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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Tralokinumab


(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGLSWVRQA PGQGLEWMGW ISANNGDTNY
GQEFQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDS SSSWARWFFD LWGRGTLVTV
SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
EGNVFSCSVM HEALHNHYTQ KSLSLSLGK
(Light chain)
SYVLTQPPSV SVAPGKTARI TCGGNIIGSK LVHWYQQKPG QAPVLVIYDD GDRPSGIPER
FSGSNSGNTA TLTISRVEAG DEADYYCQVW DTGSDPVVFG GGTKLTVLGQ PKAAPSVTLF
PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL
SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS
(Disulfide bridge: H22-H96, H149-H205, H263-H323, H369-H427, H228-H’228, H231-H’231, L22-L87, L136-L195, H136-L213)

Tralokinumab

トラロキヌマブ (遺伝子組換え)

FormulaC6374H9822N1698O2014S44
CAS1044515-88-9
Mol weight143873.2167

EU APPROVED, Adtralza, 2021/6/17

Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody

Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13,[1] and is designed for the treatment of asthma and other inflammatory diseases.[2] Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354[3] and taken through pre-clinical and early clinical development.[4] After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis.[5][6] This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.

Discovery and development

Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists[7] using protein optimization based on Ribosome Display.[8] They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims.[7] In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005.[9] On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.[10]

In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued.[9] In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.[11]

A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.[12]

On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.[13]

Society and culture

Legal status

On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.[14]

The applicant for this medicinal product is LEO Pharma A/S.

References

  1. ^ Kopf M, Bachmann MF, Marsland BJ (September 2010). “Averting inflammation by targeting the cytokine environment”. Nature Reviews. Drug Discovery9 (9): 703–18. doi:10.1038/nrd2805PMID 20811382S2CID 23769909.
  2. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Tralokinumab” (PDF). American Medical Association.
  3. ^ Thom G, Cockroft AC, Buchanan AG, Candotti CJ, Cohen ES, Lowne D, et al. (May 2006). “Probing a protein-protein interaction by in vitro evolution” [P]. Proceedings of the National Academy of Sciences of the United States of America103 (20): 7619–24. Bibcode:2006PNAS..103.7619Tdoi:10.1073/pnas.0602341103PMC 1458619PMID 16684878.
  4. ^ May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. (May 2012). “Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma”British Journal of Pharmacology166 (1): 177–93. doi:10.1111/j.1476-5381.2011.01659.xPMC 3415647PMID 21895629.
  5. ^ “Pipeline”MedImmune. Retrieved 11 June 2013.
  6. ^ “Studies found for CAT-354”ClinicalTrials.gov. Retrieved 11 June 2013.
  7. Jump up to:a b Human Antibody Molecules for Il-13, retrieved 2015-07-26
  8. ^ Jermutus L, Honegger A, Schwesinger F, Hanes J, Plückthun A (January 2001). “Tailoring in vitro evolution for protein affinity or stability”Proceedings of the National Academy of Sciences of the United States of America98 (1): 75–80. Bibcode:2001PNAS…98…75Jdoi:10.1073/pnas.98.1.75PMC 14547PMID 11134506.
  9. Jump up to:a b “Tralokinumab”Adis Insight. Springer Nature Switzerland AG.
  10. ^ Clinical trial number NCT01402986 for “A Phase 2b, Randomized, Double-blind Study to Evaluate the Efficacy of Tralokinumab in Adults With Asthma” at ClinicalTrials.gov
  11. ^ “AstraZeneca enters licensing agreements with LEO Pharma in skin diseases”.
  12. ^ Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, et al. (January 2019). “Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb”The Journal of Allergy and Clinical Immunology143 (1): 135–141. doi:10.1016/j.jaci.2018.05.029PMID 29906525.
  13. ^ “LEO Pharma starts phase 3 clinical study for tralokinumab in atopic dermatitis”leo-pharma.com. AstraZeneca. 1 July 2016.
  14. ^ “Adtralza: Pending EC decision”European Medicines Agency. 23 April 2021. Retrieved 23 April 2021.
Tralokinumab Fab fragment bound to IL-13. From PDB 5L6Y​.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetIL-13
Clinical data
ATC codeD11AH07 (WHO)
Identifiers
CAS Number1044515-88-9 
ChemSpidernone
UNIIGK1LYB375A
KEGGD09979
Chemical and physical data
FormulaC6374H9822N1698O2014S44
Molar mass143875.20 g·mol−1
  (what is this?)  (verify)

/////////Tralokinumab, Adtralza, EU 2021, APPROVALS 2021, Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody, MONOCLONAL ANTIBODY, PEPTIDE, トラロキヌマブ (遺伝子組換え) ,

wdt-1

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Dostarlimab


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
FormulaC6420H9832N1680O2014S44
CAS2022215-59-2
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

wdt-2

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ONE TIME

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]

References[

  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”Drugs.com. Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPCDP1
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2022215-59-2
PubChem SID384585344
DrugBankDB15627
UNIIP0GVQ9A4S5
KEGGD11366
Chemical and physical data
FormulaC6420H9832N1690O2014S44
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

Lenalidomide hydrate,


2D chemical structure of 847871-99-2
LENALIDOMIDE HEMIHYDRATE
Lenalidomide enantiomers.svg

Lenalidomide hydrate

レナリドミド水和物

An immunomodulator.

CC-5013 hemihydrate

2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-, hydrate (2:1)

(+/-)-2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-, hydrate (2:1)

Formula(C13H13N3O3)2. H2O
CAS847871-99-2
Mol weight536.5365

EMA APPROVED 2021/2/11,  Lenalidomide KRKA

Research Code:CDC-501; CC-5013

Trade Name:Revlimid®

MOA:Angiogenesis inhibitor

Indication:Myelodysplastic syndrome (MDS); Mantle cell lymphoma (MCL); Multiple myeloma (MM)

Status:Approved

Company:Celgene (Originator)

Sales:$5,801.1 Million (Y2015); 
$4,980 Million (Y2014);;
$4280 Million (Y2013);;
$3766.6 Million (Y2012);;
$3208.2 Million (Y2011);ATC Code:L04AX04

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2005-12-27Marketing approvalRevlimidMultiple myeloma (MM),Myelodysplastic syndrome (MDS),Mantle cell lymphoma (MCL)Capsule2.5 mg/5 mg/10 mg/15 mg/20 mg/25 mgCelgenePriority; Orphan

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Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2007-06-14Marketing approvalRevlimidMultiple myeloma (MM),Myelodysplastic syndrome (MDS)Capsule2.5 mg/5 mg/7.5 mg/10 mg/15 mg/20 mg/25 mgCelgeneOrphan

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Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2010-08-20New indicationRevlimidMyelodysplastic syndrome (MDS)Capsule5 mgCelgene 
2010-06-25Marketing approvalRevlimidMultiple myeloma (MM)Capsule5 mgCelgene 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule5 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule10 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule15 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule25 mgCelgene
Molecular Weight259.26
FormulaC13H13N3O3
CAS No.191732-72-6 (Lenalidomide);
Chemical Name3(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

Lenalidomide was first approved by the U.S. Food and Drug Administration (FDA) on Dec 27, 2005, then approved by European Medicine Agency (EMA) on June 14, 2007, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on June 25, 2010. It was developed and marketed as Revlimid® by Celgene.

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. Revlimid® is indicated for the treatment of multiple myeloma (MM), in combination with dexamethasone, in patients who have received at least one prior therapy, transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities and mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Revlimid® is available as capsule for oral use, containing 2.5, 5, 10, 15, 20 or 25 mg of free Lenalidomide. The recommended dose is 25 mg once daily for multiple myeloma (MM), in combination with 40 mg dexamethasone once daily, 10 mg once daily for myelodysplastic syndromes (MDS) and 25 mg once daily for mantle cell lymphoma (MCL).

Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma (MM) and myelodysplastic syndromes (MDS).[2] For MM it is used after at least one other treatment and generally together with dexamethasone.[2] It is taken by mouth.[2]

Common side effects include diarrhea, itchiness, joint pain, fever, headache, and trouble sleeping.[2] Severe side effects may include low blood plateletslow white blood cells, and blood clots.[2] Use during pregnancy may harm the baby.[2] The dose may need to be adjusted in people with kidney problems.[2] It has a chemical structure similar to thalidomide but has a different mechanism of action.[3][2] How it works is not entirely clear as of 2019.[2]

Lenalidomide was approved for medical use in the United States in 2005.[2] It is on the World Health Organization’s List of Essential Medicines.[4]

Medical uses

Multiple myeloma

Lenalidomide is used to treat multiple myeloma.[5] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis.[6][7][8]

Lenalidomide is effective at inducing a complete or “very good partial” response and improves progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma include neutropeniadeep vein thrombosisinfections, and an increased risk of other hematological malignancies.[9] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.[10] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.[6]

In 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in people with multiple myeloma who have received at least one prior therapy.[11] In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.[12]

In 2009, The National Institute for Health and Clinical Excellence issued a final appraisal determination approving lenalidomide in combination with dexamethasone as an option to treat people with multiple myeloma who have received two or more prior therapies in England and Wales.[13]

The use of lenalidomide combined with other drugs was evaluated. It was seen that the drug combinations of lenalidomide plus dexamethasone and continuous bortezomib plus lenalidomide plus dexamethasone probably result in an increase of the overall survival.[14]

Myelodysplastic syndromes

Lenalidomide was approved by the FDA on 27 December 2005 for patients with low- or intermediate-1-risk myelodysplastic syndromes who have chromosome 5q deletion syndrome (5q- syndrome) with or without additional cytogenetic abnormalities.[15][16][17] It was approved on 17 June 2013 by the European Medicines Agency for use in patients with low- or intermediate-1-risk myelodysplastic syndromes who have 5q- deletion syndrome but no other cytogenetic abnormalities and are dependent on red blood cell transfusions, for whom other treatment options have been found to be insufficient or inadequate.[18]

Mantle cell lymphoma

Lenalidomide is approved by FDA as a specialty drug requiring a specialty pharmacy distribution for mantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies, one of which must have included the medicine bortezomib.[3]

Amyloidosis

Although not specifically approved by the FDA for use in treating amyloidosis, Lenalidomide is widely used in the treatment of that condition, often in combination with dexamethasone. [19]

Adverse effects

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism.[3] Serious potential side effects include thrombosispulmonary embolushepatotoxicity, and bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is not the case with thalidomide.[20]

Lenalidomide may be associated with such adverse effects as second primary malignancy, severe cutaneous reactions, hypersensitivity reactionstumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism.[3]

Teratogenicity

Lenalidomide is related to thalidomide, which is known to be teratogenic. Tests in monkeys suggest that lenalidomide is likewise teratogenic.[21] It cannot be prescribed for women who are pregnant or who may become pregnant during therapy.[1] For this reason, the drug is only available in the United States through a restricted distribution system in conjunction with a risk evaluation and mitigation strategy. Females who may become pregnant must use at least two forms of reliable contraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.[3][22]

Venous thromboembolism

Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. High rates of VTE have been found in patients with multiple myeloma who received thalidomide or lenalidomide in conjunction with dexamethasonemelphalan, or doxorubicin.[23]

Stevens-Johnson syndrome

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of twenty prescription drugs under investigation for potential safety problems. The drug was investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening skin condition.[24]

FDA ongoing safety review

In 2011, the FDA initiated an ongoing review of clinical trials that found an increased risk of developing cancers such as acute myelogenous leukemia and B-cell lymphoma,[25] though it did not advise patients to discontinue treatment with lenalidomide.[26]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years.[when?] There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[27] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulationIn vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

On a molecular level, lenalidomide has been shown to interact with the ubiquitin E3 ligase cereblon[28] and target this enzyme to degrade the Ikaros transcription factors IKZF1 and IKZF3.[29] This mechanism was unexpected as it suggests that the major action of lenalidomide is to re-target the activity of an enzyme rather than block the activity of an enzyme or signaling process, and thereby represents a novel mode of drug action. A more specific implication of this mechanism is that the teratogenic and anti-neoplastic properties of lenalidomide, and perhaps other thalidomide derivatives, could be disassociated.

History

See also: Development of analogs of thalidomide

Lenalidomide was approved for medical use in the United States in 2005.[2]

Society and culture

Economics

Lenalidomide costs US$163,381 per year for the average person in the United States as of 2012.[25] Lenalidomide made almost $9.7bn for Celgene in 2018.[30]

In 2013, the UK National Institute for Health and Care Excellence (NICE) rejected lenalidomide for “use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)” in England and Scotland, arguing that Celgene “did not provide enough evidence to justify the GB£3,780 per month (US$5,746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)”.[31]

Research

Lenalidomide is undergoing clinical trial as a treatment for Hodgkin’s lymphoma,[32] as well as non-Hodgkin’s lymphomachronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.[33] One Phase III clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013, when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.[34]

SynRoute 1
Reference:

1. WO9803502A1 / US2002173658A1.

2. Bioorg. Med. Chem. Lett. 19999, 1625-1630.Route 2
Reference:

1. WO2010139266A1 / US2012077982A1.Route 3
Reference:

1. CN103497175A.Route 4
Reference:

1. WO2010139266A1 / US2012077982A1.Route 5
Reference:

1. CN103554082A.

Clip

Alternative synthesis of lenalidomide | SpringerLink

SYN

File:Lenalidomide synthesis.png - Wikimedia Commons

SCALABLE AND GREEN PROCESS FOR THE SYNTHESIS OF ANTICANCER DRUG LENALIDOMIDE

Yuri Ponomaryov, Valeria Krasikova, Anton Lebedev, Dmitri Chernyak, Larisa Varacheva, Alexandr Chernobroviy

Cover Image

Abstract

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

How to Cite
Ponomaryov, Y.; Krasikova, V.; Lebedev, A.; Chernyak, D.; Varacheva, L.; Chernobroviy, A. Chem. Heterocycl. Compd. 201551, 133. [Khim. Geterotsikl. Soedin. 201551, 133.]

For this article in the English edition see DOI 10.1007/s10593-015-1670-0

SYN

https://link.springer.com/article/10.1007/s10593-015-1670-0

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

SYN

File:Lenalidomide synthesis.png

SYN

EP 0925294; US 5635517; WO 9803502

Cyclization of N-(benzyloxycarbonyl)glutamine (I) by means of CDI in refluxing THF gives 3-(benzyloxycarbonylamino)piperidine-2,6-dione (II), which is deprotected with H2 over Pd/C in ethyl acetate/4N HCl to yield 3-aminopiperidine-2,6-dione hydrochloride (III). Bromination of 2-methyl-3-nitrobenzoic acid methyl ester (IV) with NBS in CCl4 provides 2-(bromomethyl)-3-nitrobenzoic acid methyl ester (V), which is cyclized with the aminopiperidine (III) by means of triethylamine in hot DMF to afford 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (VI). Finally, the nitro group of compound (VI) is reduced with H2 over Pd/C in methanol (1, 2).

SYN

Bioorg Med Chem Lett 1999,9(11),1625

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.

Lenalidomide

  • Synonyms:CC-5013, CDC 501
  • ATC:L04AX04
  • MW:259.27 g/mol
  • CAS-RN:191732-72-6
  • InChI Key:GOTYRUGSSMKFNF-JTQLQIEISA-N
  • InChI:InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)/t10-/m0/s1

Synthesis

References

  1. Jump up to:a b c “Lenalidomide (Revlimid) Use During Pregnancy”Drugs.com. 13 March 2020. Retrieved 13 August 2020.
  2. Jump up to:a b c d e f g h i j k “Lenalidomide Monograph for Professionals”Drugs.com. Retrieved 27 October 2019.
  3. Jump up to:a b c d e “DailyMed – Revlimid- lenalidomide capsule”dailymed.nlm.nih.gov. Retrieved 27 October 2019.
  4. ^ 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.
  5. ^ Armoiry X, Aulagner G, Facon T (June 2008). “Lenalidomide in the treatment of multiple myeloma: a review”Journal of Clinical Pharmacy and Therapeutics33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.xPMID 18452408S2CID 1228171.
  6. Jump up to:a b Li S, Gill N, Lentzsch S (November 2010). “Recent advances of IMiDs in cancer therapy”. Current Opinion in Oncology22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752cPMID 20689431S2CID 205547603.
  7. ^ Tageja N (March 2011). “Lenalidomide – current understanding of mechanistic properties”. Anti-Cancer Agents in Medicinal Chemistry11 (3): 315–26. doi:10.2174/187152011795347487PMID 21426296.
  8. ^ Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, Verma A (August 2009). “Mechanism of action of lenalidomide in hematological malignancies”Journal of Hematology & Oncology2: 36. doi:10.1186/1756-8722-2-36PMC 2736171PMID 19674465.
  9. ^ Yang B, Yu RL, Chi XH, Lu XC (2013). “Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials”PLOS ONE8 (5): e64354. Bibcode:2013PLoSO…864354Ydoi:10.1371/journal.pone.0064354PMC 3653900PMID 23691202.
  10. ^ Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, Morgan GJ (March 2012). “A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide”Blood119 (12): 2764–7. doi:10.1182/blood-2011-08-373514PMID 22323483.
  11. ^ “FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma”Food and Drug Administration (FDA). 29 June 2006. Retrieved 15 October 2015.[dead link]
  12. ^ “Lenalidomide (Revlimid)”Food and Drug Administration(FDA). 22 February 2017.
  13. ^ “REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales”Reuters. 23 April 2009.
  14. ^ Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, et al. (Cochrane Haematology Group) (November 2019). “Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis”The Cochrane Database of Systematic Reviews2019 (11). doi:10.1002/14651858.CD013487PMC 6876545PMID 31765002.
  15. ^ List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. (February 2005). “Efficacy of lenalidomide in myelodysplastic syndromes”. The New England Journal of Medicine352 (6): 549–57. doi:10.1056/NEJMoa041668PMID 15703420.
  16. ^ List AF (August 2005). “Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)”. Seminars in Oncology32 (4 Suppl 5): S31-5. doi:10.1053/j.seminoncol.2005.06.020PMID 16085015.
  17. ^ List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. (October 2006). “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion”. The New England Journal of Medicine355 (14): 1456–65. doi:10.1056/NEJMoa061292PMID 17021321.
  18. ^ “Revlimid Approved In Europe For Use In Myelodysplastic Syndromes”. The MDS Beacon. Retrieved 17 June 2013.
  19. ^ “Revlimid and Amyloidosis AL” (PDF). MyelomaUK. Retrieved 3 October 2020.
  20. ^ Rao KV (September 2007). “Lenalidomide in the treatment of multiple myeloma”. American Journal of Health-System Pharmacy64 (17): 1799–807. doi:10.2146/ajhp070029PMID 17724360.
  21. ^ “Revlimid Summary of Product Characteristics. Annex I” (PDF). European Medicines Agency. 2012. p. 6.
  22. ^ Ness, Stacey (13 March 2014). “New Specialty Drugs”. Pharmacy Times. Retrieved 5 November 2015.
  23. ^ Bennett CL, Angelotta C, Yarnold PR, Evens AM, Zonder JA, Raisch DW, Richardson P (December 2006). “Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer”. JAMA296 (21): 2558–60. doi:10.1001/jama.296.21.2558-cPMID 17148721.
  24. ^ “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2008”Food and Drug Administration(FDA). March 2008. Archived from the original on 19 April 2014. Retrieved 16 December 2019.
  25. Jump up to:a b Badros AZ (May 2012). “Lenalidomide in myeloma–a high-maintenance friend”. The New England Journal of Medicine366(19): 1836–8. doi:10.1056/NEJMe1202819PMID 22571206.
  26. ^ “FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies”Food and Drug Administration (FDA). April 2011.
  27. ^ Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma49 (7): 1238–45. doi:10.1080/10428190802005191PMID 18452080S2CID 43350339.
  28. ^ Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. (November 2011). “Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide”Blood118 (18): 4771–9. doi:10.1182/blood-2011-05-356063PMC 3208291PMID 21860026.
  29. ^ Stewart AK (January 2014). “Medicine. How thalidomide works against cancer”Science343 (6168): 256–7. doi:10.1126/science.1249543PMC 4084783PMID 24436409.
  30. ^ “Top 10 Best-Selling Cancer Drugs of 2018”. Genetic Engineering and Biotechnology News. 22 April 2019. Retrieved 25 April 2019.
  31. ^ “Revlimid faces NICE rejection for use in rare blood cancer Watchdog’s draft guidance does not recommend Celgene’s drug for NHS use in England and Wales”. Pharma News. 11 July 2013. Retrieved 5 November 2015.
  32. ^ “Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin’s Lymphoma”ClinicalTrials.gov. US National Institutes of Health. February 2009.
  33. ^ “276 current clinical trials world-wide, both recruiting and fully enrolled, as of 27 February 2009”ClinicalTrials.gov. US National Institutes of Health. February 2009.
  34. ^ “Celgene Discontinues Phase 3 Revlimid Study after ‘Imbalance’ of Deaths”. Nasdaq. 18 July 2013.

External links[edit]

Clinical data
Pronunciation/ˌlɛnəˈlɪdoʊmaɪd/
Trade namesRevlimid, Linamide, others
AHFS/Drugs.comMonograph
MedlinePlusa608001
License dataEU EMAby INNUS DailyMedLenalidomide
Pregnancy
category
AU: X (High risk)[1]
Routes of
administration
By mouth (capsules)
ATC codeL04AX04 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-onlyEU: Rx-only
Pharmacokinetic data
BioavailabilityUndetermined
Protein binding30%
MetabolismUndetermined
Elimination half-life3 hours
ExcretionKidney (67% unchanged)
Identifiers
showIUPAC name
CAS Number191732-72-6 
PubChem CID216326
IUPHAR/BPS7331
DrugBankDB00480 
ChemSpider187515 
UNIIF0P408N6V4
KEGGD04687 
ChEMBLChEMBL848 
CompTox Dashboard (EPA)DTXSID8046664 
ECHA InfoCard100.218.924 
Chemical and physical data
FormulaC13H13N3O3
Molar mass259.265 g·mol−1
3D model (JSmol)Interactive image
ChiralityRacemic mixture
hideSMILESO=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
hideInChIInChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18) Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N 

//////////Lenalidomide hydrate, Lenalidomide KRKA, EU 2021, APPROVALS 2021, レナリドミド水和物 , CC-5013 hemihydrate,

#Lenalidomide hydrate, #Lenalidomide KRKA, #EU 2021, #APPROVALS 2021, #レナリドミド水和物 , #CC-5013 hemihydrate,

O.Nc1cccc2C(=O)N(Cc12)C3CCC(=O)NC3=O.Nc4cccc5C(=O)N(Cc45)C6CCC(=O)NC6=O

Remimazolam


Remimazolam.svgChemSpider 2D Image | Remimazolam | C21H19BrN4O2GHUYIIGPWBMOGY-KRWDZBQOSA-N.png

Figure imgf000062_0002

Remimazolam

  • Molecular FormulaC21H19BrN4O2
  • Average mass439.305 Da
3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid methyl ester
CNS-7056
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
methyl 3-[(7S)-12-bromo-3-methyl-9-(pyridin-2-yl)-2,5,8-triazatricyclo[8.4.0.02,6]tetradeca-1(14),3,5,8,10,12-hexaen-7-yl]propanoate
MFCD18633229
UNII:7V4A8U16MB

CAS 308242-62-8 [RN]

PHASE 3, PAION, Anesthesia

Approved 2021/3/26 eu Byfavo

4H-Imidazo[1,2-a][1,4]benzodiazepine-4-propanoic acid, 8-bromo-1-methyl-6-(2-pyridinyl)-, methyl ester, (4S)-

7V4A8U16MB
9232
Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
Methyl 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [ 1 ,4]benzodiazepin-4-yl]propanoate
methyl 3-[(4S)-8-bromo-2-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
D0L5KU; GTPL8442; SCHEMBL13862667; Short-acting sedatives, Therasci; CNS-7056B; CNS-7056X
  1. CNS 7056
  2. methyl 3-(8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo(1,2-a)(1,4)benzodiazepin-4-yl)propanoate
  3. ONO 2745
  4. ONO-2745
  5. ONO2745

Remimazolam[1] (CNS-7056) is a benzodiazepine derivative drug, developed by PAION, in collaboration with Japanese licensee Ono Pharmaceutical as an alternative to the short-acting imidazobenzodiazepine midazolam, for use in induction of anaesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to be both faster acting and shorter lasting than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.[2][3]

Remimazolam (CNS-7056) is a water-soluble, rapid and short-acting GABA (A) benzodiazepine (BZ) site receptor agonist in phase III trials at PAION as procedural sedation in patients undergoing colonoscopy or diagnostic endoscopy of the upper gastrointestinal tract, and also with patients undergoing bronchoscopy.

PAION AG and its subsidiary PAION Inc, following its acquisition of CeNeS Pharmaceuticals (following CeNeS’ acquisition of TheraSci ), and licensees Mundipharma , Yichang Humanwell Pharmaceutical , Pendopharm , Cosmo and R-Pharm are developing remimazolam, the lead from a series of short-acting GABA A receptor agonists, as an iv sedative and/or anesthetic for potential use in day case surgical and non-surgical procedures

Image result for remimazolam

(Salt/Parent)
1
Remimazolam [INN]
308242-62-8
2D chemical structure of 308242-62-8
MW: 439.3111
2
Remimazolam besilate
1001415-66-2
2D chemical structure of 1001415-66-2
MW: 597.4875
3
Remimazolam tosylate
1425904-79-5
2D chemical structure of 1425904-79-5
MW: 611.5143

Trials

Phase I[4] and Ib[5] dose-finding studies for procedural sedation with patients recovering faster from remimazolam than midazolam. Phase II trials comparing remimazolam to the standard anesthesia protocols for cardiac surgery and colonoscopy were presented at major conferences in October 2014.[6]

A phase IIa trial comparing remimazolam to midazolam for upper endoscopy was published in December 2014, finding a similar safety profile.[7] Remimazolam was originally discovered in the late 1990s at Glaxo Wellcome in their labs in Research Triangle Park, NC.

BY CHENGDU

WO-2018103119

Novel crystalline forms of hydrobromate salt of remimazolam , processes for their preparation and compositions comprising them are claimed.

Remazolam, whose structure is shown in formula (I), has the chemical name 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole [1,2] -a] methyl [1,4]benzodiazepin- 4-yl]propanoate.
This compound is currently known as a CNS (Central Nervous System) inhibitor and has sedative, hypnotic, anxiolytic, muscle relaxing, and anticonvulsant effects. It is currently used intravenously in the following clinical treatment programs: preoperative sedation, anxiolysis and forgetfulness during surgery; awake sedation during short-term diagnosis, surgery, or endoscopic procedures; and administration of other anesthetics and analgesia Before and/or at the same time as a component for induction and maintenance of general anesthesia; ICU sedation and the like. It is reported in patent application CN101501019 that the free base stability of the compound is poor, and it is only suitable for storage at a low temperature of 5°C. Under conditions of 40°C/75% relative humidity (open), the sample is deliquescent and discolored, and the content is significantly reduced.
Due to the stability problem of the free base of the compound, researchers from various countries have studied the salts of the compound. For example, patent applications CN101501019B and WO2008/007081A1 respectively report the besylate and ethanesulfonate of the compound of formula (I). And shows that the above salts have good thermal stability, low hygroscopicity, and high water solubility, and that CN104968348A clearly states that the above benzenesulfonates and ethanesulfonates are the most preferred compounds of formula (I). Salts.
Immediately afterwards, CN 103221414B proposes a toxilate salt of a compound of formula (I) and indicates that the toxitic acid salt is less toxic than benzene sulphonate, and the thermal stability, water solubility and the like of certain crystal forms are even higher. For good.
To sort out the existing technology information, you can draw the following related content (Table 1):
Table 1
From the above table, it can be seen that regardless of whether it is a free base of remazolam or a known salt derivative of remazolam, the water solubility is not higher than 11 mg/ml, and only in the slightly soluble range, which will increase The safety risk of its use in clinical use requires resolving and dissolving for a long time during clinical reconstitution. It may also leave insoluble materials, resulting in inaccurate drug dosage and potential safety risks. In addition, it is used for general anesthesia. Indications with a large demand will increase the amount of diluent and cause extreme inconvenience for clinical use. Therefore, the solubility of the known salt derivatives of remazolam is a big disadvantage and needs to be further improved.
The raw material remazolam of the compound of the formula (I) used in the present invention can be obtained by purchasing a commercially available product or can be prepared according to a known method (for example, patent US200,700,934,75A, etc.).
Example 1 Preparation of Form III Hydrobromide Salt of Compound of Formula (I)
Accurately weigh 1.8 g of the compound of formula (I) into a 100 mL three-necked flask, add 8.2 mL of isopropanol and stir to dissolve it completely, then dissolve 0.83 g of 47% aqueous hydrobromic acid in 6.3 mL of isopropanol and drip To the solution of the compound of formula (I) in isopropanol, the crystals were stirred, filtered, and dried at 55°C under reduced pressure to give the hydrobromide salt of the compound of formula (I).
The X-ray diffraction pattern of this crystal is shown in FIG. 1, the DSC and TGA patterns are shown in FIG. 2, and the melting point is 163 DEG C. It is defined that the crystal form is the hydrobromide III crystal form of the compound of Formula (I).

PATENT

WO0069836

Family members of remimazolam’s product case WO0069836 , have production in most of the EU states until May 2020 and expire in the US in April 2020.

PRODUCT PATENT

WO 2000069836

https://encrypted.google.com/patents/WO2000069836A1?cl=en

Inventors Paul L. FeldmanDavid Kendall JungIstvan KaldorGregory J. PacofskyJeffrey A. StaffordJeffrey H. TidwellLess «
Applicant Glaxo Group Limited

Example Ic-8

Methyl 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [ 1 ,4]benzodiazepin-4-yl]propanoate

Figure imgf000062_0002

A solution of the C7-bromo-benzodiazepine Ex 1-10 (7.31 g, 18.2 mmol) in THF (21 mL) was added to a suspension of NaH (870 mg of 60% oil dispersion, 21.8 mmol) in THF (70 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature and stirred for 30 min, then cooled to 0 °C. Bis- morpholinophosphorochloridate (6.48 g, 25.5 mmol) was added, the mixture was allowed to warm to room temperature over 4.5 h, and the mixture was filtered with additional THF (ca. 10 mL). A mixture of the filtrate and DL-l-amino-2-propanol (2.80 mL, 36.4 mmol) was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was diluted with EtOAc (ca. 250 mL), washed with saturated aqueous NaHCO3 (1 x 75 mL), H2O (2 x 75 mL), saturated aqueous NaCl (1 x 75 mL), dried (Na SO ), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19:1 EtOAc-MeOH, gave 3.06 g

(37%) of the adduct as a foam; ESIMS 459 (M+H, base).

A mixture of DMSO (1.88 mL, 26.6 mmol) and oxalyl chloride (1.16 mL, 13.3 mmol) in CH2C12 (40 mL) was stirred at -78 °C for 30 min. A solution of the alcohol prepared above (3.05 g, 6.64 mmol) in CH2C1 (26 mL) was added. The reaction mixture was warmed to -15 °C and stirred 1 h, cooled to -78 °C, treated with

E-3N (5.55 mL, 39.9 mmol), and allowed to warm to room temperature over 3 h. The mixture was diluted with EtOAc (ca. 500 mL), washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (1 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na SO ), and concentrated under reduced pressure to give a foam. A mixture of this foam and a catalytic amount ofp-toluenesulfonic acid was stirred at room temperature for 18h, neutralized by the addition of saturated aqueous NaHCO3 and diluted with EtOAc (ca. 500 mL). The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (2 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na SO ), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19: 1 EtOAc-

MeOH, gave 2.56 g (88%) of Ic-8 as a foam; 1H NMR (400 MHz, CDC13) δ 8.57 (d, J = 4.6 Hz, lH), 8.17 (d J = 7.8 Hz, IH), 7.79 (dd, J = 7.7, 6.2 Hz, IH), 7.71 (dd, J = 8.6, 2.2 Hz, IH), 7.64 (d, J – 2.2 Hz, IH), 7.34 (dd, J = 7.5, 5.0 Hz, IH), 7.30 (d, J = 8.6 Hz, IH), 6.86 (s, IH), 4.05 (m, 1 H), 3.67 (s, 3H), 2.80 (comp, 4H), 2.34 (s, 3H); ESIMS 461 (M+Na, base), 439 (M+H); Anal, calcd. for C2]H19BrN4O2-0.25 H2O: C,

58.63; H, 4.43; N, 12.62. Found: C, 56.88; H, 4.43; N, 12.23.

Example lc-8 was formulated in an aqueous vehicle at a concentration of 10 mg/ml. Accordingly, 10 mg of compound (and 9 mg NaCl) was dissolved in 0.63 ml of 0.1 N HCl. Slowly and while stirring, 0.37 ml of 0.1 N NaOH was added. Adjustments are made to the dose volume depending on the dose being administered.

PATENT

CN 103232454

https://patents.google.com/patent/CN103232454A/en

The compounds of the following formula I:

[0003]

Figure CN103232454AD00051

Wherein R1 is bromine, R2 and R3 is methyl, [0004] because it contains the specific configuration, W000 / 69836 reported in the compound (60 specification Example Ic-8) is a short-acting central nervous system (CNS) to suppress agents, including having a sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant effect.They can be used for intravenous administration in the clinical treatment: preoperative sedation, such as during surgery, and forgetting anxiolytic purposes; in short diagnostic, operative or endoscopic conscious sedation during the procedure; administration of other anesthetics and analgesics before and / or simultaneously, as a component for the induction and maintenance of general anesthesia in; the ICU sedation, according CN101501019A (PA10N, application No. CN200780028964.5) reports, free base of the compound is not very stable, only suitable stored at low temperatures 5 ° C, at 40 ° C / 75% relative humidity (open) condition, the sample storage deliquescence, to the orange color turned yellow, with respect to the initial content and significantly reduced the content of the display. Thus the synthesis of salts of compounds of formula It (the I), hoping to increase the chemical stability thereof, for use in the preparation of medicaments.

[0005] existing CN101501019A and US20100075955A1 (TILBR00K) reported the benzenesulfonate salt of a compound of formula I, ethanesulfonate.CN102964349A (Henry, Application No. 201110456864.0) reported for compounds of formula ITosylate.

[0006] have reported the presence of a compound of formula I or a salt thereof concerns stability, which is disadvantageous for these compounds used in the clinical treatment of related diseases.

HPLC method [A]:

[0022] According to Chinese Pharmacopoeia 2010 Appendix VD High Performance Liquid Chromatography;

[0023] using Daicel Chrialcel OJ-H (5 μ m) 4.6 X 250mm using chiral chromatographic columns (guard column, if necessary Daicel Chrialcel OJ-H column analysis protected 5 μ m4.0 X IOmm, which is Japan Series Cat (Daicel ) brand), hexane: ethanol = 93: 7 (v / v) as the mobile phase, a flow rate of 1.0ml / min, column temperature 40 ° C, detection wavelength 225nm;

Bulk drug preparation of the present invention: [0204] Example 1

[0205] Preparation Example 4 taking the resulting compound of formula I lg, were added to 8ml of ethanol at 50 ° C – lactic acid – water (volume ratio of the three 45: 2: 53) mixed solution was stirred to dissolve; filtration, the filtrate was 5 ° C was allowed to stand at a temperature of 10~12 hours recrystallized, crystals were filtered off, 40 ° C and dried in vacuo; the above operation was repeated once, to give a compound of formula I may be formulated bulk drug used as a pharmaceutical formulation, was recrystallized twice yield rate of 86.1%.Chromatographic purity of product by HPLC 99.22% [B]; R & lt isomer impurity content of 0.39% relative peak area ratio (I / Ix) = 255 HPLC [Method A].

PATENT

EP 2305647

PATENT

WO 2011032692,

See also

References

  1. Jump up^ EP Patent 1183243
  2. Jump up^ Rogers WK, McDowell TS (December 2010). “Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures”. IDrugs : the Investigational Drugs Journal13 (12): 929–37. PMID 21154153.
  3. Jump up^ Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT (March 2011). “Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology”. Pharmacological Reviews63 (1): 243–67. doi:10.1124/pr.110.002717PMID 21245208.
  4. Jump up^ “A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics”. Anesth. Analg.accessdate =115: 274–83. Aug 2012. doi:10.1213/ANE.0b013e31823f0c28PMID 22190555.
  5. Jump up^ “A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy”. Anesth. Analg117: 1093–100. Nov 2013. doi:10.1213/ANE.0b013e3182a705aePMID 24108261.
  6. Jump up^ “Two Scientific Remimazolam Presentations Are Accepted for ASA and ACG Meeting in October 2014”MarketWired. Oct 1, 2014. Retrieved 2014-10-24.
  7. Jump up^ “A Phase IIa, Randomized, Double-Blind Study of Remimazolam (CNS 7056) Versus Midazolam for Sedation in Upper Gastrointestinal Endoscopy”. Anesthesia120: 771–80. Dec 11, 2014. doi:10.1213/ANE.0000000000000548PMID 25502841

PATENTS

WO2016011943A1 *2014-07-232016-01-28李勤耕New benzodiazepine derivative and use thereof

WO2000069836A1 *1999-05-142000-11-23Glaxo Group LimitedShort-acting benzodiazepines
WO2008007081A1 *2006-07-102008-01-17Cenes LimitedShort-acting benzodiazepine salts and their polymorphic forms
CN101501019A *2006-07-102009-08-05Paion英国有限公司Short-acting benzodiazepine salts and their polymorphic forms
WO2012062439A1 *2010-11-082012-05-18Paion Uk Ltd.Dosing regimen for sedation with cns 7056 (remimazolam)
CN102753525A *2009-09-182012-10-24Paion英国有限公司Process for preparing 3-[(4s)-8-bromo-1-methyl-6-(2-pyridinyl)-4h-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process
CN102964349A *2011-08-312013-03-13江苏恒瑞医药股份有限公司Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application
Patent ID

Patent Title

Submitted Date

Granted Date

US9737547 DOSING REGIMEN FOR SEDATION WITH CNS 7056 (REMIMAZOLAM)
2017-01-06
US2015224114 DOSING REGIMEN OF SEDATIVE
2013-08-30
2015-08-13
US2015148338 COMPOSITIONS COMPRISING SHORT-ACTING BENZODIAZEPINES
2013-05-22
2015-05-28
US9777007 SHORT-ACTING BENZODIAZEPINE SALTS AND THEIR POLYMORPHIC FORMS
2015-11-23
2016-06-23
US8642588 SHORT-ACTING BENZODIAZEPINE SALTS AND THEIR POLYMORPHIC FORMS
2010-03-25
Patent ID

Patent Title

Submitted Date

Granted Date

US2017217965 NEW BENZODIAZEPINE DERIVATIVE AND USE THEREOF
2015-07-22
US9656987 OXIDATION REACTION EXCELLENT IN CONVERSION RATE
2014-03-03
2016-01-14
US9156842 PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1, 2-A][1, 4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS
2010-09-15
2012-12-27
US7435730 Short-acting benzodiazepines
2007-06-14
2008-10-14
US7528127 Short-acting benzodiazepines
2007-06-14
2009-05-05
Patent ID

Patent Title

Submitted Date

Granted Date

US7485635 Short-acting benzodiazepines
2007-04-26
2009-02-03
US2015313913 POSITIVE ALLOSTERIC MODULATORS OF THE GABA-A RECEPTOR IN THE TREATMENT OF AUTISM
2014-02-04
2015-11-05
US9561236 DOSING REGIMEN FOR SEDATION WITH CNS 7056 (REMIMAZOLAM)
2011-11-07
2014-03-20
US2017044135 PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1, 2-A][1, 4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS
2016-10-27
US9512078 PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1, 2-A][1, 4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS
2015-09-01
2015-12-24
Patent ID

Patent Title

Submitted Date

Granted Date

US2017217925 PROCESS FOR PREPARING 3-[(S)-7-BROMO-2-(2-OXOPROPYLAMINO)-5-PYRIDIN-2-YL-3H-1, 4-BENZODIAZEPIN-3-YL]PROPIONIC ACID METHYL ESTER
2017-04-14
US9193730 SHORT-ACTING BENZODIAZEPINE SALTS AND THEIR POLYMORPHIC FORMS
2010-04-01
US7473689 Short-acting benzodiazepines
2007-06-14
2009-01-06
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2007-01-09
WO0069836 SHORT-ACTING BENZODIAZEPINES
2000-11-23
Remimazolam
Remimazolam.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C21H19BrN4O2
Molar mass 439.304 g/mol
3D model (JSmol)

//////////////CNS-7056 , CNS-7056X , ONO-2745  , CNS 7056 , CNS 7056X , ONO 2745, REMIMAZOLAM, PHASE 3, PHASE 3, PAION, Anesthesia, 308242-62-8

CC1=CN2C3=C(C=C(C=C3)Br)C(=NC(C2=N1)CCC(=O)OC)C4=CC=CC=N4

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