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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CFDA Approves Clinical Trials for Novel China AIDS Treatment


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http://www.chinabiotoday.com/articles/20130523

Peramivir, a Flu Treatment


Peramivir.svg

ChemSpider 2D Image | Peramivir | C15H28N4O4

PERAMIVIR

CAS 330600-85-6

  • Molecular FormulaC15H28N4O4
  • Average mass328.407 Da

(1S,2S,3R,4R)-4-carbamimidamido-3-[(1S)-1-acetamido-2-ethylbutyl]-2-hydroxycyclopentane-1-carboxylic acid

  • RWJ 270201
  • RWJ-270201
  • RWJ270201
(1S,2S,3R,4R)-3-(1-Acetamido-2-ethylbutyl)-4-carbamimidamido-2-hydroxycyclopentanecarboxylic acid [ACD/IUPAC Name]
(1S,2S,3R,4R)-3-[(1S)-1-(Acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)amino]-2-hydroxycyclopentanecarboxylic Acid
(1S,2S,3R,4R)-3-[(1S)-1-Acetamido-2-ethylbutyl]-4-carbamimidamido-2-hydroxycyclopentanecarboxylic acid
229614-56-6 [RN]
330600-85-6 [RN]
8184
9ZS94HQO3B
Peramivir, also known as BCX1812 and RWJ 270201, is an antiviral drug for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. Peramivir was approved to treat influenza infection in adults.

Product Ingredients

INGREDIENT UNII CAS INCHI KEY
Peramivir hydrate QW7Y7ZR15U 1041434-82-5 RFUCJKFZFXNIGB-ZBBHRWOZSA-N
Molecular Weight 382.45
Formula C15H28N4O4 • 3H2O
CAS No. 330600-85-6 (Peramivir);
1041434-82-5 (Peramivir Trihydrate);
Drug Name:
Peramivir Hydrate
Research Code:
S-021812
Trade Name:
Rapiacta® / Peramiflu®
MOA:
Neuraminidase inhibitor
Indication:
Influenza infection
Status:
Approved
Company:
BioCryst (Originator) , Shionogi
Sales:
$21.6 Million (Y2015); 
$23.7 Million (Y2014);
$20 Million (Y2013);
$24.1 Million (Y2012);
$17.7 Million (Y2011);
ATC Code:

Approved Countries or Area

Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2014-12-19 Marketing approval Rapivab Influenza infection Solution 200 mg/20 ml BioCryst Standard
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2010-01-13 Marketing approval Rapiacta Influenza infection Injection, Solution Eq. 150 mg/300 mg Peramivir BioCryst, Shionogi
Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2013-04-05 Marketing approval 力纬 Influenza infection Injection, Solution 100ml 广州南新制药 1.1

Shionogi , GC Pharma and Seqirus , under license from BioCryst Pharmaceuticals (which licensed the program from the University of Alabama ), have developed and launched an iv formulation of the influenza neuraminidase inhibitor peramivir.

Peramivir hydrate was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on January 13, 2010, and approved by the U.S. Food and Drug Administration (FDA) on December 19, 2014. It was co-developed and co-marketed as Rapiacta® by BioCryst and Shionogi in Japan.

Peramivir hydrate is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is indicated for the treatment of influenza A and B viral infections.

Rapiacta® is available as injection solution for intravenous, containing 150 mg/300 mg Peramivir hydrate. The recommended dose is once a day by an intravenous drip infusion over a period of 15 minutes or longer.

Peramivir (trade name Rapivab) is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.[1]

In October 2009, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the use of peramivir based on safety data from phase I, phase II, and limited phase III trial data. The emergency use authorization for peramivir expired in June 2010.[2][3] On 19 December 2014, the FDA approved peramivir to treat influenza infection in adults.[1]

Peramivir has also been approved in Japan and South Korea and is available in Japan as Rapiacta and in South Korea as Peramiflu.[ As of 2015, it is the only intravenous option for treating swine flu.

Peramivir is an antiviral agent developed by Biocryst Pharmaceuticals to treat influenza A/B. The development of peramivir has been supported by the US Department of Health and Human Services as part of the government’s effort to prepare for a flu pandemic. Being an influenza virus neuraminidase inhibitor, peramivir works by preventing new viruses from emerging from infected cells. Due to the poor oral bioavailability, the oral formulation of the drug was previously abandoned by Johnson and Johnson Company. The injectable intravenous formulation of peramivir was approved by the FDA in September 2017 for the treatment of acute uncomplicated influenza to pediatric patients 2 years and older who have been symptomatic for no more than two days.

History

An intramuscular (IM) peramivir phase II study for seasonal influenza in 2008–2009 found no effect for the primary endpoint of improvement in the median time to alleviation of symptoms in subjects with confirmed, acute, uncomplicated influenza infection versus placebo.

In October 2009, it was reported that the experimental antiviral drug peramivir had been “life-saving” effective in intravenous treating 8 serious cases of swine flu.[4] On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for peramivir, allowing the use of the drug in intravenous form for hospitalized patients only in cases where the other available methods of treatment are ineffective or unavailable;[5] for instance, if oseltamivir resistance develops and a person is unable to take zanamivir via the inhaled route. The U.S. government (department of Health and Human Services) gave BioCryst Pharmaceuticals more than $77 million to finish the Phase III clinical development of peramivir. In 2009 the department of Health and Human Services had already given about $180 million to the program.[6] Biocryst also donated 1200 courses of treatment to the US department of Health and Human Services.[7] The Emergency Use Authorization expired on June 23, 2010. In 2011 a phase III trial found the median durations of influenza symptoms were the same with 1 intravenous injection of peramivir against 5 days of oral oseltamivir for people with seasonal influenza virus infection.[8]

In 2012 BioCryst reported that it should halt enrollment on its study for intravenous peramivir in potentially life-threatened people after an interim analysis led trial monitors to conclude that it would be futile to continue and the trial should be terminated. The difference between peramivir and control group (oral oseltamivir) for the primary endpoint, clinical or virologic, was small.[9] In 2013 the Biomedical Advanced Research and Development Authority (BARDA/HHS) released new funding under the current $234.8 million contract to enable completion of a New Drug Application filing for intravenous (IV) peramivir.[10]

According to a research report published in June 2011, a new variant of swine flu had emerged in Asia with a genetic adaptation (a S247N neuraminidase mutation) giving some resistance to oseltamivir and zanamivir, but no significant reduction in sensitivity to peramivir.[11][12] But a H274Y virus mutation showed resistance to oseltamivir and peramivir, but not to zanamivir, and only in N1 neuraminidases.[13] Ultimately 3.2% (19/599) of A(H1N1)pdm09 viruses collected between 2009 and 2012 had highly reduced peramivir inhibition due to the H275Y NA mutation.[14]

BioCryst Pharmaceuticals submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for intravenous peramivir in December 2013.[15] Peramivir (Rapivab) was approved for intravenous administration in December 2014.[1][16]

Route 1

Reference:1. WO9933781A1 / US6562861B1.

Route 2
Route 3

Reference:1. CN102633686A.

Route 4
Route 5

Reference:1. WO2012145932A1.

PATENT

peramivir’s product case, WO9933781 ,

hold SPC protection in the EU states until December 2023, and contain one of the Orange Book (OB) listed patents, US6562861 , that was due to expire in the US in December 2023. In January 2021, the US FDA’s OB was seen to list patents describing peramivir that expire in 2027.

PATENT

WO-2021002689

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9917F9BB2C7486012996DFDDFB205C4A.wapp2nA?docId=WO2021002689&tab=FULLTEXT

Process for preparing an inhibitor of neuraminidase infection ie peramivir trihydrate crystal from the free form of the drug ie peramivir. Discloses the use of peramivir trihydrate in treating influenza infection. Represents the first PCT filing from CKD Bio Corp that focuses on peramivir; however, this case was first seen as a Korean national filing that is published in February 2020.

Influenza virus is an infectious viral disease that causes acute respiratory disease and is a virus commonly known as flu. The influenza virus was first isolated from pigs by Shope in 1931, and the isolation from humans became known after being isolated in 1933 by Smith, Andrews and Laidlow. Currently, the influenza virus causes various acute respiratory diseases in humans worldwide through several mutations, and is managed as a virus that increases the prevalence and mortality rate. In recent years, the prevalence and mortality rate are predicted to increase significantly when a new virus emerges through various mutations of the influenza virus. Due to the recognition and severity of the importance of the influenza virus, influenza surveillance systems are operated around the world.
The influenza virus is an RNA virus belonging to the Orthomyxoviridae family. It has a polymorphic spherical shape composed of 8 segments and has a diameter of about 80 to 120 nm. In the outer shell, two glycoproteins, hemagglutinin (HA) protein, neuraminidase (NA), and matrix protein (Matrix, M2) are present, and another matrix (M1) protein is present on the inner surface of the shell. exist. Influenza viruses are classified into A, B, and C types according to their antigen type. Type A influenza is determined as a subtype by surface antigens HA and NA, and HA is a role of virus attaching to somatic cells, and there are subtypes from H1 to H18. In addition, NA plays an important role in the virus being released from infected cells and spreading to new respiratory cells, and subtypes from N1 to N11 exist. In contrast, influenza B virus has less antigenic change than type A and has an immunologically stable form. In addition, as described above, only humans act as the only host, and are divided into the Victoria family and the Yamagata family. Lastly, influenza C is mostly asymptomatic and is not known to be associated with influenza outbreaks.
As a therapeutic agent for preventing such influenza virus and inhibiting the proliferation of the virus, anti-influenza infection inhibitors are oseltamivir (Oseltamivir; Tamiflu TM ), Zanamivir (Ryrenza TM ), and Peramivir (feramiflu ). TM) Has been developed, and they all have antiviral effects against influenza A and B. In contrast, the M2 inhibitors Amantadine and Rimantadine are only effective for influenza A virus, and their use is not recommended at present due to resistance. Oseltamivir, an inhibitor of influenza A and B virus infection, shows an effect on the influenza virus by blocking the function of the enzyme that proliferates the virus, and it can be taken within 48 hours after the onset of symptoms to get the maximum effect. However, it has a disadvantage that it must be taken for 5 days after symptom improvement, and recently, after taking oseltamivir, side effects caused by vomiting, nausea, and neuropsychiatric disorders are serious, which is a social problem. Zanamivir, another inhibitor of type A and type B influenza virus infection, is a viral treatment that is sprayed into the mouth rather than oral. It also inhibits neuraminidase, a proliferative enzyme on the surface of the virus, so that the virus spreads to other cells. It is known to be a therapeutic agent that inhibits all kinds of influenza viruses. However, zanamivir also has serious side effects such as diarrhea, nausea, vomiting, headache, dizziness, and nasal bleeding. Their global marketability is that the market for zanamivir is engulfing, and oseltamivir is also difficult to prescribe for patients with serious side effects such as severe neuropsychiatric disorders and difficult to take oral, and it must be taken orally about 10 times in 5 days. It is predicted that the market of oseltamivir is also likely to be encroached. On the contrary, Ferramivir is the most recently developed family of neuraminidase inhibitors and is known as a therapeutic agent for influenza virus infections against types A and B. Ferramivir has the advantage of suppressing the action of a wide range of influenza virus strains, and it can be prescribed with a single intravenous injection. Due to the intravenous prescription of ferramivir, it is evaluated as a very effective treatment compared to oseltamivir, which is taken orally, and zanamivir, which is taken by inhalation, and it is possible to prescribe patients with difficult oral administration, metabolic diseases, and chronic respiratory diseases. In addition, compared to the oral prescription, it has the advantage of having relatively few side effects such as rapid fever and vomiting and nausea. Ferramivir, as an inhibitor of influenza infection, has improved its low awareness since FDA approval in 2014 and has been showing continuous growth, and in September 2018, the expansion of the demand group due to the expansion of indications in Korea is gradually increasing.
The product name of Feramivir is Feramiflu  , which is completed as an injection in the form of a ferramivir hydrate as shown in Formula 1. In more detail, Feramiflu has the form of ferramivir trihydrate as shown in Chemical Formula 2.
[Formula 1]
(X = 1, 2, 3 in the above formula)
[Formula 2]
Ferramivir’s trihydrate manufacturing method patents are disclosed as prior patents of the original developer, KR1020017016653/US2000016013/WO200100571 and registered patents KR1020107005427/CN2008001459/WO2009021404 and KR1020127025551/CN2008001459/WO2009021404 filed in China.
The ferramivir trihydrate preparation method disclosed in the patent KR1020017016653/US2000016013/WO200100571 is shown in the following manufacturing process chart 1, and the trihydrate preparation method of KR1020107005427/CN2008001459/WO2009021404 and KR1020127025551/CN2008001459/WO2009021404 is in more detail in the following manufacturing process chart 2. Shown.
[Manufacturing process chart 1]
[Manufacturing process diagram 2]
The patent of KR1020017016653/US2000016013/WO200100571 initiated by the original developer is ferramivir using methanol, which has intrinsic toxicity corresponding to classification 2 of pharmaceutical solvents, among solvents that must regulate the use and residual amount of activated carbon as shown in the manufacturing process chart 1. Trihydrate is manufactured, and the natural drying method is used for drying into trihydrate after ferramivir hydrate manufacturing. do.
As a result of conducting vacuum drying in the absence of a water system in a dryer rather than natural drying, the present inventors were able to confirm a moisture value close to anhydrous, not trihydrate, and for this reason, the manufacturing method of the existing patents chose natural drying. Estimate. However, ferramivir trihydrate is a drug that is finished as an injection, and natural drying is difficult to maintain a homogeneous moisture value due to different drying conditions depending on internal humidity. That’s how it doesn’t.
In addition, in the patents of KR1020107005427/CN2008001459/WO2009021404 and KR1020127025551/CN2008001459/WO2009021404 shown in the manufacturing process chart 2, trihydrate is prepared using a methanol solvent, and the drying process is also a process that is not easy for GMP regulations and industrial production. To prepare ferramivir trihydrate. In addition, both manufacturing process diagrams 1 and 2 produce trihydrate in the presence of activated carbon. Their industrial yields from ferramivir to ferramivir trihydrate are 73.1% and 90%, respectively, and the purity can be produced with a purity of 99.91% and 99.86%, respectively. Has.
Accordingly, the present inventors have made intensive research efforts to develop a manufacturing method suitable for manufacturing excellent pharmaceuticals and quality control standards (GMP) without using toxic solvents such as activated carbon and methanol in the manufacture of ferramivir trihydrate.
Example 1: Feramivir trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclo Preparation of pentane-1-carboxylic acid trihydrate) (1)

[100]

[101]

[102]
In a 500.0 L capacity reactor (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid (Peramivir) 30.0 kg was added and suspended in 240.0 L of purified water. The reaction was heated to about 95° C. to completely dissolve the suspension, followed by stirring, followed by natural cooling. When the temperature of the reaction product was 85° C., 45.0 L of 1-propanol was slowly added thereto, followed by natural cooling to 25° C. with stirring. At this time, crystal grains of ferramivir trihydrate were generated at about 40°C. When the temperature of the reactor reached 25° C. through natural cooling, the mixture was stirred for about 12 hours for a phase change of the crystalline form A. In addition, the temperature of the reactor was cooled to 5° C. and further stirred for about 3 hours. After completion of the reaction, filtration and washing with 15.0 L of a 10% 1-propanol solvent were performed once. The filtered solid cake was placed in a vacuum dryer with an internal humidity of about 40% in which a purified water bowl was placed under the vacuum dryer, and the solid cake was dried at 40° C. for about 12 hours. After completion of drying, ferramivir trihydrate was obtained (yield: 95.0%, purity: 99.9%, moisture: 14.5%).

[103]

[104]
1 H NMR (500 MHz, D 2 O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, -CH), 2.65-2.63 (m, 1H, -CH), 2.48-1.45 (m, 1H, -CH), 2.16-2.12 (m, 1H, -CH), 1.88 (s, 3H, -CH 3 ), 1.75-1.71 (m, 1H, -CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, -CH 3 ), 0.82-0.79 (t, 3H, -CH 3 ); 13 C NMR (500 MHz, D 2 O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C 15 H 28 N 4 O 4 ): calcd for 329.21, found; 329.5.

[105]

[106]
Example 2: Feramivir trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclo Preparation of pentane-1-carboxylic acid trihydrate) (2)

[107]

[108]

[109]
To a 500.0L reactor (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid 30.0 kg of (Peramivir) was added and suspended in 240.0 L of purified water. The reaction mixture is heated to about 95° C. to completely dissolve the suspension, followed by stirring, followed by natural cooling. When the temperature of the reaction product was 85°C, 45.0L of 2-propanol was slowly added thereto, and the mixture was naturally cooled to 25°C with stirring. At this time, crystal particles of ferramivir trihydrate are generated at about 40°C. When the temperature of the reactor reached 25° C. through natural cooling, the mixture was stirred for about 12 hours for a phase change of the crystalline form A. In addition, the temperature of the reactor was cooled to 5° C. and further stirred for about 3 hours, followed by filtration and washing with 15.0 L of 10% 2-propanol solvent once after the reaction was completed. The filtered solid cake is placed in a vacuum dryer with an internal humidity of about 40% in which a bowl of purified water is placed under the vacuum dryer, and the solid cake is dried at 40°C for about 12 hours. After completion of drying, ferramivir trihydrate was obtained (yield: 95.5%, purity: 99.9%, moisture: 14.6%).

[110]

[111]
1 H NMR (500 MHz, D 2 O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, -CH), 2.65-2.63 (m, 1H, -CH), 2.48-1.45 (m, 1H, -CH), 2.16-2.12 (m, 1H, -CH), 1.88 (s, 3H, -CH 3 ), 1.75-1.71 (m, 1H, -CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, -CH 3 ), 0.82-0.79 (t, 3H, -CH 3 ); 13 C NMR (500 MHz, D 2 O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C 15 H 28 N 4 O 4 ): calcd for 329.21, found; 329.5.
Example 3: Feramivir trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclo Preparation of pentane-1-carboxylic acid trihydrate) (3)

[121]

[122]
In a 500.0 L reactor (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid 30.0 kg of (Peramivir) was added and suspended in 240.0 L of purified water. The reaction was heated to about 95° C. to completely dissolve the suspension, followed by stirring, and natural cooling was performed. When the temperature of the reaction product was 85° C., 45.0 L of 1-pentanol was slowly added thereto, and the mixture was naturally cooled to 25° C. with stirring. At this time, crystal grains of ferramivir trihydrate were generated at about 40°C. When the temperature of the reactor reached 25° C. through natural cooling, the mixture was stirred for about 12 hours for a phase change of the crystalline form A. In addition, the temperature of the reactor was cooled to 5° C. and further stirred for about 3 hours. After completion of the reaction, filtration and washing with 15.0 L of a 10% 1-pentanol solvent were performed once. The filtered solid cake was placed in a vacuum dryer with an internal humidity of about 40% in which a purified water bowl was placed under the vacuum dryer, and the solid cake was dried at 40°C for about 12 hours. After completion of drying, ferramivir trihydrate is obtained (yield: 95.1%, purity: 99.9%, moisture: 14.1%).

[123]
1 H NMR (500 MHz, D 2 O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, -CH), 2.65-2.63 (m, 1H, -CH), 2.48-1.45 (m, 1H, -CH), 2.16-2.12 (m, 1H, -CH), 1.88 (s, 3H, -CH 3 ), 1.75-1.71 (m, 1H, -CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, -CH 3 ), 0.82-0.79 (t, 3H, -CH 3 ); 13 C NMR (500 MHz, D 2 O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C 15 H 28 N 4 O 4 ): calcd for 329.21, found; 329.5.

PATENT

https://patents.google.com/patent/WO2012145932A1/en

Peramivir has the chemical name of

(1^,2^,3^, 4R)-3-[(llS)-l-acetamido-2-ethyl-butyl] -4-(diaminomethylideneamino)- 2-hydroxy-cyclopentane-l-carboxylicacid, and has the following structure:

Figure imgf000003_0001

(I)

[0003] Peramivir is currently being developed as an antiviral drug, and in particular, for treatment of influenza. Acting as a neuraminidase inhibitor, peramivir can efficiently inhibit the replication of all type of influenza viruses. Peramivir can be administered via injection, and is known to be well-tolerated and cause only mild adverse effect.

[0004] Several processes relating to the preparation of peramivir are disclosed in CN1227466, CN1282316, and WO01/00577A1.

[0005] As shown in Scheme 1, CN 1227466 discloses a process comprising ring-opening of chiral 2-azabicyclo [2.2.1] hept-5-en-3-one, followed by

amino-protecting reaction, Diel- Alder conjugate cycloaddition, reduction, acetylation, guanidylation and finally hydrolyzation to yield peramivir. The major drawback of this process is the use of highly expensive starting material 1. In addition, this process is not suitable for scale-up.

Scheme 1

Figure imgf000004_0001

[0006] WO2009021404 discloses a method comprising reacting

N-Boc-protected chiral 2-azabicyclo [2.2.1] hept-5-en-3-one and

2-ethylbutylaldehyde as starting material to prepare peramivir as illustrated in Scheme 2.

Scheme 2

Figure imgf000005_0001

eram v r

WO2012145932A1 - A novel process for the preparation of peramivir and intermediates thereof - Google Patents

EXAMPLES

Example 1

1 (liS’,4J/?)-methyl-4-(2,3-bis(ieri-butoxycarbonyl)guanidino)cyclopent-2-ene- carboxylate (13)

Figure imgf000024_0003

11 12 13 [0063] To a mixture of (lS^R^methyl 4-aminocyclopent-2-enecarboxylate tartaric acid salt 11 ( 7.29 g, 25 mmol) in dichloromethane (150 mL), was added Et3N (9 mL, 65 mmol) at 0 °C, and the resulting mixture was stirred for 15 min. To this, tert-butyl (lH-pyrazol-l-yl)methylenedicarbamate 12 was added. After addition, the reaction was monitored for completion by TLC ( PE: EtOAc=5 : 1 ) . The organic layers were washed with water and brine and dried over anhydrous Na2S04. The mixture was filtered and concentrated to give 13 as a white solid, which was used in the next step without further purification.

[0064] MS (M+l ) : 384.

[0065] ‘H NMR (400 MHz, CDC13) δ 11.49 (s, 1H), 8.53 (d, J= 8.4 Hz, 1H), 5.94 – 5.83 (m, 2H), 5.38 – 5.31 (m, 1H), 3.73 (s, 3H), 3.56 – 3.44 (m, 1H), 2.60 (dt, J= 14.0, 8.5 Hz, 1H), 1.94 (dt, J= 13.9, 4.7 Hz, 1H), 1.50 (d, J= 7.4 Hz, 18H) (See attached Chart 1)

Example 2

2 (3aJ/?,4J/?,6iS’,6aiS -methyl-4-(2,3-bis(ieri-butoxycarbonyl)guanidino)-3-(pentan -3-yl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate (5)

Figure imgf000025_0001

14 85% a) Preparation of 2-Ethyl-N-hydroxybutanimidoyl chloride (14):

[0066] Hydroxylamine hydrochloride (7.2g, 0.1 mol) was dissolved in water (7 mL). Toluene (27 mL) was added, followed by addition of 2-ethylbutylraldehyde (lOg, 0.1 mol). The two-phase mixture was stirred vigorously while cooling.

Sodium hydroxide solution (ca.30%, 14.6g, O. l lmol) was added slowly (addition is very exothermic) to maintain a temperature between 15-25 °C. The mixture was stirred for 60 min, then allowed to stand to separate the layers. The organic extract was washed with water and brine, dried over Na2S04, and directly used in the next step.

[0067] N-Chlorosuccinimide (NCS) (13.3g, 0.1 mol) was suspended in dimethylformamide (DMF) (17ml) and cooled to about 10 °C. The toluene solution prepared above (3 .15 mol) was added dropwise with sufficient cooling to maintain the reaction temperature betweenlO-25°C. After addition, the reaction was monitored by TLC until completion of the reaction. Water (100ml) was added slowly (slightly exothermic) while maintaining the temperature at 15-25 °C. The two-phase mixture was stirred for 15 min at 15-25 °C and the layers were separated. The water layer was extracted with toluene (10ml) and the organic layer washed with water (3 X 20ml) and brine, dried over Na2S04, and directly used in the next step. b)

Preparation of (3aJ/?,4J/?,6iS’,6aiS -methyl-4-(2,3-bis(ieri-butoxycarbonyl)-guan idine)-3 -(pentan-3 -yl)-4,5,6,6a-tetrahy dro-3 aH-cy clopenta [d] is oxazole-6- carboxylate (15)

[0068] 13 (from example 1, 9.2g, 0.024 mol) was dissolved in toluene (100 mL) and triethylamine (10. Og, 0.099 mol) and the reaction mixture was heated to 60-70 °C. 2- Ethyl-N-hydroxylbutanimidoyl chloride 14 (from example 2a, 14.8 g, 0.099 mol) in toluene (40 mL) was added to the above solution. A white solid

(triethylammonium chloride) was formed. After addition, the reaction was

monitored for completion by TLC ( PE: EtOAc=3 : 1. The reaction mixture was cooled to 20-25 °C, the precipitate was removed by filtration and the filter cake was washed with toluene (50 g). The organic filtrate was washed with water, brine, and dried over anhydrous Na2S04. The mixture was filtered and concentrated by rotary evaporation. The resulting residue was purified by silica gel flash column

chromatography using PE/EtOAc (30 : 1-4: 1, v/v) to give 15 as a white solid.

[0069] Yield : 10.0 g (85%).

[0070] MS (M+l ) :497.

[0071] ‘H NMR (400 MHz, CDC13) δ 11.29 (s, 1H), 8.55 (d, J= 6.4 Hz, 1H), 5.30 (dd, J= 9.1, 1.5 Hz, 1H), 4.53 (d, J= 4.8 Hz, 1H), 3.78 (s, 3H), 3.70 (d, J = 9.1 Hz, 1H), 3.25 (t, J= 5.4 Hz, 1H), 2.93 – 2.84 (m, 1H), 2.20 (dd, J= 7.6, 3.7 Hz, 2H), 1.87 – 1.60 (m, 4H), 1.49 (d, J= 5.0 Hz, 18H), 0.95 (t, J= 7.4 Hz, 3H), 0.87 (t, J= 7.5 Hz, 3H). (See attached Chart 2)

Example 3 3. (1^,2^,3^,4^)-ιη6ίΗγ1-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4-(2,3- Ϊ8(ί^ί- butoxycarb -onyl) guanidino)-2-hydroxycyclopentanecarboxylate (16):

Figure imgf000028_0001

[0072] Compound 15 ( from example 2, 5.0 g, 10.08 mmol) and nickel chloride hexahydrate (2.5g, 10.5 mmol) were dissolved in methanol (40 mL). The green solution was cooled to -15 °C, while a suspension formed. Sodium borohydride

( 0.456 g, 12 mmol) was added to the reaction mixture at -10 to -5 °C (reaction is highly exothermic). A black suspension was formed along with gas evolution.

After complete addition of the sodium borohydride solution, the reaction mixture was stirred until TLC showed 15 was fully consumed. A solution of acetic

anhydride ( 15g, 0.13 mol) was added slowly and maintained the reaction temperature at 0-5 °C, the reaction mixture was stirred for 2-12 h at 0 °C (The black solution change into green solution ), The pH of the mixture was adjusted to ~9 by addition of 25% aq. ammonium hydroxide. The mixture was concentrated by rotary evaporator. The resulting residue was diluted with water (30 mL) and extracted with EtOAc (50 mL><3). The combined organic extracts were washed with water and brine and dried over anhydrous Na2S04. The mixture was filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography using DCM/Methanol (100:0 to 100:2, v/v) to give 16 as a white solid. [0073] Yield: 3.8 g (71%).

[0074] MS (M+l ) : 543.

[0075] ‘H NMR (400 MHz, CDC13) δ 11.39 (s, 1H), 8.72 (d, J= 9.9 Hz, 1H), 8.59 (d, J= 8.5 Hz, 1H), 4.53 – 4.39 (m, 1H), 4.26 (d, J= 16.4 Hz, 2H), 3.96 (t, J = 10.2 Hz, 1H), 3.71 (s, 3H), 2.90 – 2.75 (m, 1H), 2.53 (dt, J= 13.6, 8.8 Hz, 1H), 2.10 (s, 3H), 2.03 (d, J= 6.3 Hz, 1H), 1.90 – 1.76 (m, 1H), 1.38 (dd, J= 73.9, 7.9 Hz, 18H), 1.25 (ddd, J= 15.2, 13.1, 7.3 Hz, 4H), 0.79 (t, J= 7.3 Hz, 3H), 0.75 (dd, J = 14.1, 6.9 Hz, 3H). (See attached Chart 3)

Example 4

4. (1^,2^,3^,4^)-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4-(2,3- Ϊ8(ί^ί- butoxycarbonyl)gu -anidino)-2-hydroxycyclopentanecarboxylic acid (17)

Figure imgf000029_0001

[0076] To a mixture of compound 16 ( from example 3, 2.0 g, 3.69 mmol) in MeOH/THF (1 : 1, v/v, 12 mL), was added aq. NaOH (IN, 7 mL) at room

temperature. After completion of the reaction (monitored by TLC,

DCM:MeOH=10: l, the mixture was concentrated by rotary evaporation. The resulting solution was neutralized to pH 7 using ice-cold 1 N HCl aq. solution and quickly extracted with EtOAc twice. The combined organic extracts were washed with water, brine, and dried over anhydrous Na2S04. The mixture was filtered and the filtrate was concentrated by rotary evaporation. The resulting white foam was washed triturated by hexane, filtered, dried to give 17 as a white solid

[0077] Yield: 1.6 g (84%).

[0078] MS (M+l ) : 529 o

[0079] ‘H NMR (400 MHz, CDC13) δ 11.41 (s, 1H), 8.80 (d, J= 9.8 Hz, 1H), 8.62 (d, J= 8.3 Hz, 1H), 4.43 (dd, J= 23.3, 14.3 Hz, 2H), 4.00 (t, J= 9.8 Hz, 1H), 2.83 (s, 1H), 2.53 (dt, J= 16.9, 8.4 Hz, 1H), 2.14 (s, 3H), 1.91 (dd, J= 12.5, 6.0 Hz, 1H), 1.46 (dd, J = 30.1, 9.5 Hz, 18H), 1.47 – 1.14 (m, 6H), 0.97 – 0.69 (m, 6H). (See attached Chart 4)

Example 5

5. (1^,2^,3^,4^)-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4^υαηΐ(1ΐηο-2- hydroxycyclopent -anecarboxylic acid (Peramivir I)

Figure imgf000030_0001

[0080] Compound 17 ( from example 4, 1.1 g, 2 mmol) was dissolved in aq. HC1 ( 6N, 6 mL, 36 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The resulting solution was neutralized to pH 6-7 using ice-cold 1 N NaOH aq. solution. The mixture was concentrated to 1.5 ml by rotary evaporation. To this, methanol (20 mL) was added. The precipitate was filtered, and the filtrate was concentrated. The resulting white solid was recrystallized from

methanol/water (1 : 1, v/v) to give Peramivir I as a white solid.

[0081] Yield: 500 mg (73%).

[0082] MS (M+l ) : 329.

[0083] H NMR (400 MHz, D20) δ 4.21 (d, J= 10.6 Hz, 2H), 3.70 (dd, J= 14.6, 9.0 Hz, 1H), 2.57 (d, J= 4.8 Hz, 1H), 2.40 (dt, J= 17.7, 8.9 Hz, 1H), 2.14 – 2.01 (m, 1H), 1.81 (s, 3H), 1.75 – 1.58 (m, 1H), 1.31 (s, 3H), 0.78 (ddd, J= 21.6, 18.6, 6.8 Hz, 8H). (See attached Chart 5)

SYN

Practical synthesis of the anti-influenza drug RWJ-270201 (Peramivir) Emergency Use Authorization (EUA) for Intravenous (IV) peramivir  
SYN

Method of synthesis

i. Lactan is dissolved I alcoholic solution, esterification by ring opening under HCl and acid catalysis.

ii. Compound formed is reacted with hydrochloride and tert-butyl dicarbonate.

iii. Reaction with oxammonium hydrochloride reactant salt in alcohol-carbonate system.

iv. Cycloaddition reaction takes place under base catalysis.

v. Hydrogenation in alcoholic solution to generate intermediate compound.

vi. Taking off BOC protect hydrochloride

vii. Two guanidine radicals are put in the reaction vessel, system made of alcohol, organic solvent, aqueous sodium hydroxide solution.

viii. Taking off BOC, product is obtained under organic acid.

 

SYN

https://www.tandfonline.com/doi/abs/10.1080/00397911.2012.729279?journalCode=lsyc20

Abstract

An improved and convenient synthetic route for the synthesis of peramivir has been developed with a total 34% yield. The process was improved from previous methods in three key reaction steps including 1,3-dipolar cycloaddition, reductive ring cleavage of the isoxazoline, and incorporation of the peripheral guanidino group. First, an activated sodium hypochlorite (Cl% = 10%) was employed for the catalytic 1,3-dipolar cycloaddition, and 61–68% yields were obtained. Second, the NaBH4-NiCl2 was used as a new reducing reagent instead of the expensive catalyst PtO2. Most important, an innovative and environmentally friendly method of guanylation in the final step was developed using chloroformamidine hydrochloride as the amidino reagent, which avoided the use of the highlytoxic reagent of HgCl2 and made the process greener.

Supplemental materials are available for this article. Go to the publisher’s online edition of Synthetic Communications® to view the free supplemental file.

GRAPHICAL ABSTRACT

Graphical abstract
Practical synthesis of the anti-influenza drug RWJ-270201 (Peramivir) Emergency Use Authorization (EUA) for Intravenous (IV) peramivir
SYN
Synthesis Synthesis of Peramivir. [2]
SYN

Peramivir – Synthetic Route 1

Synthetic Reference

Chand, Pooran; Kotian, Pravin L.; Dehghani, Ali; El-Kattan, Yahya; Lin, Tsu-Hsing; Hutchison, Tracy L.; Babu, Y. Sudhakar; Bantia, Shanta; Elliott, Arthur J.; Montgomery, John A. Systematic Structure-Based Design and Stereoselective Synthesis of Novel Multi-Substituted Cyclopentane Derivatives with Potent Anti-influenza Activity. Journal of Medicinal Chemistry. Volume 44. Issue 25. Pages 4379-4392. Journal. (2001).

Synthetic Reference

Jia, Fei; Hong, Juan; Sun, Ping-Hua; Chen, Jian-Xin; Chen, Wei-Min. Facile synthesis of the neuraminidase inhibitor peramivir. Synthetic Communications. Volume 43. Issue 19. Pages 2641-2647. Journal; Online Computer File. (2013).

Peramivir – Synthetic Route 3

Peramivir – Synthetic Route 4

Synthetic Reference

Li, Mingjie; Zhu, Quanming; Wang, Chunyan. A process for preparing peramivir. Assignee Shandong Luoxin Pharmacy Stock Co., Ltd., Peop. Rep. China. CN 103524383. (2014).

Synthetic Reference

Ge, Min; Li, Liang; Hu, Chunchen; Wang, Huaiqiu; Fu, Mingwei; Li, Lingchao. Synthesis of Peramivir via 3+2 ring closure. Assignee Acesys Pharmatech Ltd., Peop. Rep. China. CN 108997171. (2018).

SYN 1

WO 9933781

Ring opening of cis-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with HCl in refluxing methanol gives cis-4-amino-2-cyclopentene-1-carboxylic acid (II), which is esterified with HCl/methanol, yielding the methyl ester (III). The protection of (III) with tert-butoxycarbonyl anhydride and triethylamine in dichloromethane affords carbamate (IV), which is cyclized with 2-ethyl-1-nitrobutane (V) by means of phenyl isocyanate in refluxing benzene to give the cyclopenta-oxazoline (VI). Ring opening of (VI) by hydrogenation with H2 over PtO2 in HCl/methanol yields amine (VII), which is acylated with acetic anhydride and triethylamine in dichloromethane to afford acetamide (VIII). The deprotection of (VIII) with HCl in ethyl ether gives the cyclopentylamine (IX), which is condensed with N,N’-bis(tert-butoxycarbonyl)-O-methylisourea (X) by means of HgCl2 in DMF to yield the protected guanidino compound (XI). Deprotection of the guanidino group of (XI) with trifluoroacetic acid in dichloromethane affords the methyl ester (XII), which is finally hydrolyzed with NaOH in THF/methanol.

SYN 2

J Med Chem 2000,43(19),3482

The stereospecific synthesis of BCX-1812(RWJ-270201) has been reported: Ring opening of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA yielding the carbamate (III). Cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) and other isomers. Compound (V) is isolated from the mixture and then hydrogenated with H2 over PtO2 in MeOH and a catalytic amount of HCl to provide amine (VI). Reaction of (VI) with acetic anhydride gives the acetamide (VII), which is Boc-deprotected with ethereal HCl yielding amine (VIII). The guanylation of (VIII) with pyrazolecarboxamidine hydrochloride (IX) and DIEA affords the guanidino derivative (X), which is finally hydrolyzed with NaOH to the desired (1S,2S,3R,4R,1’S)-diastereomer.

SYN 3

J Med Chem 2001,44(25),4379

The ring opening of (-)-2-azabicyclo [2,2,1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA, yielding the carbamate (III). The cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) along with other isomers that are separated by column chromatography. Compound (V) is hydrogenated with H2 over PtO2 in methanol to provide amine (VI), which is acylated with Ac2O, giving the acetamide (VII). N-Boc deprotection of (VII) by means of HCl in ethyl ether yields the amine (VIII), which is condensed with protected isothiourea (IX) by means of HgCl2 to afford the guanidine derivative (X). The hydrolysis of (X) with NaOH provides the carboxylic acid (XI), which is finally deprotected with trifluoroacetic acid to yield the target cyclopentanecarboxylic acid derivative.

References

  1. Jump up to:a b c “Drug Approval Package: Rapivab (peramivir) Injection NDA #206426”U.S. Food and Drug Administration (FDA). 16 January 2015. Retrieved 11 February 2020.
  2. ^ Thorlund K, Awad T, Boivin G, Thabane L (May 2011). “Systematic review of influenza resistance to the neuraminidase inhibitors”BMC Infectious Diseases11 (1): 134. doi:10.1186/1471-2334-11-134PMC 3123567PMID 21592407.
  3. ^ “Peramivir authorized for Emergency use”. LifeHugger. 2009-12-04. Archived from the original on 2011-07-13. Retrieved 2009-12-04.
  4. ^ “Life-Saving H1N1 Drug Unavailable to Most”CBS Evening News. Atlanta, GA, USA: CBS Interactive. 2009-10-19. Retrieved 2009-10-20.
  5. ^ “Emergency Use Authorization Granted For BioCryst’s Peramivir”Reuters. 2009-10-24.
  6. ^ “Feds hand BioCryst $77M for anti-viral trial”Fierce biotech. September 21, 2009.
  7. ^ “FDA Authorizes Emergency Use of Intravenous Antiviral Peramivir for 2009 H1N1 Influenza for Certain Patients, Settings”Reuters. 2009-10-24.
  8. ^ Kohno S, Yen MY, Cheong HJ, Hirotsu N, Ishida T, Kadota J, et al. (November 2011). “Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection”Antimicrobial Agents and Chemotherapy55 (11): 5267–76. doi:10.1128/AAC.00360-11PMC 3195028PMID 21825298.
  9. ^ “BioCryst scraps $235M late-stage flu drug program backed by feds”Fierce Biotech. November 8, 2012.
  10. ^ “BioCryst to File Peramivir NDA Supported by BARDA/HHS Funding”Fierce Biotech. July 11, 2013.
  11. ^ Hurt, A.C. (9 June 2011). “Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation”Eurosurveillance.
  12. ^ Hirschler, Ben (2011-06-10). “Swine flu starting to show resistance to drugs”Reuters.
  13. ^ McKimm-Breschkin JL (January 2013). “Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance”Influenza and Other Respiratory Viruses. 7 Suppl 1: 25–36. doi:10.1111/irv.12047PMC 4942987PMID 23279894.
  14. ^ Leang SK, Kwok S, Sullivan SG, Maurer-Stroh S, Kelso A, Barr IG, Hurt AC (March 2014). “Peramivir and laninamivir susceptibility of circulating influenza A and B viruses”Influenza and Other Respiratory Viruses8 (2): 135–9. doi:10.1111/irv.12187PMC 4186459PMID 24734292.
  15. ^ “BioCryst Files Peramivir NDA for the Treatment of Influenza”(Press release). BioCryst Pharmaceuticals. 2013-12-20.
  16. ^ “Rapivab: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 11 February 2020.

External links

Peramivir
Peramivir.svg
Clinical data
Trade names Rapivab
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU: B3
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Bioavailability 100% (IV)
Elimination half-life 7.7 to 20.8 hours (in patients with normal renal function)
Excretion Kidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
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Chemical and physical data
Formula C15H28N4O4
Molar mass 328.413 g·mol−1
3D model (JSmol)
 ☒check (what is this?)  (verify)

////////////////PERAMIVIR, RWJ 270201, RWJ-270201, RWJ270201M, BCX 1812, RWJ 270201

/////////////////

PERAMIVIR

(1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4- (diaminomethylideneamino)-2-hydroxy-cyclopentane- 1-carboxylic acid

8th, APRIL 2013

In the wake of the growing bird flu outbreak, China’s SFDA will fast-track approvals of a flu treatment – not a vaccine – known as peramivir (peramivir sodium chloride injection). The drug is a neuraminidase inhibitor, which works by preventing the virus from moving from an infected cell to infect other cells. Guangzhou Nanxin Pharma has been approved to produce the medicine, and it expects to begin distributing the drug in 30 days. Other China pharmas have also filed for approval to make the drug or conduct human clinical trials

Peramivir is an experimental antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. It has been authorized for the emergency use of treatment of certain hospitalized patients with known or suspected 2009 H1N1 influenza.[1]

Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.

The development of peramivir is supported by the US Department of Health and Human Services as part of the US government’s effort to prepare against the threat of an influenza pandemic.[2]

Peramivir is already available in Japan as RAPIACTA (R) and also available in South Korea as PERAMIFLU. Peramivir is currently the only intravenous option for treating swine flu. The drug is in Phase III studies in US.[3][4]

Use in treating Influenza A (H1N1) “Swine Flu”

In October 2009, it was reported that the experimental antiviral drug peramivir had been effective in treating serious cases of swine flu.[5] On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for Peramivir, allowing the use of the drug in intravenous form for hospitalized patients only in cases where the other available methods of treatment are ineffective or unavailable;[6] for instance, if oseltamivir (Tamiflu) resistance develops and a person is unable to take Relenza via the inhaled route. The Emergency Use Authorization expired on June 23, 2010.

Biocryst also donated 1200 courses of treatment to the US department of Health and Human Services.[7]

According to a research report published in June 2011, a novel variant of swine flu has emerged in Asia with a genetic adaptation giving some resistance to Roche’s (ROG.VX) Tamiflu and GlaxoSmithKline’s (GSK.L) Relenza, the two mainstay drugs used to tackle the disease. There was no significant reduction in sensitivity to Peramivir. [8]

Initial treatment courses are for 5 to 10 days duration. Treatment beyond 10 days is permitted depending on clinical presentation such as critical illness (e.g., respiratory failure or intensive care unit admission), continued viral shedding or unresolved clinical influenza illness.[9]

  1.  “Peramivir authorized for Emergency use”. LifeHugger. 2009-12-04. Retrieved 2009-12-04.
  2.  “HHS Pursues Advance Development of New Influenza Antiviral Drug” (Press release). USDepartment of Health and Human Services. 2007-01-04. Retrieved 2007-05-25.
  3.  “Evaluation of the Efficacy and Safety of Peramivir in Subjects With Uncomplicated Acute Influenza”.National Institutes of Health. 2007-03-16. Retrieved 2007-05-25.
  4.  “Evaluation of the Efficacy and Safety of Peramivir in Adults With Acute Serious or Potentially Life-Threatening Influenza”National Institutes of Health. 2007-03-28. Retrieved 2007-05-25.
  5.  “Life-Saving H1N1 Drug Unavailable to Most”CBS Evening News (Atlanta, GA, USA: CBS Interactive). 2009-10-19. Retrieved 2009-10-20.
  6.  “Emergency Use Authorization Granted For BioCryst’s Peramivir”Reuters. 2009-10-24.
  7.  “FDA Authorizes Emergency Use of Intravenous Antiviral Peramivir for 2009 H1N1 Influenza for Certain Patients, Settings”Reuters. 2009-10-24.
  8.  Hirschler, Ben (2011-06-10). “Swine flu starting to show resistance to drugs”Reuters.
  9.  “Peramivir: Dosage and Administration”. LifeHugger. 2009-12-04. Retrieved 2009-12-04.

TLC388 (Lipotecan®) Taiwan Liposome Company Hepatic cancer drug candidate gets fast track approval status from SFDA


TLC388 (Lipotecan®) structure can be figured out from a link below of a poster

http://www.tlcbio.com/files/news/2011111701580783.pdf

IT IS A CAMPOTHECIN ANALOGUE

The str can be concluded from above picture from a poster by TLC BIO

TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors.

Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients.

http://mct.aacrjournals.org/cgi/content/meeting_abstract/10/11_MeetingAbstracts/A89

http://clinicaltrials.gov/show/NCT00747474

MAR19 2013

China SFDA has granted fast track approval status to Taiwan Liposome company hepatic cancer drug  Lipotecan, shortening the review period. The drug will enter Phase 2 clinical trials  in China in the second half of this year. Lipotecan has been granted orphan drug status by US FDA and EU EMEA for the treatment of hepatocellular carcinoma (HCC)

Nexavar is the standard of care in first line advanced liver cancer patients. Lipotecan as a second-line treatment allows patients who have failed prior treatment with Nexavar to maintain a six month course of the disease without progressing

Lipotecan is a  second generation camptothecin drug emphasize on modification on E-ring with a group which not only stabilizes the active site but also functions as a strong radio-sensitizer to overcome radio- and chemo-resistance that is frequently encountered in clinical therapies, enabling Lipotecan® to tailor at unmet needs.

Pfizer Gains China Approval of Kinase-Specific Lung Cancer Drug, Xalkori (crizotinib)


File:Crizotinib structure.svg

Xalkori, crizotinib,
(PF-02341066)
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine

Crizotinib; 877399-52-5; Xalkori; PF-2341066; PF-02341066; (R)-crizotinib; 877399-52-5

Molecular Formula: C21H22Cl2FN5O
Molecular Weight: 450.336683 g/mol

Crizotinib an inhibitor of receptor tyrosine kinase for the treatment of non-small cell lung cancer (NSCLC). Verification of the presence of ALK fusion gene is done by Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit. This verification is used to select for patients suitable for treatment. FDA approved in August 26, 2011.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients

Feb 25, 2013

Pfizer has been granted China approval for Xalkori (crizotinib), an innovative treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive. The ALK-positive variation, which comprises between 3% and 5% of all NSCLC tumors, must be proved by a biomarker test. Pfizer said China’s approval came just eleven months after it submitted a new drug application to the SFDA for Xalkori

Crizotinib (trade name Xalkori,[1] Pfizer), is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.[2]

  1. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. U.S. Food and Drug Administration.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm
  2. ClinicalTrials.gov NCT00932451 An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene

Crizotinib the core structure is a substituted pyridine, the 3 – position of the ether as a chiral center adjacent, so with Mitsunobu reaction to complete, as is a typical Mitsunobu SN2 reaction, the reaction chiral center occurs in reverse, so easy to control, no racemization occurs. Pyridine substituted at position 5 by Suzuki reaction constructed.
Compound 1 The activation of the hydroxyl groups of methanesulfonyl chloride, and then with a 4 – iodopyrazole reaction 2 , 2 to 4 Suzuki reaction conversion can be used, but will generate a large quantity of the reaction product of their coupling, the first 2 converted to a Grignard reagent, and then with a boronic acid ester of 3 reaction 4 .

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http://www.specchemonline.com/articles/view/biocatalyst-breakthroughs#.VTcW9yxabEs

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http://www.google.com/patents/WO2014020467A2?cl=en

(R)-3-[l-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(l-piperidin-4-yl-lH-py- razol-4-yl)-pyridin-2-ylamine, also known as Crizotinib, is represented by the Formula (I):

Formula (I)

Crizotinib is a potent small-molecule inhibitor of c-Met/HGFR (hepatocyte growth factor receptor) kinase and ALK (anaplastic lymphoma kinase) activity. Enantiomerically pure compound of formula I was first disclosed in US Patent No. 7,858,643. Additionally, the racemate of compound of formula I was disclosed in U.S. patent application 2006/0128724, both of these references discloses similar methods for the synthesis of Compound of Formula I.

Conventionally, the compounds of formula I are prepared by reacting Bis(pinacolato)diboron with protected 5-bromo-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine in the presence of Pd catalyst. The obtained product after deprotection is reacted with N- protected 4-(4-bromo-pyrazol-l-yl)-piperidine in the presence of Pd Catalyst. The obtained product is filtered through celite pad and purified by Column Chromatography. The final product of formula I was obtained by deprotection of the purified compound by using HCl/dioxane. US Patent No. 7,858,643 provides enantiomerically pure aminoheteroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity. More particularly, US 7,858,643 describes process for the preparation of 3-[(lR)-l-(2,6- dichloro-3-fluorophenyl)ethoxy]-5-(l-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine. The Scheme is summarized below in Scheme- 1 :

Scheme-1

wherein, “Boc” means tert-butoxycarbonyl; and a) (Boc)2, DMF, Dimethylaminopyridine b) Pd(dppf)Cl2, KOAc, Dichloromethane; c) HC1, Dioxane, Dichloromethane; d) Pd(PPh3)2Cl2, Na2C03, DME/H20; e) 4M HCl/Dioxane, Dichloromethane

A similar process has been disclosed in the U.S. patent application 2006/0128724 for the preparation of Crizotinib. J. Jean Cui et. al. in J. Med. Chem. 2011, 54, 6342-6363, also provides a similar process for the preparation of Crizotinib and its derivatives.

However, above mentioned synthetic process requires stringent operational conditions such as filtration at several steps through celite pad. Also column chromatography is required at various steps which is not only tedious but also results in significant yield loss. Another disadvantage of above process involves extensive use of palladium catalysts, hence metal scavengers are required to remove palladium content from the desired product at various steps which makes this process inefficient for commercial scale.

Yet another disadvantage of above process is the cost of Bis(pinacolato)diboron. This reagent is used in excess in the reaction mixture resulting in considerable cost, especially during large-scale syntheses.

US Patent No. 7,825,137 also discloses a process for the preparation of Crizotinib where Boc protected 4-(4-iodo-pyrazol-l-yl)-piperidine is first reacted with Bis(pinacolato)diboron in the presence of Pd catalyst. The reaction mixture is filtered through a bed of celite and the obtained filtrate is concentrated and purified by silica gel chromatography to give to form tert-butyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l- carboxylate. To this compound, 5-bromo-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]- pyridin-2-ylamine is added in the presence of a Pd catalyst. The reaction mixture is stirred for 16h at 87°C. The reaction mixture is filtered through celite pad and the concentrated filtrate is purified on silica gel column to obtain (4-{6-amino-5-[(R)-l-(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-pyri- din-3-yl}-pyrazol-l-yl)-piperidine-l-carboxylic acid tert-butyl ester of 95% purity. To the solution of resulting compound in dichloromethane 4N HCl/Dioxane is added and thereby getting the reaction suspension is filtered in Buchner funnel lined with filter paper. The obtained solid is dissolved in HPLC water and pH is adjusted to 10 with the addition of Na2C03 Compound is extracted using dichloroform and is purified on a silica gel column by eluting with CH2Cl2 MeOH/NEt3 system to obtain Crizotinib. The scheme is summarized below in scheme 2:

Formula (i) Formula (ii)

Formula (iii) Formula (ii) ula (iv)

Formula (v) Formula (I)

Scheme-2

Preparation of Crizotinib:

To a stirred solution of Tert-butyl 4-(4-{ 6-amino-5-[(li?)-l-(2,6-dichloro-3- fluorophenyl)ethoxy]pyridin-3 -yl } – lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate (material obtained in Example 3) (l.Og, 0.00181 moles) in dichloromethane (-13 ml) at 0°C was added 4.0 M dioxane HQ (6.7 ml, 0.0272 moles). Reaction mixture was stirred at room temperature for 4h. After the completion of reaction monitored by TLC, solid was filtered and washed with dichloromethane (10 ml). The obtained solid was dissolved in water (20 ml); aqueous layer was extracted with dichloromethane (10×2). The pH of aqueous layer was adjusted to 9-10 with Na2C03 and compound was extracted with dichloromethane (10 x 3), combined organic layers were washed with water (20 ml), evaporated under vacuum to get solid product. The solid was stirred with ether (10 ml), filtered off, washed well with ether, dried under vacuum to get Crizotinib.

Yield: 0.45g (55 %)

HPLC Purity: 99.35 %

1HNMR (400 MHz, CDC13) δ: 7.76 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.30 (dd, J = 9.2 Hz), 7.0 (m, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.09 ( q, J= 6.8 Hz, 1H), 4.75 (brs, 1H), 4.19 (m, 1H), 3.25 (m, 2H), 2.76 (m, 2H), 2.16 (m, 2H), 1.92 (m, 2H), 1.85 (d, J= 6.8 Hz, 3H), 1.67 (brs, 1H)

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http://www.sciencedirect.com/science/article/pii/S0040403914000872

Abstract

A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4), the key intermediates required for the synthesis of Crizotinib.


Graphical abstract

Full-size image (16 K)
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http://www.sciencedirect.com/science/article/pii/S0040403911021745

Abstract

4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key intermediate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, followed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all required optimization to ensure successful scale-up.


Graphical abstract

Full-size image (6 K)

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Org. Process Res. Dev., 2011, 15 (5), pp 1018–1026
DOI: 10.1021/op200131n
Abstract Image

A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.

3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine 1

crizotinib1 (20.7 kg, 80%) as a white solid.

Mp 192 °C;

1H NMR (400 MHz, CDCl3) δ: 7.78 (d, J = 1.8 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.31 (dd, J = 9.0, 4.9 Hz, 1H), 7.06 (m, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.09 (q, 1H), 4.79 (br s, 2H), 4.21 (m, 1H), 3.26 (m, 2H), 2.78 (m, 2H), 2.17 (m, 2H), 1.90 (m, 2H), 1.87 (d, J = 6.7 Hz, 3H), 1.63 (br s, 1H).

13C NMR (100.6 MHz, CDCl3) δ: 157.5 (d, J = 250.7 Hz), 148.9, 139.8, 137.0, 135.7, 135.6, 129.9, 129.0 (d, J = 3.7 Hz), 122.4, 122.1 (d, J = 19.0 Hz), 119.9, 119.3, 116.7 (d, J = 23.3 Hz), 115.0, 72.4, 59.9, 45.7, 34.0, 18.9.

LC-MS: found m/z 450.0, 451.0, 452.0, 453.0, 454.0, 455.0.

Anal. Calcd for C21H22Cl2FN5O: C, 56.01; H, 4.92; N, 15.55. Found: C, 56.08; H, 4.94; N, 15.80.

Cui, J. J.; Botrous, I.; Shen, H.; Tran-Dube, M. B.; Nambu, M. D.; Kung, P.-P.; Funk, L. A.; Jia, L.; Meng, J. J.; Pairish, M. A.; McTigue, M.; Grodsky, N.; Ryan, K.; Alton, G.; Yamazaki, S.; Zou, H.; Christensen, J. G.; Mroczkowski, B.Abstracts of Papers; 235th ACS National Meeting, New Orleans, LA, United States, April 6–10, 2008.

Cui, J. J.; Funk, L. A.; Jia, L.; Kung, P.-P.; Meng, J. J.; Nambu, M. D.; Pairish, M. A.; Shen, H.; Tran-Dube, M. B. U.S. Pat. Appl. U. S. 2006/0046991 A1, 2006.
WO2010048131A1 * Oct 20, 2009 Apr 29, 2010 Vertex Pharmaceuticals Incorporated C-met protein kinase inhibitors
WO2011042389A2 * Oct 4, 2010 Apr 14, 2011 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles
US7825137 Nov 23, 2006 Nov 2, 2010 Pfizer Inc. Method of treating abnormal cell growth
US7858643 Aug 26, 2005 Dec 28, 2010 Agouron Pharmaceuticals, Inc. Crizotinib, a c-Met protein kinase inhibitor anticancer agent; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine is crizotinib
US20060128724 Aug 26, 2005 Jun 15, 2006 Agouron Pharmaceuticals, Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
1 J. JEAN CUI J. MED. CHEM. vol. 54, 2011, pages 6342 – 6363
2 ORG. PROCESS RES. DEV. vol. 15, 2011, pages 1018 – 1026
3 * PIETER D. DE KONING ET AL: “Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066)“, ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15, no. 5, 16 September 2011 (2011-09-16), pages 1018-1026, XP055078841, ISSN: 1083-6160, DOI: 10.1021/op200131n

State Food and Drug Administration, China Grants Approval to Sihuan Pharmaceutical for Clinical Trial of Innovative Drug — Pinoxacin Hydrochloride


HONG KONG, Feb. 22, 2013, Sihuan Pharmaceutical Holdings Group Ltd. a leading pharmaceutical company with the largest cardio-cerebral vascular (“CCV”) drug franchise in China’s prescription market, today announced that Pinoxacin Hydrochloride, a Category 1.1 new drug developed by the Company’s innovative drug research and development team, received Approval for Clinical Studies from the State Food and Drug Administration. Phase I of clinical studies are set to begin in the first half of this year. It is the fourth Category 1 innovative drug for which the Company has received Approval for Clinical Studies.

Pinoxacin Hydrochloride is DPP-4 inhibitor class of oral hypoglycemic agents, a drug with a brand new structure for treating type II diabetes. It is clinically used to enhance the function of endogenous insulin for improving glycemic control, and long-term use can improve islet beta-cells function. Pre-clinical research has shown that DPP-4 inhibitors have potent in vitro and in vivo activities, a good selection profile, great stability and controllable quality, as well as better tolerance, with long-term administration showing a protective effect on pancreatic beta-cells. In addition, the DPP-4 inhibitor will not cause serious side effects such as weight gain and hypoglycaemia seen in traditional diabetes drugs. Pinoxacin Hydrochloride has good pharmacokinetic characteristics, high oral bioavailability, quick absorption, rapid onset and a longer duration. A once daily dosage is expected to keep the patients’ symptoms under control. The advantages of Pinoxacin Hydrochloride have proven the drug’s growth potential present in the market.

Celgene gains SFDA China, approval for marketing Revlimid (lenalidomide) to treat multiple myeloma


File:Lenalidomide.png

(RS)-3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol- 2-yl)piperidine-2,6-dione

Lenalidomide

sun, feb17, 2013
Celgene Corporation was granted approval for Revlimid ® (lenalidomide) by the SFDA to treat multiple myeloma. The approval, which is the first for Celgene in China, includes an Import Drug License. Revlimid is indicated for use in combination with dexamethasone in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
REVLIMID® is an oral immunomodulatory drug marketed in the United States and many international markets, in combination with dexamethasone, for treatment of patients with multiple myeloma who have received at least one prior therapy. It is also marketed in the United States and certain international markets for the treatment of transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes, or MDS, associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalitie.Revlimid Worldwide annual sales in 2011 was $3.2bLenalidomide (Revlimid) is a derivative of thalidomideintroduced in 2004.It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Lenalidomide has significantly improved overall survival in myeloma (which generally carries a poor prognosis), although toxicity remains an issue for users. [1]It costs $163,381 per year for the average patient.[2]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past 10 years. There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[3] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of the microenvironment support for tumor cells, and immunomodulatory role. In vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

  1. McCarthy; Philip L. McCarthy, Kouros Owzar, Craig C. Hofmeister, et al. (May 10, 2012). “Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma”N Engl J Med 366 (19): 1770–1781. doi:10.1056/NEJMoa1114083PMID 22571201.
  2. Badros, Ashraf Z. Badros (May 10, 2012). “Lenalidomide in Myeloma — A High-Maintenance Friend”N Engl J Med 366 (19): 1836–1838. doi:10.1056/NEJMe1202819PMID 22571206.
  3. Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma 49 (7): 1238–45. doi:10.1080/10428190802005191PMID 18452080.
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