferred antisolvent for citrulline is acetone, when mixed with approximately two volumes of water (e.g., 1 volume of water to 1.8 volumes of acetone). Acetone is preferably pre-cooled so that the resultant suspension is 0°C- 10°C. The cooled suspension may be collected in a reservoir or processed by filtration immediately to recover the citrulline precipitate.

Microbial control:

[00020] Because citrulline synthesis and purification occur in aqueous solution, there is increased risk of microbial contamination and endotoxin accumulation in the product. Washing the citrulline: copper precipitate, and addition of H2S to acid solution minimize any accumulation of microbes. From the exposure of the complex to FES until treatment with acetone the aqueous solutions of citrulline are preferably kept in sealed vessels to limit microbial contamination and growth. Enclosing the purification steps to minimize contact with the environment and use of sterile filters to capture potential microbial contamination allows the manufacturing to be performed in an ISO 8 cleanroom. Alternatively, the final purification steps can be carried out in a sterile GMP environment of the sort used for aseptic filling of sterile dosage products (e.g., ISO Class 5/6).

[00021] If examination of the solution prior to the anti-solvent precipitation shows the amounts of microbes or endotoxin levels exceed those aceptable for injectable therapeutic compositions (e.g., 50 EU/g API, more preferably 20 EU/g), the product may be subjected to nano-filtration to remove microbes and endotoxin, before being recovered by anti-solvent precipitation and drying. The citrulline and water molecules pass through the nano-filtration membrane, but the larger bacteria and bacterial cell wall fragments are retained by the filter.

Filter press

[00022] The reaction mixtures may be pumped through a filter press to collect / remove the

suspended solids. See the general picture in Figure 3, and the attached photograph in Figure 4. The press is composed of a series of plates 1 which are then hydraulically pressed together. The hydraulic pressure ensures that the system is sealed. The suspension is then pumped through a central tube 2 where it spreads-out across several chambers 3 between the plates. The walls of the plates have a filter sheet, which allows the filtrate to flow past and exit via an internal cavity 4.

[00023] The general advantage of a filter press is that it allows a high surface area for filtration.

This effect greatly accelerates the portion-wise collection and washing of the complex and API. This system may be used to collect the copper salts after exposure to hydrogen sulfide. In the latter case, the suspension is pumped from the reactor into the press, and the filtrate may then be passed through an in-line 5 pm filter to catch any residual particulate copper, then an in-line sterile 0.2 pm filter at the entry port of a semi-sterile container for holding.

The press may be used to collect:

• Crude citrulline copper complex

• The complex after the pH-driven re-precipitation

• Precipitated copper salts (where citrulline leaves as solution in the filtrate)

• Precipitated citrulline from anti-solvent precipitation prior to drying

Semi-sterile containers

[00024] A useful semi-sterile container is basically a closed vessel equipped with a stirrer and ports for the addition and removal of liquid, and a pH meter. The container should be sterilized (e.g., treated with isopropyl alcohol solution and rinsed with water) directly prior to use and not opened during use. A sterile, air filter attached to the lid allows air to flow into the container as the liquid is being pumped out. The pH adjustment may be performed in this container, before treatment with activated carbon. The container is not particularly suitable for the long-term storage of the solutions.

Activated carbon adsorber bed

[00025] The solution may be pumped from the semi sterile container through the activated carbon bed (a column packed with granulated activated carbon) pre-flushed with argon. The liquid is then returned to the semi-sterile container via an in-line 5 pm filter and the 0.2 pm sterile filter at the entry port. If the solution is pumped in a cyclic manner with the stirrer activated for not less than 6 hours, the sterile filter acts as a“microbial scrubber” continually collecting any microbes in the solution. The activated carbon primarily removes any organic impurities and will also remove any residual dissolved copper ions. The 5 pm filter catches any carbon particles which detach from the bed.

Sterile bags

[00026] After processing in the activated carbon adsorber bed, the solution may be passed into a single use sterile bag via another sterile filter. The solution may be stored longer in the bag than in the semi-sterile container. At this point, a test for the presence of microbes and/or bacterial endotoxins can be carried out. If endotoxins are observed, then the cut off (nano-filtration) membrane may be employed. If not, the citrulline is ready to be

recovered from the solution by anti-solvent precipitation. Collection of the solution in a sterile bag allows the citrulline solution to be processed batch-wise, where conveniently sized portions of citrulline are precipitated and recovered in the filter press.

Solvent/Anti-solvent Mixing

[00027] The aqueous citrulline solution is mixed with pre-cooled anti-solvent to precipitate the citrulline from solution. After mixing with anti-solvent, the threat posed by bacterial growth is not higher than that for other APIs. The addition of the organic solvent makes the resulting solution bacteriostatic at a minimum. This precipitation improves the purity of citrulline, reducing, in particular, the ornithine levels, and allows for the rapid extraction of citrulline from solution.

Final drying

[00028] The precipitate is dried to remove residual acetone and water. Drying may be carried-out in a conical dryer, firstly to drive off the acetone anti-solvent, then moisture and finally the water of crystallization. The conical dryer can also be used to homogenize the product. The final, dry product of anti-solvent precipitation may be stored, and ultimately dissolved in sterile aqueous diluent for therapeutic administration.

[00029] On dissolution in sterile aqueous media, citrulline prepared as described herein may be used to treat pulmonary hypertension (WO/2000/073322), bronchopulmonary dysplasia (WO/2009/099998), sickle cell crisis (WO/2018/157137), cardiac surgery patients (WO/2005/082042), cardiopulmonary bypass patients (WO/2018/125999), and vasospasm as a complication of subarachnoid hemorrhage (WO/2009/099999), by parenteral administration as described in these documents, incorporated herein by reference.

EXAMPLES

Example 1. Synthesis of citrulline from ornithine using urea.

[00030] L-Citrulline is synthesized from L-omithine and urea. A flow chart of the reaction is shown in Figure 1 A.

[00031] L-Citrulline is prepared synthetically starting from L-ornithine hydrochloride. Into a 120- L reactor containing approximately 50 liters of water, 10 kilograms of L-omithine hydrochloride is added and dissolved. The solution is neutralized with potassium hydroxide and then converted to its copper complex by the addition of 15kg copper sulfate (molar equivalent amount). The copper complex protects the 2-amino carboxylic acid functionality in the molecule while chemistry is performed on the terminal amino group. The L-ornithine copper complex is then exposed to an excess of urea at reflux, which promotes its conversion to the copper complex of L-citrulline. The resulting copper complex of L-citrulline then is precipitated and collected by filtration.

[00032] The isolated copper complex of L-citrulline is dried and testing is performed. The

appearance is verified, and an in-use performance test is done to determine suitability to proceed.

Example 2. Purification of citrulline from copper-citrulline complex.

[00033] L-Citrulline synthesized from L-ornithine and urea is purified by resin-based purification and recrystallization. A flow chart of the reaction is shown in Figure IB.

[00034] In a 120-L reactor, ~13 kilograms of the L-citrulline copper complex prepared in

Example 1 is added to a stirring solution of sodium sulfide (Na2S) in water

(approximately 8 kilograms Na2S in 50 liters of water), causing the precipitation of copper sulfide and the freeing of L-citrulline. The solution is filtered to remove the copper salts. The pH of the resulting aqueous solution containing the sodium salt of L- citrulline and residual sodium sulfide is lowered to 4 by the addition of an acidic ion exchange resin (such as Amberlite™). A constant stream of argon gas is passed through the solution to remove the residual sulfide as hydrogen disulfide. The pH of the solution is then raised to 5.9 ± 0.2 using sodium hydroxide to form isoelectric L-citrulline.

Activated carbon is then added to the reaction mixture to remove residual impurities, in particular residual copper ions. The solids (Amberlite™ and activated carbon) are then removed by filtration, and the filtrate is concentrated to approximately 50 liters (either by evaporation or reverse osmosis). L-citrulline is then precipitated from the aqueous solution by the addition of an equal part of acetone, and the mixture is cooled to near 0°C. The precipitate is collected by filtration and dried in a vacuum oven.

[00035] The non-sterile bulk powder is then reconstituted and processed for endotoxin reduction and sterile filtration steps followed by crystallization, drying and micronization in an aseptic environment. The sterile bulk powder is then used as the“raw material” for aseptic filling into glass vials to produce the finished drug product which may be reconstituted with a sterile diluent prior to use.

Example 3. Synthesis of citrulline from ornithine using cyanate

[00036] L-Citrulline was prepared synthetically starting from L-omithine hydrochloride. Into a reactor containing sodium hydroxide (11 kg) in water (170 kg), L-ornithine hydrochloride (44 kg) was added and dissolved. The temperature was maintained at no more than 40°C by active cooling. The ornithine was then converted to its copper complex by the addition of 0.5 molar equivalents of copper sulfate (33 kg) and stirring at ambient temperature for more than 15 minutes. The copper complex protects the 2-amino carboxylic acid functionality of the molecule while chemistry is performed on the terminal amino group. A molar excess of potassium cyanate (32 kg) is then added to the L-ornithine copper complex, and the solution is held at 55°C-65°C for 4.0-4.5 hours, which promotes its conversion to the copper complex of L-citrulline. The resulting copper complex of L-citrulline precipitates during the reaction, and it is collected by filtration.

Example 4. Purification of therapeutic grade citrulline.

[00037] The dry copper: citrulline complex produced in Example 3 is added to a reactor

containing water, which is stirred to resuspend the complex. Concentrated hydrogen chloride solution is added to convert the complex into a solution of copper (II) chloride and citrulline hydrochloride, while the temperature of the reactor is maintained at no more than 45°C by active cooling. Once the contents of the reactor are in solution, sodium hydroxide is added to raise the pH to 7-10, while the temperature is maintained at no more than 40°C. The copper complex of citrulline then precipitates. The precipitate is collected and washed with water until no blue coloration persists in the filtrate.

[00038] The washed precipitate is tested to determine the relative ornithine content. If ornithine is greater than 10 mole%, the precipitate is redissolved and resuspended as described above, until the ornithine content is lowered to not more than 10 mole%.

[00039] Once the precipitate achieves the desired ornithine content, it is resuspended in water in a stirred reactor, and hydrogen sulfide gas is introduced into the suspension to precipitate copper sulfide and dissolve citrulline. The solution is warmed to 30°C ± 2°C to ensure citrulline is fully solubilized, and precipitated copper salts are removed by filtration. The citrulline-containing filtrate is passed thorough micro- and sterile-filtrations and collected in a semi-sterile reactor.

[00040] Activated carbon is used to remove residual impurities, in particular an organic

component and residual copper ions. The pH of the resulting aqueous solution containing L-citrulline and residual copper is adjusted to 5.9 ± 0.2 with sodium hydroxide to form isoelectric citrulline solution. The isoelectric citrulline solution is treated with active carbon granules, preferably by passing the solution through an active carbon adsorber bed, and passed through micro and sterile filters after the active carbon treatment.

[00041] L-citrulline is then precipitated from the aqueous solution by the addition of acetone anti solvent, and the mixture is cooled to near 0°C. Addition of 1.5 to 2 volume equivalents of acetone produce dihydrate crystals of citrulline. The precipitate is collected by filtration. The crystals are dried in a vacuum in a conical dryer at temperature of no more than 45°C to remove acetone and water, resulting in an anhydrous crystalline solid. This solid citrulline corresponds to the orthorhombic d form anhydrous crystals reported by Allouchi, et al., 2014 ( Cryst . Growth Des., 14: 1279-1286).

[00042] Either the dihydrate crystals or the anhydrous crystals may be used therapeutically. The solid or an aqueous solution/suspension may be administered enterally, or the solid may be redissolved for parenteral administration. To produce a final therapeutic product, the non-sterile bulk powder was reconstituted and underwent endotoxin reduction and sterile filtration steps followed by crystallization, drying and micronization in an aseptic environment. The sterile bulk powder was then used as the“raw material” for aseptic filling into glass vials to produce the finished drug product which was reconstituted with a sterile diluent prior to use.

References

^ “Citrulline – Compound Summary”. PubChem Compound. USA: National Center for Biotechnology Information. 16 September 2004. Identification. Retrieved 1 May 2012.
^ Jump up to:^a ^b Banerjee, Aryamitra (2014-01-01), Gupta, Ramesh C. (ed.), “Chapter 15 – Gastrointestinal toxicity biomarkers”, Biomarkers in Toxicology, Boston: Academic Press, pp. 269–277, doi:10.1016/b978-0-12-404630-6.00015-4, ISBN 978-0-12-404630-6, retrieved 2020-11-10
^ Fragkos, Konstantinos C.; Forbes, Alastair (September 2011). “Was citrulline first a laxative substance? The truth about modern citrulline and its isolation” (PDF). Nihon Ishigaku Zasshi. [Journal of Japanese History of Medicine]. 57 (3): 275–292. ISSN 0549-3323. PMID 22397107.
^ Fearon, William Robert (1939). “The Carbamido Diacetyl Reaction: A Test For Citrulline”. Biochemical Journal. 33 (6): 902–907. doi:10.1042/bj0330902. PMC 1264464. PMID 16746990.
^ “Nos2 – Nitric Oxide Synthase”. Uniprot.org. Uniprot Consortium. Retrieved 10 February 2015.
^ Cox M, Lehninger AL, Nelson DR (2000). Lehninger principles of biochemistry (3rd ed.). New York: Worth Publishers. p. 449. ISBN 978-1-57259-153-0. Retrieved 13 March 2020.
^ Rogers, G. E.; Rothnagel, J. A. (1983). “A sensitive assay for the enzyme activity in hair follicles and epidermis that catalyses the peptidyl-arginine-citrulline post-translational modification”. Current Problems in Dermatology. 11: 171–184. doi:10.1159/000408673. ISBN 978-3-8055-3752-0. PMID 6653155.
^ DeLegge, Mark H. (2019-01-01), Corrigan, Mandy L.; Roberts, Kristen; Steiger, Ezra (eds.), “Chapter 7 – Enteral Access and Enteral Nutrition in Patients With Short Bowel Syndrome”, Adult Short Bowel Syndrome, Academic Press, pp. 81–96, doi:10.1016/b978-0-12-814330-8.00007-x, ISBN 978-0-12-814330-8, retrieved 2020-11-10
^ Fragkos, Konstantinos C.; Forbes, Alastair (2017-10-12). “Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis”. United European Gastroenterology Journal. 6 (2): 181–191. doi:10.1177/2050640617737632. PMC 5833233. PMID 29511548.
^ Crenn, P.; et al. (2000). “Post-absorptive plasma citrulline concentration is a marker of intestinal failure in short bowel syndrome patients”. Gastroenterology. 119 (6): 1496–505. doi:10.1053/gast.2000.20227. PMID 11

Names


IUPAC name2-Amino-5-(carbamoylamino)pentanoic acid^[1]
Identifiers
CAS Number	627-77-0^[SciFinder]13594-51-9 R^[SciFinder]372-75-8 S
3D model (JSmol)	Interactive image
3DMet	B01217
Beilstein Reference	1725417, 1725415 R, 1725416 S
ChEBI	CHEBI:18211
ChEMBL	ChEMBL444814
ChemSpider	810553200 R9367 S
DrugBank	DB00155
ECHA InfoCard	100.006.145
EC Number	211-012-2
Gmelin Reference	774677 S
IUPHAR/BPS	722
KEGG	D07706
MeSH	Citrulline
PubChem CID	833 637599 R9750 S
UNII	29VT07BGDA
CompTox Dashboard (EPA)	DTXSID80883373
InChI [show]
SMILES [show]
Properties
Chemical formula	C₆H₁₃N₃O₃
Molar mass	175.188 g·mol⁻¹
Appearance	White crystals
Odor	Odourless
log P	−1.373
Acidity (pK_a)	2.508
Basicity (pK_b)	11.489
Thermochemistry
Heat capacity (C)	232.80 J K⁻¹ mol⁻¹
Std molar entropy (S^o₂₉₈)	254.4 J K⁻¹ mol⁻¹
Related compounds
Related alkanoic acids	N-Acetylaspartic acid Aceglutamide N-Acetylglutamic acid Pivagabine
Related compounds	Bromisoval Carbromal
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
verify (what is ?)
Infobox references

///////CITRULLINE, L-Citrulline, 瓜氨酸 ,

Melatonin

December 14, 2020 1:35 am / Leave a comment

Melatonin

メラトニン

Formula	C13H16N2O2
CAS73-31-4	73-31-4
Mol weight	232.2783

APPROVED, Melatobel, JAPAN 2020/3/25

200-659-6[EINECS]

200-797-7[EINECS]

205542[Beilstein]

73-31-4[RN]

Acetamide, N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-Acetamide

MelatoninCAS Registry Number: 73-31-4CAS Name:N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide

Additional Names:N-acetyl-5-methoxytryptamine

Trademarks: Regulin (Young)

Molecular Formula: C13H16N2O2Molecular Weight: 232.28Percent Composition: C 67.22%, H 6.94%, N 12.06%, O 13.78%

Literature References: A hormone of the pineal gland, also produced by extra-pineal tissues, that lightens skin color in amphibians by reversing the darkening effect of MSH, q.v. Melatonin has been postulated as the mediator of photic-induced antigonadotrophic activity in photoperiodic mammals and has also been shown to be involved in thermoregulation in some ectotherms and in affecting locomotor activity rhythms in sparrows. Isoln from the pineal glands of beef cattle: Lerner et al.,J. Am. Chem. Soc.80, 2587 (1958); Wurtman et al.,Science141, 277 (1963). Structure: Lerner et al.,J. Am. Chem. Soc.81, 6084 (1959). Crystal and molecular structure: A. Wakahara, Chem. Lett.1972, 1139. Synthesis from 5-methoxyindole as starting material by two different routes: Szmuszkovicz et al.,J. Org. Chem.25, 857 (1960). Biochemical role of melatonin: Chem. Eng. News45, 40 (May 1, 1967). Pharmacological studies: Barchas et al.,Nature214, 919 (1967). Identification of antigonadal action sites in mouse brain: J. D. Glass, G. R. Lynch, Science214, 821 (1981). Binding studies in human hypothalamus: S. M. Reppert et al.,Science242, 78 (1988). Efficacy in control of estrus in red deer: G. W. Asher, Anim. Reprod. Sci.22, 145 (1990). Reviews: M. K. Vaughn, Int. J. Rev. Physiol.24, 41-95 (1981); D. C.Klein et al.,Life Sci.28, 1975-1986 (1981). Book: Advan. Biosci.vol. 29, N. Birau, W. Schlott, Eds. (Pergamon Press, New York, 1981) 420 pp. Review of etiological role in clinical disease: A. Miles, D. Philbrick, Crit. Rev. Clin. Lab. Sci.25, 231-253 (1987); in psychiatric disorders: eidem,Biol. Psychiatry23, 405-425 (1988).Properties: Pale yellow leaflets from benzene, mp 116-118°. uv max: 223, 278 nm (e 27550, 6300).Melting point: mp 116-118°Absorption maximum: uv max: 223, 278 nm (e 27550, 6300)Therap-Cat-Vet: Control of estrus.

Melatonin is a hormone primarily released by the pineal gland that regulates the sleep–wake cycle.^[3]^[4] As a dietary supplement, it is often used for the short-term treatment of insomnia, such as from jet lag or shift work, and is typically taken by mouth.^[5]^[6]^[7] Evidence of its benefit for this use, however, is not strong.^[8] A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.^[6] The melatonin receptor agonist medication ramelteon may work as well as melatonin supplements,^[6] at greater cost but with different adverse effects, for some sleep conditions.^[9]

Side effects from melatonin supplements are minimal at low doses for short durations.^[3]^[10] They may include somnolence (sleepiness), headaches, nausea, diarrhea, abnormal dreams, irritability, nervousness, restlessness, insomnia, anxiety, migraine, lethargy, psychomotor hyperactivity, dizziness, hypertension, abdominal pain, heartburn, mouth ulcers, dry mouth, hyperbilirubinaemia, dermatitis, night sweats, pruritus, rash, dry skin, pain in the extremities, symptoms of menopause, chest pain, glycosuria (sugar in the urine), proteinuria (protein in the urine), abnormal liver function tests, increased weight, tiredness, mood swings, aggression and feeling hungover.^[11]^[12]^[10]^[13]^[14] Its use is not recommended during pregnancy or breastfeeding or for those with liver disease.^[7]^[14]

In animals (including humans), melatonin is involved in synchronizing the circadian rhythm, including sleep–wake timing, blood pressure regulation, and seasonal reproduction.^[15] Many of its effects are through activation of the melatonin receptors, while others are due to its role as an antioxidant.^[16]^[17]^[18] In plants, it functions to defend against oxidative stress.^[19] It is also present in various foods.^[10]

Melatonin was discovered in 1958.^[3] It is sold over the counter in Canada and the United States;^[10]^[13] in the United Kingdom, it is a prescription-only medication.^[7] It is not approved by the US Food and Drug Administration (FDA) for any medical use.^[10] In Australia and the European Union, it is indicated for difficulty sleeping in people over the age of 54.^[20]^[11] In the European Union, it is indicated for the treatment of insomnia in children and adolescents.^[12] It was approved for medical use in the European Union in 2007.^[11]

SYN

https://www.ch.ic.ac.uk/local/projects/s_thipayang/synth.html

SYNTHESIS

Chemical Synthesis of Melatonin
The methods for the chemical synthesis of melatonin are generally not so complicated and do not involve more than three steps of conversion. Three synthesis reactions of melatonin from primary literatures are shown below;

Reaction 1

In 1958 melatonin was first isolated and characterised by A.B.Lerner. It was know as one of a substituted 5-hydroxyindole derivative in the pineal gland that could lighten pigment cells. It had not been know to exist in biological tissue although it had been isolated as a urinary excretion product in rats after administration of 5-hydroxytryptamine.
Melatonin or N-acetyl-5-methoxytryptamine (40 mg) was prepared by reducing 100 mg of 5-methoxyindole-3-acetonitrile with 160 mg of sodium and 2 ml of ethanol. Then the product was acetylated with 4 ml of both glacial acetic acid and acetic anhydride at 100 ^oC for 1 minute. Purification was achieved by countercerrent distribution and silicic acid chromatography.

Reaction 2

5-Methoxytryptamine hydrochloride (1g, 4.75 mmole) was dissolved in pyridine (10 ml) and acetic anhydride (10 ml) and kept overnight at 20 ^oC. The solution was poured onto iced, neutralised with dilute hydrochloric acid and extracted with chloroform (2×25 ml). The combined extracts were washed with water, dried in MgSO₄ and evaporated to afford a liquid of N,N diacetyltryptamine derivative. The liquid was then poured into water (50 ml) and extracted with chlroform (2×25 ml). The combined organic layers were washed with water (25 ml), dried in MgSO₄ and evaporated to dryness. The residual solid crystallised from benzene to afford melatonin 819 mg, 80% yield.

Reaction 3

The more reactive indoles (1a-1d) were alkylated at the 3 position by reaction with nitroethene generated in situ by thermolysis of nitroethyl acetate. The nitroethyl acetate used for this purpose was prepared by acetylation of nitroethanol with acetic anhydride using NaOAc as a catalyst. These conditions constitute a substantial improvement of the overal yield of the reation. Reduction of the nitroethylated indoles (2a-d) by hydrogenation over PtO₂, followed by acetylation fo the resluting tryptamines with acetic anhydride-pyridine completed the synthesis of melatonin and its derivatives (4a-d).

Biological Synthesis and Metabolism of Melatonin

The biosynthesis of melatonin (Fig.1) is initiated by the uptake of the essential amino acid tryptophan into pineal parenchymal cells. Tryptophan is the least abundant of essential amino acids in normal diets. It is converted to another amino acid, 5-hydroxytryptophan, through the action of the enzyme tryptopahn hydroxylase and then to 5-hydroxytryptamine (serotonin) by the enzyme aromatic amino acid decarboxylase. Serotonin concentrations are higher in the pineal than in any other organ or in any brain region. They exhibit a striking diurnal rhythm remaining at a maximum level during the daylight hours and falling by more than 80% soon after the onset of darkness as the serotonin is converted to melatonin, 5-hydroxytryptophol and other methoxyindoles. Serotonin’s conversion to melatonin involves two enzymes that are characteristic of the pineal : SNAT (serotonin-N-acetyltransferase) which converts the serotonin to N-acetylserotonin, and HIOMT (hydroxyindole-O-methyltrasferase) which trasfers a methyl group from S-adenosylmethionine to the 5-hydroxyl of the N-acetylserotonin. The activities of both enzymes rise soon after the onset of darkness because of the enhanced release of norepinephrine from sympathetic neurons terminating on the pineal parenchymal cells.
Another portion of the serotonin liberated from pineal cells after the onset of darkness is deaminated by the enzyme monoamine oxidase (MAO) and then either oxidized to form 5-hydroxyindole acetic acid or reduced to form 5-hydroxytryptophol (Fig.1). Both of these compounds are also substrates for HIOMT and can thus be converted in the pineal to 5-methoxyindole acetic acid 5-methoxytryptophol (Fig.1). The level of this latter indole, like that of melatonin, rises markedly in the pineal with the onset of darkness. Since 5-methoxytryptophol synthesis does not require the acetylation of serotonin, the nocturnal increase in pineal SNAT activity cannot be the trigger that causes pineal methoxyindole levels to rise. More likely, a single unexplained process- the intraparenchymal release of stored pineal serotonin, which then becomes accessible to both SNAT and MAO. This process ultimately controls the rates at which all three major pineal methoxyindoles are synthesized and generates the nocturnal increases in pineal melatonin and 5-methoxytryptophol. The proportion of available serotonin acetylated at any particular time of day or night depends on the relative activities of pineal SNAT and MAO at that time. The rates of methylation of all three 5-hydroxyindoles formed from pinela serotonin depends on HIOMT activity.Fig.1 Biosynthesis of pineal methoxyindoles from serotonin

Serotonin may be either acetylated to form N-acetylserotonin through the action of the enzyme serotonin-N-acetyltransferase (SNAT), or oxidatively deaminated by monoamine oxidase (MAO) to yield an unstable aldehyde. This compound is then either oxidized to 5-hydroxyindole acetic acid by the enzyme aldehyde dehydrogenase (ADH), or reduced to from 5-hydroxytryptophol by aldehyde reductase (AR). Each of these 5-hydroxyindole derivatives of serotonin is a substrate for hydroxyindole-O-methyltrasferase (HIMOT). The enzymatic trasfer of a methyl group from S-adenosylmethionine to these hydroxyindoles yields melatonin (5-hydroxy-N-acetyltryptamine), 5-methoxyindole acetic acid and 5-methoxytryptophol respectively. Pineal serotonin is synthesized from the essential amino acid tryptophan by 5-hydroxylation folloed by decarboxylation. The first step in ths enzymic sequence is catalysed by tryptophan hydroxylase. The second step is catalysed by aromatic L-amino acid decarboxylase.

Medical uses

In the European Union it is indicated for the treatment of insomnia in children and adolescents aged 2–18 with autism spectrum disorder (ASD) and / or Smith–Magenis syndrome, where sleep hygiene measures have been insufficient^[12] and for monotherapy for the short-term treatment of primary insomnia characterized by poor quality of sleep in people who are aged 55 or over.^[11]

Sleep disorders

Positions on the benefits of melatonin for insomnia are mixed.^[8] An Agency for Healthcare Research and Quality (AHRQ) review from 2015 stated that evidence of benefit in the general population was unclear.^[8] A review from 2017, found a modest effect on time until onset of sleep.^[3] Another review from 2017 put this decrease at six minutes to sleep onset but found no difference in total sleep time.^[6] Melatonin may also be useful in delayed sleep phase syndrome.^[3] Melatonin appears to work as well as ramelteon but costs less.^[6]

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson’s disease and dementia with Lewy bodies.^[21]^[22]^[23] In Europe it is used for short-term treatment of insomnia in people who are 55 years old or older.^[24] It is deemed to be a first line agent in this group.^[6]

Melatonin reduces the time until onset of sleep and increases sleep duration in children with neurodevelopmental disorders.^[25]

Dementia

A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer’s disease.^[26] A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer’s it has little to no effect.^[27] Melatonin may, however, help with sundowning.^[28]

Jet lag and shift work

Melatonin is known to reduce jet lag, especially in eastward travel. If the time it is taken is not correct, however, it can instead delay adaption.^[29]

Melatonin appears to have limited use against the sleep problems of people who work shift work.^[30] Tentative evidence suggests that it increases the length of time people are able to sleep.^[30]

Adverse effects

Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses.^{[clarification needed]} Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo.^[31]^[32] Prolonged-release melatonin is safe with long-term use of up to 12 months.^[33] Although not recommended for long term use beyond this, low-dose melatonin is generally safer, and a better alternative, than many prescription and over the counter sleep aids if a sleeping medication must be used for an extended period of time. Low-doses of melatonin are usually sufficient to produce a hypnotic effect in most people. Higher doses do not appear to result in a stronger effect, but instead appear to cause drowsiness for a longer period of time.^[34]

Melatonin can cause nausea, next-day grogginess, and irritability.^[35] In the elderly, it can cause reduced blood flow and hypothermia.^[36]^{[needs update]} In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.^[37]^[38]^{[needs update]}

Melatonin can lower follicle-stimulating hormone levels.^[39] Melatonin’s effects on human reproduction remain unclear.^[40]

In those taking warfarin, some evidence suggests there may exist a potentiating drug interaction, increasing the anticoagulant effect of warfarin and the risk of bleeding.^[41]

Functions

When eyes receive light from the sun, the pineal gland’s production of melatonin is inhibited and the hormones produced keep the human awake. When the eyes do not receive light, melatonin is produced in the pineal gland and the human becomes tired.

Circadian rhythm

In animals, melatonin plays an important role in the regulation of sleep–wake cycles.^[42] Human infants’ melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.^[43] Human melatonin production decreases as a person ages.^[44] Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.^[45]

Antioxidant

Melatonin was first reported as a potent antioxidant and free radical scavenger in 1993.^[46] In vitro, melatonin acts as a direct scavenger of oxygen radicals and reactive nitrogen species including OH^•, O₂⁻^•, and NO^•.^[47]^[48] In plants, melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.^[48] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.^[49] Via signal transduction through melatonin receptors, melatonin promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase.^[50]^[51]

Melatonin occurs at high concentrations within mitochondrial fluid which greatly exceed the plasma concentration of melatonin.^[52]^[53]^[54] Due to its capacity for free radical scavenging, indirect effects on the expression of antioxidant enzymes, and its significant concentrations within mitochondria, a number of authors have indicated that melatonin has an important physiological function as a mitochondrial antioxidant.^[50]^[52]^[53]^[54]^[55]

The melatonin metabolites produced via the reaction of melatonin with reactive oxygen species or reactive nitrogen species also react with and reduce free radicals.^[51]^[55] Melatonin metabolites generated from redox reactions include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).^[51]^[55]

Immune system

While it is known that melatonin interacts with the immune system,^[56]^[57] the details of those interactions are unclear. An antiinflammatory effect seems to be the most relevant. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,^[58] and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease^[59] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

Biosynthesis

Overview of melatonin biosynthesis

In animals, biosynthesis of melatonin occurs through hydroxylation, decarboxylation, acetylation and a methylation starting with L-tryptophan.^[60] L-tryptophan is produced in the shikimate pathway from chorismate or is acquired from protein catabolism. First L-tryptophan is hydroxylated on the indole ring by tryptophan hydroxylase to produce 5-hydroxytryptophan. This intermediate (5-HTP) is decarboxylated by pyridoxal phosphate and 5-hydroxytryptophan decarboxylase to produce serotonin.

Serotonin is itself an important neurotransmitter, but is also converted into N-acetylserotonin by serotonin N-acetyltransferase with acetyl-CoA.^[61] Hydroxyindole O-methyltransferase and S-adenosyl methionine convert N-acetylserotonin into melatonin through methylation of the hydroxyl group.^[61]

In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimate pathway. In these cells, synthesis starts with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the synthesising reactions are similar, but with slight variations in the last two enzymes.^[62]^[63]

It has been hypothesized that melatonin is made in the mitochondria and chloroplasts.^[64]

Mechanism

Mechanism of melatonin biosynthesis

In order to hydroxylate L-tryptophan, the cofactor tetrahydrobiopterin (THB) must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:

1. A slow transfer of one electron from the THB to O₂ could produce a superoxide which could recombine with the THB radical to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.

2. O₂ could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the THB to form an iron-peroxypterin intermediate.

Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a carbocation at the C5 position of the indole ring. A 1,2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes aromaticity to furnish 5-hydroxy-L-tryptophan.^[65]

A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO₂ from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine.^[66] PLP forms an imine with the amino acid derivative. The amine on the pyridine is protonated and acts as an electron sink, enabling the breaking of the C-C bond and releasing CO₂. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP.^[67]

It has been proposed that histidine residue His122 of serotonin N-acetyl transferase is the catalytic residue that deprotonates the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A serves as a good leaving group when attacked by a general base to give N-acetylserotonin.^[68]

N-acetylserotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.^[67]^[69]

Regulation

In vertebrates, melatonin secretion is regulated by activation of the beta-1 adrenergic receptor by norepinephrine.^[70] Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis.^[71] Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.

Blue light, principally around 460–480 nm, suppresses melatonin biosynthesis,^[72] proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light.^{[citation needed]} The incandescent light bulb widely used in the 20th century produced relatively little blue light.^[73] Light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.^[74] Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.^[75]

Pharmacology

Pharmacodynamics

In humans, melatonin is a full agonist of melatonin receptor 1 (picomolar binding affinity) and melatonin receptor 2 (nanomolar binding affinity), both of which belong to the class of G-protein coupled receptors (GPCRs).^[51]^[76] Melatonin receptors 1 and 2 are both G_i/o-coupled GPCRs, although melatonin receptor 1 is also G_q-coupled.^[51] Melatonin also acts as a high-capacity free radical scavenger within mitochondria which also promotes the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase via signal transduction through melatonin receptors.^[50]^[51]^[52]^[53]^[54]^[55]

Pharmacokinetics

When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3 mg^[77]) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.^[78] Melatonin is rapidly absorbed and distributed, reaching peak plasma concentrations after 60 minutes of administration, and is then eliminated.^[61] Melatonin has a half life of 35–50 minutes.^[79] In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.^[5] The bioavalibility of melatonin is between 10 and 50%.^[61]

Melatonin is metabolized in the liver by cytochrome P450 enzyme CYP1A2 to 6-hydroxymelatonin. Metabolites are conjugated with sulfuric acid or glucuronic acid for excretion in the urine. 5% of melatonin is excreted in the urine as the unchanged drug.^[61]

Some of the metabolites formed via the reaction of melatonin with a free radical include cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK).^[51]^[55]

The membrane transport proteins that move melatonin across a membrane include, but are not limited to, glucose transporters, including GLUT1, and the proton-driven oligopeptide transporters PEPT1 and PEPT2.^[51]^[55]

For research as well as clinical purposes, melatonin concentration in humans can be measured either from the saliva or blood plasma.^[80]

History

Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin.^[81]^[82] As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores.^[83]^[84]

In 1958, dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.^[85] In the mid-70s Lynch et al. demonstrated that the production of melatonin exhibits a circadian rhythm in human pineal glands.^[86]

The discovery that melatonin is an antioxidant was made in 1993.^[87] The first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.^[88] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.^[89] The New England Journal of Medicine editorialized in 2000: “With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear.”^[90]

It was approved for medical use in the European Union in 2007.^[11]

Other animals

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland^[91] located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes^[92]^[93] rather than the melatonin signal (as was once postulated). Known as “the hormone of darkness”, the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans.

Many animals use the variation in duration of melatonin production each day as a seasonal clock.^[94] In animals including humans,^[95] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage coloring in seasonal animals.^[95] In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds^[96] and hamsters.^[97] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

During the night, melatonin regulates leptin, lowering its levels.

Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors.^[98] This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.^[98]

Plants

Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions.^[19]^[99] Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram.^[63]^[100] Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats.^[19] In some common foods and beverages, including coffee^[19] and walnuts,^[101] the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.^[63]^[102]^[103]

Occurrence

Dietary supplement

Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada.^[5] FDA regulations applying to medications are not applicable to melatonin,^[15] though the FDA has found false claims that it cures cancer.^[104] As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin.^[29] In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.^[105]

Food products

Naturally-occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,^[106] bananas and grapes, rice and cereals, herbs, plums,^[107] olive oil, wine^[108] and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.^[109] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.^[110]

Beverages and snacks containing melatonin were being sold in grocery stores, convenience stores, and clubs in May 2011.^[111] The FDA considered whether these food products could continue to be sold with the label “dietary supplements”. On 13 January 2010, it issued a Warning Letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin, while legal as a dietary supplement, was not approved as a food additive.^[112] A different company selling a melatonin-containing beverage received a warning letter in 2015.^[113]

Commercial availability

Immediate-release melatonin is not tightly regulated in countries where it is available as an over-the-counter medication. It is available in doses from less than half a milligram to 5 mg or more. Immediate-release formulations cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, or liquids. It is also available for use sublingually, or as transdermal patches.^{[medical citation needed]}

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic, which limits the risk of contamination or the means of transmitting infectious material.^[15]^[114]

Melatonin is the most popular over-the-counter sleep remedy in the US, resulting in sales in excess of US$400 million during 2017.^[115]

Research

A bottle of melatonin tablets. Melatonin is available in timed-release and in liquid forms.

Various uses and effects of melatonin have been studied. A 2015 review of studies of melatonin in tinnitus found the quality of evidence low, but not entirely without promise.^[116]

Headaches

Tentative evidence shows melatonin may help reduce some types of headaches including cluster and hypnic headaches.^[117]^[118]

Cancer

A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive.^[119] A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.^[120]

Protection from radiation

Both animal^[121] and human^[122]^[123]^[124] studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure.^[125] Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without known, major side effects.^[126]

Epilepsy

A 2016 review found no beneficial role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy.^[127]

Secondary dysmenorrhoea

A 2016 review suggested no strong evidence of melatonin compared to placebo for dysmenorrhoea secondary to endometriosis.^[128]

Delirium

A 2016 review suggested no clear evidence of melatonin to reduce the incidence of delirium.^[129]

Gastroesophageal reflux disease

A 2011 review said melatonin is effective in relieving epigastric pain and heartburn.^[130]

Psychiatry

Melatonin might improve sleep in people with autism.^[131] Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin.^[132]^[133] Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings.^[132]^[134]^[135] However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed.

While the packaging of melatonin often warns against use in people under 18 years of age, studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD, including children. However, larger and longer studies are needed to establish long-term safety and optimal dosing.^[136]

Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with midazolam in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.^[137]

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy.^[138] Some evidence supports an antidepressant effect.^[139]

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^ Mills E, Wu P, Seely D, Guyatt G (November 2005). “Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis”. Journal of Pineal Research. 39 (4): 360–6. doi:10.1111/j.1600-079X.2005.00258.x. PMID 16207291. S2CID 22225091.
^ Meltz ML, Reiter RJ, Herman TS, Kumar KS (March 1999). “Melatonin and protection from whole-body irradiation: survival studies in mice”. Mutation Research. 425 (1): 21–7. doi:10.1016/S0027-5107(98)00246-2. PMID 10082913.
^ Reiter RJ, Herman TS, Meltz ML (December 1996). “Melatonin and radioprotection from genetic damage: in vivo/in vitro studies with human volunteers”. Mutation Research. 371 (3–4): 221–8. doi:10.1016/S0165-1218(96)90110-X. PMID 9008723.
^ Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J (March 2016). “Dietary supplements for dysmenorrhoea”. The Cochrane Database of Systematic Reviews. 3 (3): CD002124. doi:10.1002/14651858.cd002124.pub2. PMC 7387104. PMID 27000311.
^ Reiter RJ, Herman TS, Meltz ML (February 1998). “Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes”. Mutation Research. 397 (2): 203–8. doi:10.1016/S0027-5107(97)00211-X. PMID 9541644.
^ Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (January 2007). “One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?”. Journal of Pineal Research. 42 (1): 28–42. doi:10.1111/j.1600-079X.2006.00407.x. PMID 17198536. S2CID 40005308.
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^ Pattanittum P, Kunyanone N, Brown J, Sangkomkamhang US, Barnes J, Seyfoddin V, Marjoribanks J (March 2016). “Dietary supplements for dysmenorrhoea”. The Cochrane Database of Systematic Reviews. 3: CD002124. doi:10.1002/14651858.CD002124.pub2. PMC 7387104. PMID 27000311.
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External links

"Melatonin". Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Pronunciation	/ˌmɛləˈtoʊnɪn/ (listen)
Trade names	Circadin, Slenyto, others^[1]
Other names	N-acetyl-5-methoxy tryptamine^[2]
AHFS/Drugs.com	Consumer Drug Information
License data	EU EMA: by INNUS DailyMed: Melatonin
Routes of administration	By mouth, sublingual, transdermal
ATC code	N05CH01 (WHO)
Physiological data
Source tissues	pineal gland
Target tissues	wide spread, including brain, retina, and circulatory system
Receptors	melatonin receptor
Precursor	N-acetylserotonin
Metabolism	Liver via CYP1A2 mediated 6-hydroxylation
Legal status
Legal status	AU: OTC / Rx-onlyCA: OTCUK: POM (Prescription only)EU: Rx-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	30–50%
Metabolism	Liver via CYP1A2 mediated 6-hydroxylation
Metabolites	6-hydroxymelatonin, N-acetyl-5lhydroxytryptamine, 5-methoxytryptamine
Elimination half-life	30–50 minutes^[3]
Excretion	Kidney
Identifiers
IUPAC name [show]
CAS Number	73-31-4
PubChem CID	896
IUPHAR/BPS	224
DrugBank	DB01065
ChemSpider	872
UNII	JL5DK93RCL
KEGG	D08170
ChEBI	CHEBI:16796
ChEMBL	ChEMBL45
CompTox Dashboard (EPA)	DTXSID1022421
ECHA InfoCard	100.000.725
Chemical and physical data
Formula	C₁₃H₁₆N₂O₂
Molar mass	232.283 g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	117 °C (243 °F)
SMILES [hide]COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
InChI [hide]InChI=1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)Key:DRLFMBDRBRZALE-UHFFFAOYSA-N

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