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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Serdexmethylphenidate


Skeletal formula of serdexmethylphenidate
SERDEXMETHYLPHENIDATE CHLORIDE

Serdexmethylphenidate

  • Molecular FormulaC25H30ClN3O8
  • Average mass535.974 Da

CAS

1996626-30-2 

L-Serine, N-[[1-[[[[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]-1-piperidinyl]carbonyl]oxy]methyl]-3-pyridiniumyl]carbonyl]-, chloride (1:1)
N-[(1-{[({(2R)-2-[(1R)-2-Methoxy-2-oxo-1-phenylethyl]-1-piperidinyl}carbonyl)oxy]methyl}-3-pyridiniumyl)carbonyl]-L-serine chloride

Azstarys, FDA APPROVED, 3/2/2021, Products on NDA 212994, Type 1 – New Molecular Entity and Type 4 – New Combination

Serdexmethylphenidate Chloride (SDX), SDX or KP145

Serdexmethylphenidate chloride.png
Molecular FormulaC25H30ClN3O8
SynonymsUNII-FN54BT298YKP415 ClSerdexmethylphenidate chlorideFN54BT298YSerdexmethylphenidate chloride (USAN) 
Molecular Weight536 g/mol

CAS 1996626-30-2

(2S)-3-hydroxy-2-[[1-[[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]piperidine-1-carbonyl]oxymethyl]pyridin-1-ium-3-carbonyl]amino]propanoic acid;chloride

Serdexmethylphenidate is a derivative of dexmethylphenidate created by pharmaceutical company KemPharm. The compound is under investigation for the treatment of ADHD in children, adolescents, and adults as of 2020.[2] The drug was approved for medical use by the FDA in March, 2021. Serdexmethylphenidate is a prodrug which has a delayed onset of action and a prolonged duration of effects compared to dexmethylphenidate, its parent compound.

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Formulations

Serdexmethylphenidate/dexmethylphenidate (Azstarys), a co-formulation of serdexmethylphenidate and dexmethylphenidate, was approved by the Food and Drug Administration (FDA) in March 2021, for the treatment of ADHD in those above six years of age. Co-formulation of serdexmethylphenidate with dexmethylphenidate allows for a more rapid onset of action while still retaining up to 13 hours of therapeutic efficacy.[3][4]

Due to serdexmethylphenidate’s delayed onset and prolonged duration of effects, several dosage forms containing serdexmethylphenidate have been investigated for use as long-acting psychostimulants in the treatment of ADHD. Under the developmental codename KP484, serdexmethylphenidate has been investigated as a “super-extended duration” psychostimulant, with therapeutic efficacy lasting up to 16 hours following oral administration. In 2011, MonoSol Rx entered into a partnership with KenPharm to develop oral films containing KP415.[5]

Abuse potential

The abuse potential of serdexmethylphenidate is theorized to be lower than other psychostimulants because serdexmethylphenidate is an inactive prodrug of dexmethylphenidate, and must undergo enzymatic metabolism prior to exerting any stimulant effects.[6] Common routes of administration used during the abuse of psychostimulants such as insufflation and intravenous injection have little impact on the pharmacokinetics and metabolism of serdexmethylphenidate and do not result in a faster onset of action.[7]

SYN

SYN

US 20200237742

Title(EN) Serdexmethylphenidate Conjugates, Compositions And Methods Of Use Thereof

front page image

Abstract

(EN)

The present technology is directed to one or more compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more compositions and oral formulations comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more methods of using compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to one or more pharmaceutical kits containing a composition comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof.

Synthetic Process for Making Serdexmethylphenidate
      1. Synthesis of nicotinoyl-Ser(tBu)-OtBu
      In one embodiment, the nicotinoyl-Ser(tBu)-OtBu precursor is prepared according to Scheme 1.

 (MOL) (CDX)

      2. Synthesis of d-MPH-N-CO 2CH 2—Cl
      In one embodiment, the d-MPH-N-CO 2CH 2—Cl precursor can be prepared according to Scheme 2.

 (MOL) (CDX)

      In an alternate embodiment, d-MPH-N-CO 2CH 2—Cl can be prepared according to Scheme 3.

 (MOL) (CDX)

      3. Preparation of Protected Serdexmethylphenidate
      In one embodiment, the protected serdexmethylphenidate intermediate can be prepared as shown in Scheme 4.

 (MOL) (CDX)

      In an alternate embodiment, the protected serdexmethylphenidate intermediate can be prepared according to Scheme 5.

 (MOL) (CDX)

      4. Deprotection of Protected Serdexmethylphenidate
      In one embodiment, serdexmethylphenidate chloride can be prepared according to Scheme 6.

 (MOL) (CDX)

      In an alternate embodiment, serdexmethylphenidate chloride can be prepared according to Scheme 7.

 (MOL) (CDX)

      Following deprotection (for example, but not limited to, deprotection methods as illustrated by Scheme 6 or Scheme 7) of a protected serdexmethylphenidate intermediate (for example, but not limited to, the serdexmethylphenidate intermediate prepared according to Scheme 4 or Scheme 5) , crude serdexmethylphenidate can be purified by several methods, including, but not limited to, the method according to Scheme 8.

 (MOL) (CDX)

      An alternative embodiment for preparing serdexmethylphenidate is shown in FIG. 1.
      Novel intermediates are produced during the process of synthesizing serdexmethylphenidate (i.e., process intermediates). These process intermediates may be isolated or form in situ, and include, but are not limited to, 3-(((S)-2-(tert-butoxy)-1-carboxyethyl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; tert-butyl O-(tert-butyl)-N-nicotinoyl-L-serinate; chloromethyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; and 3-(((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium.
      Novel metabolites and/or novel degradants are produced during the breakdown of serdexmethylphenidate in vitro and/or in vivo. These metabolites and/or degradants include, but are not limited to, 1-((((R)-2-((R)-carboxy(phenyl)methyl)piperidine-1-carbonyl)oxy)methyl)-3-(((S)-1-carboxy-2-hydroxyethyl)carbamoyl)pyridin-1-ium; and 3-carboxy-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; nicotinic acid (niacin); and nicotinoyl-L-serine.
      In certain embodiments of synthesizing serdexmethylphenidate other compounds may be produced including, but not limited to, dichloromethyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; 3-((1-carboxy-2-(((1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium-3-carbonyl)-L-seryl)oxy)ethyl)carbamoyl)-1-((((S)-2-((S)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; N,N-diethyl-N-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)ethanaminium; 1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)-2,6-dimethylpyridin-1-ium; (((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl)amino)methyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; ((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidin-1-yl)methyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; 3-(((R)-1-carboxy-2-chloroethyl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; and 3-(((S)-3 -hydroxy-1-isopropoxy-1-oxopropan-2-yl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium.

PATENT

US 20190381017

Title(EN) Compositions Comprising Serdexmethylphenidate Conjugates And Methods Of Use Thereof

front page image

Abstract

(EN)

The present technology is directed to one or more compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more compositions and oral formulations comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more methods of using compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to one or more pharmaceutical kits containing a composition comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof.

PATENT

WO 2019241019

PAT

WO 2018107131

WO 2018107132

References

  1. ^ “Azstarys Prescribing Information” (PDF). United States Food and Drug Administration. Retrieved 18 March 2021.
  2. ^ “KemPharm’s KP415 and Serdexmethylphenidate (SDX) Prodrug to be Featured in Multiple Sessions at the AACAP 2020 Virtual Meeting”http://www.globenewswire.com.
  3. ^ Mickle T. “Prodrugs for ADHD Treatments: Opportunities & Potential to Fill Unmet Medical Needs” (PDF). Retrieved 15 November 2020.
  4. ^ Eric Bastings, MD (2 March 2021). “NDA 212994 Approval” (PDF). United States Food and Drug Administration. Retrieved 6 March 2021.
  5. ^ Van Arnum P (1 March 2012). “Meeting Solubility Challenges”Pharmaceutical Technology2012 (2): S6–S8. Retrieved 15 November 2020.
  6. ^ Mickle T. “Prodrugs for ADHD Treatments: Opportunities & Potential to Fill Unmet Medical Needs” (PDF). Retrieved 15 November 2020.
  7. ^ Braeckman R (1 October 2018). “Human Abuse Potential of Intravenous Serdexmethylphenidate (SDX), A Novel Prodrug of D-Methylphenidate, in Recreational Stimulant Abusers”Journal of the American Academy of Child & Adolescent Psychiatry57 (10): 176. doi:10.1016/j.jaac.2018.09.141. Retrieved 15 November 2020.

External links

Clinical data
Other namesKP484
License dataUS DailyMedSerdexmethylphenidate
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
Bioavailability3%[1]
Identifiers
showIUPAC name
CAS Number1996626-30-2 
PubChem CID134823897
ChemSpider81368035
UNIIFN54BT298Y
KEGGD11401
ChEMBLChEMBL4298139
Chemical and physical data
FormulaC25H30ClN3O8
Molar mass535.98 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

//////////Serdexmethylphenidate, Azstarys, FDA 2021 APPROVALS 2021, SDX, KP 145,

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Sacituzumab govitecan-hziy


TRODELVY structure
Sacituzumab govitecan.png
Sacituzumab govitecan.png
Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer -  National Cancer Institute

Sacituzumab govitecan-hziy

1601.8 g/mol

C76H104N12O24S

(2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid

Trodelvy 

  • hRS 7SN38
  • hRS7-SN38
  • IMMU 132
  • IMMU-132

CAS: 1491917-83-9

M9BYU8XDQ6

EX-A4354

UNII-DA64T2C2IO component ULRUOUDIQPERIJ-PQURJYPBSA-N

UNII-SZB83O1W42 component ULRUOUDIQPERIJ-PQURJYPBSA-N

EfficacyAntineoplastic, Topoisomerase I inhibitor
  DiseaseBreast cancer (triple negative)
sacituzumab govitecan-hziy Archives | Access Market Intelligence

Sacituzumab Govitecan is an antibody drug conjugate containing the humanized monoclonal antibody, hRS7, against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) and linked to the active metabolite of irinotecan7-ethyl-10-hydroxycamptothecin (SN-38), with potential antineoplastic activity. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis. TROP2, also known as epithelial glycoprotein-1 (EGP-1), is a transmembrane calcium signal transducer that is overexpressed by a variety of human epithelial carcinomas; this antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis.

wdt-13

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https://www.businesswire.com/news/home/20210407006027/en/FDA-Approves-Trodelvy%C2%AE-the-First-Treatment-for-Metastatic-Triple-Negative-Breast-Cancer-Shown-to-Improve-Progression-Free-Survival-and-Overall-Survival?fbclid=IwAR16bUSCbkK98d8j01NNKVnJ-7r8nHSvCOGE4ogCp_Aex79mNh8AOwQFIQc

FDA Approves Trodelvy®, the First Treatment for Metastatic Triple-Negative Breast Cancer Shown to Improve Progression-Free Survival and Overall Survival

– Trodelvy Significantly Reduced the Risk of Death by 49% Compared with Single-Agent Chemotherapy in the Phase 3 ASCENT Study –

– Trodelvy is Under Regulatory Review in the EU and in the United Kingdom, Canada, Switzerland and Australia as Part of Project Orbis April 07, 2021 07:53 PM Eastern Daylight Time

FOSTER CITY, Calif.–(BUSINESS WIRE)–Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to Trodelvy® (sacituzumab govitecan-hziy) for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval is supported by data from the Phase 3 ASCENT study, in which Trodelvy demonstrated a statistically significant and clinically meaningful 57% reduction in the risk of disease worsening or death (progression-free survival (PFS)), extending median PFS to 4.8 months from 1.7 months with chemotherapy (HR: 0.43; 95% CI: 0.35-0.54; p<0.0001). Trodelvy also extended median overall survival (OS) to 11.8 months vs. 6.9 months (HR: 0.51; 95% CI: 0.41-0.62; p<0.0001), representing a 49% reduction in the risk of death.

Trodelvy is directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including TNBC, where high expression is associated with poor survival and relapse. Prior to the FDA approval of Trodelvy, patients with previously treated metastatic TNBC had few treatment options in this high unmet-need setting. The FDA granted accelerated approval to Trodelvy in April 2020 based on objective response rate and duration of response results in a Phase 1/2 study. Today’s approval expands the previous Trodelvy indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

“Women with triple-negative breast cancer have historically had very few effective treatment options and faced a poor prognosis,” said Aditya Bardia, MD, MPH, Director of Breast Cancer Research Program, Mass General Cancer Center and Assistant Professor of Medicine at Harvard Medical School, and global principal investigator of the ASCENT study. “Today’s FDA approval reflects the statistically significant survival benefit seen in the landmark ASCENT study and positions sacituzumab govitecan-hziy as a potential standard of care for pre-treated TNBC.”

“A metastatic TNBC diagnosis is frightening. As an aggressive and difficult-to-treat disease, it’s a significant advance to have an FDA-approved treatment option with a proven survival benefit for patients with metastatic disease that continues to progress,” said Ricki Fairley, Founder and CEO of Touch, the Black Breast Cancer Alliance. “For far too long, people with metastatic TNBC had very few treatment options. Today’s news continues the progress of bringing more options to treat this devastating disease.”

Among all patients evaluable for safety in the ASCENT study (n=482), Trodelvy had a safety profile consistent with the previously approved FDA label. The most frequent Grade ≥3 adverse reactions for Trodelvy compared to single-agent chemotherapy were neutropenia (52% vs. 34%), diarrhea (11% vs. 1%), leukopenia (11% vs. 6%) and anemia (9% vs. 6%). Adverse reactions leading to treatment discontinuation occurred in 5% of patients receiving Trodelvy.

“Today’s approval is the culmination of a multi-year development program and validates the clinical benefit of this important treatment in metastatic TNBC,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Building upon this milestone, we are committed to advancing Trodelvy with worldwide regulatory authorities so that, pending their decision, Trodelvy may become available to many more people around the world who are facing this difficult-to-treat cancer.”

Regulatory submissions for Trodelvy in metastatic TNBC have been filed in the United Kingdom, Canada, Switzerland and Australia as part of Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners, as well as in Singapore through our partner Everest Medicines.The European Medicines Agency has also validated a Marketing Authorization Application for Trodelvy in the European Union. All filings are based on data from the Phase 3 ASCENT study.

Trodelvy Boxed Warning

The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (TNBC), where high expression is associated with poor survival and relapse.

Trodelvy is also being developed as an investigational treatment for metastatic urothelial cancer, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER 2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER 2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer (TNBC) who had received two or more prior systemic therapies (including a taxane), at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS). More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

  • Severe, life-threatening, or fatal neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay.
  • Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses.

CONTRAINDICATIONS

  • Severe hypersensitivity to TRODELVY

WARNINGS AND PRECAUTIONS

Neutropenia: Dose modifications may be required due to neutropenia. Neutropenia occurred in 62% of patients treated with TRODELVY, leading to permanent discontinuation in 0.5% of patients. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 6%.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3 diarrhea occurred in 12% of patients. Neutropenic colitis occurred in 0.5% of patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤ Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: TRODELVY can cause severe and life-threatening hypersensitivity and infusion-related reactions, including anaphylactic reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 1% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.4%. Pre-infusion medication is recommendedObserve patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use.

Nausea and Vomiting: Nausea occurred in 67% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 5% of patients. Vomiting occurred in 40% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤ 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia in genotyped patients was 69% in patients homozygous for the UGT1A1*28, 48% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia in genotyped patients was 24% in patients homozygous for the UGT1A1*28 allele, 8% in patients heterozygous for the UGT1A1*28 allele, and 10% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced hemoglobin, lymphocytes, leukocytes, and neutrophils.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate indicated for the treatment of metastatic triple-negative breast cancer (mTNBC) in adult patients that have received at least two prior therapies.[1][2]

The most common side effects are nauseaneutropeniadiarrheafatigueanemiavomitingalopecia (hair loss), constipationdecreased appetiterash and abdominal pain.[1][2] Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea.[1][2] Sacituzumab govitecan may cause harm to a developing fetus or newborn baby.[1] Women are advised not to breastfeed while on sacituzumab govitecan and 1 month after the last dose is administered.[3]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[4]

Mechanism

Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.[5] Each antibody having on average 7.6 molecules of SN-38 attached.[6] SN-38 is too toxic to administer directly to patients, but linkage to an antibody allows the drug to specifically target cells containing Trop-2.

Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells.[1] Approximately two of every ten breast cancer diagnoses worldwide are triple-negative.[1] Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein.[1] Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.[1]

Development

Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.[7][8] In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.[9][10]

History

Sacituzumab govitecan was added to the proposed INN list in 2015,[11] and to the recommended list in 2016.[12]

Sacituzumab govitecan-hziy was approved for use in the United States in April 2020.[1][13][14][2]

Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 subjects with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease.[1][14][2] Of the 108 patients involved within the study, 107 were female and 1 was male.[15] Subjects received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days.[14][15] Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity.[15] Tumor imaging was obtained every eight weeks.[14][2] The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of subjects that had a certain amount of tumor shrinkage.[1][14] The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1). [1][14][15] Additionally, with the 33.3% of study participants who achieved a response, 2.8% of patients experienced complete responses.[15] The median time to response in patients was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months.[15] Of the subjects that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.[1][14]

Sacituzumab govitecan-hziy was granted accelerated approval along with priority reviewbreakthrough therapy, and fast track designations.[1][14] The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.[1]

References

  1. Jump up to:a b c d e f g h i j k l m n o “FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 22 April 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f “Drug Trial Snapshot: Trodelvy”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 29 April 2020. This article incorporates text from this source, which is in the public domain.
  3. ^ (PDF)https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf. Missing or empty |title= (help)
  4. ^ “New Drug Therapy Approvals 2020”U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January2021.  This article incorporates text from this source, which is in the public domain.
  5. ^ Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. 2015
  6. ^ “Novel Agents are Targeting Drivers of TNBC”http://www.medpagetoday.com. 28 June 2016.
  7. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  8. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  9. ^ “New Therapy Shows Early Promise, Continues to Progress in Triple-Negative Breast Cancer”Cure Today.
  10. ^ “U.S. Food and Drug Administration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients With Triple-Negative Breast Cancer”(Press release). Immunomedics. 5 February 2016. Retrieved 25 April 2020 – via GlobeNewswire.
  11. ^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 113”. WHO Drug Information29 (2): 260–1. hdl:10665/331080.
  12. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 151–3. hdl:10665/331046.
  13. ^ “Trodelvy: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 April 2020.
  14. Jump up to:a b c d e f g h “FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 23 April 2020.  This article incorporates text from this source, which is in the public domain.
  15. Jump up to:a b c d e f “Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer”The New England Journal of Medicine.

Further reading

External links

 
Monoclonal antibody
Type?
SourceHumanized (from mouse)
TargetTrop-2
Clinical data
Trade namesTrodelvy
Other namesIMMU-132, hRS7-SN-38, sacituzumab govitecan-hziy
AHFS/Drugs.comMonograph
MedlinePlusa620034
License dataUS DailyMedSacituzumab_govitecan
Pregnancy
category
Contraindicated
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
CAS Number1491917-83-9
PubChem CID91668186
DrugBankDB12893
ChemSpidernone
UNIIM9BYU8XDQ6
KEGGD10985
Chemical and physical data
FormulaC76H104N12O24S
Molar mass1601.79 g·mol−1
3D model (JSmol)Interactive image
showSMILES
show 

//////////sacituzumab govitecan-hziy, fda 2021, approvals 2021, Trodelvy , hRS 7SN38, hRS7-SN38, IMMU 132, IMMU-132, MONOCLONAL ANTIBODY, Sacituzumab govitecan, sacituzumab govitecan-hziy, CANCER, MONOCLONAL ANTIBODIES

#sacituzumab govitecan-hziy, #fda 2021, #approvals 2021, #Trodelvy , #hRS 7SN38, #hRS7-SN38, #IMMU 132, #IMMU-132, #MONOCLONAL ANTIBODY, #Sacituzumab govitecan, #sacituzumab govitecan-hziy, #CANCER, #MONOCLONAL ANTIBODIES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O

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PF-07321332


str1
str2

PF-07321332

https://clinicaltrials.gov/ct2/show/NCT04756531

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PFIZER INITIATES PHASE 1 STUDY OF NOVEL ORAL ANTIVIRAL THERAPEUTIC AGENT AGAINST SARS-COV-2

Tuesday, March 23, 2021 – 11:00am

  • In-vitro studies conducted to date show that the clinical candidate PF-07321332 is a potent protease inhibitor with potent anti-viral activity against SARS-CoV-2
  • This is the first orally administered coronavirus-specific investigational protease inhibitor to be evaluated in clinical studies, and follows Pfizer’s intravenously administered investigational protease inhibitor, which is currently being evaluated in a Phase 1b multi-dose study in hospitalized clinical trial participants with COVID-19

NEW YORK–(BUSINESS WIRE)– Pfizer Inc. (NYSE: PFE) announced today that it is progressing to multiple ascending doses after completing the dosing of single ascending doses in a Phase 1 study in healthy adults to evaluate the safety and tolerability of an investigational, novel oral antiviral therapeutic for SARS-CoV-2, the virus that causes COVID-19. This Phase 1 trial is being conducted in the United States. The oral antiviral clinical candidate PF-07321332, a SARS-CoV2-3CL protease inhibitor, has demonstrated potent in vitro anti-viral activity against SARS-CoV-2, as well as activity against other coronaviruses, suggesting potential for use in the treatment of COVID-19 as well as potential use to address future coronavirus threats.

“Tackling the COVID-19 pandemic requires both prevention via vaccine and targeted treatment for those who contract the virus. Given the way that SARS-CoV-2 is mutating and the continued global impact of COVID-19, it appears likely that it will be critical to have access to therapeutic options both now and beyond the pandemic,” said Mikael Dolsten, MD, PhD., Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer. “We have designed PF-07321332 as a potential oral therapy that could be prescribed at the first sign of infection, without requiring that patients are hospitalized or in critical care. At the same time, Pfizer’s intravenous antiviral candidate is a potential novel treatment option for hospitalized patients. Together, the two have the potential to create an end to end treatment paradigm that complements vaccination in cases where disease still occurs.”

Protease inhibitors bind to a viral enzyme (called a protease), preventing the virus from replicating in the cell. Protease inhibitors have been effective at treating other viral pathogens such as HIV and hepatitis C virus, both alone and in combination with other antivirals. Currently marketed therapeutics that target viral proteases are not generally associated with toxicity and as such, this class of molecules may potentially provide well-tolerated treatments against COVID-19.

The Phase 1 trial is a randomized, double-blind, sponsor-open, placebo-controlled, single- and multiple-dose escalation study in healthy adults evaluating the safety, tolerability and pharmacokinetics of PF-07321332.

Initiation of this study is supported by preclinical studies that demonstrated the antiviral activity of this potential first-in-class SARS-CoV-2 therapeutic designed specifically to inhibit replication of the SARS-CoV2 virus. The structure of PF-07321332, together with the pre-clinical data, will be shared in a COVID-19 session of the Spring American Chemical Society meeting on April 6.

Pfizer is also investigating an intravenously administered investigational protease inhibitor, PF-07304814, which is currently in a Phase 1b multi-dose trial in hospitalized clinical trial participants with COVID-19.

About Pfizer: Breakthroughs That Change Patients’ Lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com. In addition, to learn more, please visit us on www.Pfizer.com and follow us on Twitter at @Pfizer and @Pfizer NewsLinkedInYouTube and like us on Facebook at Facebook.com/Pfizer.

.CLIP

https://cen.acs.org/content/cen/articles/99/i13/Pfizer-unveils-oral-SARS-CoV.html

09913-scicon3-struct.jpg

Drugmaker Pfizer revealed its oral COVID-19 antiviral clinical candidate PF-07321332 on Tuesday at the American Chemical Society Spring 2021 meeting. The compound, which is currently in Phase 1 clinical trials, is the first orally administered compound in the clinic that targets the main protease (also called the 3CL protease) of SARS-CoV-2, the virus that causes COVID-19. By inhibiting the main protease, PF-07321332 prevents the virus from cleaving long protein chains into the parts it needs to reproduce itself. Dafydd Owen, director of medicinal chemistry at Pfizer, presented the compound in a symposium of the Division of Medicinal Chemistry.

Last year, Pfizer reported PF-07304814, a different small molecule inhibitor of SARS-CoV-2’s main protease. The work to develop that compound began during the 2002-2003 outbreak of SARS-CoV, severe acute respiratory syndrome. But that molecule can only be given intravenously, which limits its use to hospital settings.

Because PF-07321332 can be taken orally, as a pill or capsule, it could be given outside of hospitals if it proves to be safe and effective. People who have been exposed to SARS-CoV-2 could take it as a preventative measure, for example.

“For the foreseeable future, we will expect to see continued outbreaks from COVID-19. And therefore, as with all viral pandemics, it’s important we have a full toolbox on how to address it,” Charlotte Allerton, Pfizer’s head of medicine design, told C&EN.

PF-07321332 was developed from scratch during the current pandemic. It’s a reversible covalent inhibitor that reacts with one of the main protease’s cysteine residues. Owen also discussed the chemistry involved in scaling up the compound. The first 7 mg of the compound were synthesized in late July 2020. Encouraged by the early biological data, the Pfizer team aimed to scale up the synthesis. By late October, they’d made 100 g of the compound. Just two weeks later, the chemists had scaled up the synthesis to more than 1 kg. Owen said 210 researchers had worked on the project. Ana Martinez, who studies COVID-19 treatments at the Spanish National Research Council CSIC and also presented during the symposium, told C&EN that having a COVID-19 antiviral is of critical importance. She eagerly anticipates the safety and efficacy data from the trials of PF-07321332. “Hopefully we will have a new drug to fight against COVID-19,” Martinez said. And because the molecule targets the main protease, she said that it might be useful for fighting other coronaviruses and preventing future pandemics.Chemical & Engineering News 

./////////////////PF-07321332, PF 07321332, COVID 19, CORONA VIRUS, SARS-CoV-2 inhibitor, PHASE 1

C1N(C([C@@H]2C1[C@]2(C)C)C(=O)N[C@@H](CC3C(NCC3)=O)C#N)C(C([C@@](C)(C)C)NC(=O)C(F)(F)F)=O

C1N(C(C2C1C2(C)C)C(=O)N[C@@H](CC3C(NCC3)=O)C#N)C(C([C@@](C)(C)C)NC(=O)C(F)(F)F)=O

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Pabinafusp alfa


(Heavy chain)
EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYWLGWVRQM PGKGLEWMGD IYPGGDYPTY
SEKFKVQVTI SADKSISTAY LQWSSLKASD TAMYYCARSG NYDEVAYWGQ GTLVTVSSAS
TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL
YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS
VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSRDELT
KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ
GNVFSCSVMH EALHNHYTQK SLSLSPGKGS SETQANSTTD ALNVLLIIVD DLRPSLGCYG
DKLVRSPNID QLASHSLLFQ NAFAQQAVCA PSRVSFLTGR RPDTTRLYDF NSYWRVHAGN
FSTIPQYFKE NGYVTMSVGK VFHPGISSNH TDDSPYSWSF PPYHPSSEKY ENTKTCRGPD
GELHANLLCP VDVLDVPEGT LPDKQSTEQA IQLLEKMKTS ASPFFLAVGY HKPHIPFRYP
KEFQKLYPLE NITLAPDPEV PDGLPPVAYN PWMDIRQRED VQALNISVPY GPIPVDFQRK
IRQSYFASVS YLDTQVGRLL SALDDLQLAN STIIAFTSDH GWALGEHGEW AKYSNFDVAT
HVPLIFYVPG RTASLPEAGE KLFPYLDPFD SASQLMEPGR QSMDLVELVS LFPTLAGLAG
LQVPPRCPVP SFHVELCREG KNLLKHFRFR DLEEDPYLPG NPRELIAYSQ YPRPSDIPQW
NSDKPSLKDI KIMGYSIRTI DYRYTVWVGF NPDEFLANFS DIHAGELYFV DSDPLQDHNM
YNDSQGGDLF QLLMP
(Light chain)
DIVMTQTPLS LSVTPGQPAS ISCRSSQSLV HSNGNTYLHW YLQKPGQSPQ LLIYKVSNRF
SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP WTFGQGTKVE IKRTVAAPSV
FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL
SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC
(Disulfide bridge: H22-H96, H145-H201, H221-L219, H227-H’227, H230-H’230, H262-H322, H368-H426, H596-H609, H847-H857, H’22-H’96, H’145-H’201, H’221-L’219, H’262-H’322, H’368-H’426, H’596-H’609, H’847-H’857, L23-L93, L139-L199, L’23-L’93, L’139-L’199)

Pabinafusp alfa

CAS 2140211-48-7

PMDA 2021/3/23, JAPAN 

Pabinafusp alfa (genetical recombination) (JAN)

Pabinafusp alfa (INN)

2140211-48-7, UNII: TRF8S0U6ON

Immunoglobulin G1, anti-(human transferrin receptor) (human-mus musculus monoclonal JR-141 gamma1-chain) fusion protein with peptide (synthetic 2-amino acid linker) fusion protein with human iduronate-2-sulfatase, disulfide with human-mus musculus mono

Immunoglobulin G1-kappa, anti-(human transferrin receptor 1, tfr1) humanized monoclonal antibody, fused with human iduronate-2-sulfatase, glycoform alfa:

Pabinafusp alfa is under investigation in clinical trial NCT03568175 (A Study of JR-141 in Patients With Mucopolysaccharidosis II).

JR-141

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JCR Pharmaceuticals Announces Approval of IZCARGO® (Pabinafusp Alfa) for Treatment of MPS II (Hunter Syndrome) in Japan

– First Approved Enzyme Replacement Therapy for MPS II to Penetrate Blood-Brain Barrier via Intravenous Administration, Validating JCR’s J-Brain Cargo® Technology –March 23, 2021 07:30 AM Eastern Daylight Time

HYOGO, Japan–(BUSINESS WIRE)–JCR Pharmaceuticals Co., Ltd. (TSE 4552; “JCR”) today announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has approved IZCARGO® (pabinafusp alfa 10 mL, intravenous drip infusion) for the treatment of mucopolysaccharidosis type II (MPS II, or Hunter syndrome). IZCARGO® (formerly known as JR-141) is a recombinant iduronate-2-sulfatase enzyme replacement therapy (ERT) that relies on J-Brain Cargo®, a proprietary technology developed by JCR, to deliver therapeutics across the blood-brain barrier (BBB). It is the first-ever approved ERT that penetrates the BBB via intravenous administration, a potentially life-changing benefit for individuals with lysosomal storage disorders (LSDs) such as MPS II.

“Subsequent to this approval in Japan, I look forward to further accumulation of clinical evidence for pabinafusp alfa in Brazil, the US and EU”Tweet this

Many patients with MPS II show complications not only in somatic symptoms but also in the central nervous system (CNS), which are often severe, with significant effects on patients’ neurocognitive development, independence, and quality of life. By delivering the enzyme to both the body and the brain, IZCARGO® treats the neurological complications of Hunter syndrome that other available therapies have been unable or inadequate to address so far.

“Approval of IZCARGO® in Japan under SAKIGAKE designation is a key milestone in JCR Pharmaceuticals’ global expansion. It comes on the heels of Fast Track designation from the US FDA, orphan designation from the European Medicines Agency, and the FDA’s acceptance of the JR-141 Investigational New Drug application, enabling JCR to begin our Phase 3 trial in the US,” said Shin Ashida, chairman and president of JCR Pharmaceuticals. “These critical regulatory milestones in Japan, where we have such a strong record of success, and those in the US and Europe, provide important validation of the value of our J-Brain Cargo® technology to deliver therapies across the blood-brain barrier, which we believe is essential to addressing the central nervous system complications of lysosomal storage disorders. We will continue our uncompromising effort to take on the challenge of providing new treatment options for patients with lysosomal storage disorders around the world as soon as possible.”

The MHLW’s approval of IZCARGO® is based on totality of evidence from non-clinical and clinical studies1-4. In a phase 2/3 clinical trial conducted in Japan, all 28 patients experienced significant reductions in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF) – a biomarker for effectiveness against CNS symptoms of MPS II – after 52 weeks of treatment, thus meeting the trial’s primary endpoint. IZCARGO® maintained somatic disease control in patients who switched from standard ERT to IZCARGO®. The study also confirmed an improvement in somatic symptoms in participants who had not previously received standard ERT prior to the start of the trial. Additionally, a neurocognitive development assessment demonstrated maintenance or improvement of age-equivalent function in 21 of the 28 patients. There were no reports of serious treatment-related adverse events in the trial, suggestive of a favorable safety and tolerability profile for IZCARGO®.4

“Subsequent to this approval in Japan, I look forward to further accumulation of clinical evidence for pabinafusp alfa in Brazil, the US and EU,” said Dr. Paul Harmatz of University of California – San Francisco (UCSF) Benioff Children’s Hospital Oakland, Oakland, CA, United States. “The availability of an enzyme replacement therapy that crosses the blood-brain barrier is expected to treat both CNS and somatic symptoms associated with this devastating and life-threatening disorder, including developmental and cognitive delays, bone deformities, and abnormal behavior, which have, historically, been unaddressed.”

JCR recently filed an application with the Brazilian Health Surveillance Agency (Agência Nacional de Vigilância Sanitária [ANVISA]) for marketing approval of IZCARGO® for the treatment of patients with MPS II. JCR is also preparing to launch a Phase 3 trial of IZCARGO® in the US, Brazil, the UK, Germany, and France.

About pabinafusp alfa

Pabinafusp alfa (10 mL, intravenous drip infusion) is a recombinant fusion protein of an antibody against the human transferrin receptor and idursulfase, the enzyme that is missing or malfunctioning in subjects with Hunter syndrome. It incorporates J-Brain Cargo®, JCR’s proprietary BBB-penetrating technology, to cross the BBB through transferrin receptor-mediated transcytosis, and its uptake into cells is mediated through the mannose-6-phosphate receptor. This novel mechanism of action is expected to make pabinafusp alfa effective against the CNS symptoms of Hunter syndrome.

In pre-clinical trials, JCR has confirmed both high-affinity binding of pabinafusp alfa to transferrin receptors, and passage across the BBB into neuronal cells, as evidenced by electron microscopy. In addition, JCR has confirmed enzyme uptake in various brain tissues. The company has also confirmed a reduction of substrate accumulation in the CNS and peripheral organs in an animal model of Hunter syndrome.1

In several clinical trials of pabinafusp alfa, JCR obtained evidence of reduced HS concentrations in the CSF, a biomarker for assessing effectiveness against CNS symptoms. The results were consistent with those obtained in pre-clinical studies. Clinical studies have also demonstrated positive effects of pabinafusp alfa on CNS symptoms.2

About J-Brain Cargo® Technology

JCR’s first-in-class proprietary technology, J-Brain Cargo®, enables the development of therapies that cross the BBB and penetrate the CNS. The CNS complications of diseases are often severe, resulting in developmental delays, an impact on cognition and, above all, poor prognosis, which affect patients’ independence as well as the quality of life of patients and their caregivers. With J-Brain Cargo®, JCR seeks to address the unresolved clinical challenges of LSDs by delivering the enzyme to both the body and the brain.

About Mucopolysaccharidosis II (Hunter Syndrome)

Mucopolysaccharidosis II (Hunter syndrome) is an X-linked recessive LSD caused by a deficiency of iduronate-2-sulfatase, an enzyme that breaks down complex carbohydrates called glycosaminoglycans (GAGs, also known as mucopolysaccharides) in the body. Hunter syndrome, which affects an estimated 7,800 individuals worldwide (according to JCR research), gives rise to a wide range of somatic and neurological symptoms. The current standard of care for Hunter syndrome is ERT. CNS symptoms related MPS II have been unmet medical needs so far.

About JCR Pharmaceuticals Co., Ltd.

JCR Pharmaceuticals Co., Ltd. (TSE 4552) is a global specialty pharmaceuticals company that is redefining expectations and expanding possibilities for people with rare and genetic diseases worldwide. We continue to build upon our 45-year legacy in Japan while expanding our global footprint into the US, Europe, and Latin America. We improve patients’ lives by applying our scientific expertise and unique technologies to research, develop, and deliver next-generation therapies. Our approved products in Japan include therapies for the treatment of growth disorder, Fabry disease, acute graft-versus host disease, and renal anemia. Our investigational products in development worldwide are aimed at treating rare diseases including MPS I (Hurler syndrome, Hurler-Scheie, and Scheie syndrome), MPS II (Hunter syndrome), Pompe disease, and more. JCR strives to expand the possibilities for patients while accelerating medical advancement at a global level. Our core values – reliability, confidence, and persistence – benefit all our stakeholders, including employees, partners, and patients. Together we soar. For more information, please visit https://www.jcrpharm.co.jp/en/site/en/.

1 Sonoda H, Morimoto H, Yoden E, et al. A blood-brain-barrier-penetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Molecular Therapy. 2018;26(5):1366-1374.

2 Morimoto H, Kida K, Yoden E, et al. Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice. Molecular Therapy. 2021;S1525-0016(21)00027-7.

3 Okuyama T, Eto Y, Sakai N, et al. Iduronate-2-sulfatase with anti-human transferrin receptor antibody for neuropathic mucopolysaccharidosis II: a phase 1/2 trial. Molecular Therapy. 2019;27(2):456-464.

Okuyama T, Eto Y, Sakai N, et al. A phase 2/3 trial of pabinafusp alfa, IDS fused with anti-human transferrin receptor antibody, targeting neurodegeneration in MPS-II. Molecular Therapy. 2021;29(2):671-679.

//////////Pabinafusp alfa, JR-141, JR 141,APPROVALS 21, JAPAN 2021

#Pabinafusp alfa, #JR-141, #JR 141, #APPROVALS 21, #JAPAN 2021

Diclofenac etalhyaluronate sodium


Display Structure of DICLOFENAC ETALHYALURONATE SODIUM
2D chemical structure of 1398396-25-2

Diclofenac etalhyaluronate sodium

RN: 1398396-25-2
UNII: LG1II3835L

Molecular Formula, [(C30-H35-Cl2-N3-O12)a-(C14-H20-N-Na-O11)b]n-H2-O

Molecular Weight, 1101.8195

HYALURONIC ACID PARTLY AMIDIFIED WITH 2-(2-(2-((2,6-DICHLOROPHENYL)AMINO)PHENYL)ACETYLOXY)ETHANAMINE, SODIUM SALT

HYALURONAMIDE, N-(2-((2-(2-((2,6-DICHLOROPHENYL)AMINO)PHENYL)ACETYL)OXY)ETHYL), SODIUM SALT

SI 613

APPROVED PMDA JAPAN 2021/3/23, Joycle

Anti-inflammatory, Joint function improving agent

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Treatment of Signs and Symptoms of Osteoarthritis of the Knee

Chemical structure of N-[2-[[2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]ethyl]hyaluronamide (diclofenac etalhyaluronate, SI-613)

Diclofenac Etalhyaluronate Sodium

Sodium hyaluronate partially amidated with 2- (2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetyloxy) ethaneamine

Hyaluronic acid sodium salt partly amidified with 2- (2- {2-[(2,6-dichlorophenyl) amino] phenyl} acetyloxy) ethanamine

[(C 30 H 35 Cl 2 N 3 O 12 ) a (C 14 H 20 NNaO 11 ) b ] n
[ 1398396-25-2 ]

Hyaluronic acid/non-steroidal anti-inflammatory drug; Hyaluronic acid/NSAID; JOYCLU; ONO 5704; ONO-5704/SI-613; SI-613

  • OriginatorSeikagaku Corporation
  • DeveloperOno Pharmaceutical; Seikagaku Corporation
  • ClassAmides; Analgesics; Antirheumatics; Drug conjugates; Glycosaminoglycans; Nonsteroidal anti-inflammatories
  • Mechanism of ActionCyclooxygenase inhibitors
  • RegisteredOsteoarthritis
  • Phase IITendinitis
  • 23 Mar 2021Registered for Osteoarthritis in Japan (Intra-articular)
  • 25 Sep 2020Phase II for Osteoarthritis is still ongoing in USA (Seikagaku Corporation pipeline, September 2020)
  • 25 Sep 2020Phase II for Tendinitis is still ongoing in Japan (Seikagaku Corporation pipeline, September 2020)

In today’s aging society, osteoarthritis (hereinafter also referred to as “OA” in the present specification), which is a dysfunction caused by joint pain and joint degeneration, is the most common joint disease in the world. It is one of the major causes of physical disorders that interfere with daily life in the elderly. Further, as a disease accompanied by swelling and pain in joints, rheumatoid arthropathy (hereinafter, also referred to as “RA” in the present specification), which is polyarthritis, is known. In RA as well, when the condition progresses over a long period of time, cartilage and bones are destroyed and degeneration or deformation occurs, resulting in physical disorders that interfere with daily life, such as narrowing the range in which joints can be moved.

Currently, preparations using hyaluronic acid and its derivatives are used as medicines for arthropathy such as osteoarthritis and rheumatoid arthropathy. Hyaluronic acid preparations are usually formulated as injections, and for the purpose of improving dysfunction due to arthropathy and suppressing pain through the lubricating action, shock absorption action, cartilage metabolism improving action, etc. of hyaluronic acid, the affected knee, It is administered directly to joints such as the shoulders. Commercialized hyaluronic acid preparations include, for example, those containing purified sodium hyaluronate as an active ingredient (for example, Alz (registered trademark) and Svenir (registered trademark)). The preparation requires continuous administration of 3 to 5 times at a frequency of once a week.
In addition, preparations containing crosslinked hyaluronan as an active ingredient require three consecutive doses once a week (for example, Synvisc®), or treatment is completed with a single dose. For single dose administration (eg, Synvisc-One®, Gel-One®, MONOVISC®) are known.On the other hand, steroids and non-steroidal anti-inflammatory compounds are known as quick-acting drugs, and are also used for treatments aimed at relieving joint pain caused by OA and RA. For example, the steroid triamcinolone acetonide has been used as a therapeutic target for joint diseases such as rheumatoid arthritis. Triamcinolone acetonide is commercially available as a drug that is injected intra-articularly and requires administration every 1 to 2 weeks for treatment. Further, as non-steroidal anti-inflammatory compounds, for example, ointments containing diclofenac sodium as an active ingredient and oral administration agents are known.It is also known that a mixture or a conjugate of hyaluronic acid or a derivative thereof and a steroid or a non-steroidal anti-inflammatory compound is used as an active ingredient. For example, a mixture of crosslinked hyaluronic acid and triamcinolone hexaacetonide (CINGAL®) has been commercialized as a single-dose drug. Further, a compound in which hyaluronic acid or a derivative thereof is linked to a steroid or a non-steroidal anti-inflammatory compound is also known. For example, Patent Documents 1 and 2 describe derivatives in which an anti-inflammatory compound is introduced into hyaluronic acid via a spacer. These aim to achieve both fast-acting pain relief and long-term pain relief through improvement of dysfunction. However, it has not yet reached the stage where it can be said that sufficient treatment methods for OA and RA have been established and provided.

PATENT

 WO 2018168920

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018168920

<Synthesis Example>
 Aminoethanol-diclofenac-introduced sodium hyaluronate (test substance) was synthesized according to the method described in Examples of International Publication No. 2005/066241 (hyaluronic acid weight average molecular weight: 800,000, introduction rate). : 18 mol%).
 More specifically, it was synthesized by the following method.
 2.155 g (10.5 mmol) of 2-bromoethylamine hydrobromide is dissolved in 20 mL of dichloromethane, 1.436 mL (10.5 mmol) of triethylamine is added under ice-cooling, and di-tert-butyl-dicarbonate (Boc) is added. 2 O) 2.299 g (10.5 mmol) of a dichloromethane solution of 5 mL was added and stirred. After stirring at room temperature for 90 minutes, ethyl acetate was added, and the mixture was washed successively with 5 wt% citric acid aqueous solution, water and saturated brine. After dehydration with sodium sulfate, the solvent was distilled off under reduced pressure to obtain Boc-aminoethyl bromide.
 5 mL of a dimethylformamide (DMF) solution of 2.287 g (10.2 mmol) of Boc-aminoethyl bromide obtained above is ice-cooled, 6 mL of a DMF solution of 3.255 g (10.2 mmol) of diclofenac sodium is added, and the mixture is added at room temperature. Stirred overnight. The mixture was stirred at 60 ° C. for 11 hours and at room temperature overnight. Ethyl acetate was added, and the mixture was sequentially separated and washed with a 5 wt% aqueous sodium hydrogen carbonate solution, water, and saturated brine. After dehydration with sodium sulfate, ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1 (v / v), 0.5% by volume triethylamine) to obtain Boc-aminoethanol-diclofenac.
 2.108 g (4.80 mmol) of Boc-aminoethanol-diclofenac obtained above was dissolved in 5 mL of dichloromethane, 20 mL of 4M hydrochloric acid / ethyl acetate was added under ice-cooling, and the mixture was stirred for 2.5 hours. Diethyl ether and hexane were added and precipitated, and the precipitate was dried under reduced pressure. As a result, aminoethanol-diclofenac hydrochloride was obtained. Structure 1 was identified by-NMR
  H: 1 H-NMR (500 MHz, CDCl 3 ) [delta] (ppm) = 3.18 (2H, t, NH 2 CH 2 CH 2 O-), 3.94 (2H, s, Ph-CH 2 -CO), 4.37 (2H, t, NH 2 CH 2 CH 2 O-), 6.47-7.31 (8H, m, Aromatic H, NH).
 After dissolving 500 mg (1.25 mmol / disaccharide unit) of hyaluronic acid having a weight average molecular weight of 800,000 in 56.3 mL of water / 56.3 mL of dioxane, imide hydroxysuccinate (1 mmol) / 0.5 mL of water, water-soluble carbodiimide Hydrochloride (WSCI / HCl) (0.5 mmol) / water 0.5 mL, aminoethanol-diclofenac hydrochloride (0.5 mmol) / (water: dioxane = 1: 1 (v / v), 5 mL obtained above ) Was added in sequence, and the mixture was stirred all day and night. 7.5 mL of a 5 wt% sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was stirred for about 4 hours. 215 μL of a 50% (v / v) acetic acid aqueous solution was added to the reaction solution for neutralization, and then 2.5 g of sodium chloride was added and the mixture was stirred. 400 ml of ethanol was added to precipitate, and the precipitate was washed twice with an 85% (v / v) aqueous ethanol solution, twice with ethanol, and twice with diethyl ether, dried under reduced pressure overnight at room temperature, and aminoethanol-diclophenac. Introduction Sodium hyaluronate (test substance) was obtained. The introduction rate of diclofenac measured by a spectrophotometer was 18 mol%.

PATENT

 WO 2018168921

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018168921

//////////Diclofenac etalhyaluronate sodium, JOYCLU, ONO 5704, ONO-5704/SI-613, SI 613, JAPAN 2021, Joycle, APPROVALS 2021

#Diclofenac etalhyaluronate sodium, #JOYCLU, #ONO 5704, #ONO-5704/SI-613, #SI 613, #JAPAN 2021, #Joycle, #APPROVALS 2021

Dasiglucagon


Dasiglucagon.png
2D chemical structure of 1544300-84-6
str1

Dasiglucagon

Treatment of Hypoglycemia in Type 1 and Type 2 Diabetes Patients

FormulaC152H222N38O50
CAS1544300-84-6
Mol weight3381.6137

FDA APPROVED,  2021/3/22, Zegalogue

Zealand Pharma A/S

UNIIAD4J2O47FQ

HypoPal rescue pen

SVG Image
IUPAC CondensedH-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-Trp-Leu-Glu-Ser-Thr-OH
SequenceHSQGTFTSDYSKYLDXARAEEFVKWLEST
HELMPEPTIDE1{H.S.Q.G.T.F.T.S.D.Y.S.K.Y.L.D.[Aib].A.R.A.E.E.F.V.K.W.L.E.S.T}$$$$
IUPACL-histidyl-L-seryl-L-glutaminyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-alpha-aspartyl-alpha-methyl-alanyl-L-alanyl-L-arginyl-L-alanyl-L-alpha-glutamyl-L-alpha-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-alpha-glutamyl-L-seryl-L-threonine

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-2-methylpropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid

. [16-(2-methylalanine)(S>X),17-L-alanine(R>A),20-L-α-glutamyl(Q>E),21-L-αglutamyl(D>E),24-L-lysyl(Q>K),27-L-α-glutamyl(M>E),28-L-serine(N>S)]human glucagon

L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L- phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L- lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L- arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L- valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl

ZP-4207

His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-Trp-Leu-Glu-Ser-Thr

L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-alpha-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-alpha-glutamyl-L-alphaC152 H222 N38 O50L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl-Molecular Weight3381.61

Other Names

  • L-Histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl-L-threonine
  • Developer Beta Bionics; Zealand Pharma
  • ClassAntihyperglycaemics; Antihypoglycaemics; Peptides
  • Mechanism of ActionGlucagon receptor agonists
  • Orphan Drug StatusYes – Hypoglycaemia; Congenital hyperinsulinism
  • RegisteredHypoglycaemia
  • Phase IIICongenital hyperinsulinism
  • Phase II/IIIType 1 diabetes mellitus
  • 22 Mar 2021Registered for Hypoglycaemia (In children, In adolescents, In adults, In the elderly) in USA (SC) – First global approval
  • 22 Mar 2021Zealand Pharma anticipates the launch of dasiglucagon in USA (SC, Injection) in June 2021
  • 22 Mar 2021Pooled efficacy and safety data from three phase III trials in Hypoglycaemia released by Zealand Pharma

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PATENTS

WO 2014016300

US 20150210744

PAPER

Pharmaceutical Research (2018), 35(12), 1-13

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.[1]

The most common side effects include nausea, vomiting, headache, diarrhea, and injection site pain.[1]

Dasiglucagon was approved for medical use in the United States in March 2021.[1][2][3] It was designated an orphan drug in August 2017.[4]

Dasiglucagon is under investigation in clinical trial NCT03735225 (Evaluation of the Safety, Tolerability and Bioavailability of Dasiglucagon Following Subcutaneous (SC) Compared to IV Administration).

Medical uses

Dasiglucagon is indicated for the treatment of severe hypoglycemia in people aged six years of age and older with diabetes.[1][2]

Contraindications

Dasiglucagon is contraindicated in people with pheochromocytoma or insulinoma.[1]

References

  1. Jump up to:a b c d e f https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214231s000lbl.pdf
  2. Jump up to:a b “Dasiglucagon: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 March 2021.
  3. ^ “Zealand Pharma Announces FDA Approval of Zegalogue (dasiglucagon) injection, for the Treatment of Severe Hypoglycemia in People with Diabetes” (Press release). Zealand Pharma. 22 March 2021. Retrieved 22 March 2021 – via GlobeNewswire.
  4. ^ “Dasiglucagon Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 10 August 2017. Retrieved 22 March 2021.

External links

  • “Dasiglucagon”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03378635 for “A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects” at ClinicalTrials.gov
  • Clinical trial number NCT03688711 for “Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM” at ClinicalTrials.gov
  • Clinical trial number NCT03667053 for “Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children” at ClinicalTrials.gov
Clinical data
Trade namesZegalogue
AHFS/Drugs.comZegalogue
License dataUS DailyMedDasiglucagon
Routes of
administration
Subcutaneous
Drug classGlucagon receptor agonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number1544300-84-6
PubChem CID126961379
DrugBankDB15226
UNIIAD4J2O47FQ
KEGGD11359
Chemical and physical data
FormulaC152H222N38O50
Molar mass3381.664 g·mol−1
3D model (JSmol)Interactive image

///////////Dasiglucagon, FDA 2021,  APPROVALS 2021, Zegalogue, ダシグルカゴン, ZP 4207, ZP-GA-1 Hypoglycemia, Type 1, Type 2 , Diabetes Patients, Zealand Pharma A/S, Orphan Drug Status,  Hypoglycaemia, Congenital hyperinsulinism,  HypoPal rescue pen, DIABETES

#Dasiglucagon, #FDA 2021,  #APPROVALS 2021, #Zegalogue, #ダシグルカゴン, #ZP 4207, ZP-GA-1 #Hypoglycemia, #Type 1, #Type 2 , #Diabetes Patients, #Zealand Pharma A/S, #Orphan Drug Status,  #Hypoglycaemia, #Congenital hyperinsulinism,  #HypoPal rescue pen, #DIABETESSMILES

  • C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)NC(C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CNC=N7)N)O

CLARITHROMYCIN


Clarithromycin structure.svg

Clarithromycin

Clarithromycin

Synonyms:A-56268, TE-031, 6-O-methylerythromycin, ATC:J01FA09Use:macrolide antibioticChemical name:6-O-methylerythromycinFormula:C38H69NO13

  • MW:747.96 g/mol
  • CAS-RN:81103-11-9
  • 81103-11-9

klacid XL / Klaricid XL / Macladin / Naxy / Veclam / Zeclar

(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-14-ethyl-12,13-dihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-7-methoxy-3,5,7,9,11,13-hexamethyl-1-oxacyclotetradecane-2,10-dione

Synthesis Reference

Jih-Hua Liu, David A. Riley, “Preparation of crystal form II of clarithromycin.” U.S. Patent US5844105, issued May, 1997. US5844105

wdt-1

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Product Ingredients

INGREDIENTUNIICASINCHI KEY
Clarithromycin citrate16K08R7NG0848130-51-8MDRWXDRMSKEMRE-AZFLODHXSA-N

 ClarithromycinCAS Registry Number: 81103-11-9CAS Name: 6-O-MethylerythromycinManufacturers’ Codes: A-56268; TE-031Trademarks: Biaxin (Abbott); Clarosip (Grñenthal); Clathromycin (Taisho); Cyllind (Abbott); Klacid (Abbott); Klaricid (Abbott); Macladin (Guidotti); Naxy (Sanofi Winthrop); Veclam (Zambon); Zeclar (Abbott)Molecular Formula: C38H69NO13Molecular Weight: 747.95Percent Composition: C 61.02%, H 9.30%, N 1.87%, O 27.81%Literature References: Semisynthetic macrolide antibiotic; derivative of erythromycin, q.v. Prepn: Y. Watanabe et al.,EP41355eidem,US4331803 (1981, 1982 both to Taisho); and in vitro antibacterial activity: S. Morimoto et al.,J. Antibiot.37, 187 (1984). In vitro and in vivo antibacterial activity: P. B. Fernandes et al.,Antimicrob. Agents Chemother.30, 865 (1986). Comparative antibacterial spectrum in vitro: C. Benson et al.,Eur. J. Clin. Microbiol.6, 173 (1987); H. M. Wexler, S. M. Finegold, ibid. 492. HPLC determn in biological fluids: D. Croteau et al.,J. Chromatogr.419, 205 (1987); in plasma: H. Amini, A. Ahmadiani, J. Chromatogr. B817, 193 (2005). Acute toxicity study: S. Abe et al.,Chemotherapy (Tokyo)36, Suppl. 3, 274 (1988). Symposium on pharmacology and comparative clinical studies: J. Antimicrob. Chemother.27, Suppl. A, 1-124 (1991). Comprehensive description: I. I. Salem, Anal. Profiles Drug Subs. Excip.24, 45-85, (1996).Properties: Colorless needles from chloroform + diisopropyl ether (1:2), mp 217-220° (dec). Also reported as crystals from ethanol, mp 222-225° (Morimoto). uv max (CHCl3): 288 nm (e 27.9). uv max (CHCl3): 240, 288 nm; (methanol): 211, 288 nm. [a]D24 -90.4° (c = 1 in CHCl3). Stable at acidic pH. LD50 in male, female mice, male, female rats (mg/kg): 2740, 2700, 3470, 2700 orally, 1030, 850, 669, 753 i.p., >5000 all s.c. (Abe).Melting point: mp 217-220° (dec); mp 222-225° (Morimoto)Optical Rotation: [a]D24 -90.4° (c = 1 in CHCl3)Absorption maximum: uv max (CHCl3): 288 nm (e 27.9). uv max (CHCl3): 240, 288 nmToxicity data: LD50 in male, female mice, male, female rats (mg/kg): 2740, 2700, 3470, 2700 orally, 1030, 850, 669, 753 i.p., >5000 all s.c. (Abe)Therap-Cat: Antibacterial.Keywords: Antibacterial (Antibiotics); Macrolides.

Clarithromycin, a semisynthetic macrolide antibiotic derived from erythromycin, inhibits bacterial protein synthesis by binding to the bacterial 50S ribosomal subunit. Binding inhibits peptidyl transferase activity and interferes with amino acid translocation during the translation and protein assembly process. Clarithromycin may be bacteriostatic or bactericidal depending on the organism and drug concentration.

Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections.[2] This includes strep throatpneumonia, skin infections, H. pylori infection, and Lyme disease, among others.[2] Clarithromycin can be taken by mouth as a pill or liquid.[2]

Common side effects include nausea, vomiting, headaches, and diarrhea.[2] Severe allergic reactions are rare.[2] Liver problems have been reported.[2] It may cause harm if taken during pregnancy.[2] It is in the macrolide class and works by decreasing protein production of some bacteria.[2]

Clarithromycin was developed in 1980 and approved for medical use in 1990.[3][4] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[5] Clarithromycin is available as a generic medication.[2] It is made from erythromycin and is chemically known as 6-O-methylerythromycin.[6]

Medical uses

Clarithromycin is primarily used to treat a number of bacterial infections including pneumoniaHelicobacter pylori, and as an alternative to penicillin in strep throat.[2] Other uses include cat scratch disease and other infections due to bartonellacryptosporidiosis, as a second line agent in Lyme disease and toxoplasmosis.[2] It may also be used to prevent bacterial endocarditis in those who cannot take penicillin.[2] It is effective against upper and lower respiratory tract infections, skin and soft tissue infections and helicobacter pylori infections associated with duodenal ulcers.

Spectrum of bacterial susceptibility


Staphylococcus aureus
Aerobic Gram-positive bacteria

Aerobic Gram-negative bacteria

Helicobacter

Mycobacteria

Mycobacterium avium complex consisting of:

Other bacteria

Safety and effectiveness of clarithromycin in treating clinical infections due to the following bacteria have not been established in adequate and well-controlled clinical trials:[7]

Aerobic Gram-positive bacteria

Aerobic Gram-negative bacteria

Anaerobic Gram-positive bacteria

Anaerobic Gram-negative bacteria

Contraindications

Side effects

The most common side effects are gastrointestinal: diarrhea (3%), nausea (3%), abdominal pain (3%), and vomiting (6%). It also can cause headaches, insomnia, and abnormal liver function tests. Allergic reactions include rashes and anaphylaxis. Less common side effects (<1%) include extreme irritability, hallucinations (auditory and visual), dizziness/motion sickness, and alteration in senses of smell and taste, including a metallic taste. Dry mouth, panic attacks, and nightmares have also been reported, albeit less frequently.[8]

Cardiac

In February 2018, the FDA issued a Safety Communication warning with respect to an increased risk for heart problems or death with the use of clarithromycin, and has recommended that alternative antibiotics be considered in those with heart disease.[9]

Clarithromycin can lead to a prolonged QT interval. In patients with long QT syndrome, cardiac disease, or patients taking other QT-prolonging medications, this can increase risk for life-threatening arrhythmias.[10]

In one trial, the use of short-term clarithromycin treatment was correlated with an increased incidence of deaths classified as sudden cardiac deaths in stable coronary heart disease patients not using statins.[11] Some case reports suspect it of causing liver disease.[12]

Liver and kidney

Clarithromycin has been known to cause jaundicecirrhosis, and kidney problems, including kidney failure.[citation needed]

Central nervous system

Common adverse effects of clarithromycin in the central nervous system include dizziness, headaches. Rarely, it can cause ototoxicity, delirium and mania.

Infection

A risk of oral candidiasis and vaginal candidiasis, due to the elimination of the yeast’s natural bacterial competitors by the antibiotic, has also been noted.

Pregnancy and breastfeeding

Clarithromycin should not be used in pregnant women except in situations where no alternative therapy is appropriate.[7] Clarithromycin can cause potential hazard to the fetus hence should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[7] For lactating mothers it is not known whether clarithromycin is excreted in human milk.[7]

Interactions

Clarithromycin inhibits a liver enzyme, CYP3A4, involved in the metabolism of many other commonly prescribed drugs. Taking clarithromycin with other medications that are metabolized by CYP3A4 may lead to unexpected increases or decreases in drug levels.

A few of the common interactions are listed below.

Colchicine

Clarithromycin has been observed to have a dangerous interaction with colchicine as the result of inhibition of CYP3A4 metabolism and P-glycoprotein transport. Combining these two drugs may lead to fatal colchicine toxicity, particularly in people with chronic kidney disease.[7]

Statins

Taking clarithromycin concurrently with certain statins (a class of drugs used to reduce blood serum cholesterol levels) increases the risk of side effects, such as muscle aches and muscle break down (rhabdomyolysis).[13]

Calcium channel blockers

Concurrent therapy with calcium channel blocker may increase risk of low blood pressurekidney failure, and death, compared to pairing calcium channel blockers with azithromycin, a drug similar to clarithromycin but without CYP3A4 inhibition.[14] Administration of clarithromycin in combination with verapamil have been observed to cause low blood pressurelow heart rate, and lactic acidosis.[7]

Carbamazepine

Clarithromycin may double the level of carbamazepine in the body by reducing its clearance, which may lead to toxic symptoms of carbamazepine, such as double visionloss of voluntary body movement, nausea, as well as hyponatremia.[15]

HIV medications

Depending on the combination of medications, clarithromycin therapy could be contraindicated, require changing doses of some medications, or be acceptable without dose adjustments.[16] For example, clarithromycin may lead to decreased zidovudine concentrations.[17]

Mechanism of action

Clarithromycin prevents bacteria from multiplying by acting as a protein synthesis inhibitor. It binds to 23S rRNA, a component of the 50S subunit of the bacterial ribosome, thus inhibiting the translation of peptides.[citation needed]

Pharmacokinetics

MetabolismUnlike erythromycin, clarithromycin is acid-stable, so can be taken orally without having to be protected from gastric acids. It is readily absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, clarithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of clarithromycin are released; its concentration in the tissues can be over 10 times higher than in plasma. Highest concentrations are found in liver, lung tissue, and stool.

Clarithromycin has a fairly rapid first-pass metabolism in the liver. Its major metabolites include an inactive metabolite, N-desmethylclarithromycin, and an active metabolite, 14-(R)-hydroxyclarithromycin. Compared to clarithromycin, 14-(R)-hydroxyclarithromycin is less potent against mycobacterial tuberculosis and the Mycobacterium avium complex. Clarithromycin (20%-40%) and its active metabolite (10%-15%) are excreted in urine. Of all the drugs in its class, clarithromycin has the best bioavailability at 50%, which makes it amenable to oral administration. Its elimination half-life is about 3 to 4 hours with 250 mg administered every 12 h, but increased to 5 to 7 h with 500 mg administered every 8 to 12 h. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.[18]

History

Clarithromycin was invented by researchers at the Japanese drug company Taisho Pharmaceutical in 1980.[3] The product emerged through efforts to develop a version of the antibiotic erythromycin that did not experience acid instability in the digestive tract, causing side effects, such as nausea and stomachache. Taisho filed for patent protection for the drug around 1980 and subsequently introduced a branded version of its drug, called Clarith, to the Japanese market in 1991. In 1985, Taisho partnered with the American company Abbott Laboratories for the international rights, and Abbott also gained FDA approval for Biaxin in October 1991. The drug went generic in Europe in 2004 and in the US in mid-2005.

Society and culture

A pack of Clarithromycin tablets manufactured by Taisho Pharmaceutical

Available forms

Clarithromycin is available as a generic medication.[2] In the United States, clarithromycin is available as immediate release tablets, extended release tablets, and granules for oral suspension.[2]

Brand names

Clarithromycin is available under several brand names in many different countries, for example Biaxin, Crixan, Claritron, Clarihexal, Clacid, Claritt, Clacee, Clarac, Clariwin, Claripen, Clarem, Claridar, Cloff, Fromilid, Infex, Kalixocin, Karicin, Klaricid, Klaridex, Klacid, Klaram, Klabax, MegaKlar, Monoclar, Resclar, Rithmo, Truclar, Vikrol and Zeclar.

Manufacturers

In the UK the drug product is manufactured in generic form by a number of manufacturers including Somex Pharma, Ranbaxy, Aptil and Sandoz.

SYN

CN 109705180

SYN

Indian Pat. Appl., 2014DE00731, 31 Aug 2016

SYN

Heterocycles, 31(12), 2121-4; 1990

SYN

https://patents.google.com/patent/WO2006064299A1/enErythromycin A is known to be a useful macrolide antibiotic having a strong activity against Gram-positive bacteria, this compound has an undesirable property that it loses rapidly the antibacterial activity by the acid in stomach when administered orally, where- upon its blood concentration remains at a low level. 6-0-Alkyl derivatives of Erythromycin- A are well known as an useful antibacterial agents. 6-O-Methyl-Erythromycin-A (Clarithromycin) and a pharmaceutically acceptable salt is a potent macrolide antibiotic as reported in US Patent No. 4,331 ,803. Clarithromycin is stable in acidic medium and also remarkable in vivo activity and has a strong antibacterial property against Gram-positive bacteria compared to Erythromycin- A. This compound shows excellent effect for the treatment of infections by oral administration.A number of synthetic processes have been reported for preparing 6-O-alkyl erythromycin. US Patent No. 4,331 ,803 discloses a method for the preparation of Clarithromycin by methylating 6-OH group of 2′-O-3′-N-benzyloxycarbonyl erythromycinFormula (III)

Figure imgf000003_0001

21,3′-O-Protected ErythromycinMethylation of 6-OH group of the 2′,3′-benzyloxycarbonyl erythromycin was carried out using methyl iodide in the presence of a suitable base in a solvent. Clarithromycin was obtained from the compound after removing benzyloxycarbonyl group by hydrogenolysis and then subjecting to the reductive methylation in the presence of excess amount of farmaldehyde. Clarithromycin can also be synthesized by the methylation of 6-OH position of Erythromycin-A-9-OximeFormula (II)

Figure imgf000004_0001

Erythromycin-9-OximeSynthesis of Clarithromycin using 9-oxime or its derivatives are well reported in US Patent Nos. 5,274,085; 4,680,386; 4,668,776; 4,670,549 and 4,672,109. In case of Erythromycin-9-Oxime derivatives, the oxime is protected before methylation step with 2- alkenyl group (US Patent Nos. 4,670,549; 4,668,776) or benzyl group (US Patent Nos. 4,680,386 and 4,670,549). However, it has been reported (Ref. Journal of Antibiotics 46, No. 6, Page No. 647, year 1993) that when the Erythromycin-A-9-Oxime is protected by trimethylsilyl group, which is very unstable under basic condition pose potential impurities formation during methylation. There are some methods reported in US Patent Nos., e.g. , 4,680,386; 4,670,549 and US Patent No. 4,311,803 for the synthesis of Clarithromycin by using chlorobenzyloxycarbonyl group for protection at 2′ and 3′ function of of Erythromycin-A-9-Oxime derivatives.For the protection of 2′-OH group (US Patent No. 4,311 ,803) requires large amounts of benzyl chloroformate which poses problems in handling because of its severe irritating and toxic properties. This protection step also leads to the formation of 3′ -N- demethylation, which requires an additional re-methylation step. The de-protection of chlorobenzyloxy carbonyl group leads to the formation of undesired side products. In earlier reported processes, e.g. , US Patent No. 4,990,602; EP 0,272,110 Al where the methylation has been done on Erythromycin-A-9-Oxime derivatives by the protection of 2′ and 4″ hydroxyl groups using DMSO and THF as a solvent at 0° to 50C or at room temperature, smooth methylation takes place with less side product formation. However, by using the above methylation processes the formation of 6, 11-O-dimethyl erythromycin- A (Compound- A) is always more than 1.0 % in Clarithromycin. Hence, there is a need for an efficient methylation process for the production of Clarithromycin with lesser amount of 6,11-O-dimethyl erythromycin-A than reported previously.

Figure imgf000009_0001
Figure imgf000008_0002
Figure imgf000008_0001
Figure imgf000006_0001

EXAMPLE 1Erythromycin-A-9-OximeTo a solution of 201 Ltr water in 561 Kg isopropyl alcohol is added 282 Kg (4057 mol) of hydroxyl amine hydrochloride under stirring and the reaction mixture is brought to 10 to 200C. Caustic flakes (162 Kg, 4050 mol) is added slowly to the reaction mixture by keeping temperature between 10° to 200C. After 15 minutes of completion of addition, pH of reaction mixture is adjusted to 6.5 to 7.0 by the slow addition of glacial acetic acid (96 Ltr, 100.8 Kg, 1678.6 mole). To the stirred reaction mass is added 300 Kg (408.8 mole) of Erythromycin-A base and reaction mixture is stirred at 55° C for 28 hours. After completion of the reaction, mixture is brought to ambient temperature and to it a mixture of ammonia solution (270 Kg) and water (600 Ltr) is added within 1 hour followed by 3000 Ltr of fresh water in next two hours and stirred the reaction mass for further 1 hour. White solid product obtained is centrifuged, wet cake is washed with water and dried at 6O0C for 12 hours to give 270 Kg of erythromycin-A Oxime. Melting point = 156° to 158°C.EXAMPLE 22′,4″-O-Bis(trimethylsilyl)-erythro?nycin-A-9[O-(l-methoxy-l-methyl ethyl)oximeTo a solution of 80 Kg (106.8 mole) of Erythromycin-A-9-Oxime in 400 Ltr of dichloromethane is added 38.50 Kg (534 mole) of 2-methoxy propene at 100C temperature 19.25 Kg (166.6 mole) of pyridine hydrochloride is added under stirring and the reaction mixture is stirred at 8 to 12° C for 6 hours then to it is added 19.30 Kg (119.5 mole) of HMDS and stirring is continued for 12 to 15 hours at 15° to 18°C temperature. After completion of reaction, 400 Ltr of saturated aqueous sodium carbonate solution is added and the mixture is stirred thoroughly at room temperature. Aqueous layer is further extracted with fresh DCM (100 Ltr). Both DCM extracts are mixed together and washed with water (200 Ltr) followed by brine solution (200 Ltr). The solvent is evaporated under reduced pressure. To the obtained crude solid mass is charged isopropyl alcohol (240 Ltr) and distilled out 80 Ltr of isopropyl alcohol. To the reaction mixture 160 Ltr of water is charged and stirring continued at room temperature for 1 hour. Solid crystalline product obtained is centrifuged and dried at 60° to 650C for 8 hours under vacuum to give 85 Kg of title compound. Melting point = 125° to 126°C. HPLC Purity = More than 90 % .EXAMPLE 3Clarithromycin-9- OximeTo a solution of 80 Kg (82.98 mole) of 2′,4″-O-bis(trimethylsilyl)-erythromycin-A- 9-[O-(l-methoxy methyl ethyl)Oxime] in 1200 Ltr of a mixture of dimethyl sulfoxide and diethylether (1 : 1) are added methyl iodide (20.62 Kg, 145.2 mole) and 6.48 Kg (98.35 mole) of 85 % potassium hydroxide powder and the reaction mixture is stirred for 90 minutes at room temperature. To the reaction mass is added 53 Kg of 40 % dimethylamine solution and stirring is continued for 1 hour diethylether layer is separated and DMSO layer is further extracted with fresh diethylether (200 Ltr). Combined ether layer is washed with water and concentrated in vacuum. To the obtained semi solid mass 330 Ltr of isopropyl alcohol is charged and then distilled out 165 Ltr of isopropyl alcohol. To the obtained slurry 165 Ltr of water and 21.71 Kg formic acid (99%) are added and the mixture is stirred at room temperature for 30 minutes. 622 Ltr of water is added to the reaction mixture and pH is adjusted between 10.5 and 11.5 with 25 % aqueous sodium hydroxide solution. Solid compound obtained is centrifuged and wet cake is kept as such for further reaction on the basis of moisture content. Wet weight = 95 Kg, Moisture Content = 33 %, Dried weight = 62 KgEXAMPLE 46-O-Methyl erythromycin- A (Clarithromycin)62 Kg of 6-O-Methyl erythromycin-9-Oxime is charged into a mixture of 434 Ltr of isopropyl alcohol and water (1: 1) and to it is added 38.80 Kg of sodium metabisulphite (203 mole) and then the mixture is heated to reflux for 6 to 8 hours. To the reaction mixture is charged water (620 Ltr) at ambient temperature and then the mixture is adjusted to pH about 10.5 to 11.5 by adding 25% aqueous sodium hydroxide solution and stirred for further 1 hour. White solid crude product is centrifuged, washed with water (300 Ltr), dried at 65° to 750C for 8 hours to give 40 Kg of crude Clarithromycin which on re- crystallization with chloroform isopropyl alcohol mixture provided 20 Kg of Clarithromycin (Form II). 
SYNEP 0041355; US 4331803J Antibiot 1984,37(2),187-189

EP 0147062

The methylation of 2′-O,N-bis(benzyloxycarbonyl)-N-demethylerythromycin A (I) with methyl iodide and KOH or NaHI in DMSO-dimethoxyethane gives the 6-O-methyl derivative (II), which is deprotected by hydrogenation with H2 over Pd/C in ethanol acetic acid affording 6-O-methyl-N-demethylerythromycin A (III). Finally, this compound is methylated with formaldehyde under reductive conditions (H2-Pd/C) in ethanol/acetic acid. 
CLIP 

2 Clarithromycin. Initial attempts of making clarithromycin (2) from erythromycin (1) by methylation of 8 gave approximately equal amounts of 2 and 10 by methylation at O-6 and O-11, respectively (Scheme 2, route A).[28–30] This allowed 2 to be obtained in approximately 39% yield, but it contained a small impurity of di-O-methylated 9. To improve the yields and obtain 2 in pure form, other alternatives were explored. During methylation of analogues of 8 it was observed that the conformation of the macrocyclic core plays an important role for the regioselectivity of the O-methylation.[31] As oximes are readilyhydrolysed and may have different conformations than ketone 8, oximes 11 and 13 were subjected to methylation. Interestingly, methylation of 13, but not of 11, proved to be highly selective for O-6 and provided 14 in 86% yield (Scheme2 route B); an observation which supports that 13 populates different conformations compared to 8 and 11 under the methylation conditions.[31] Compound 14 was then hydrogenated with Pd/C to deprotect the two benzyloxycarbonyl groups and the 2-chlorobenzyl group. The N-methylamine was then methylated by reductive amination and the oxime was deprotected by hydrolysis to provide clarithromycin (2). This procedure was further modified for process-scale synthesis so that clarithromycin (2) could be obtained in 70% yield starting from oxime 11 without the isolation of any intermediate.[32][28] M. Shigeo, T. Yoko, W. Yoshiaki, O. Sadafumi, J. Antibiot. 1984, 37, 187 – 189. [29] Y. Watanabe, T. Adachi, T. Asaka, M. Kashimura, S. Morimoto, Heterocycles 1990, 31, 2121 – 2124. [30] E. H. Flynn, H. W. Murphy, R. E. McMahon, J. Am. Chem. Soc. 1955, 77, 3104 – 3106. [31] Y. Watanabe, S. Morimoto, T. Adachi, M. Kashimura, T. Asaka, J. Antibiot. 1993, 46, 647 – 660.32] R. A. Dominguez, M. D. C. C. Rodriguez, L. . D. Tejo, R. N. Rib, J. S. Cebrin, J. I. B. Bilbao, 2003, US6642364B2.

References

  1. ^ https://www.ema.europa.eu/documents/psusa/clarithromycin-list-nationally-authorised-medicinal-products-psusa/00000788/202004_en.pdf
  2. Jump up to:a b c d e f g h i j k l m n “Clarithromycin”. The American Society of Health-System Pharmacists. Archivedfrom the original on September 3, 2015. Retrieved September 4, 2015.
  3. Jump up to:a b Greenwood D (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1 ed.). Oxford: Oxford University Press. p. 239. ISBN 9780199534845Archived from the original on 2016-03-05.
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  5. ^ 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.
  6. ^ Kirst HA (2012). Macrolide Antibiotics (2 ed.). Basel: Birkhäuser Basel. p. 53. ISBN 9783034881050Archived from the original on 2016-03-05.
  7. Jump up to:a b c d e f g h i j k l “BIAXIN® Filmtab® (clarithromycin tablets, USP) BIAXIN® XL Filmtab® (clarithromycin extended-release tablets) BIAXIN® Granules (clarithromycin for oral suspension, USP)” (PDF). November 2, 2015. Archived (PDF) from the original on August 24, 2015. Retrieved November 2, 2015.
  8. ^ “Clarithromycin Side Effects in Detail – Drugs.com”Drugs.comArchived from the original on 2017-08-19. Retrieved 2017-08-18.
  9. ^ “Safety Alerts for Human Medical Products – Clarithromycin (Biaxin): Drug Safety Communication – Potential Increased Risk of Heart Problems or Death in Patients With Heart Disease”FDA. Retrieved 24 February 2018.
  10. ^ Yamaguchi S, Kaneko Y, Yamagishi T, et al. [Clarithromycin-induced torsades de pointes]. Nippon Naika Gakkai Zasshi. 2003;92(1):143–5.
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  19. ReferencesAllevi, P. et al.: Bioorg. Med. Chem. (BMECEP) 7, 12, 2749 (1999)Watanabe, Y. et al.: Heterocycles (HTCYAM) 31, 12, 2121 (1990).EP 158 467 (Taisho Pharmaceutical Co.; 22.3.1985; J-prior. 6.4.1984).EP 272 110 (Taisho Pharmaceutical Co.; 16.12.1987; J-prior. 17.12.1986).US 2 001 037 015 (Teva Pharm.; 15.12.2000; USA-prior. 29.2.2000).KR 2 000 043 839 (Hanmi Pharm.; ROK-prior. 29.12.1998).EP 1 150 990 (Hanmi Pharm.; 7.11.2001; ROK-prior. 29.12.1998)EP 41 355 (Taisho Pharmaceutical Co.; 27.5.1981; J-prior. 4.6.1980).Preparation of O,N-dicarbobenzoxy-N-demethylerythromycin:Flynn, E. H. et al.: J. Am. Chem. Soc. (JACSAT) 77, 3104 (1955).Process for preparation of erythromycin A oxime:US 5 808 017 (Abbott; 15.9.1998; USA-prior. 10.4.1996).Alternative synthesis of clarithromycin:Liao, G.; Zhang, G.; He, T.: Zhongguo Kangshengsu Zazhi (ZKZAEY) 27, 3, 148 (2002) (in Chinese).EP 1 134 229 (Hanmi Pharmac. Co.; 19.9.2001; ROK-prior. 15.3.2000).Crystal form 0 of clarithromycin:The Merck Index, 13th Ed., 2362, p. 408.US 5 945 405 (Abbott; 31.8.1999; USA-prior. 17.1.1997).

External links

Clinical data
Trade namesBiaxin, others
AHFS/Drugs.comMonograph
MedlinePlusa692005
License dataEU EMAby INNUS DailyMedClarithromycin
Pregnancy
category
AU: B3
Routes of
administration
By mouthintravenous
Drug classMacrolides
ATC codeJ01FA09 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)US: ℞-onlyEU: Rx-only [1]In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50%
Protein bindinglow binding
Metabolismhepatic
Elimination half-life3–4 h
Identifiers
showIUPAC name
CAS Number81103-11-9 
PubChem CID84029
DrugBankDB01211 
ChemSpider10342604 
UNIIH1250JIK0A
KEGGD00276 
ChEMBLChEMBL1741 
CompTox Dashboard (EPA)DTXSID3022829 
ECHA InfoCard100.119.644 
Chemical and physical data
FormulaC38H69NO13
Molar mass747.964 g·mol−1
3D model (JSmol)Interactive image
hideSMILESCC[C@@H]1[C@@]([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)O)(C)O
hideInChIInChI=1S/C38H69NO13/c1-15-26-38(10,45)31(42)21(4)28(40)19(2)17-37(9,47-14)33(52-35-29(41)25(39(11)12)16-20(3)48-35)22(5)30(23(6)34(44)50-26)51-27-18-36(8,46-13)32(43)24(7)49-27/h19-27,29-33,35,41-43,45H,15-18H2,1-14H3/t19-,20-,21+,22+,23-,24+,25+,26-,27+,29-,30+,31-,32+,33-,35+,36-,37-,38-/m1/s1 Key:AGOYDEPGAOXOCK-KCBOHYOISA-N 
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////////////////////CLARITHROMYCIN, Antibacterial, Antibiotics, Macrolides, A-56268, TE-031,

#CLARITHROMYCIN, #Antibacterial, #Antibiotics, #Macrolides, #A-56268, #TE-031,

ERYTHROMYCIN


Erythromycin A skeletal.svg
ChemSpider 2D Image | (-)-Erythromycin | C37H67NO13

Erythromycin

NSC-55929

UNII63937KV33D

CAS number114-07-8

  • Molecular FormulaC37H67NO13
  • Average mass733.927 Da
  • эритромицин [Russian] [INN]إيريثروميسين [Arabic] [INN]红霉素 [Chinese] [INN]

IUPAC Name(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-1-oxacyclotetradecane-2,10-dione

Synthesis ReferenceTakehiro Amano, Masami Goi, Kazuto Sekiuchi, Tomomichi Yoshida, Masahiro Hasegawa, “Process for preparing erythromycin A oxime or a salt thereof.” U.S. Patent US5274085, issued October, 1966.

US5274085ErythromycinCAS Registry Number: 114-07-8Additional Names: E-Base; E-Mycin; Erythromycin ATrademarks: Aknemycin (Hermal); Aknin (Lichtenstein); Emgel (GSK); Ery-Derm (Abbott); Erymax (Merz); Ery-Tab (Abbott); Erythromid (Abbott); ERYC (Warner-Chilcott); Erycen (APS); Erycin (Nycomed); Erycinum (Cytochemia); Ermysin (Orion); Gallimycin (Bimeda); Ilotycin (Lilly); Inderm (Dermapharm); PCE (Abbott); Retcin (DDSA); Staticin (Westwood); Stiemycin (Stiefel)Molecular Formula: C37H67NO13Molecular Weight: 733.93Percent Composition: C 60.55%, H 9.20%, N 1.91%, O 28.34%Literature References: Antibiotic substance produced by a strain of Streptomyces erythreus (Waksman) Waksman & Henrici, found in a soil sample from the Philippine Archipelago. Isoln: McGuire et al.,Antibiot. Chemother.2, 281 (1952); Bunch, McGuire, US2653899 (1953 to Lilly); Clark, Jr., US2823203 (1958 to Abbott). Properties: Flynn et al.,J. Am. Chem. Soc.76, 3121 (1954). Solubility data: Weiss et al.,Antibiot. Chemother.7, 374 (1957). Structure: Wiley et al.,J. Am. Chem. Soc.79, 6062 (1957). Configuration: Hofheinz, Grisebach, Ber.96, 2867 (1963); Harris et al.,Tetrahedron Lett.1965, 679. There are three erythromycins produced during fermentation, designated A, B, and C; A is the major and most important component. Erythromycins A and B contain the same sugar moieties, desosamine, q.v., and cladinose (3-O-methylmycarose). They differ in position 12 of the aglycone, erythronolide, A having an hydroxyl substituent. Component C contains desosamine and the same aglycone present in A but differs by the presence of mycarose, q.v., instead of cladinose. Structure of B: P. F. Wiley et al.,J. Am. Chem. Soc.79, 6070 (1957); of C: eidem,ibid. 6074. Synthesis of the aglycone, erythronolide B: E. J. Corey et al.,ibid.100, 4618, 4620 (1978); of erythronolide A: eidem,ibid.101, 7131 (1979). Asymmetric total synthesis of erythromycin A: R. B. Woodward et al.,ibid.103, 3215 (1981). NMR spectrum of A: D. J. Ager, C. K. Sood, Magn. Reson. Chem.25, 948 (1987). HPLC determn in plasma: W. Xiao et al.J. Chromatogr. B817, 153 (2005). Biosynthesis: Martin, Goldstein, Prog. Antimicrob. Anticancer Chemother., Proc. 6th Int. Congr. Chemother.II, 1112 (1970); Martin et al.,Tetrahedron31, 1985 (1975). Cloning and expression of clustered biosynthetic genes: R. Stanzak et al.,Biotechnology4, 229 (1986). Reviews: T. J. Perun in Drug Action and Drug Resistance in Bacteria1, S. Mitsuhashi, Ed. (University Park Press, Baltimore, 1977) pp 123-152; Oleinick in Antibioticsvol. 3, J. W. Corcoran, F. E. Hahn, Eds. (Springer-Verlag, New York, 1975) pp 396-419; Infection10, Suppl. 2, S61-S118 (1982). Comprehensive description: W. L. Koch, Anal. Profiles Drug Subs.8, 159-177 (1979).Properties: Hydrated crystals from water, mp 135-140°, resolidifies with second mp 190-193°. Melting point taken after drying at 56° and 8 mm. [a]D25 -78° (c = 1.99 in ethanol). uv max (pH 6.3): 280 nm (e 50). pKa1 8.8. Basic reaction. Readily forms salts with acids. Soly in water: ~2 mg/ml. Freely sol in alcohols, acetone, chloroform, acetonitrile, ethyl acetate. Moderately sol in ether, ethylene dichloride, amyl acetate.Melting point: mp 135-140°, resolidifies with second mp 190-193°pKa: pKa1 8.8Optical Rotation: [a]D25 -78° (c = 1.99 in ethanol)Absorption maximum: uv max (pH 6.3): 280 nm (e 50) Derivative Type: EthylsuccinateCAS Registry Number: 41342-53-4Trademarks: Anamycin (Chephasaar); Arpimycin (Rosemont); E.E.S. (Abbott); Eritrocina (Abbott); Eryliquid (Linden); Eryped (Abbott); Erythroped (Abbott); Esinol (Toyama); Monomycin (Grñenthal); Paediathrocin (Abbott); Pediamycin (Abbott); Refkas (Maruko)Molecular Formula: C43H75NO16Molecular Weight: 862.05Percent Composition: C 59.91%, H 8.77%, N 1.62%, O 29.70%Literature References: Prepn: GB830846; R. K. Clark, US2967129 (1960, 1961 both to Abbott).Properties: Hydrated crystals from acetone + water, mp 109-110°. [a]D -42.5°.Melting point: mp 109-110°Optical Rotation: [a]D -42.5° Therap-Cat: Antibacterial.Therap-Cat-Vet: Antibacterial.Keywords: Antibacterial (Antibiotics); Macrolides.

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Product Ingredients

INGREDIENTUNIICASINCHI KEY
Erythromycin estolateXRJ2P631HP3521-62-8AWMFUEJKWXESNL-JZBHMOKNSA-N
Erythromycin ethylsuccinate1014KSJ86F1264-62-6NSYZCCDSJNWWJL-YXOIYICCSA-N
Erythromycin gluceptate2AY21R0U6423067-13-2ZXBDZLHAHGPXIG-VTXLJDRKSA-N
Erythromycin lactobionate33H58I7GLQ3847-29-8NNRXCKZMQLFUPL-WBMZRJHASA-N
Erythromycin phosphateI8T8KU14X74501-00-2VUEMAFLGEMYXIH-YZPBMOCRSA-N
Erythromycin stearateLXW024X05M643-22-1YAVZHCFFUATPRK-YZPBMOCRSA-N
Erythromycin sulfateKVW9N83AME7184-72-7XTSSJGRRFMNXGO-YZPBMOCRSA-N
Erythromycin thiocyanateY7A95YRI887704-67-8WVRRTEYLDPNZHR-YZPBMOCRSA-N

Erythromycin is an antibiotic which belongs to the group of macrolide antibiotics. The pharmaceutically distributed product consists of three components: Erythromycin A, B, and C where Erythromycin A represents the main component. Naturally this antibiotic is synthesized by the grampositive bacteria Streptomyces erythreus (Saccharopolyspora erythrea).

In 1949 Erythromycin was found for the first time in a soil sample in the Philippine region Iloilo. A research team, led by J. M. McGuire, was able to isolate Erythromycin which was part of the soil sample. Under the brand name Ilosone the product was launched commercially in 1952. They named the brand after the region where the antibiotic was found. Analogically the first product name was Ilotycin. Furthermore, in 1953 the U.S. patent was granted. Since 1957 the structure of Erythromycin is known and in 1965 the X-ray structure analysis gave awareness of the absolute configuration. In 1981, almost 30 years after the detection of Erythromycin, Robert B. Woodward, the Nobel prize laureate of chemistry in 1965, and his coworkers posthumously reported the first synthesis of Erythromycin A

The structural characteristic of macrolides, to which Erythromycin affiliates, is a macrocyclic lactone ring of fourteen, fifteen or sixteen members. In case of Erythromycin the lactone ring consists of 14-members. Substituents on the mainchain are cladinose on C-3 and desosamine on C-5. Erythromycin is not a single compound but represents an alloy of structural very similar components. The main constituents are Erythromycin A, B and C. As shown in Table 1 and Figure 1 they only differ in two rests on the lactone ring or on the cladinose each case. In addition to the variants already mentioned, further variants, like Erythromycin D and E are known. They are pre- and post-stages in the biosynthesis and often do not have antibiotic effects

str1

Chemical and Pharmacokinetic Properties Formula: C37H67NO13 CAS-Number: 114-07-8 Molar Mass: 733.93g/mol Half Hife 1.5 hours pkA: 8,6 – 8,8 Melting Point: 411K (hydrat) 463-466K (anhydrous)

Erythromycin is an antibiotic used for the treatment of a number of bacterial infections.[1] This includes respiratory tract infectionsskin infectionschlamydia infectionspelvic inflammatory disease, and syphilis.[1] It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn,[1] as well as to improve delayed stomach emptying.[3] It can be given intravenously and by mouth.[1] An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.[4]

Common side effects include abdominal cramps, vomiting, and diarrhea.[1] More serious side effects may include Clostridium difficile colitis, liver problems, prolonged QT, and allergic reactions.[1] It is generally safe in those who are allergic to penicillin.[1] Erythromycin also appears to be safe to use during pregnancy.[2] While generally regarded as safe during breastfeeding, its use by the mother during the first two weeks of life may increase the risk of pyloric stenosis in the baby.[5][6] This risk also applies if taken directly by the baby during this age.[7] It is in the macrolide family of antibiotics and works by decreasing bacterial protein production.[1]

Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea.[1][8] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[9] The World Health Organization classifies it as critically important for human medicine.[10] It is available as a generic medication.[5] In 2017, it was the 215th most commonly prescribed medication in the United States, with more than two million prescriptions.[11][12]

img

Table 4.2.1 Therapeutic indications for the macrolide antibiotics.

Medical uses

Erythromycin can be used to treat bacteria responsible for causing infections of the skin and upper respiratory tract, including StreptococcusStaphylococcusHaemophilus and Corynebacterium genera. The following represents MIC susceptibility data for a few medically significant bacteria:[13]

  • Haemophilus influenzae: 0.015 to 256 μg/ml
  • Staphylococcus aureus: 0.023 to 1024 μg/ml
  • Streptococcus pyogenes: 0.004 to 256 μg/ml
  • Corynebacterium minutissimum: 0.015 to 64 μg/ml

It may be useful in treating gastroparesis due to this promotility effect. It has been shown to improve feeding intolerances in those who are critically ill.[14] Intravenous erythromycin may also be used in endoscopy to help clear stomach contents.

Available forms

Enteric-coated erythromycin capsule from Abbott Labs

Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, enteric-coated capsules, non enteric-coated tablets, non enteric-coated capsules, and injections. The following erythromycin combinations are available for oral dosage:[15]

  • erythromycin base (capsules, tablets)
  • erythromycin estolate (capsules, oral suspension, tablets), contraindicated during pregnancy[16]
  • erythromycin ethylsuccinate (oral suspension, tablets)
  • erythromycin stearate (oral suspension, tablets)

For injection, the available combinations are:[15]

  • erythromycin gluceptate
  • erythromycin lactobionate

For ophthalmic use:

  • erythromycin base (ointment)

Adverse effects

Gastrointestinal disturbances, such as diarrheanauseaabdominal pain, and vomiting, are very common because erythromycin is a motilin agonist.[17] Because of this, erythromycin tends not to be prescribed as a first-line drug.

More serious side effects include arrhythmia with prolonged QT intervals, including torsades de pointes, and reversible deafness. Allergic reactions range from urticaria to anaphylaxisCholestasisStevens–Johnson syndrome, and toxic epidermal necrolysis are some other rare side effects that may occur.

Studies have shown evidence both for and against the association of pyloric stenosis and exposure to erythromycin prenatally and postnatally.[18] Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants.[19][20] Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.[19]

Erythromycin estolate has been associated with reversible hepatotoxicity in pregnant women in the form of elevated serum glutamic-oxaloacetic transaminase and is not recommended during pregnancy. Some evidence suggests similar hepatotoxicity in other populations.[21]

It can also affect the central nervous system, causing psychotic reactions, nightmares, and night sweats.[22]

Interactions

Erythromycin is metabolized by enzymes of the cytochrome P450 system, in particular, by isozymes of the CYP3A superfamily.[23] The activity of the CYP3A enzymes can be induced or inhibited by certain drugs (e.g., dexamethasone), which can cause it to affect the metabolism of many different drugs, including erythromycin. If other CYP3A substrates — drugs that are broken down by CYP3A — such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor)—are taken concomitantly with erythromycin, levels of the substrates increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated.[22] Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4.[24] Hence, erythromycin should not be administered to people using these drugs, or drugs that also prolong the QT interval. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline, which is used mostly in asthma, is also contraindicated.

Erythromycin and doxycycline can have a synergistic effect when combined and kill bacteria (E. coli) with a higher potency than the sum of the two drugs together. This synergistic relationship is only temporary. After approximately 72 hours, the relationship shifts to become antagonistic, whereby a 50/50 combination of the two drugs kills less bacteria than if the two drugs were administered separately.[25]

It may alter the effectiveness of combined oral contraceptive pills because of its effect on the gut flora. A review found that when erythromycin was given with certain oral contraceptives, there was an increase in the maximum serum concentrations and AUC of estradiol and dienogest.[26][27]

Erythromycin is an inhibitor of the cytochrome P450 system, which means it can have a rapid effect on levels of other drugs metabolised by this system, e.g., warfarin.

Pharmacology

Mechanism of action

Erythromycin displays bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations.[28] By binding to the 50s subunit of the bacterial rRNA complex, protein synthesis and subsequent structure and function processes critical for life or replication are inhibited.[28] Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied, thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action.

Erythromycin increases gut motility by binding to Motillin, thus it is a Motillin receptor agonist in addition to its antimicrobial properties.

Pharmacokinetics

Erythromycin is easily inactivated by gastric acid; therefore, all orally administered formulations are given as either enteric-coated or more-stable salts or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released.

Metabolism

Most of erythromycin is metabolised by demethylation in the liver by the hepatic enzyme CYP3A4. Its main elimination route is in the bile with little renal excretion, 2%-15% unchanged drug. Erythromycin’s elimination half-life ranges between 1.5 and 2.0 hours and is between 5 and 6 hours in patients with end-stage renal disease. Erythromycin levels peak in the serum 4 hours after dosing; ethylsuccinate peaks 0.5-2.5 hours after dosing, but can be delayed if digested with food.[29]

Erythromycin crosses the placenta and enters breast milk. The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding.[30] Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients.[29]

Chemistry

Composition

Standard-grade erythromycin is primarily composed of four related compounds known as erythromycins A, B, C, and D. Each of these compounds can be present in varying amounts and can differ by lot. Erythromycin A has been found to have the most antibacterial activity, followed by erythromycin B. Erythromycins C and D are about half as active as erythromycin A.[13][31] Some of these related compounds have been purified and can be studied and researched individually.

Synthesis

Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were made to synthesize it in the laboratory. The presence of 10 stereogenic carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task.[32] Complete syntheses of erythromycins’ related structures and precursors such as 6-deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials.[33] Woodward successfully completed the synthesis of erythromycin A.[34][35][36]

Erythromycin related compounds

History

In 1949 Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer Eli Lilly. Eli Lilly’s research team, led by J. M. McGuire, managed to isolate erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to Saccharopolyspora erythraea) found in the samples.[37]

Lilly filed for patent protection on the compound which was granted in 1953.[38] The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected). Erythromycin was formerly also called Ilotycin.

The antibiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.

Scientists at Chugai Pharmaceuticals discovered an erythromycin-derived motilin agonist called mitemcinal that is believed to have strong prokinetic properties (similar to erythromycin) but lacking antibiotic properties. Erythromycin is commonly used off-label for gastric motility indications such as gastroparesis. If mitemcinal can be shown to be an effective prokinetic agent, it would represent a significant advance in the gastrointestinal field, as treatment with this drug would not carry the risk of unintentional selection for antibiotic-resistant bacteria.

Society and culture

Cost

It is available as a generic medication.[5]

In the United States in 2014 the price increased to seven dollars per tablet.[39]

The price of Erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015.[40] In 2017, a Kaiser Health News study found that the per-unit cost of dozens of generics doubled or even tripled from 2015 to 2016, increasing spending by the Medicaid program. Due to price increases by drug manufacturers, Medicaid paid on average $2,685,330 more for Erythromycin in 2016 compared to 2015 (not including rebates).[41] By 2018, generic drug prices had climbed another 5% on average.[42]

Brand names

Brand names include Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, E.E.S.-400, E.E.S.-400 Filmtab, Erymax, Ery-Tab, Eryc, Ranbaxy, Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin Stearate Filmtab, Erythrocot, E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, PCE Dispertab, Stiemycine, Acnasol, and Tiloryth.

See also

Erythromycin/tretinoin, a combination of tretinoin and the antibiotic erythromycin

SYN

Macrolide Antibiotics

https://basicmedicalkey.com/macrolide-antibiotics/embed/#?secret=VMg8PBg4K9

Synthesis

The total synthesis of the erythromycins (Figure 4.2.2) poses a supreme challenge and has attracted the attention of some of the world’s most eminent synthetic chemists, leading to many elegant examples of the total synthesis of complex natural products. The total synthesis of the erythronolide A aglycone (lacking the sugar units) was first reported by E. J. Corey (Nobel Prize in Chemistry in 1990) in a series of articles in the late 1970s (Scheme 4.2.2) (Corey et al., 1979 and references cited therein), and the total synthesis of erythromycin (known then as erythromycin A) by R. B. Woodward (Nobel Prize in Chemistry in 1965) in a series of articles in 1981, after his death (Scheme 4.2.3) (Woodward et al., 1981 and references cited therein). The Woodward synthesis is particularly elegant, as the dithiadecalin intermediate supplies both the C3-C8 and C9-C13 fragments (Scheme 4.2.3).

Figure 4.2.2 Erythromycins A and B and their aglycones, erythronolides A and B

img

Scheme 4.2.2 Corey’s total synthesis of erythronolide A (38 steps from the cyclohexadiene fragment; 0.04% overall yield)

img

Scheme 4.2.3 Woodward’s total synthesis of erythromycin (56 steps from 4-thianone; 0.01% overall yield)

img

Once again, erythromycin is such a complex antibiotic that its commercial production by total synthesis will never be feasible, and it is obtained from the submerged culture of free or immobilised Saccharopolyspora erythraea (El-Enshasy et al., 2008).

We have now seen a number of examples of how very complex semi-synthetic antibiotics can be prepared through the combination of fermentation (to give the complex natural product) and chemical modification, so you will no doubt already have spotted that both clarithromycin and roxithromycin are semi-synthetic macrolide antibiotics. Clarithromycin can be obtained in a five-step synthetic procedure, from erythromycin oxime (Brunet et al., 2007), while roxithromycin can also be prepared from this oxime (Massey et al., 1970) in a single step (Scheme 4.2.4) (Gouin d’Ambrieres et al., 1982). What is not so obvious is that azithromycin is also a semi-synthetic macrolide, having originally been produced by PLIVA Pharmaceuticals from erythromycin oxime via a sequence of reactions which included the well-known Beckmann rearrangement (Djokiimg et al., 1986). For more on the synthesis of the erythromycins, see Paterson and Mansuri (1985).

Scheme 4.2.4 Preparation of the semi-synthetic macrolide antibiotic roxithromycin

img

CLIP

Erythromycin. Erythromycin (1) was discovered in 1952 during the investigation of soil samples from Iloilo, Philippines for antibiotic activity[18, 19] and its molecular structure was assigned in 1957.[20] The microorganism that produced erythromycin was isolated and characterised as Streptomyces erythreus, strain NRRL 2338.[18, 19] Over the years, strain improvements and genetic engineering has allowed the yield of erythromycin to be increased so that 8–10 g L1 can now be produced from a tryptic soy broth.[21–25] Erythromycin forms anhydro-erythromycin 6 and 6:9, 9:12 spiroketal 7 under the acidic conditions in the stomach (Scheme 1), which results in the loss of its antibacterial activity and induction of abdominal pain.[26, 27] Generation of by-products 6 and 7 occurs through an acid-catalysed intramolecular reaction of the C-6 hydroxyl group with the C-9 keto moiety. To avoid this by-product formation several different semi-synthetic derivatives of erythromycin have been prepared in which either of these two functionalities are modified. They led to the discovery of clarithromycin (2) by O-6 methylation of erythromycin (Figure 3). Removal of the C-9 ketone by the formation of an oxime followed by Beckmann rearrangement and reduction led to azithromycin (3), which belongs to a new class of macrolides called “azalides”. Alternatively, conversion of the C-9 ketone to an amine, followed by reaction with an aldehyde, gave dirithromycin (4). Yet another approach involved the transformation of clarithromycin to the conformationally restricted telithromycin

SYN

Chemical Synthesis

Erythromycin, (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-Cmethyl-3-O-methyl-α-L-ribo-hexopyranosyl)-oxy]-14-ethyl-7,12,13-trihydroxy- 3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy ]oxacyclotetradecan-2,10-dione (32.2.1), is more specifically called erythromycin A. It was first isolated in 1952 from the culture liquid of microorganisms of the type Streptomyces erytherus. Minor amounts of erythromycin B and C were also found in the culture fluid. Erythromycin B differs from A in that a hydrogen atom is located at position 12 in the place of a hydroxyl group, while erythromycin C differs from A in that the residue of a different carbohydrate, micarose (2-6-di-deoxy-3-C-methyl-L-ribohexose), is bound to the macrocycle in position 3 in the place of cladinose (4-methoxy-2,4-dimethyl-tetrahydropyran-3,6-diol).
Erythromycin A is produced only microbiologically using active strains of microorganisms of the type Saccharopolospora erythraea.

SYN

https://www.researchgate.net/figure/Fig-5-Erythromycin-synthesis-by-modular-polyketide-synthases-The-three-genes_fig2_41909207

Erythromycin synthesis by modular polyketide synthases. The three genes EryAI-III encode three proteins of PKS: DEBS1 (the loading module, modules 1, 2) DEBS2 (modules 3, 4), DEBS3 (modules 5, 6, TE domain). Thus, PKS consists of the loading module, six extension modules, and TE domain. Each module includes from three to six domains: AT-acyl transferase, ACP-acyl carrier protein, KS-ketosynthase, KR-ketoreductase, DH-dehydratase, ERenoyl reductase. 

Erythromycin synthesis by modular polyketide synthases. The three genes EryAI-III encode three proteins of PKS: DEBS1 (the loading module, modules 1, 2) DEBS2 (modules 3, 4), DEBS3 (modules 5, 6, TE domain). Thus, PKS consists of the loading module, six extension modules, and TE domain. Each module includes from three to six domains: AT-acyl transferase, ACP-acyl carrier protein, KS-ketosynthase, KR-ketoreductase, DH-dehydratase, ERenoyl reductase.

CLIP

The chemical synthesis of Erythromycin poses a huge challenge. The molecule contains ten stereogenic centers of which five are arranged consecutively. R. B. Woodward and his research team first succeeded in synthesizing Erythromycin A. The reaction sequence, however, is so complicated that the yield was only about 0,02 % and, thus, the synthesis is not utilizable comercially. This is the reason for the preferred use of the biosynthesis of Erythromycin via fermentation of Streptomyces erythreus. Other scientists and research teams dealt with the synthesis of Erythromycin as well and developed very similar approaches. Most methods for the Erythromycin synthesis are based on the construction of the aglycon from secoic acid via glycosylation. Indeed the process is also possible inversely: first, a glycosylation, then a lactonization occurs. The yield, however, is considerably less. While earlier scientist mainly dealt with the production of the different secoic acids, the lactonization process is the major problem today because there is no fully developed method for it yet. A lot of side reactions such as dimerization and polymerization appear, because a 14 membered ring is hard to enclose. Even if the chemical synthesis of Erythromycin has no importance for the comercial fabrication of the antibiotic, it is still important for the development and fabrication of its derivatives.

References

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  2. Jump up to:a b “Prescribing medicines in pregnancy database”Australian Government. August 23, 2015. Archived from the original on April 8, 2014.
  3. ^ Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L (January 2013). “Clinical guideline: management of gastroparesis”The American Journal of Gastroenterology108 (1): 18–37, quiz 38. doi:10.1038/ajg.2012.373PMC 3722580PMID 23147521.
  4. ^ Matejcek A, Goldman RD (November 2013). “Treatment and prevention of ophthalmia neonatorum”Canadian Family Physician59 (11): 1187–90. PMC 3828094PMID 24235191.
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  6. ^ Kong YL, Tey HL (June 2013). “Treatment of acne vulgaris during pregnancy and lactation”. Drugs73 (8): 779–87. doi:10.1007/s40265-013-0060-0PMID 23657872S2CID 45531743.
  7. ^ Maheshwai N (March 2007). “Are young infants treated with erythromycin at risk for developing hypertrophic pyloric stenosis?”Archives of Disease in Childhood92 (3): 271–3. doi:10.1136/adc.2006.110007PMC 2083424PMID 17337692Archived from the original on 7 November 2012.
  8. ^ Vedas JC (2000). Biosynthesis : polyketides and vitamins. Berlin [u.a.]: Springer. p. 52. ISBN 9783540669692.
  9. ^ 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.
  10. ^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266ISBN 9789241515528. License: CC BY-NC-SA 3.0 IGO.
  11. ^ “The Top 300 of 2020”ClinCalc. Retrieved 11 April 2020.
  12. ^ “Erythromycin – Drug Usage Statistics”ClinCalc. Retrieved 11 April 2020.
  13. Jump up to:a b “Erythromycin Susceptibility and Minimum Inhibitory Concentration (MIC) Data” (PDF). TOKU-E.
  14. ^ Lewis K, Alqahtani Z, Mcintyre L, Almenawer S, Alshamsi F, Rhodes A, et al. (August 2016). “The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials”Critical Care20 (1): 259. doi:10.1186/s13054-016-1441-zPMC 4986344PMID 27527069.
  15. Jump up to:a b “Erythromycin Oral, Parenteral Advanced Patient Information”Drugs.comArchived from the original on 2009-11-30.
  16. ^ Sexually Transmitted Diseases Treatment Guidelines 2006Archived 2010-02-11 at the Wayback Machine Centers for Disease Control and Prevention. MMWR 2006;55
  17. ^ Weber FH, Richards RD, McCallum RW (April 1993). “Erythromycin: a motilin agonist and gastrointestinal prokinetic agent”. The American Journal of Gastroenterology88 (4): 485–90. PMID 8470625.
  18. ^ “Pregnancy and lactation”Archived from the original on 2014-04-20.
  19. Jump up to:a b Maheshwai N (March 2007). “Are young infants treated with erythromycin at risk for developing hypertrophic pyloric stenosis?”Archives of Disease in Childhood92 (3): 271–3. doi:10.1136/adc.2006.110007PMC 2083424PMID 17337692.
  20. ^ Lund M, Pasternak B, Davidsen RB, Feenstra B, Krogh C, Diaz LJ, et al. (March 2014). “Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study”BMJ348: g1908. doi:10.1136/bmj.g1908PMC 3949411PMID 24618148.
  21. ^ McCormack WM, George H, Donner A, Kodgis LF, Alpert S, Lowe EW, Kass EH (November 1977). “Hepatotoxicity of erythromycin estolate during pregnancy”Antimicrobial Agents and Chemotherapy12 (5): 630–5. doi:10.1128/AAC.12.5.630PMC 429989PMID 21610.
  22. Jump up to:a b “Erythromycine”Belgisch Centrum voor Farmacotherapeutische InformatieArchived from the original on 2015-10-06.
  23. ^ Hunt CM, Watkins PB, Saenger P, Stave GM, Barlascini N, Watlington CO, et al. (January 1992). “Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol” (PDF). Clinical Pharmacology and Therapeutics51 (1): 18–23. doi:10.1038/clpt.1992.3hdl:2027.42/109905PMID 1732074S2CID 28056649.
  24. ^ Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM (September 2004). “Oral erythromycin and the risk of sudden death from cardiac causes”. The New England Journal of Medicine351 (11): 1089–96. doi:10.1056/NEJMoa040582PMID 15356306.
  25. ^ Pena-Miller R, Laehnemann D, Jansen G, Fuentes-Hernandez A, Rosenstiel P, Schulenburg H, Beardmore R (April 23, 2013). “When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition”PLOS Biology11 (4): e1001540. doi:10.1371/journal.pbio.1001540PMC 3635860PMID 23630452.
  26. ^ Blode H, Zeun S, Parke S, Zimmermann T, Rohde B, Mellinger U, Kunz M (October 2012). “Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women”Contraception86 (4): 337–44. doi:10.1016/j.contraception.2012.01.010PMID 22445438.
  27. ^ Simmons KB, Haddad LB, Nanda K, Curtis KM (January 2018). “Drug interactions between non-rifamycin antibiotics and hormonal contraception: a systematic review”American Journal of Obstetrics and Gynecology218 (1): 88–97.e14. doi:10.1016/j.ajog.2017.07.003PMID 28694152S2CID 36567820.
  28. Jump up to:a b Katzung PHARMACOLOGY, 9e Section VIII. Chemotherapeutic Drugs Chapter 44. Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, & Streptogramins
  29. Jump up to:a b “unknown”Archived from the original on 2014-04-19. Cite uses generic title (help)
  30. ^ American Academy of Pediatrics Committee on Drugs (September 2001). “Transfer of drugs and other chemicals into human milk” (PDF). Pediatrics108 (3): 776–89. doi:10.1542/peds.108.3.776PMID 11533352. Archived from the original (PDF) on 2016-03-05.
  31. ^ Kibwage IO, Hoogmartens J, Roets E, Vanderhaeghe H, Verbist L, Dubost M, et al. (November 1985). “Antibacterial activities of erythromycins A, B, C, and D and some of their derivatives”Antimicrobial Agents and Chemotherapy28 (5): 630–3. doi:10.1128/aac.28.5.630PMC 176346PMID 4091529.
  32. ^ Pal S (2006). “A journey across the sequential development of macrolides and ketolides related to erythromycin”. Tetrahedron62(14): 3171–3200. doi:10.1016/j.tet.2005.11.064.
  33. ^ Evans DA, Kim AS (1997). “Synthesis of 6-Deoxyerythronolide B. Implementation of a General Strategy for the Synthesis of Macrolide Antibiotics”. Tetrahedron Lett38: 53–56. doi:10.1016/S0040-4039(96)02258-7.
  34. ^ Woodward RB, Logusch E, Nambiar KP, Sakan K, Ward DE, Au-Yeung, Balaram P, Browne LJ, Card PJ, et al. (1981). “Asymmetric Total Synthesis of Erythromycin. 1. Synthesis of an Erythronolide A Seco Acid Derivative via Asymmetric Induction”. J. Am. Chem. Soc103 (11): 3210–3213. doi:10.1021/ja00401a049.
  35. ^ Woodward RB, Logusch E, Nambiar KP, Sakan K, Ward DE, Au-Yeung, Balaram P, Browne LJ, Card PJ, et al. (1981). “Asymmetric Total Synthesis of Erythromycin. 2. Synthesis of an Erythronolide A Lactone System”. J. Am. Chem. Soc103 (11): 3213–3215. doi:10.1021/ja00401a050.
  36. ^ Woodward RB, Logusch E, Nambiar KP, Sakan K, Ward DE, Au-Yeung, Balaram P, Browne LJ, Card PJ, et al. (1981). “Asymmetric Total Synthesis of Erythromycin. 3. Total Synthesis of Erythromycin”. J. Am. Chem. Soc103 (11): 3215–3217. doi:10.1021/ja00401a051.
  37. ^ Hibionada, F. Remembering the battle of Dr. Abelardo Aguilar: Cure for millions, deprived of millions. The News Today. Retrieved 22 September 2015
  38. ^ U.S. Patent 2,653,899
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External links

Clinical data
Trade namesEryc, Erythrocin, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa682381
License dataUS DailyMedErythromycin
Pregnancy
category
AU: A[2]
Routes of
administration
By mouthintravenous (IV), intramuscular (IM), topicaleye drops
Drug classMacrolide antibiotic
ATC codeD10AF02 (WHOJ01FA01 (WHOS01AA17 (WHOQJ51FA01 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
BioavailabilityDepends on the ester type between 30% – 65%
Protein binding90%
Metabolismliver (under 5% excreted unchanged)
Elimination half-life1.5 hours
Excretionbile
Identifiers
showIUPAC name
CAS Number114-07-8 
PubChem CID12560
IUPHAR/BPS1456
DrugBankDB00199 
ChemSpider12041 
UNII63937KV33D
KEGGD00140 
ChEBICHEBI:42355 
ChEMBLChEMBL532 
PDB ligandERY (PDBeRCSB PDB)
CompTox Dashboard (EPA)DTXSID4022991 
ECHA InfoCard100.003.673 
Chemical and physical data
FormulaC37H67NO13
Molar mass733.937 g·mol−1
hideSMILESCC[C@@H]1[C@@]([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)O)C)C)O)(C)O
hideInChIInChI=1S/C37H67NO13/c1-14-25-37(10,45)30(41)20(4)27(39)18(2)16-35(8,44)32(51-34-28(40)24(38(11)12)15-19(3)47-34)21(5)29(22(6)33(43)49-25)50-26-17-36(9,46-13)31(42)23(7)48-26/h18-26,28-32,34,40-42,44-45H,14-17H2,1-13H3/t18-,19-,20+,21+,22-,23+,24+,25-,26+,28-,29+,30-,31+,32-,34+,35-,36-,37-/m1/s1 Key:ULGZDMOVFRHVEP-RWJQBGPGSA-N 
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//////////erythromycin, NSC-55929, NSC 55929, эритромицин , إيريثروميسين , 红霉素 , ANTIBACTERIAL, MACROLIDES, ANTIBIOTICS

#erythromycin, #NSC-55929, #NSC 55929, #эритромицин , #إيريثروميسين , #红霉素 , #ANTIBACTERIAL, #MACROLIDES, #ANTIBIOTICS

Dirithromycin


Dirithromycin.svg

Dirithromycin

LY 237216

  • LY-237216

(1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,15R,17S)-9-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-3-ethyl-2,10-dihydroxy-7-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-15-[(2-methoxyethoxy)methyl]-2,6,8,10,12,17-hexamethyl-4,16-dioxa-14-azabicyclo[11.3.1]heptadecan-5-one

UNII1801D76STL

CAS number62013-04-1

Synthesis Reference

Counter FT, Ensminger PW, Preston DA, Wu CY, Greene JM, Felty-Duckworth AM, Paschal JW, Kirst HA: Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob Agents Chemother. 1991 Jun;35(6):1116-26. Pubmed.DirithromycinCAS Registry Number: 62013-04-1CAS Name: (1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,15R,17S)-7-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-3-ethyl-2,10-dihydroxy-15-[(2-methoxyethoxy)methyl]-2,6,8,10,12,17-hexamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-4,16-dioxa-14-azabicyclo[11.3.1]heptadecan-5-oneAdditional Names: [9S(R)]-9-deoxo-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)ethylidene]oxy]erythromycinManufacturers’ Codes: LY-237216; AS-E 136Trademarks: Dynabac (Lilly); Noriclan (Lilly); Nortron (Lilly); Valodin (Ferrer)Molecular Formula: C42H78N2O14Molecular Weight: 835.07Percent Composition: C 60.41%, H 9.41%, N 3.35%, O 26.82%Literature References: Semi-synthetic derivative of erythromycin, q.v. Prepn: BE840431 (1976 to Thomae); R. Maier et al.,US4048306 (1977 to Boehringer, Ing.). Synthesis, 1H- and 13C-NMR, and antimicrobial evaluation: F. T. Counter et al.,Antimicrob. Agents Chemother.35, 1116 (1991). X-ray structure determn: P. Luger, R. Maier, J. Cryst. Mol. Struct.9, 329 (1979). HPLC determn in plasma: G. W. Whitaker, T. D. Lindstrom, J. Liq. Chromatogr.11, 3011 (1988). Symposium on antibacterial activity, pharmacology, and clinical experience: J. Antimicrob. Chemother.31, Suppl. C, 1-185 (1993).Properties: Crystals from ethanol/water, mp 186-189° (dec) (Counter). pKa 9.0 in 66% aq dimethyl fluoride. LD50 in mice (g/kg): >1 s.c.; >1 orally (Maier).Melting point: mp 186-189° (dec) (Counter)pKa: pKa 9.0 in 66% aq dimethyl fluorideToxicity data: LD50 in mice (g/kg): >1 s.c.; >1 orally (Maier)Therap-Cat: Antibacterial.Keywords: Antibacterial (Antibiotics); Macrolides.

Dirithromycin is a macrolide glycopeptide antibiotic.[1]

For the treatment of the following mild-to-moderate infections caused by susceptible strains of microorganisms: acute bacterial exacerbations of chronic bronchitis, secondary bacterial infection of acute bronchitis, community-acquired pneumonia, pharyngitis/tonsilitis, and uncomplicated skin and skin structure infections.

Dirithromycin (Dynabac) is a more lipid-soluble prodrug derivative of 9S-erythromycyclamine prepared by condensation of the latter with 2-(2-methoxyethoxy)acetaldehyde. The 9N, 11O-oxazine ring thus formed is a hemi-aminal that is unstable under both acidic and alkaline aqueous conditions and undergoes spontaneous hydrolysis to form erythromycyclamine. Erythromycyclamine is a semisynthetic derivative of erythromycin in which the 9-ketogroup of the erythronolide ring has been converted to an amino group. Erythromycyclamine retains the antibacterial properties of erythromycin oral administration. The prodrug, dirithromycin, is provided as enteric coated tablets to protect it from acid catalyzed hydrolysis in the stomach. Orally administered dirithromycin is absorbed rapidly into the plasma, largely from the small intestine. Spontaneous hydrolysis to erythromycyclamine occurs in the plasma. Oral bioavailability is estimated to be about 10%, but food does not affect absorption of the prodrug.

NEW DRUG APPROVALS

one time

$10.00

Discontinuation

Dirithromycin is no longer available in the United States.[2] Since the production of dirithromycin is discontinued in the U.S, National Institutes of Health recommend that people taking dirithromycin should consult their physicians to discuss switching to another treatment.[3] However, dirithromycin is still available in many European countries.

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https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.201902716

In attempts to modify the C-9 keto moiety of erythromycin, (9S)-erythromycinylamine (21) was prepared by the reduction of oxime 17 with sodium borohydride (Scheme 4).[13] Amine 21 displayed good in vitro antimicrobial activity against Staphylococcus aureus, [38–44] but had poor bioavailability due to the polar primary amine. In search of compounds in this class with better oral bioavailability, efforts were directed towards masking the amine in 21 as an imine with aromatic and aliphatic aldehydes.[40] These efforts were based on the idea that such imines would be hydrolysed at physiological pH after absorption from the intestine, but somewhat unexpectedly, lead to the discovery of dirithromycin (4) when 21 was treated with aldehyde 22. In this reaction, 9- N-11-O-oxazine epi-dirithromycin (23) is first formed as the kinetic product, which then undergoes conversion into the thermodynamically stable dirithromycin (4).[45–47] Due to issues with the stability of aldehyde 22 on process-scale synthesis, this procedure was later modified so that dimethyl acetal 24 was used for commercial production.[48]

13] S. Djokic´, Z. Tamburasˇev, Tetrahedron Lett. 1967, 8, 1645 – 1647.

[38] R. Maier, E. Woitun, B. Wetzel, W. Reuter, H. Goeth, U. Lechner, 1977, US4048306A. [39] E. Wildsmith, 1974, US3780019A. [40] E. H. Massey, B. S. Kitchell, L. D. Martin, K. Gerzon, J. Med. Chem. 1974, 17, 105 – 107. [41] E. Wildsmith, Tetrahedron Lett. 1972, 13, 29 – 30. [42] K. Gerzon, M. H. William, DPMA Deutsches Patent, 1972, DE1966310A1. [43] G. H. Timms, E. Wildsmith, Tetrahedron Lett. 1971, 12, 195 – 198. [44] E. H. Massey, B. Kitchell, L. D. Martin, K. Gerzon, H. W. Murphy, Tetrahedron Lett. 1970, 11, 157 – 160. [45] P. Luger, R. Maier, J. Cryst. Mol. Struct. 1979, 9, 329 – 338. [46] F. T. Counter, P. W. Ensminger, D. A. Preston, C. Y. Wu, J. M. Greene, A. M. Felty-Duckworth, J. W. Paschal, H. A. Kirst, Antimicrob. Agents Chemother. 1991, 35, 1116 – 1126. [47] J. Firl, A. Prox, P. Luger, R. Maier, E. Woitun, K. Daneck, J. Antibiot. 1990, 43, 1271 – 1277. [48] J. M. Mcgill, Synthesis 1993, 11, 1089 – 1091.

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Dirithromycin is the second-generation erythromycin macrocyclic (fourteen member ring) lactone antibiotics; made from the condensation reaction between 2-methoxyethoxy acetaldehyde and erythromycylamine. It has similar structure to erythromycin. It can subject to in vivo non-enzymatic hydrolysis into erythromycin cyclic amines. It takes effect through targeting the 50S ribosomal subunit of sensitive pathogenic microorganisms, blocking the bacterial peptide bond formation, which further inhibits protein synthesis to play antibacterial activity.

Compared with erythromycin and other new macrocyclic lactone antibiotics, this drug has the following characteristics: (1) antibacterial effect: in addition to retaining the antibacterial effect against gram positive bacteria; it also has strong effect on a variety of G- bacteria, Anaerobic bacteria and other pathogens, such as Mycoplasma, Chlamydia and spirochete. Dirithromycin has stronger effect than erythromycin on Staphylococcus aureus and Staphylococcus epidermidis. (2) Pharmacokinetics: compared with other macrolide antibiotics in the vine, the half-life of erythromycin is longer with the plasma elimination tl/2 being longer than 24h. Its tissue permeability is strong. It can be administered once a day. So it will also be competitive in the market with characteristics that are different from other antibiotics.
Lilly’s products in the United States was listed in Spain in September 1993, listed in 1996 in US after the approval of FDA and had been included in Pharmacopoeia USP 23; it was listed in 2005 in the domestic market. At present, there are a number of domestic dysthromycin enteric-coated tablets and enteric-coated capsules approved for clinical use.

Synthetic route

Route 1: erythromycin is first reacted with hydrazine hydrate to generate erythromycin hydrazone (2), erythromycin hydrazone is used for synthesizing erythromycylamine (3), and finally reacted with 2-methoxyethoxy acetaldehyde (5) to generate dysthromycin (1), as shown in the figure:
Route 2: Erythromycin is reacted with hydroxylamine to generate erythromycin oxime; erythromycin oxime can be reduced to obtain erythromycin amine, and is then condensed with 2- (2- methoxyethoxy) acetaldehyde ethylene glycol to generate dysthromycin (DRM), the specific reaction route is as follows:

Clip

https://link.springer.com/article/10.1007/s00894-003-0172-7

References

  1. ^ McConnell SA, Amsden GW (April 1999). “Review and comparison of advanced-generation macrolides clarithromycin and dirithromycin”. Pharmacotherapy19 (4): 404–15. doi:10.1592/phco.19.6.404.31054PMID 10212011.
  2. ^ “Dynabac Drug Details”. U.S. Food and Drug Administration. Retrieved 2007-05-25.
  3. ^ “Dirithromycin”MedlinePlus. U.S. National Library of Medicine. January 1, 2006. Archived from the original on 2007-03-29. Retrieved 2007-05-25.
Clinical data
Trade namesDynabac
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa604026
License dataUS FDAClarithromycin
Pregnancy
category
B
Routes of
administration
Oral
ATC codeJ01FA13 (WHO)
Pharmacokinetic data
Bioavailability10%
Protein binding15 to 30%
MetabolismHyrolized to erythromycyclamine in 1.5 hours
Identifiers
showIUPAC name
CAS Number62013-04-1 
PubChem CID6917067
DrugBankDB00954 
ChemSpider5292341 
UNII1801D76STL
KEGGD03865 
ChEBICHEBI:474014 
ChEMBLChEMBL3039471 
CompTox Dashboard (EPA)DTXSID7048956 
ECHA InfoCard100.152.704 
Chemical and physical data
FormulaC42H78N2O14
Molar mass835.086 g·mol−1
3D model (JSmol)Interactive image
Melting point186 to 189 °C (367 to 372 °F) (dec.)
hideSMILESO=C4O[C@@H]([C@](O)(C)[C@H]1O[C@@H](N[C@H]([C@@H]1C)[C@H](C)C[C@](O)(C)[C@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@H]([C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@](OC)(C)C3)[C@H]4C)C)COCCOC)CC
hideInChIInChI=1S/C42H78N2O14/c1-15-29-42(10,49)37-24(4)32(43-30(56-37)21-52-17-16-50-13)22(2)19-40(8,48)36(58-39-33(45)28(44(11)12)18-23(3)53-39)25(5)34(26(6)38(47)55-29)57-31-20-41(9,51-14)35(46)27(7)54-31/h22-37,39,43,45-46,48-49H,15-21H2,1-14H3/t22-,23-,24+,25+,26-,27+,28+,29-,30-,31+,32+,33-,34+,35+,36-,37+,39+,40-,41-,42-/m1/s1 Key:WLOHNSSYAXHWNR-NXPDYKKBSA-N 
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/////////// Dirithromycin, LY 237216, LY-237216, Antibacterial 

#Dirithromycin, #LY 237216, #LY-237216, #Antibacterial 

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 

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