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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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Tixagevimab


(Heavy chain)
QMQLVQSGPE VKKPGTSVKV SCKASGFTFM SSAVQWVRQA RGQRLEWIGW IVIGSGNTNY
AQKFQERVTI TRDMSTSTAY MELSSLRSED TAVYYCAAPY CSSISCNDGF DIWGQGTMVT
VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL
QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSCDKTH TCPPCPAPEF
EGGPSVFLFP PKPKDTLYIT REPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE
QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPASIEK TISKAKGQPR EPQVYTLPPS
REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK
SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK
(Light chain)
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP
DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ HYGSSRGWTF GQGTKVEIKR TVAAPSVFIF
PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST
LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC
(Disulfide bridge: H22-H96, H101-H106, H150-H206, H216-L216, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’101-H’106, H’150-H’206, H’226-L’216, H’267-H’327, H’373-H’431, L23-L89, L136-L196, L’23-L’89, L’136-L’196)

Tixagevimab

FDA 2021, 2021/12/8

ANTI VIRAL, CORONA VIRUS, PEPTIDE

Monoclonal antibody
Treatment and prevention of SARS-CoV-2 infection

FormulaC6488H10034N1746O2038S50
CAS2420564-02-7
Mol weight146704.817
  • 2196
  • AZD-8895
  • AZD8895
  • COV2-2196
  • Tixagevimab
  • Tixagevimab [INN]
  • UNII-F0LZ415Z3B
  • WHO 11776
  • OriginatorVanderbilt University
  • DeveloperAstraZeneca; INSERM; National Institute of Allergy and Infectious Diseases
  • ClassAntivirals; Monoclonal antibodies
  • Mechanism of ActionVirus internalisation inhibitors
  • RegisteredCOVID 2019 infections
  • 24 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
  • 16 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
  • 10 Dec 2021Registered for COVID-2019 infections (In the elderly, Prevention, In adults) in USA (IM) – Emergency Use Authorization

Tixagevimab/cilgavimab is a combination of two human monoclonal antibodiestixagevimab (AZD8895) and cilgavimab (AZD1061) targeted against the surface spike protein of SARS-CoV-2[4][5] used to prevent COVID-19. It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca.[6][7] It is co-packaged and given as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession).[2]

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Development

In 2020, researchers at Vanderbilt University Medical Center discovered particularly potent monoclonal antibodies, isolated from COVID-19 patients infected with a SARS-CoV-2 circulating at that time. Initially designated COV2-2196 and COV2-2130, antibody engineering was used to transfer their SARS-CoV-2 binding specificity to IgG scaffolds that would last longer in the body, and these engineered antibodies were named AZD8895 and AZD1061, respectively (and the combination was called AZD7442).[8]

To evaluate the antibodies’ potential as monoclonal antibody based prophylaxis (prevention), the ‘Provent’ clinical trial enrolled 5,000 high risk but not yet infected individuals and monitored them for 15 months.[9][10] The trial reported that those receiving the cocktail showed a 77% reduction in symptomatic COVID-19 and that there were no severe cases or deaths. AstraZeneca also found that the antibody cocktail “neutralizes recent emergent SARS-CoV-2 viral variants, including the Delta variant“.[7]

In contrast to pre-exposure prophylaxis, the Storm Chaser study of already-exposed people (post-exposure prophylaxis) did not meet its primary endpoint, which was prevention of symptomatic COVID-19 in people already exposed. AZD7442 was administered to 1,000 volunteers who had recently been exposed to COVID.[9]

Regulatory review

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of tixagevimab/cilgavimab, which is being developed by AstraZeneca AB, for the prevention of COVID-19 in adults.[11]

Also in October 2021, AstraZeneca requested Emergency Use Authorization for tixagevimab/cilgavimab to prevent COVID-19 from the U.S. Food and Drug Administration (FDA).[12][13]

Emergency use authorization

On 14 November 2021, Bahrain granted emergency use authorization.[14]

On 8 December 2021, the U.S. Food and Drug Administration (FDA) granted emergency use authorization of this combination to prevent COVID-19 (before exposure) in people with weakened immunity or who cannot be fully vaccinated due to a history of severe reaction to coronavirus vaccines.[15] The FDA issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain people aged 12 years of age and older weighing at least 40 kilograms (88 lb).[2] The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2.[2]

References

  1. ^ “Evusheld- azd7442 kit”DailyMed. Retrieved 4 January 2022.
  2. Jump up to:a b c d “Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals”U.S. Food and Drug Administration (FDA) (Press release). 8 December 2021. Retrieved 9 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ O’Shaughnessy, Jacqueline A. (20 December 2021). “Re: Emergency Use Authorization 104” (PDF). Food and Drug Administration. Letter to AstraZeneca Pharmaceuticals LP | Attention: Stacey Cromer Berman, PhD. Archived from the original on 29 December 2021. Retrieved 18 January 2022.
  4. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  5. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  6. ^ Ray, Siladitya (21 August 2021). “AstraZeneca’s Covid-19 Antibody Therapy Effective In Preventing Symptoms Among High-Risk Groups, Trial Finds”ForbesISSN 0015-6914Archived from the original on 21 August 2021. Retrieved 18 January 2022.
  7. Jump up to:a b Goriainoff, Anthony O. (20 August 2021). “AstraZeneca Says AZD7442 Antibody Phase 3 Trial Met Primary Endpoint in Preventing Covid-19”MarketWatchArchived from the original on 21 August 2021. Retrieved 18 January 2022.
  8. ^ Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, et al. (October 2021). “Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail”. Nature Microbiology6 (10): 1233–1244. doi:10.1038/s41564-021-00972-2ISSN 2058-5276PMC 8543371. PMID 34548634.
  9. Jump up to:a b Haridy, Rich (23 August 2021). “”Game-changing” antibody cocktail prevents COVID-19 in the chronically ill”New Atlas. Retrieved 23 August 2021.
  10. ^ “AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19”AstraZeneca (Press release). 20 August 2021. Retrieved 15 October 2021.
  11. ^ “EMA starts rolling review of Evusheld (tixagevimab and cilgavimab)”European Medicines Agency. 14 October 2021. Retrieved 15 October 2021.
  12. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”AstraZeneca US (Press release). 5 October 2021. Retrieved 15 October 2021.
  13. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”AstraZeneca (Press release). 5 October 2021. Retrieved 15 October 2021.
  14. ^ Abd-Alaziz, Moaz; Elhamy, Ahmad (14 November 2021). Macfie, Nick (ed.). “Bahrain authorizes AstraZeneca’s anti-COVID drug for emergency use”ReutersArchived from the original on 23 November 2021. Retrieved 18 January 2022.
  15. ^ Mishra, Manas; Satija, Bhanvi (8 December 2021). Dasgupta, Shounak (ed.). “U.S. FDA authorizes use of AstraZeneca COVID-19 antibody cocktail”ReutersArchived from the original on 13 January 2022. Retrieved 18 January 2022.

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

  • “Cilgavimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT04625972 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-exposure Prophylaxis of COVID-19 in Adults (STORM CHASER)” at ClinicalTrials.gov
  • Clinical trial number NCT04625725 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult. (PROVENT)” at ClinicalTrials.gov
Tixagevimab (teal, right) and cilgavimab (purple, left) binding the spike protein RBD. From PDB7L7E.
Combination of
TixagevimabMonoclonal antibody
CilgavimabMonoclonal antibody
Clinical data
Trade namesEvusheld
Other namesAZD7442
License dataUS DailyMedTixagevimab
Routes of
administration
Intramuscular
ATC codeJ06BD03 (WHO)
Legal status
Legal statusUS: ℞-only via emergency use authorization[1][2][3]
Identifiers
KEGGD12262
Clinical data
Drug classAntiviral
ATC codeNone
Identifiers
CAS Number2420564-02-7
DrugBankDB16394
UNIIF0LZ415Z3B
KEGGD11993
Chemical and physical data
FormulaC6488H10034N1746O2038S50
Molar mass146706.82 g·mol−1
Clinical data
Drug classAntiviral
ATC codeNone
Identifiers
CAS Number2420563-99-9
DrugBankDB16393
UNII1KUR4BN70F
KEGGD11994
Chemical and physical data
FormulaC6626H10218N1750O2078S44
Molar mass149053.44 g·mol−1

/////////////////Tixagevimab, ANTI VIRAL, CORONA VIRUS, PEPTIDE, Monoclonal antibody,  SARS-CoV-2 , WHO 11776, 2196, AZD-8895, AZD 8895, COV2-2196, COVID 19

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Regdanvimab


Best Monoclonal Antibodies GIFs | Gfycat
Celltrion plans to expand the supply of its Covid-19 antibody drug, Regkirona (ingredient: regdanvimab), to more medical facilities treating early-stage patients.
(Heavy chain)
QITLKESGPT LVKPTQTLTL TCSFSGFSLS TSGVGVGWIR QPPGKALEWL ALIDWDDNKY
HTTSLKTRLT ISKDTSKNQV VLTMTNMDPV DTATYYCARI PGFLRYRNRY YYYGMDVWGQ
GTTVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT
FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT
KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK
LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK
(Light chain)
ELVLTQPPSV SAAPGQKVTI SCSGSSSNIG NNYVSWYQQL PGTAPKLLIY DNNKRPSGIP
DRFSGSKSGT SATLGITGLQ TGDEADYYCG TWDSSLSAGV FGGGTELTVL GQPKAAPSVT
LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK AGVETTKPSK QSNNKYAASS
YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS
(Disulfide bridge: H22-H97, H155-H211, H231-L215, H237-H’237, H240-H’240, H272-H332, H378-H436, H’22-H’97, H’155-H’211, H’231-L’215, H’272-H’332, H’378-H’436, L22-L89, L138-L197, L’22-L’89, L’138-L’197)
>Regdanvimab light chain:
ELVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIP
DRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAGVFGGGTELTVLGQPKAAPSVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS
YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
>Regdanvimab heavy chain:
QITLKESGPTLVKPTQTLTLTCSFSGFSLSTSGVGVGWIRQPPGKALEWLALIDWDDNKY
HTTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIPGFLRYRNRYYYYGMDVWGQ
GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT
FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT
KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK
LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Regdanvimab

レグダンビマブ;

EMA APPROVED, 2021/11/12, Regkirona

Treatment of adults with coronavirus disease 2019 (COVID-19)

MONOCLONAL ANTIBODY, ANTI VIRAL, PEPTIDE

CAS: 2444308-95-4, CT-P59

Regdanvimab, sold under the brand name Regkirona, is a human monoclonal antibody used for the treatment of COVID-19.[1] The antibody is directed against the spike protein of SARS-CoV-2. It is developed by Celltrion.[2][3] The medicine is given by infusion (drip) into a vein.[1][4]

The most common side effects include infusion-related reactions, including allergic reactions and anaphylaxis.[1]

Regdanvimab was approved for medical use in the European Union in November 2021.[1]

Regdanvimab is a monoclonal antibody targeted against the SARS-CoV-2 spike protein used to treat patients with COVID-19 who are at risk of progressing to severe COVID-19.

Regdanvimab (CT-P59) is a recombinant human IgG1 monoclonal antibody directed at the receptor binding domain (RBD) of the SARS-CoV-2 spike protein.4 It blocks the interaction between viral spike proteins and angiotensin-converting enzyme 2 (ACE2) that allows for viral entry into the cell, thereby inhibiting the virus’ ability to replicate. Trials investigating the use of regdanvimab as a therapeutic candidate for the treatment of COVID-19 began in mid-2020.1,3 It received its first full approval in South Korea in September 2021,3 followed by the EU in November 2021.5

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Synthesis Reference

Kim C, Ryu DK, Lee J, Kim YI, Seo JM, Kim YG, Jeong JH, Kim M, Kim JI, Kim P, Bae JS, Shim EY, Lee MS, Kim MS, Noh H, Park GS, Park JS, Son D, An Y, Lee JN, Kwon KS, Lee JY, Lee H, Yang JS, Kim KC, Kim SS, Woo HM, Kim JW, Park MS, Yu KM, Kim SM, Kim EH, Park SJ, Jeong ST, Yu CH, Song Y, Gu SH, Oh H, Koo BS, Hong JJ, Ryu CM, Park WB, Oh MD, Choi YK, Lee SY: A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat Commun. 2021 Jan 12;12(1):288. doi: 10.1038/s41467-020-20602-5.

Celltrion’s Monoclonal Antibody Treatment regdanvimab, Approved by the European Commission for the Treatment of COVID-19

https://www.businesswire.com/news/home/20211114005312/en/Celltrion%E2%80%99s-Monoclonal-Antibody-Treatment-regdanvimab-Approved-by-the-European-Commission-for-the-Treatment-of-COVID-19

  • The European Commission (EC) granted marketing authorisation for Celltrion’s regdanvimab following positive opinion by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) last week (11/11/2021)
  • Celltrion continues to discuss supply agreements with regulatory agencies and contractors in more than 30 countries in Europe, Asia and LATAM to accelerate global access to regdanvimab
  • The use of regdanvimab across the Republic of Korea is rapidly increasing to address the ongoing outbreaks

November 14, 2021 08:04 PM Eastern Standard Time

INCHEON, South Korea–(BUSINESS WIRE)–Celltrion Group announced today that the European Commission (EC) has approved Regkirona (regdanvimab, CT-P59), one of the first monoclonal antibody treatments granted marketing authorisation from the European Medicines Agency (EMA). The EC granted marketing authorisation for adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19. The decision from the EC follows a positive opinion by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on November 11th, 2021.1

“Today’s achievement, coupled with CHMP positive opinion for regdanvimab, underscores our ongoing commitment to addressing the world’s greatest health challenges,” said Dr. HoUng Kim, Ph.D., Head of Medical and Marketing Division at Celltrion Healthcare. “Typically, the recommendations from the CHMP are passed on to the EC for rapid legally binding decisions within a month or two, however, given the unprecedented times, we have received the EC approval within a day. As part of our global efforts to accelerate access, we have been communicating with the governments and contractors in 30 countries in Europe, Asia and LATAM. We will continue working with all key stakeholders to ensure COVID-19 patients around the world have access to safe and effective treatments.”

Monoclonal antibodies are proteins designed to attach to a specific target, in this case the spike protein of SARS-CoV-2, which works to block the path the virus uses to enter human cells. The EC approval is based on the global Phase III clinical trial involving more than 1,315 people to evaluate the efficacy and safety of regdanvimab in 13 countries including the U.S., Spain, and Romania. Data showed regdanvimab significantly reduced the risk of COVID-19 related hospitalisation or death by 72% for patients at high-risk of progressing to severe COVID-19.

Emergency use authorisations are currently in place in Indonesia and Brazil, and the monoclonal antibody treatment is fully approved in the Republic of Korea. In the U.S., regdanvimab has not yet been approved by the Food and Drug Administration (FDA), but the company is in discussion with the FDA to submit applications for an Emergency Use Authorisation (EUA).

As of November 12th, 2021, more than 22,587 people have been treated with regdanvimab in 129 hospitals in the Republic of Korea.

Notes to Editors:

About Celltrion Healthcare

Celltrion Healthcare is committed to delivering innovative and affordable medications to promote patients’ access to advanced therapies. Its products are manufactured at state-of-the-art mammalian cell culture facilities, designed and built to comply with the US FDA cGMP and the EU GMP guidelines. Celltrion Healthcare endeavours to offer high-quality cost-effective solutions through an extensive global network that spans more than 110 different countries. For more information please visit: https://www.celltrionhealthcare.com/en-us.

About regdanvimab (CT-P59)

CT-P59 was identified as a potential treatment for COVID-19 through screening of antibody candidates and selecting those that showed the highest potency in neutralising the SARS-CoV-2 virus. In vitro and in vivo pre- clinical studies showed that CT-P59 strongly binds to SARS-CoV-2 RBD and significantly neutralise the wild type and mutant variants of concern. In in vivo models, CT-P59 effectively reduced the viral load of SARS-CoV-2 and inflammation in lung. Results from the global Phase I and Phase II/III clinical trials of CT-P59 demonstrated a promising safety, tolerability, antiviral effect and efficacy profile in patients with mild-to-moderate symptoms of COVID-19.2 Celltrion also has recently commenced the development of a neutralising antibody cocktail with CT-P59 against new emerging variants of SARS-CoV-2.

Medical uses

In the European Union, regdanvimab is indicated for the treatment of adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19.[1]

Society and culture

Names

Regdanvimab is the proposed international nonproprietary name (pINN).[5]

In March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on regdanvimab.[6][7] In October 2021, the EMA started evaluating an application for marketing authorization for the monoclonal antibody regdanvimab (Regkirona) to treat adults with COVID-19 who do not require supplemental oxygen therapy and who are at increased risk of progressing to severe COVID 19.[8] The applicant is Celltrion Healthcare Hungary Kft.[8] The European Medicines Agency (EMA) concluded that regdanvimab can be used for the treatment of confirmed COVID-19 in adults who do not require supplemental oxygen therapy and who are at high risk of progressing to severe COVID-19.[4]

In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting a marketing authorization in the European Union for regdanvimab (Regkirona) for the treatment of COVID-19.[9][10] The company that applied for authorization of Regkirona is Celltrion Healthcare Hungary Kft.[10] Regdanvimab was approved for medical use in the European Union in November 2021.[1]

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetSpike protein of SARS-CoV-2
Clinical data
Trade namesRegkirona
Other namesCT-P59
License dataEU EMAby INN
Routes of
administration
Intravenous infusion
ATC codeNone
Legal status
Legal statusEU: Rx-only [1]
Identifiers
CAS Number2444308-95-4
DrugBankDB16405
UNIII0BGE6P6I6
KEGGD12241
  1. Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, Maggi F, Focosi D: Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. MAbs. 2020 Jan-Dec;12(1):1854149. doi: 10.1080/19420862.2020.1854149. [Article]
  2. Kim C, Ryu DK, Lee J, Kim YI, Seo JM, Kim YG, Jeong JH, Kim M, Kim JI, Kim P, Bae JS, Shim EY, Lee MS, Kim MS, Noh H, Park GS, Park JS, Son D, An Y, Lee JN, Kwon KS, Lee JY, Lee H, Yang JS, Kim KC, Kim SS, Woo HM, Kim JW, Park MS, Yu KM, Kim SM, Kim EH, Park SJ, Jeong ST, Yu CH, Song Y, Gu SH, Oh H, Koo BS, Hong JJ, Ryu CM, Park WB, Oh MD, Choi YK, Lee SY: A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat Commun. 2021 Jan 12;12(1):288. doi: 10.1038/s41467-020-20602-5. [Article]
  3. Syed YY: Regdanvimab: First Approval. Drugs. 2021 Nov 1. pii: 10.1007/s40265-021-01626-7. doi: 10.1007/s40265-021-01626-7. [Article]
  4. EMA Summary of Product Characteristics: Regkirona (regdanvimab) concentrate for solution for intravenous infusion [Link]
  5. EMA COVID-19 News: EMA recommends authorisation of two monoclonal antibody medicines [Link]
  6. EMA CHMP Assessment Report: Celltrion use of regdanvimab for the treatment of COVID-19 [Link]
  7. Protein Data Bank: Crystal Structure of COVID-19 virus spike receptor-binding domain complexed with a neutralizing antibody CT-P59 [Link]

References

  1. Jump up to:a b c d e f g “Regkirona EPAR”European Medicines Agency. Retrieved 12 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ^ “Celltrion Develops Tailored Neutralising Antibody Cocktail Treatment with CT-P59 to Tackle COVID-19 Variant Spread Using Its Antibody Development Platform” (Press release). Celltrion. 11 February 2021. Retrieved 4 March 2021 – via Business Wire.
  3. ^ “Celltrion Group announces positive top-line efficacy and safety data from global Phase II/III clinical trial of COVID-19 treatment candidate CT-P59” (Press release). Celltrion. 13 January 2021. Retrieved 4 March 2021 – via Business Wire.
  4. Jump up to:a b “EMA issues advice on use of regdanvimab for treating COVID-19”European Medicines Agency. 26 March 2021. Retrieved 15 October 2021.
  5. ^ World Health Organization (2020). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 124 – COVID-19 (special edition)” (PDF). WHO Drug Information34 (3): 660–1.
  6. ^ “EMA starts rolling review of Celltrion antibody regdanvimab for COVID-19” (Press release). European Medicines Agency (EMA). 24 February 2021. Retrieved 4 March 2021.
  7. ^ “EMA review of regdanvimab for COVID-19 to support national decisions on early use” (Press release). European Medicines Agency (EMA). 2 March 2021. Retrieved 4 March 2021.
  8. Jump up to:a b “EMA receives application for marketing authorisation Regkirona (regdanvimab) treating patients with COVID-19”European Medicines Agency. 4 October 2021. Retrieved 15 October 2021.
  9. ^ “Regkirona: Pending EC decision”European Medicines Agency. 11 November 2021. Retrieved 11 November 2021.
  10. Jump up to:a b “COVID-19: EMA recommends authorisation of two monoclonal antibody medicines”European Medicines Agency (EMA) (Press release). 11 November 2021. Retrieved 11 November 2021.

Further reading

///////////Regdanvimab, Regkirona, MONOCLONAL ANTIBODY, ANTI VIRAL, EU 2021, APPROVALS 2021, EMA 2021, COVID 19, CORONAVIRUS, PEPTIDE, レグダンビマブ , CT-P59, CT P59

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Ropeginterferon alfa-2b


PCDLPQTHSL GSRRTLMLLA QMRRISLFSC LKDRHDFGFP QEEFGNQFQK AETIPVLHEM
IQQIFNLFST KDSSAAWDET LLDKFYTELY QQLNDLEACV IQGVGVTETP LMKEDSILAV
RKYFQRITLY LKEKKYSPCA WEVVRAEIMR SFSLSTNLQE SLRSKE
(Disulfide bridge: 2-99, 30-139)

Ropeginterferon alfa-2b

  • AOP2014

CAS 1335098-50-4

UNII981TME683S

FDA APPROVED, 2021/11/12, BESREMI

PEPTIDE, Antineoplastic, Antiviral

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia.1,2 Interferon alfa-2b has been used for decades to treat PV but requires frequent dosing and is not tolerated by all patients.2 Ropeginterferon alfa-2b is a next-generation mono-pegylated type I interferon produced from proline-IFN-α-2b in Escherichia coli that has high tolerability and a long half-life.4,6 Ropeginterferon alfa-2b has shown efficacy in PV in in vitro and in vivo models and clinical trials.3,4

Ropeginterferon alfa-2b was approved by the FDA on November 12, 2021, and is currently marketed under the trademark BESREMi by PharmaEssentia Corporation.6

Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera.[1][2][3][4] It is an interferon.[1][3] It is given by injection.[1][3]

The most common side effects include low levels of white blood cells and platelets (blood components that help the blood to clot), muscle and joint pain, tiredness, flu-like symptoms and increased blood levels of gamma-glutamyl transferase (a sign of liver problems).[3] Ropeginterferon alfa-2b can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness.[2] Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).[2]

It was approved for medical use in the European Union in February 2019,[3] and in the United States in November 2021.[2][5] Ropeginterferon alfa-2b is the first medication approved by the U.S. Food and Drug Administration (FDA) to treat polycythemia vera that people can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.[2]

https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-rare-blood-disease#:~:text=FDA%20NEWS%20RELEASE-,FDA%20Approves%20Treatment%20for%20Rare%20Blood%20Disease,FDA%2DApproved%20Option%20Patients%20Can%20Take%20Regardless%20of%20Previous%20Therapies,-ShareFor Immediate Release:November 12, 2021

Today, the U.S. Food and Drug Administration approved Besremi (ropeginterferon alfa-2b-njft) injection to treat adults with polycythemia vera, a blood disease that causes the overproduction of red blood cells. The excess cells thicken the blood, slowing blood flow and increasing the chance of blood clots.

“Over 7,000 rare diseases affect more than 30 million people in the United States. Polycythemia vera affects approximately 6,200 Americans each year,” said Ann Farrell, M.D., director of the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research. “This action highlights the FDA’s commitment to helping make new treatments available to patients with rare diseases.”

Besremi is the first FDA-approved medication for polycythemia vera that patients can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.

Treatment for polycythemia vera includes phlebotomies (a procedure that removes excess blood cells though a needle in a vein) as well as medicines to reduce the number of blood cells; Besremi is one of these medicines. Besremi is believed to work by attaching to certain receptors in the body, setting off a chain reaction that makes the bone marrow reduce blood cell production. Besremi is a long-acting drug that patients take by injection under the skin once every two weeks. If Besremi can reduce excess blood cells and maintain normal levels for at least one year, then dosing frequency may be reduced to once every four weeks.

The effectiveness and safety of Besremi were evaluated in a multicenter, single-arm trial that lasted 7.5 years. In this trial, 51 adults with polycythemia vera received Besremi for an average of about five years. Besremi’s effectiveness was assessed by looking at how many patients achieved complete hematological response, which meant that patients had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots. Overall, 61% of patients had a complete hematological response.

Besremi can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness. Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).

Interferon alfa products like Besremi may cause or worsen neuropsychiatric, autoimmune, ischemic (not enough blood flow to a part of the body) and infectious diseases, which could lead to life-threatening or fatal complications. Patients who must not take Besremi include those who are allergic to the drug, those with a severe psychiatric disorder or a history of a severe psychiatric disorder, immunosuppressed transplant recipients, certain patients with autoimmune disease or a history of autoimmune disease, and patients with liver disease.

People who could be pregnant should be tested for pregnancy before using Besremi due to the risk of fetal harm.

Besremi received orphan drug designation for this indication. Orphan drug designation provides incentives to assist and encourage drug development for rare diseases.

The FDA granted the approval of Besremi to PharmaEssentia Corporation.

Medical uses

In the European Union, ropeginterferon alfa-2b is indicated as monotherapy in adults for the treatment of polycythemia vera without symptomatic splenomegaly.[3] In the United States it is indicated for the treatment of polycythemia vera.[1][2][5]

History

The effectiveness and safety of ropeginterferon alfa-2b were evaluated in a multicenter, single-arm trial that lasted 7.5 years.[2] In this trial, 51 adults with polycythemia vera received ropeginterferon alfa-2b for an average of about five years.[2] The effectiveness of ropeginterferon alfa-2b was assessed by looking at how many participants achieved complete hematological response, which meant that participants had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots.[2] Overall, 61% of participants had a complete hematological response.[2] The U.S. Food and Drug Administration (FDA) granted the application for Ropeginterferon_alfa-2b orphan drug designation and granted the approval of Besremi to PharmaEssentia Corporation[2]

REF

  1. Bartalucci N, Guglielmelli P, Vannucchi AM: Polycythemia vera: the current status of preclinical models and therapeutic targets. Expert Opin Ther Targets. 2020 Jul;24(7):615-628. doi: 10.1080/14728222.2020.1762176. Epub 2020 May 18. [Article]
  2. How J, Hobbs G: Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020 Jul 18;12(7). pii: cancers12071954. doi: 10.3390/cancers12071954. [Article]
  3. Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0. [Article]
  4. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, Wolf D, Kralovics R, Gisslinger B, Strecker K, Egle A, Melchardt T, Burgstaller S, Willenbacher E, Schalling M, Them NC, Kadlecova P, Klade C, Greil R: Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015 Oct 8;126(15):1762-9. doi: 10.1182/blood-2015-04-637280. Epub 2015 Aug 10. [Article]
  5. EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]
  6. FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]
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References

  1. Jump up to:a b c d e https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761166s000lbl.pdf
  2. Jump up to:a b c d e f g h i j k l “FDA Approves Treatment for Rare Blood Disease”U.S. Food and Drug Administration (FDA) (Press release). 12 November 2021. Retrieved 12 November 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e f g “Besremi EPAR”European Medicines Agency (EMA). Retrieved 14 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^ Wagner SM, Melchardt T, Greil R (March 2020). “Ropeginterferon alfa-2b for the treatment of patients with polycythemia vera”. Drugs of Today. Barcelona, Spain. 56 (3): 195–202. doi:10.1358/dot.2020.56.3.3107706PMID 32282866S2CID 215758794.
  5. Jump up to:a b “U.S. FDA Approves Besremi (ropeginterferon alfa-2b-njft) as the Only Interferon for Adults With Polycythemia Vera” (Press release). PharmaEssentia. 12 November 2021. Retrieved 14 November 2021 – via Business Wire.
Clinical data
Trade namesBesremi
Other namesAOP2014, ropeginterferon alfa-2b-njft
License dataEU EMAby INNUS DailyMedRopeginterferon_alfa
Pregnancy
category
Contraindicated
Routes of
administration
Subcutaneous
Drug classInterferon
ATC codeL03AB15 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]EU: Rx-only [3]
Identifiers
CAS Number1335098-50-4
DrugBankDB15119
UNII981TME683S
KEGGD11027

/////////Ropeginterferon alfa-2b, FDA 2021, APPROVALS 2021,  BESREMI, PEPTIDE, Antineoplastic, Antiviral, AOP 2014, PharmaEssentia

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RITONAVIR


Ritonavir structure.svg
ChemSpider 2D Image | Ritonavir | C37H48N6O5S2
Ritonavir

RITONAVIR

  • Molecular FormulaC37H48N6O5S2
  • Average mass720.944 Da

1,3-Thiazol-5-ylmethyl-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-({(2S)-3-methyl-2-[(methyl{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]butanoyl}amino)-5-phenylpentyl]carbamat

155213-67-5[RN]

7449Abbott 84538

UNII-O3J8G9O825

ритонавир

ريتونافير

利托那韦

(1E,2S)-N-[(2S,4S,5S)-4-Hydroxy-5-{(E)-[hydroxy(1,3-thiazol-5-ylmethoxy)methylene]amino}-1,6-diphenyl-2-hexanyl]-2-[(E)-(hydroxy{[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino}methylene)amino]-3- methylbutanimidic acid


(2S,3S,5S)-5-[N-[N-[[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]amino]carbonyl]valinyl]amino]-2-[N-[(5-thiazolyl)methoxycarbonyl]amino]-1,6-diphenyl-3-hydroxyhexane

  • A-84538
  • Abbott 84538
  • ABBOTT-84538
  • ABT 538
  • ABT-538
  • DRG-0244
  • NSC-693184
  • TMC 114r

Ritonavir

CAS Registry Number: 155213-67-5 
CAS Name: (5S,8S,10S,11S)-10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester 
Additional Names: (2S,3S,5S)-5-[N-[N-[[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]amino]carbonyl]valinyl]amino]-2-[N-[(5-thiazolyl)methoxycarbonyl]amino]-1,6-diphenyl-3-hydroxyhexane 
Manufacturers’ Codes: A-84538; Abbott 84538; ABT-538 
Trademarks: Norvir (Abbott) 
Molecular Formula: C37H48N6O5S2 
Molecular Weight: 720.94 
Percent Composition: C 61.64%, H 6.71%, N 11.66%, O 11.10%, S 8.90% 
Literature References: Peptidomimetic HIV-1 protease inhibitor. Prepn: D. J. Kempf et al.,WO9414436eidem,US5541206 (1994, 1996 both to Abbott). Antiretroviral spectrum, pharmacokinetics: idemet al.,Proc. Natl. Acad. Sci. USA92, 2484 (1995). Structural model for drug resistance: M. Markowitz et al.,J. Virol.69, 701 (1995). HPLC determn in biological fluids: R. M. W. Hoetelmans et al.,J. Chromatogr. B705, 119 (1998). Review of clinical experience: A. P. Lea, D. Faulds, Drugs52, 541-546 (1996). Clinical trial with nucleoside analogs in HIV-infected children: S. A. Nachman et al.,J. Am. Med. Assoc.283, 492 (2000). Clinical trial with lopinavir, q.v., in HIV infection: S. Walmsley et al.,N. Engl. J. Med.346, 2039 (2002). 
Therap-Cat: Antiviral. 
Keywords: Antiviral; Peptidomimetics; HIV Protease Inhibitor.Company:Abbvie (Originator)Sales:$389 Million (Y2012); 
$419 Million (Y2011);ATC Code:J05AE03

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2010-02-10New dosage formNorvirHIV infectionTablet100 mgAbbvie 
1999-06-29Additional approvalNorvirHIV infectionCapsule100 mgAbbvie 
1996-03-01New dosage formNorvirHIV infectionCapsule100 mgAbbviePriority
1996-03-01First approvalNorvirHIV infectionSolution80 mg/mLAbbvie 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
1996-08-26First approvalNorvirHIV infectionCapsule100 mgAbbvie 
1996-08-26First approvalNorvirHIV infectionTablet, Film coated100 mgAbbvie 
1996-08-26First approvalNorvirHIV infectionSolution80 mg/mLAbbvie 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2011-02-28New dosage formNorvirHIV infectionTablet100 mgAbbvie 
1998-09-25First approvalNorvirHIV infectionSolution80 mg/mLAbbvie 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-10-15Marketing approval HIV infectionTablet100 mgAbbvie 
2010-07-29Marketing approval爱治威/NorvirHIV infectionCapsule100 mgAbbott 
2010-07-13Marketing approval迈可欣HIV infectionSolution75 ml:6 g美吉斯制药(厦门)3.1类

Ritonavir was first approved by the U.S. Food and Drug Administration (FDA) on March 1, 1996, then approved by European Medicine Agency (EMA) on August 26, 1996, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on September 25, 1998. It was developed and marketed as Norvir® by Abbvie.

Ritonavir is an HIV protease inhibitor. It is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Norvir® is available as solution for oral use, containing 80 mg of free Ritonavir per mL. The recommended dose is 600 mg twice-day with meals for adult patients.
Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection.

Ritonavir (RTV), sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.[2] This combination treatment is known as highly active antiretroviral therapy (HAART).[2] Often a low dose is used with other protease inhibitors.[2] It may also be used in combination with other medications for hepatitis C.[3] It is taken by mouth.[2] The capsules of the medication do not work the same as the tablets.[2]

Common side effects include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[2] Serious side effects include liver problems, pancreatitisallergic reactions, and arrythmias.[2] Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[2] At low doses it is considered to be acceptable for use during pregnancy.[4] Ritonavir is of the protease inhibitor class.[2] Typically, however, it is used to inhibit the enzyme that metabolizes other protease inhibitors.[5] This inhibition allows lower doses of these latter medication to be used.[5]

Ritonavir was patented in 1989 and came into medical use in 1996.[6][7] It is on the World Health Organization’s List of Essential Medicines.[8] Ritonavir capsules were approved as a generic medication in the United States in 2020.[9]

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Ritonavir synthesis.svg

In the first step shown, an aldehyde derived from phenylalanine is treated with zinc dust in the presence of vanadium(III) chloride. This results in a pinacol coupling reaction which dimerises the material to provide an intermediate which is converted to its epoxide and then reduced to (2S,3S,5S)-2,5-diamino-1,6-diphenylhexan-3-ol. Importantly, this retains the absolute stereochemistry of the amino acid precursor. The diamine is then treated sequentially with two thiazole derivatives, each linked by an amide bond, to provide ritonavir.[23][24]

REF 23, 24 BELOW

  1.  WO patent 1994014436, Kempf, Dale J.; Norbeck, Daniel W.; Sham, Hing Leung; Zhao, Chen; Sowin, Thomas J.; Reno, Daniel S.; Haight, Anthony R. and Cooper, Arthur J., “Retroviral protease inhibiting compounds”, published 1994-07-07, assigned to Abbott Laboratories
  2. ^ Vardanyan, Ruben; Hruby, Victor (2016). “34: Antiviral Drugs”. Synthesis of Best-Seller Drugs. pp. 698–701. doi:10.1016/B978-0-12-411492-0.00034-1ISBN 9780124114920S2CID 75449475.

SYN


EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436

The oxidation of N-(benzyloxycarbonyl)-L-phenylalaninol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which by dimerization with Zn dust in dichloromethane yields (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexane-3,4-diol (III) [along with the (2S,3S,4S,5S)-isomer]. The reaction of (III) with alpha-acetoxyisobutyryl bromide (IV) in hexane/dichloromethane affords (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-4-bromo-1,6-diphenylhexan-3-ol acetate ester (V), which is converted into the corresponding epoxide (VI) with NaOH in dioxane/water. The reduction of the epoxide (VI) with NaBH4 in THF affords (2S,3S,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexan-3-ol (VII), which is deprotected with Ba(OH)2 in refluxing dioxane/water yielding the corresponding diamine (VIII). The cyclization of (VIII) with phenylboronic acid (IX) in refluxing toluene gives (4S,6S)-6-[1(S)-amino-2-phenylethyl]-4-benzyl-2-phenyl-1,3,2-oxaazaborinane (X), which is condensed with (5-thiazolylmethyl)(4-nitrophenyl)carbonate (XI) in THF to afford (2S,3S,5S)-5-amino-1,6-diphenyl-2-(5-thiazolylmethoxycarbonylamino) hexan-3-ol (XII). Finally, this compound is condensed with N-[N-(2-isopropylthiazol-4-ylmethyl)-N-methylaminocarbonyl]-L-valine (XIII) by means of 1-hydroxybenzotriazole (HBT) and N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide (DEC) in THF.

SYN

The thiazolyl carbonate (XI) has been synthesized as follows: The reaction of formamide (XIV) with P2S5 in ethyl ether gives thioformamide (XV), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (XVI) [obtained by condensation of ethyl chloroacetate (XVII) with ethyl formate (XVIII) by means of t-BuOK in THF] yielding thiazol-5-carboxylic acid ethyl ester (XIX). The reduction of (XIX) with LiAlH4 in THF affords 5-thiazolylmethanol (XX), which is then esterified with 4-nitrophenyl chloroformate (XXI) by means of 4-methylmorpholine (MPH) in dichloromethane to give the desired product (XI).

SYN

The N-substituted valine (XIII) has been synthesized as follows: The reaction of isobutyramide (XXII) with phosphorus pentasulfide (P4S10) in ethyl ether gives the corresponding thioamide (XXIII), which is cyclized with 1,3-dichloroacetone (XXIV) by means of MgSO4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (XXV). The reaction of (XXV) with methylamine in water affords N-(2-isopropylthiazol-4-ylmethyl)-N-methylamine (XXVI), which is condensed with N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) by means of 4-(dimethylamino)pyridine (DMAP) and triethylamine in refluxing THF to give the thiazol-substituted L-valine ester (XXVIII). Finally, this compound is converted into the corresponding free acid with LiOH in dioxane/water. The N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) has been synthesized by reaction of chloroformate (XXI) with L-valine methyl ester (XXIX) by means of 4-methylmorpholine (MPH) in dichloromethane.

SYN


Org Process Res Dev 1999,3(2),94

A new method for the preparation of a key diaminoalcohol intermediate in the synthesis of ritonavir has been described: The reaction of L-phenylalanine (XXIX) with benzyl chloride by means of K2CO3 and KOH in hot water gives N,N-dibenzyl-L-phenylalanine benzyl ester (XXX), which is condensed first with acetonitrile by means of NaNH2 and then with benzylmagnesium chloride, both reactions in methyl tert-butyl ether, yielding 5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one (XXXI). The reduction of (XXXI) with NaBH4 with an accurate control of the solvent and acidity, results in an enhanced enantioselectivity towards the desired (S,S,S)-enantiomer of 5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol (XXXII). Finally, this compound is deprotected by hydrogenation with ammonium formate over Pd/C in methanol/water to provide the target chiral diaminoalcohol (VIII).

SYN


Chem Commun (London) 2001,(2),203

he reaction of N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester (I) with trimethylphosphonate lithium salt (II) in THF gives the dimethyl L-phenylalanylmethylphosphonate (III), which is condensed with 2-phenylacetaldehyde (IV) by means of Na2CO3 in ethanol yielding the diphenylhexenone (V). The reduction of the carbonyl group of (V) with NaBH4 in methanol affords a diastereomeric mixture of alcohols (VI) and (VII) from which the desired major isomer (VII) is separated by column chromatography.. The epoxidation of the double bond of (VII) with MCPBA in dichloromethane gives the epoxide (VIII) (1), which is cleaved with Red-Al in THF providing the diol (IX). The reaction of (IX) with Ms-Cl and DIEA yields the intermediate dimesylate (X) which, without isolation, affords oxazolidinone (XI). The reaction of (XI) with sodium azide and 18-C-6 in DMSO gives the azide (XII), which is treated with NaH and Boc2O in THF in order to cleave the oxazolidine ring and furnish the protected aminoalcohol (XIII). Finally the azido group of (XIII) is hydrogenate with H2 over Pd/C in methanol to afford the monoprotected diaminoalcohol (XIV) the target compound.

SYN

https://www.scielo.br/j/mioc/a/FT4WXwhbCPCkm7W6XdX4GHm/?lang=en

Ritonavir (2) – The first disclosure of ritonavir (2) is presented in a patent from 1994, assigned to Abbott Laboratories. Even though the patent consists of a range of Markush structures, among which is found (2), its synthesis is not presented.249 The synthetic pathway to obtain (2) was disclosed for the first time in a second-generation patent in 1995, by the same company.250,251 Some drawbacks related to the synthesis presented by Abbott include the employment of expensive condensing agents, as 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and poor reaction yields on the first steps of the synthetic pathway, making this strategy too expensive and not suitable for scale-up production. Considering the above deficiencies, a recent Chinese patent concerning the synthesis of ritonavir (2) has been released.

The synthetic pathway described in the patent starts with a nucleophilic addition-elimination reaction between the starting material (2-isopropylthiazol-4-yl)- nitro-methylamine (71) and N-[(2,2,2-trichloroethoxy)carbonyl]-L-valine (72), generating intermediate (73). The intermediate is mixed with p-toluenesulfonyl chloride and triethylamine to activate the acid function, followed by the addition of reagent (74) in a one-pot procedure. The condensation allows the formation of intermediate (75), which is submitted to acidic conditions for a Boc deprotection, followed by another nucleophilic addition-elimination reaction with reagent (76), thus obtaining the final product ritonavir (2) (Fig. 16).252 When comparing both patents, it is possible to highlight important advantages present in the latest one, including the use of cheap and easily available reagents, for instance, the use of p-toluenesulfonyl chloride as an amide condensing agent, the synthetic pathway has a high yield (79% overall), low cost and it is ease to scale-up the production.

SYN

US5543551

File:Ritonavir synthesis.png

Route 1

Reference:1. US5541206A / EP0402646B1.

2. US5484801A.Route 2

Reference:1. Org. Process Res. Dev19993, 94-100.

https://pubs.acs.org/doi/abs/10.1021/op9802071

Patent

2. WO2006090264A1.

3. WO2006090270A1.Route 3

Reference:1. Tetrahedron Lett201152, 6968-6970.

SYN

Synthesis ReferenceUS5484801

SYN

Method of synthesis

i. Valine condensed with bis-trichloromethyl carbonate to give an intermediate compound 4-isopropyloxazolidine-2,5-dione.

ii. The intermediate compound is reacted with compound (1) to give compound (2).

ii. (2) reacts with bis-trichloromethyl carbonate followed by reaction with (2-isopropylthiazol-4-yl)-N-methylmethanamine to give compound (3).

iv. Primary amine group of (3) is subjected to deprotection by the removal of two benzyl groups to give compound (4).

v. (4) reacts with (5) to give Ritonavir in good yield.

CLICK ON BELOW IMAGE

CLIP

Scheme 1. Synthesis of ritonavir showing the formation of three phenol impurities (phenol, 4-nitrophenol and NPV) at different stages.

SYN

US5543551

File:Ritonavir synthesis.png

SYN

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

Lopinavir–Kaletra

The first report of a new protease inhibitor candidate lopinavir (34.1.21) seems to be Abbott’s patent [134].

The core of lopinavir is identical to that of ritonavir. The 5-thiazolyl end group in ritonavir was replaced by the phenoxyacetyl group, and the 2-isopropylthiazolyl group in ritonavir was replaced by a modified valine in which the amino terminus had a six-membered cyclic urea attached.

Synthetic strategy employed for the synthesis of multikilogram quantities of lopinavir is very similar to that implemented for ritonavir (34.1.22), but using the protected version (34.1.79) of the “core” diamino alcohol (34.1.55), which was sequentially acylated with the acid chlorides of (S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoic acid (34.1.89) and 2-(2,6-dimethylphenoxy)acetic acid (34.1.94) [135,136].

The bulk synthesis of protected diamino alcohol (34.1.79) was proposed [137,138] by a method closely related to the method [122,123] for ritonavir. For that purpose L-phenylalanine (34.1.74) was sequentially trialkylated with benzyl chloride using a K2CO3/water system at reflux to produce a tribenzylated product (34.1.75). A solution with generated acetonitrile anion in THF was added to the benzylated product (34.1.75) at less than −40°C to yield the cyanomethylketone (34.1.76), which was exposed to Grignard reagent–benzyl magnesium chloride to produce an enaminone (34.1.77). No racemization was observed in these two steps. The addition of the obtained enaminone (34.1.77) in THF/PrOH to a solution of NaBH4 and MsOH in THF at 5°C produced an intermediate aminoketone (34.1.78). No further reduction of the keto group occurs under these conditions. Reduction of the keto group could proceed by addition of a preformed solution of sodium tris(trifluoroacetoxy)borohydride in tetrahydrofuran [NaBH3(OTFA)], which produces a mixture of amino alcohols composed of 93% of the desired (2S)-5-amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol (34.1.79) along with 7% of the three undesired diastereomers. The crude mixture was debenzylated (Pd-C, HCONH4), and the product was purified by precipitation from iPrOH/HCl (aq) to produce (34.1.55) in greater than 99% purity and in high yield (Scheme 34.8.).

An efficient synthesis of each of the side chain moieties and their coupling with the “core” diamino alcohol derivatives was developed as follows: (S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoic acid (34.1.85) was prepared starting from L-valine (34.1.80), which was first converted to N-phenoxycarbonyl-L-valine (34.1.82) with phenylchloroformate (34.1.81). Accurate pH monitoring (pH 9.5 to 10.2) was necessary and LiOH was found to be a superior base. Control of pH was essential as the valine dimer and its derivatives were formed as reaction byproducts outside of this pH margin. LiCl was added to provide a lower freezing point to the aqueous solution and neutral Al2O3 was added to prevent gumming and emulsion formation during the course of the reaction.

Treatment of N-phenoxycarbonyl-L-valine (34.1.82) with 3-chloropropylamine hydrochloride (34.1.3) and solid NaOH in THF produced the unisolated salt of chloropropylurea (34.1.84), which was then treated with t-BuOK, effecting cyclization to produce the desired acid (34.1.85) in 75 to 85% yield and in greater than 99% enantiomeric excess. Acylation of (34.1.79) with synthesized acid (34.1.85) was initially achieved by well-known peptide coupling methods. Optimization of this transformation allowed the discovery of a more cost-effective method for implementing acyl chloride (34.1.86), which was easily prepared using thionyl chloride in THF at room temperature.

The reaction of dibenzylamino alcohols (34.1.79) with acyl chloride (34.1.86) in the presence of 3.0 equivalents of imidazole in EtOAc and DMF produced acylated intermediate (34.1.87) as a mixture of diastereomers, which, without any further purification, was subjected to debenzylation with Pd/C and HCO2NH4 in MeOH at 50°C, which proceeded without significant complications to produce (34.1.88).

Exposure of crude (34.1.88) to L-pyroglutamic acid (34.1.89) in dioxane at 50°C followed by cooling, allowed for the isolation of (S)-N-((2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide (34.1.90) pyroglutamic salt as virtually a single diastereomer in high yield (Scheme 34.9.).

Acyl chloride (34.1.92) was prepared by the reaction of 2-(2,6-dimethylphenoxy)acetic acid (34.1.91) with thionyl chloride in EtOAc, at room temperature adding a single drop of DMF, and warming the slurry to 50°C, which produced a clear solution of (34.1.92) that was used in the subsequent acylation of amine (34.1.90). Reaction of pyroglutamate salt (34.1.90) with acyl chloride (34.1.95) in ethyl acetate under Schotten-Baumann reaction conditions (use of a two-phase solvent system) in the presence of a water solution of NaHCO3 for liberation of free amine, produced the desired lopinavir (34.1.21) in high yield and purity (Scheme 34.10.).

Lopinavir is a novel and strong protease inhibitor developed from ritonavir with high specificity for HIV-1 protease [139-141]. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. Numerous clinical trials have shown that lopinavir/ritonavir (Kaletra) is highly effective as a component of highly active antiretroviral therapy [142,143].

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients (adults and children of two years of age and older).[1][2]

PATENT

https://patents.google.com/patent/EP1133485B1/en

  • Ritonavir (CAS Number [155213-67-5]), the structural formula of which is given below,is an inhibitor of human HIV protease which was described for the first time by Abbott in International Patent Application WO 94/14436, together with the process for the preparation thereof.
  • [0002]
    In the synthesis scheme given in WO 94/14436, Ritonavir is manufactured starting from valine and from compounds 1, 4 and 7, the structural formulae of which are also given below.
  • [0003]
    The synthesis process in question was subsequently optimised in its various parts by Abbot, who then described and claimed the individual improvements in the patent documents listed below: US 5,354,866, US 5,541,206, US 5,491,253, WO98/54122, WO 98/00393 and WO 99/11636.
  • [0004]
    The process for the synthesis of Ritonavir carried out on the basis of the above-mentioned patent documents requires, however, a particularly large number of intermediate stages; it is also unacceptable from the point of view of so-called “low environmental impact chemical synthesis” (B.M.Trost Angew. Chem. Int. Ed. Engl. (1995) 34, 259-281) owing to the increased use of activating groups and protective groups which necessitate not inconsiderable additional work in disposing of the by-products of the process, with a consequent increase in the overall manufacturing costs.
  • [0005]
    The object of the present invention is therefore to find a process for the synthesis of Ritonavir which requires a smaller number of intermediate stages and satisfies the requirements of low environmental impact chemical synthesis, thus limiting “waste of material”.
  • [0006]
    A process has now been found which, by using as starting materials the same compounds as those used in WO 94/14436, leads to the formation of Ritonavir in only five stages and with a minimum use of carbon atoms that are not incorporated in the final molecule.

EXAMPLESStage 1

  • [0014]
    ReagentMolecular weightAmountMmolEq.Amine 1464.6515 g32.2821Val-NCA 2142.136.9 g48.5471.5Triethylamine101.194.5 ml32.2831 (d = 0.726)   Dichloromethane 108 ml Sol. 0.3 M
  • [0015]
    Compound Val-NCA 2 was added to a solution of amine 1 (note 1, 2) in dichloromethane (60 ml) at -15°C under nitrogen followed by a solution of triethylamine in dichloromethane (48 ml) (note 3). The reaction mixture was maintained under agitation at from -15° to -13°C for two hours (note 4). The solution was used directly for the next stage without further purification.
  • Note 1. Amine 1 was prepared using the procedure described in A.R. Haight et al. Org. Proc. Res. Develop. (1999) 3, 94-100.
  • Note 2. Amine 1 was a mixture of stereoisomers with a ratio of 80 : 3.3 : 2.1 : 1.9.
  • Note 3. This solution was added dropwise over a period of 25 minutes.
  • Note 4. HPLC analysis after 2 hours: Amide 3 70.2 % – starting material 4.3 %

Stage 2

  • [0016]
    ReagentMolecular weightAmountMmolEq.Amine 3 Solution from stage 1563.78 32.2821Triethylamine101.19 (d = 0.726)2.6 ml18.6540.6Bis(trichloromethyl) carbonate (BTC)296.753.5 g11.7940.36dichloromethane 65 ml  N-Methyl-4-aminomethyl-2-isopropylthiazole 4170.275.5 g32.2821triethylamine101.196.9 ml49.5041.5 (d = 0.726)   Dichloromethane 52 ml  
  • [0017]
    The triethylamine was added slowly to the solution of amine 3 resulting from stage 1 and this mixture was in turn added slowly to a solution of BTC in dichloromethane (65 ml) at from -15° to -13°C and the reaction mixture was maintained under agitation at that temperature for 1.5 hours (note 1). A solution of amine 4 and triethylamine in dichloromethane (52 ml) was then added slowly to the reaction mixture (note 2) and maintained under agitation at that temperature for one hour (note 3). The reaction was stopped with water (97 ml) and the two phases were separated. The organic phase was washed with a 10% aqueous citric acid solution, filtered over Celite and evaporated with a yield of 25 g of crude urea 5 which was purified by flash chromatography on silica gel (eluant: toluene – ethyl acetate 6:4) to give 9.4 g of pure compound 5 (total yield of the two stages 38%) (note 4).
  • Note 1. HPLC analysis after 1.5 hours of the reaction stopped in tert-butylamine: Amide 3 = 0.41 % – intermediate isocyanate = 61.3 %
  • Note 2. The solution of amine 4 was added over a period of approximately 20 minutes.
  • Note 3. HPLC analysis after 1 hour: Amide 3 = 7 % – Urea 5 = 54 %
  • Note 4. 1H-NMR (CDCl3, 600 MHz) δ 7.31 (m, 4H), 7.28-7.24 (m, 4H), 7.21-7.14 (m, 8H), 7.11 (d, 2H), 7.05 (d, 2H), 6.96 (s, 1H), 6.75 (bd, 1H), 5.96 (bs, 1H), 4.48 (d, 1H), 4.39 ( d, 1H), 4.13 (dd, 1H), 4.09 (m, 1H), 3.93 (bd, 2H), 3.56 (bt, 1H), 3.39 (d, 2H), 3.28 (m, 1H), 3.04 (dd, 1H), 2.97 (s, 3H), 2.89 (m, 1H), 2.74 (q, 1H), 2.61 (m, 2H), 2.25 (m, 1H), 1.53 ( ddd, 1H), 1.38 (d, 6H), 1.28 (dt, 1H), 0.98 (d, 3H), 0.91 (d, 3H).

Stage 3

  • [0018]
    ReagentMolecular weightAmountMmolEq.Urea 5760.053.5 g4.6051Pd(OH)2/C 20% 5.25 g 30% w/wAcetic acid 31 ml Sol. 0.15 M
  • [0019]
    The Pearlman catalyst (note 1) was added to a solution of urea 5 in acetic acid and the mixture was hydrogenated for 5 hours at from 4 to 4.5 bar and from 78 to 82°C (note 2). The catalyst was filtered and the solvent was removed under reduced pressure. The crude product was dissolved in water (35 ml), the pH was adjusted to a value of 8 with NaOH, and extracted with CH2Cl2 (2×15 ml). The organic phase was washed with water (10 ml) and the solvent was evaporated under reduced pressure with a yield of 1.8 g of amine 6 as a free base which was used for the next stage without further purification (note 3, 4).
  • Note 1. Of the various reaction conditions tested, such as HCOONH4/Pd-C in MeOH, H2/Pd-C in methanol, H2Pd-C/CH3SO3H in methanol, H2/Pd(OH)2/C in methanol, etc., the best conditions we have found hitherto are those described in this Example.
  • Note 2. HPLC analysis after 5 hours: amine 6 = 52 % – monobenzyl derivative = 9.3%.
  • Note 3. HPLC analysis on the free base: amine 6 = 54 % – monobenzyl derivative = 6%.
  • Note 4. 1H-NMR (CDCl3, 600 MHz) δ 7.29 (m, 4H), 7.22-7.14 (m, 6H), 7.00 (s, 1H), 6.83 (bd, 1H), 6.15 (bs, 1H), 4.49 (d, 1H), 4.41 ( d, 1H), 4.25 (m, 1H), 4.08 (m, 1H), 3.38 (m, 1H), 3.29 (m, 1H), 2.99 (s, 3H), 2.92 (dd 1H), 2.84 (m, 2H), 2.76 (m, 1H), 2.47 (m, 1H), 2.28 (m, 1H), 1.76 ( dt, 1H), 1.61 (dt, 1H), 1.38 (d, 6H), 0.95 (d, 3H), 0.89 (d, 3H).

Stage 4

  • [0020]
    ReagentMolecular weightAmountMmolEq.Amine 6579.801.8 g3.101Compound 7.HCl316.701.28 g4.031.3NaHCO384.00370 mg4.401.4Ethyl acetate 31 ml Sol. 0.1M
  • [0021]
    A solution of the chloride of compound 7 in ethyl acetate was treated with an aqueous sodium bicarbonate solution. The phases were separated and the organic phase was added to a solution of amine 6 in ethyl acetate. The reaction mixture was heated at 60°C for 12 hours, then concentrated; ammonia was added and the solution was maintained under agitation for 1 hour. The organic phase was washed with a 10% aqueous potassium carbonate solution (3x5ml) and with a saturated sodium chloride solution (5 ml); the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluant ethyl acetate) to give 900 mg of pure Ritonavir (total yield of the two stages 27 %) (note 1).
  • Note 1. 1H-NMR (DMSO, 600 MHz) δ 9.05(s, 1H), 7.86 (s, 1H), 7.69 (d, 1H), 7.22-7.10 (m,11H), 6.88 (d, 1H), 6.02 (d, 1H), 5.16 (d, 1H), 5.12 (d, 1H), 4.60 (bs, 1H), 4.48 (d, 1H), 4.42 (d, 1H), 4.15 (m, 1H), 3.94 (dd, 1H), 3.83 (m, 1H), 3.59 (bt, 1H), 3.23 (m, 1H), 2.87 (s, 3H), 2.69-2.63 (m, 3H), 2.60 (m, 1H), 1.88 (m, 1H), 1.45 (m, 2H), 1.30 (d, 6H), 0.74 (d, 6H).

Side effects

When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below.[10]

One of ritonavir’s side effects is hyperglycemia, through inhibition of the GLUT4 insulin-regulated transporter, thus keeping glucose from entering fat and muscle cells.[medical citation needed] This can lead to insulin resistance and cause problems for people with type 2 diabetes.[medical citation needed]

Drug interactions

 

Ritonavir induces CYP 1A2 and inhibits the major P450 isoforms 3A4 and 2D6.[according to whom?][medical citation needed] Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[11] The list of clinically significant interactions of ritonavir includes the following drugs:

Mechanism of action

Ritonavir was originally developed as an inhibitor of HIV protease, one of a family of pseudo-C2-symmetric small molecule inhibitors.

Ritonavir (center) bound to the active site of HIV protease.[medical citation needed]

Ritonavir is now rarely used for its own antiviral activity but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular enzyme, in intestines, liver, and elsewhere, that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[16] The drug binds to and inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART. However, because of the general role of CYP3A4 in xenobiotic metabolism, dosing with ritonavir also affects the efficacy of numerous other medications, adding to the challenge of prescribing drugs concurrently.[medical citation needed][17][better source needed]

Pharmocodymanics and pharmacokinetics

The capsules of the medication do not have the same bioavailability as the tablets.[2]

History

New HIV infections and deaths, before and after the FDA approval of “highly active antiretroviral therapy”,[18] of which saquinavir and ritonavir were key as the first two protease inhibitors.[medical citation needed] As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.[18]

Ritonavir is manufactured as Norvir by AbbVie, Inc..[citation needed] The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996,[19] making it the seventh U.S.-approved antiretroviral drug and the second U.S.-approved protease inhibitor (after saquinavir four months earlier).[citation needed] As a result of the introduction of new “highly active antiretroviral thearap[ies]”—of which the protease inhibitors ritonavir and saquinavir were critical[citation needed]—the annual U.S. HIV-associated death rate fell from over 50,000 to about 18,000 over a period of two years.[20][21]

In 2003, Abbott (now AbbVie, Inc.) raised the price of a Norvir course from US$1.71 per day to US$8.57 per day, leading to claims of price gouging by patients’ groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004, that it lacked the legal right to allow generic production of Norvir.[22]

In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4,[3] where the presence of ritonavir again capitalizes on its inhibitory interaction with the human drug metabolic enzyme CYP3A4.

Polymorphism and temporary market withdrawal

Ritonavir was originally dispensed as an ordinary capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I.[23] However, like many drugs, crystalline ritonavir can exhibit polymorphism, i.e., the same molecule can crystallize into more than one crystal type, or polymorph, each of which contains the same repeating molecule but in different crystal packings/arrangements. The solubility and hence the bioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.[24]

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,[25] more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market.[24] As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II, the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir; and indeed, form II was found in production lines, effectively halting ritonavir production.[23] Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension.[citation needed]

The company’s research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap.[when?][citation needed] In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration.[26]

Research

In 2020, the fixed-dose combination of lopinavir/ritonavir was found not to work in severe COVID-19.[27] In the trial the medication was started around thirteen days after the start of symptoms.[27] Virtual screening of the 1930 FDA-approved drugs followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS-CoV-2 spike (S) protein to the human angiotensin-converting enzyme-2 (hACE2) receptor, which is critical for the virus entry into human cells.[28]

References

  1. Jump up to:a b “Norvir EPAR”European Medicines Agency (EMA). Retrieved 20 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. Jump up to:a b c d e f g h i j k “Ritonavir”. The American Society of Health-System Pharmacists. Archived from the original on 2015-10-17. Retrieved Oct 23, 2015.
  3. Jump up to:a b “FDA approves Viekira Pak to treat hepatitis C”Food and Drug Administration. December 19, 2014. Archived from the original on October 31, 2015.
  4. ^ “Ritonavir Pregnancy and Breastfeeding Warnings”drugs.comArchived from the original on 7 September 2015. Retrieved 23 October 2015.
  5. Jump up to:a b British National Formulary 69 (69 ed.). Pharmaceutical Pr. March 31, 2015. p. 426. ISBN 9780857111562.
  6. ^ Hacker, Miles (2009). Pharmacology principles and practice. Amsterdam: Academic Press/Elsevier. p. 550. ISBN 9780080919225.
  7. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN 9783527607495.
  8. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ^ “First Generic Drug Approvals”U.S. Food and Drug Administration (FDA). Retrieved 13 February 2021.
  10. ^ “Norvir side effects (Ritonavir) and drug interactions – prescription drugs and medications at RxList”. June 27, 2007. Archived from the original on 2007-06-27.
  11. ^ “Ritonavir: Drug Information Provided by Lexi-Comp: Merck Manual Professional”. April 30, 2008. Archived from the originalon 2008-04-30.
  12. ^ Henry, J. A.; Hill, I. R. (1998). “Fatal interaction between ritonavir and MDMA”. Lancet352 (9142): 1751–1752. doi:10.1016/s0140-6736(05)79824-xPMID 9848354S2CID 45334940.
  13. ^ Papaseit, E.; Vázquez, A.; Pérez-Mañá, C.; Pujadas, M.; De La Torre, R.; Farré, M.; Nolla, J. (2012). “Surviving life-threatening MDMA (3,4-methylenedioxymethamphetamine, ecstasy) toxicity caused by ritonavir (RTV)”. Intensive Care Medicine38 (7): 1239–1240. doi:10.1007/s00134-012-2537-9PMID 22460853S2CID 19375709.
  14. ^ Nieminen, Tuija H.; Hagelberg, Nora M.; Saari, Teijo I.; Neuvonen, Mikko; Neuvonen, Pertti J.; Laine, Kari; Olkkola, Klaus T. (2010). “Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir”European Journal of Clinical Pharmacology66 (10): 977–985. doi:10.1007/s00228-010-0879-1ISSN 0031-6970PMID 20697700S2CID 25770818.
  15. ^ Hsieh, Yi-Ling; Ilevbare, Grace A.; Van Eerdenbrugh, Bernard; Box, Karl J.; Sanchez-Felix, Manuel Vincente; Taylor, Lynne S. (2012-05-12). “pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties”. Pharmaceutical Research29 (10): 2738–2753. doi:10.1007/s11095-012-0759-8ISSN 0724-8741PMID 22580905S2CID 15502736.
  16. ^ Zeldin RK, Petruschke RA (2004). “Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients”Journal of Antimicrobial Chemotherapy53 (1): 4–9. doi:10.1093/jac/dkh029PMID 14657084.
  17. ^ “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”U.S. Food and Drug Administration(FDA). December 3, 2019.
  18. Jump up to:a b (PDF)https://web.archive.org/web/20150924044850/http://www.cdc.gov/mmwr/PDF/wk/mm6021.pdf. Archived from the original (PDF)on 2015-09-24. Retrieved 2020-02-17. Missing or empty |title=(help)
  19. ^ “Ritonavir FDA approval package” (PDF). 1 March 1996.
  20. ^ “HIV Surveillance—United States, 1981-2008”Archived from the original on 9 November 2013. Retrieved 8 November 2013.
  21. ^ The CDC, in its Morbidity and Mortality Weekly Report, ascribes this to “highly active antiretroviral therapy”, without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.
  22. ^ Ceci Connolly (2004-08-05). “NIH Declines to Enter AIDS Drug Price Battle”The Washington PostArchived from the original on 2008-08-20. Retrieved 2006-01-16.
  23. Jump up to:a b Bauer J; et al. (2001). “Ritonavir: An Extraordinary Example of Conformational Polymorphism”. Pharmaceutical Research18 (6): 859–866. doi:10.1023/A:1011052932607PMID 11474792S2CID 20923508.
  24. Jump up to:a b S. L. Morissette; S. Soukasene; D. Levinson; M. J. Cima; O. Almarsson (2003). “Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization”Proc. Natl. Acad. Sci. USA100 (5): 2180–84. doi:10.1073/pnas.0437744100PMC 151315PMID 12604798.
  25. ^ Lüttge, Andreas (February 1, 2006). “Crystal dissolution kinetics and Gibbs free energy”. Journal of Electron Spectroscopy and Related Phenomena150 (2): 248–259. doi:10.1016/j.elspec.2005.06.007.
  26. ^ “Kaletra FAQ”AbbVie’s Kaletra product information. AbbVie. 2011. Archived from the original on 7 July 2014. Retrieved 5 July2014.
  27. Jump up to:a b Cao, Bin; Wang, Yeming; Wen, Danning; Liu, Wen; Wang, Jingli; Fan, Guohui; et al. (18 March 2020). “A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19”New England Journal of Medicine382 (19): 1787–1799. doi:10.1056/NEJMoa2001282PMC 7121492PMID 32187464.
  28. ^ Bagheri, Milad; Niavarani, Ahmadreza (2020-10-08). “Molecular dynamics analysis predicts ritonavir and naloxegol strongly block the SARS-CoV-2 spike protein-hACE2 binding”Journal of Biomolecular Structure and Dynamics: 1–10. doi:10.1080/07391102.2020.1830854ISSN 0739-1102PMID 33030105S2CID 222217607.

Further reading

  • Chemburkar, Sanjay R.; Bauer, John; Deming, Kris; Spiwek, Harry; Patel, Ketan; Morris, John; Henry, Rodger; Spanton, Stephen; et al. (2000). “Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development”. Organic Process Research & Development4 (5): 413–417. doi:10.1021/op000023y.
  • “Ritonavir”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Trade namesNorvir
AHFS/Drugs.comMonograph
MedlinePlusa696029
License dataEU EMAby INNUS DailyMedRitonavir
Pregnancy
category
AU: B3
Routes of
administration
By mouth
ATC codeJ05AE03 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-onlyEU: Rx-only [1]
Pharmacokinetic data
Protein binding98-99%
MetabolismLiver
Elimination half-life3-5 hours
Excretionmostly fecal
Identifiers
showIUPAC name
CAS Number155213-67-5 
PubChem CID392622
DrugBankDB00503 
ChemSpider347980 
UNIIO3J8G9O825
KEGGD00427 
ChEBICHEBI:45409 
ChEMBLChEMBL163 
NIAID ChemDB028478
PDB ligandRIT (PDBeRCSB PDB)
CompTox Dashboard (EPA)DTXSID1048627 
ECHA InfoCard100.125.710 
Chemical and physical data
FormulaC37H48N6O5S2
Molar mass720.95 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

/////////////RITONAVIR, Antiviral, Peptidomimetics, HIV Protease Inhibitor, A-84538, Abbott 84538, ABBOTT-84538, ABT 538, ABT-538, DRG-0244, NSC-693184, TMC 114r

CC(C)[C@H](NC(=O)N(C)CC1=CSC(=N1)C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC1=CC=CC=C1)NC(=O)OCC1=CN=CS1)CC1=CC=CC=C1

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Brivudine


Brivudine - Brivudin.svg
69304-47-8.png

Brivudine

ブリブジン;

D07249

Zostex (TN)

FormulaC11H13BrN2O5
CAS69304-47-8
Mol weight333.1353

(E)-5-(2-Bromovinyl)-2′-deoxyuridine2M3055079H5-[(E)-2-bromoethenyl]-2′-deoxyuridine5-[(E)-2-Bromovinyl]-2′-deoxyuridine
626769304-47-8[RN]BrivudineCAS Registry Number: 69304-47-8CAS Name: 5-[(1E)-2-Bromoethenyl]-2¢-deoxyuridineAdditional Names: (E)-5-(2-bromovinyl)-2¢-deoxyuridine; brivudin; BVDUTrademarks: Brivex (Menarini); Brivirac (Menarini); Nervinex (Menarini); Zecovir (Guidotti); Zostex (Berlin-Chemie)Molecular Formula: C11H13BrN2O5Molecular Weight: 333.14Percent Composition: C 39.66%, H 3.93%, Br 23.99%, N 8.41%, O 24.01%Literature References: Analog of thymidine, q.v., with selective activity against herpes simplex virus type 1 and varicella-zoster virus. Prepn: A. S. Jones et al.,DE2915254eidemUS4424211 (1979, 1984 both to University of Birmingham and Rega Institut); and antiviral activity: E. De Clercq et al,Proc. Natl. Acad. Sci. USA76, 2947 (1979). Mechanism of action studies: H. S. Allaudeen et al.,ibid.78, 2698 (1981); J. Balzarini, E. De Clercq, Methods Find. Exp. Clin. Pharmacol.11, 379 (1989). Cytotoxic properties vs viral tumor cells: C. Grignet-Debrus et al.,Cancer Gene Ther.7, 215 (2000). CE determn in plasma and urine: J. Olgemöller et al.,J. Chromatogr. B726, 261 (1999). Clinical evaluation in herpetic keratitis: P. C. Maudgal, E. De Clercq, Curr. Eye Res.10, Suppl., 193 (1991). Clinical comparison with acyclovir, q.v., in herpes zoster: S. W. Wassilew et al.Antiviral Res.59, 49, 57 (2003). Review of pharmacology and clinical efficacy in herpes zoster: S. J. Keam et al.,Drugs64, 2091-2097 (2004); of antiviral activity, mechanism of action, and clinical efficacy: E. De Clercq, Med. Res. Rev.25, 1-20 (2005).Properties: White needles from methanol-water, mp 123-125° (dec). uv max: 253, 295 nm (e 13100, 10300).Melting point: mp 123-125°Absorption maximum: uv max: 253, 295 nm (e 13100, 10300)Therap-Cat: Antiviral.Keywords: Antiviral; Purines/Pyrimidinones.

Brivudine (trade names ZostexMevirBrivir, among others) is an antiviral drug used in the treatment of herpes zoster (“shingles”). Like other antivirals, it acts by inhibiting replication of the target virus.

Medical uses

Brivudine is used for the treatment of herpes zoster in adult patients. It is taken orally once daily, in contrast to aciclovirvalaciclovir and other antivirals.[1] A study has found that it is more effective than aciclovir, but this has been disputed because of a possible conflict of interest on part of the study authors.[2]

Contraindications

The drug is contraindicated in patients undergoing immunosuppression (for example because of an organ transplant) or cancer therapy, especially with fluorouracil (5-FU) and chemically related (pro)drugs such as capecitabine and tegafur, as well as the antimycotic drug flucytosine, which is also related to 5-FU. It has not been proven to be safe in children and pregnant or breastfeeding women.[1]

Adverse effects

The drug is generally well tolerated. The only common side effect is nausea (in 2% of patients). Less common side effects (<1%) include headache, increased or lowered blood cell counts (granulocytopeniaanaemialymphocytosismonocytosis), increased liver enzymes, and allergic reactions.[1]

Interactions

Brivudine interacts strongly and in rare cases lethally with the anticancer drug fluorouracil (5-FU), its prodrugs and related substances. Even topically applied 5-FU can be dangerous in combination with brivudine. This is caused by the main metabolite, bromovinyluracil (BVU), irreversibly inhibiting the enzyme dihydropyrimidine dehydrogenase (DPD) which is necessary for inactivating 5-FU. After a standard brivudine therapy, DPD function can be compromised for up to 18 days. This interaction is shared with the closely related drug sorivudine which also has BVU as its main metabolite.[1][3]

There are no other relevant interactions. Brivudine does not significantly influence the cytochrome P450 enzymes in the liver.[1]

Pharmacology

Spectrum of activity

The drug inhibits replication of varicella zoster virus (VZV) – which causes herpes zoster – and herpes simplex virus type 1 (HSV-1), but not HSV-2 which typically causes genital herpes. In vitroinhibitory concentrations against VZV are 200- to 1000-fold lower than those of aciclovir and penciclovir, theoretically indicating a much higher potency of brivudine. Clinically relevant VZV strains are particularly sensitive.[4]

Mechanism of action

Brivudine is an analogue of the nucleoside thymidine. The active compound is brivudine 5′-triphosphate, which is formed in subsequent phosphorylations by viral (but not human) thymidine kinase and presumably by nucleoside-diphosphate kinase. Brivudine 5′-triphosphate works because it is incorporated into the viral DNA, but then blocks the action of DNA polymerases, thus inhibiting viral replication.[1][4]

Pharmacokinetics

Brivudine is well and rapidly absorbed from the gut and undergoes first-pass metabolism in the liver, where the enzyme thymidine phosphorylase[5] quickly splits off the sugar component, leading to a bioavailability of 30%. The resulting metabolite is bromovinyluracil (BVU), which does not have antiviral activity. BVU is also the only metabolite that can be detected in the blood plasma.[1][6]

Highest blood plasma concentrations are reached after one hour. Brivudine is almost completely (>95%) bound to plasma proteinsTerminal half-life is 16 hours; 65% of the substance are found in the urine and 20% in the faeces, mainly in form of an acetic acid derivative (which is not detectable in the plasma), but also other water-soluble metabolites, which are urea derivatives. Less than 1% is excreted in form of the original compound.[1]

  • Brivudine 5′-triphosphate, the active metabolite
  • Bromovinyluracil (BVU), the main inactive metabolite
  • The acetic acid derivative predominantly found in urine

Chemistry

The molecule has three chiral carbon atoms in the deoxyribose (sugar) part all of which have defined orientation; i.e. the drug is stereochemically pure.[1] The substance is a white powder.

Manufacturing

Main supplier is Berlin-Chemie, now part of Italy’s Menarini Group. In Central America is provided by Menarini Centro America and Wyeth.

History

The substance was first synthesized by scientists at the University of Birmingham in the UK in 1976. It was shown to be a potent inhibitor of HSV-1 and VZV by Erik De Clercq at the Rega Institute for Medical Research in Belgium in 1979. In the 1980s the drug became commercially available in East Germany, where it was marketed as Helpin by a pharmaceutical company called Berlin-Chemie. Only after the indication was changed to the treatment of herpes zoster in 2001 did it become more widely available in Europe.[7][8]

Brivudine is approved for use in a number of European countries including Austria, Belgium, Germany, Greece, Italy, Portugal, Spain and Switzerland.[9]

Etymology

The name brivudine derives from the chemical nomenclature bromovinyldeoxyuridine or BVDU for short. It is sold under trade names such as Bridic, Brival, Brivex, Brivir, Brivirac, Brivox, Brivuzost, Zerpex, Zonavir, Zostex, and Zovudex.[9]

Research

Cochrane Systematic Review examined the effectiveness of multiple antiviral drugs in the treatment of herpes simplex virus epithelial keratitis. Brivudine was found to be significantly more effective than idoxuridine in increasing the number of successfully healed eyes of participants.[10]

PATENT

EP-03792271

Process for preparing brivudine, useful for treating herpes zoster infection and cancer (eg pancreatic cancer). Also claims novel intermediate of brivudine. Brivudine is an antiviral drug approved under the brand name Zostex®. Represents the first patenting to be seen from Aurobindo that focuses on brivudine.

 Brivudine is chemically known as 5-[(lE)-2-bromoethenyl]-2′-deoxyuridine. Brivudine is an analogue of the nucleoside thymidine with high and selective antiviral activity against varicella zoster virus and herpes simplex virus. Brivudine is an antiviral drug approved under the brand name Zostex® for treatment of herpes zoster. Brivudine is also useful to inhibit the upregulation of chemoresistance genes (Mdr1 and DHFR) during chemotherapy. Overall, the gene expression changes associated with Brivudine treatment result in the decrease or prevention of chemoresistance. In addition, it has been shown to enhance the cytolytic activity of NK-92 natural killer cells towards a pancreatic cancer cell line in vitro.

[0003]  Brivudine (I) is disclosed first time in DE 2915254. This patent discloses a process for the preparation of Brivudine by coupling E-5-(2-bromovinyl) uracil with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose to obtain E-5-(2-bromovinyl)-3′,5′-di-O-p-toluoyl-2′-deoxyuridine as a mixture of α and β isomers. This mixture was subjected to chromatographic purification to obtain pure β-isomer. In the subsequent stage E-5-(2-bromovinyl)-3′,5′-di-O-p-toluoyl-2′-deoxyuridine was treated with sodium methoxide to yield Brivudine. The process is depicted in the below as Scheme I:



[0004]  The major disadvantages associated with the process disclosed in DE 2915254 includes the use of expensive starting material, formation of unwanted excess of α-isomer. The undesired α-isomer result in a final product of low purity, making chromatographic purification methods not feasible at an industrial scale. Additionally, the process involves the use of bromine for the synthesis of E-5-(2-bromovinyl)uracil, which is a well known carcinogen.

[0005]  GB 2125399 describe another process for the preparation of Brivudine involves the bromination and simultaneous dehydrohalogenation of 5-ethyl-2′-deoxyuridine in the presence of halogenated hydrocarbon solvent. The process is depicted in the below as Scheme – II:



[0006]  The major disadvantages associated with the process disclosed in GB 2125399 includes the use of bromine for bromination, which make the process carcinogenic and the use of halogenated solvents like chloroform, carbon tetrachloride and dichloroethane for bromination makes the process environmentally hazardous.

[0007]  US 2010298530 A1 discloses a process for the preparation of Brivudine by coupling 5-Iodo deoxyuridine with methyl acrylate in presence of palladium acetate to form (E)-5-(carbomethoxyvinyl)-2′-deoxyuridine, which is hydrolyzed with sodium hydroxide solution to obtain (E)-5-(carboxyvinyl)-2′-deoxyuridine, which undergoes bromination by using N-Bromo succinimide [NBS] to obtain Brivudine. The process is depicted in the below as Scheme – III:



[0008]  The major disadvantages associated with the process disclosed in US 2010298530 A1 includes the use of expensive palladium acetate as catalyst and chromatographic purification method not feasible at an industrial scale. In addition, the above process involves the use of methyl acrylate and the process liberates iodine, which are highly carcinogenic. It makes the process environment unfriendly.

[0009]  The inventors of the present invention found an alternative route to prepare Brivudine (I), which is industrial feasible, can avoid the use of potentially hazardous, expensive chemicals and to minimize the formation of undesired α-isomer and the other process related impurities. The present invention directed towards a process for the preparation of Brivudine of Formula – I with high purity and high yield.

EXAMPLE-1:

PREPARATION OF URIDINE ACRYLIC ACID



[0026]  Trimethylchlorosilane (0.6 ml, 5 mmol) was added to the suspension of uracil acrylic acid (6.35g, 34.9 mmol) in hexamethyldisilazane (70 ml) and resulting mixture was refluxed till the clear solution was obtained. Hexamethyldisilazane was evaporated under vacuum and further co-evaporated with o-xylene to remove the traces of hexamethyldisilazane to yield viscous oily silylated uracil acrylic acid. The silylated uracil acrylic acid was dissolved in dichloromethane (100 ml) under nitrogen atmosphere, cooled at 0-10 °C. Anhydrous zinc chloride (0.63 grams, 4.6 mmol) and chloro-sugar (10 grams, 23.2 mmol) were added to the above solution. The reaction was monitored by qualitative HPLC and was essentially completed in 3 hours. After completion of the reaction dichloromethane was evaporated under vacuum. Methyl tert-butyl ether (100 ml) was added and stirred for 1 hour at 40-45 °C. The product was isolated after filtration at 25-30 °C. HPLC analysis showed the complete consumption of chloro-sugar and the ratio β/α = 98.
Yield: 75%

EXAMPLE-2:

PREPARATION OF DIBENZOYL BRIVUDINE



[0027]  Uridine acrylic acid (5.0 grams, 8.69 mmol) was suspended in a mixture of tetrahydrofuran (45.0 ml) and water (5.0 ml). Potassium acetate (0.93 grams, 9.56 mmol) and N-bromosuccinamide (1.70 grams, 9.56 mmol) was added to the suspension and the resulting mixture was stirred for 2 hours at 25-30 °C. The solvent was removed under reduced pressure to the dryness and methanol (50 ml) was poured, suspension was stirred for 1 hour at 25-30 °C. The product was isolated after filtration.
Yield: 55%

EXAMPLE-3:

PREPARATION OF BRIVUDINE (FORMULA – I)



[0028]  Dibenzoyl Brivudine (6 grams, 9.83 mmol) was suspended in methanol (30 ml) at 20-30 °C. A solution of 25 % w/w sodium methoxide (2.76 grams, 12.78 mmol) in methanol was added to the suspension and was allowed for 1hour at the same temp. The reaction was monitored by qualitative HPLC. Methanol was evaporated under vacuum and resulting residue was dissolved in water (25 ml). The aqueous mass was washed with methylene dichloride (2×20 ml) and the product was isolated from water at pH 2-3.
Yield: 85%

SYN

http://sioc-journal.cn/Jwk_yjhx/EN/10.6023/cjoc201410034

In this paper, a simple and practical method for the preparation of brivudine (BVDU) and its analog nucleoside derivatives via condensation of the easily obtainable 5-formyl pyrimidine nucleosides with carbon tetrabromide followed by an efficient and stereoselective debromination promoted by diethyl phosphite and triethylamine is presented.

Li Peiyuan, Zhang Jianrui, Guo Shenghai, Zhang Xinying, Fan Xuesen. New Synthesis of Brivudine and Its Analogs[J]. Chin. J. Org. Chem., 2015, 35(4): 910-916.

SYN 1

Tetrahedron Lett 1979,454415-8

J Carbohydates Nucleosides Nucleotides 1977,4(5),4415

5-Chloromercuri-2′-deoxyuridine (II) is prepared from 2′-deoxyuridine (I) by reaction with mercuriacetate and natrium chloride (1). Condensation of (II) with ethylacrylate (A) and lithium palladium chloride gives (E)-5-(2-carbethoxyvinyl)-2′-deoxyuridine (III), which is readily hydrozyled to (E)-5-(2-carboxyvinyl)-2′-deoxyuridine (IV) under basic conditions (0.5M NaOH). The final step involves the reaction of (IV) with N-bromosuccinimide to produce (E)-5-(2-bromovinyl)-2′-deoxyuridine.

SYN 2

he condensation of 2-deoxy-3,5-di-O-(phenylacetyl)-beta-D-erythro-pentofuranosyl chloride (I) with 2,4-bis-O-(trimethylsilyl)-5(E)-(2-bromovinyl)uracil (II) in acetonitrile (Lewis acid catalyst), or in CHCl3-pyridine (Bronsted acid catalyst), gives 3′,5′-di-O-(phenylacetyl)-5(E)-(2-bromovinyl)-2′-deoxyuridine (III) and its anomer that is eliminated by TLC (silicagel). Finally, (III) is treated with sodium methoxide in methanol.

Int Symp: Basic Clin Approach Virus Chemother 1988,Poster M17

SYN

  • Synthetic Method of Brivudine
  • (CAS NO.: ), with its systematic name of (E)-5-(2-Bromovinyl)-2′-deoxyuridine, could be produced through many synthetic methods.Following is one of the reaction routes:Systematic Method of Brivudine2-Deoxy-3,5-di-O-(phenylacetyl)-beta-D-erythro-pentofuranosyl chloride (I) is condensed with 2,4-bis-O-(trimethylsilyl)-5(E)-(2-bromovinyl)uracil (II) in acetonitrile (Lewis acid catalyst), or in CHCl3-pyridine (Bronsted acid catalyst), to produce 3,5-di-O-(phenylacetyl)-5(E)-(2-bromovinyl)-2-deoxyuridine (III) and its anomer that is eliminated by TLC (silicagel). Finally, (III) is treated with sodium methoxide in methanol.

References

  1. Jump up to:a b c d e f g h i Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 5246–8. ISBN 978-3-85200-181-4.
  2. ^ “Brivudin (Zostex) besser als Aciclovir (Zovirax a.a.)?”Arznei-telegramm (in German). 5/2007.
  3. ^ “UAW – Aus Fehlern lernen – Potenziell tödlich verlaufende Wechselwirkung zwischen Brivudin (Zostex) und 5-Fluoropyrimidinen” (PDF). Deutsches Ärzteblatt (in German). 103 (27). 7 July 2006.
  4. Jump up to:a b Steinhilber D, Schubert-Zsilavecz M, Roth HJ (2005). Medizinische Chemie (in German). Stuttgart: Deutscher Apotheker Verlag. pp. 581–2. ISBN 3-7692-3483-9.
  5. ^ Desgranges C, Razaka G, Rabaud M, Bricaud H, Balzarini J, De Clercq E (December 1983). “Phosphorolysis of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and other 5-substituted-2′-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets”. Biochemical Pharmacology32 (23): 3583–90. doi:10.1016/0006-2952(83)90307-6PMID 6651877.
  6. ^ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 847. ISBN 3-8047-1763-2.
  7. ^ De Clercq E (December 2004). “Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster”. Biochemical Pharmacology68 (12): 2301–15. doi:10.1016/j.bcp.2004.07.039PMID 15548377.
  8. ^ Tringali C, ed. (2012). Bioactive Compounds from Natural Sources (2nd ed.). CRC Press. p. 170.
  9. Jump up to:a b International Drug Names: Brivudine.
  10. ^ Wilhelmus KR (January 2015). “Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis”The Cochrane Database of Systematic Reviews1: CD002898. doi:10.1002/14651858.CD002898.pub5PMC 4443501PMID 25879115.
Clinical data
Trade namesZostex, Mevir, Brivir, many others
Other namesBVDU
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
Contraindicated
Routes of
administration
Oral
ATC codeJ05AB15 (WHO)
Legal status
Legal statusIn general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability30%
Protein binding>95%
MetabolismThymidine phosphorylase
MetabolitesBromovinyluracil
Elimination half-life16 hours
Excretion65% renal (mainly metabolites), 20% faeces
Identifiers
showIUPAC name
CAS Number69304-47-8 
PubChem CID446727
ChemSpider394011 
UNII2M3055079H
KEGGD07249 
ChEMBLChEMBL31634 
CompTox Dashboard (EPA)DTXSID0045755 
Chemical and physical data
FormulaC11H13BrN2O5
Molar mass333.138 g·mol−1
3D model (JSmol)Interactive image
Specific rotation+9°±1°
Density1.86 g/cm3
Melting point165 to 166 °C (329 to 331 °F) (decomposes)
hideSMILESBr[C@H]=CC=1C(=O)NC(=O)N(C=1)[C@@H]2O[C@@H]([C@@H](O)C2)CO
hideInChIInChI=1S/C11H13BrN2O5/c12-2-1-6-4-14(11(18)13-10(6)17)9-3-7(16)8(5-15)19-9/h1-2,4,7-9,15-16H,3,5H2,(H,13,17,18)/b2-1+/t7-,8+,9+/m0/s1 Key:ODZBBRURCPAEIQ-PIXDULNESA-N 

///////Brivudine, ブリブジン, D07249Zostex, ANTIVIRAL

#Brivudine, #ブリブジン, #D07249, #Zostex, #ANTIVIRAL

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