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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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Adagrasib


Adagrasib.svg

Adagrasib

FormulaC32H35ClFN7O2
cas 2326521-71-3
Mol weight604.1174
Antineoplastic
  DiseaseNon-small cell lung cancer
2022/12/12

FDA APPROVED, KRAZATI (Mirati Therapeutics)

  • MRTX-849
  • MRTX849
  • KRAS G12C inhibitor MRTX849

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer.[1][2] Adagrasib is an inhibitor of the RAS GTPase family.[1] It is taken by mouth.[1] It is being developed by Mirati Therapeutics.[1][3]

The most common adverse reactions include diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.[2] The most common laboratory abnormalities include decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.[2]

It was approved for medical use in the United States in December 2022.[1][3]

Synthesis Reference

Fell, Jay B et al. “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.” Journal of medicinal chemistry vol. 63,13 (2020): 6679-6693. doi:10.1021/acs.jmedchem.9b02052

Journal of Medicinal Chemistry (2020), 63(13), 6679-6693

PATENT

WO2020101736 https://patents.google.com/patent/WO2020101736A1/en

EXAMPLE 7

Figure imgf000140_0001

2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

Figure imgf000140_0002

[0432] 2-fluoroprop-2-enoyl chloride. To a solution of 2-fluoroprop-2-enoic acid (400 mg, 4.44 mmol, 1 eq) in DCM (4 mL) was added (COCl)2 (846 mg, 6.66 mmol, 583 µL, 1.5 eq) and DMF (32.5 mg, 444 umol, 34.2 µL, 0.1 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove a part of solvent and give a residue in DCM. Compound 2-fluoroprop-2-enoyl chloride (400 mg, crude) was obtained as a yellow liquid and used into the next step without further purification. [0433] Step A: 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile. To a solution of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)- 1-methylpyrrolidin- 2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (300 mg, 528 umol, 1 eq, HCl) in DCM (5 mL) was added DIEA (1.73 g, 13.4 mmol, 2.33 mL, 25.4 eq) and 2-fluoroprop-2-enoyl chloride (286 mg, 2.64 mmol, 5 eq) in DCM (5 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Al2O3, Dichloromethane/Methanol = 10/1 to 10/1). The residue was purified by prep-HPLC (column: Gemini 150 * 25 5u; mobile phase: [water (0.05% ammonia hydroxide v / v) – ACN]; B%: 55% – 85%, 12min). The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 * 30mm * 4um; mobile phase: [water (0.225% FA) – ACN]; B%: 20% – 50%, 10.5min). The residue was concentrated under reduced pressure to remove ACN, and then lyophlization. Title compound 2-[(2S)-4-[7-(8-chloro- 1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (EXAMPLE 7, 24.1 mg, 36.7 umol, 7% yield, 99.1% purity, FA) was obtained as a brown solid. [0434] SFC condition: “AD – 3S_3_5_40_3ML Column: Chiralpak AD – 3 100 × 4.6mm I.D., 3um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3mL/min Wavelength: 220nm”. [0435] 1H NMR (400 MHz, Acetic) d = 7.82 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 – 7.30 (m, 2H), 5.58 – 5.25 (m, 2H), 5.17 – 4.59 (m, 4H), 4.57 – 4.28 (m, 3H), 4.24 – 3.78 (m, 4H), 3.67 – 3.13 (m, 7H), 3.08 (br d, J = 2.4 Hz, 3H), 2.98 (br d, J = 6.4 Hz, 1H), 2.83 – 2.61 (m, 1H), 2.45 – 2.29 (m, 1H), 2.24 – 2.08 (m, 3H). 

PATENT

US20190144444 https://patents.google.com/patent/US20190144444A1/en

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Adagrasib (MRTX849) is an oral, small-molecule KRAS inhibitor developed by Mirati Therapeutics. KRAS mutations are highly common in cancer and account for approximately 85% of all RAS family mutations.5 However, the development of KRAS inhibitors has been challenging due to their high affinity for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), as well as the lack of a clear binding pocket.1 Adagrasib targets KRASG12C, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling.2 In a phase I/IB clinical study that included patients with KRASG12C-mutated advanced solid tumors (NCT03785249), adagrasib exhibited anti-tumor activity. The phase II of the same study showed that in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC), adagrasib was efficient without new safety signals.2,3,6

In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRASG12C–positive NSCLC.7 In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.8,9 Adagrasib joins sotorasib as another KRASG12C inhibitor approved by the FDA.4

Medical uses

Adagrasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy.[1][2][4]

History

Approval by the US Food and Drug Administration (FDA) was based on KRYSTAL-1, a multicenter, single-arm, open-label clinical trial (NCT03785249) which included participants with locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations.[2] Efficacy was evaluated in 112 participants whose disease has progressed on or after platinum-based chemotherapy and an immune checkpoint inhibitor, given either concurrently or sequentially.[2]

The FDA granted the application for adagrasib fast-trackbreakthrough therapy, and orphan drug designations.[2]

Research

It is undergoing clinical trials.[5][6][7][8][9][10]

References

  1. Jump up to:a b c d e f g https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf
  2. Jump up to:a b c d e f g h “FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSC”U.S. Food and Drug Administration (FDA). 12 December 2022. Retrieved 14 December 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b “Mirati Therapeutics Announces U.S. FDA Accelerated Approval of Krazati (adagrasib) as a Targeted Treatment Option for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation” (Press release). Mirati Therapeutics Inc. 12 December 2022. Retrieved 13 December 2022 – via MultiVu.
  4. ^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/216340Orig1s000ltr.pdf Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. (January 2020). “The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients”Cancer Discovery10 (1): 54–71. doi:10.1158/2159-8290.CD-19-1167PMC 6954325PMID 31658955.
  6. ^ Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, et al. (July 2020). “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer”Journal of Medicinal Chemistry63 (13): 6679–6693. doi:10.1021/acs.jmedchem.9b02052PMID 32250617.
  7. ^ Thein KZ, Biter AB, Hong DS (January 2021). “Therapeutics Targeting Mutant KRAS”. Annual Review of Medicine72: 349–364. doi:10.1146/annurev-med-080819-033145PMID 33138715S2CID 226242453.
  8. ^ Christensen JG, Olson P, Briere T, Wiel C, Bergo MO (August 2020). “Targeting Krasg12c -mutant cancer with a mutation-specific inhibitor”Journal of Internal Medicine288 (2): 183–191. doi:10.1111/joim.13057PMID 32176377.
  9. ^ Dunnett-Kane V, Nicola P, Blackhall F, Lindsay C (January 2021). “Mechanisms of Resistance to KRASG12C Inhibitors”Cancers13 (1): 151. doi:10.3390/cancers13010151PMC 7795113PMID 33466360.
  10. ^ Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, et al. (July 2022). “Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation”New England Journal of Medicine387 (2): 120–131. doi:10.1056/NEJMoa2204619PMID 35658005S2CID 249352736.

External links

  • “Adagrasib”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03785249 for “Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1” at ClinicalTrials.gov

///////Adagrasib, KRAZATI, FDA 2022, APPROVALS 2022, MRTX-849, MRTX849,  Mirati Therapeutics

[H][C@@]1(COC2=NC3=C(CCN(C3)C3=CC=CC4=C3C(Cl)=CC=C4)C(=N2)N2CCN(C(=O)C(F)=C)[C@@]([H])(CC#N)C2)CCCN1C

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Nirsevimab


(Heavy chain)
QVQLVQSGAE VKKPGSSVMV SCQASGGLLE DYIINWVRQA PGQGPEWMGG IIPVLGTVHY
GPKFQGRVTI TADESTDTAY MELSSLRSED TAMYYCATET ALVVSETYLP HYFDNWGQGT
LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP
AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKRVEPKSCD KTHTCPPCPA
PELLGGPSVF LFPPKPKDTL YITREPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP
REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL
PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT
VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK
(Light chain)
DIQMTQSPSS LSAAVGDRVT ITCQASQDIV NYLNWYQQKP GKAPKLLIYV ASNLETGVPS
RFSGSGSGTD FSLTISSLQP EDVATYYCQQ YDNLPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H153-H209, H229-L214, H235-H’235, H238-H’238, H270-H330, H376-H434, H’22-H’96, H’153-H’209, H’229-L’214, H’270-H’330, H’376-H’434, L23-L88, L’23-L’88, L134-L194, L’134-L’194)

>Heavy_chain
QVQLVQSGAEVKKPGSSVMVSCQASGGLLEDYIINWVRQAPGQGPEWMGGIIPVLGTVHY
GPKFQGRVTITADESTDTAYMELSSLRSEDTAMYYCATETALVVSETYLPHYFDNWGQGT
LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
REEQYNSTYRVVSVLTVLHQDWLEGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Light_chain
DIQMTQSPSSLSAAVGDRVTITCQASQDIVNYLNWYQQKPGKAPKLLIYVASNLETGVPS
RFSGSGSGTDFSLTISSLQPEDVATYYCQQYDNLPLTFGGGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Nirsevimab

EMS APPROVED 2022/10/31, Beyfortus, AstraZeneca AB

FormulaC6494H10060N1708O2050S46
CAS1989556-22-0
Mol weight146334.5658

Monoclonal antibody
Prevention of respiratory syncytial virus infection

  • Immunoglobulin g1-kappa, anti-(human respiratory syncytial virus fusion glycoprotein f0 (protein f))human monoclonal antibody.gamma.1 heavy chain (1-456) (human vh (homo sapiens ighv1-69*01(ighd)-ighj4*01 (90.1%)) (8.8.19) (1-126) -homo sapiens ighg1*03
  • Immunoglobulin g1, anti-(human respiratory syncytial virus fusion protein)(human monoclonal med18897 .gamma.1-chain), disulfide with monoclonal med18897 .kappa.-chain, dimer

Synthesis Reference

Khan, AA et al. (2020) Dosage regimens for and compositions including anti-rsv antibodies. (U.S. Patent No. 2020/0347120 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/6b/d2/10/a841b66e0c90cf/US20200347120A1.pdf

Nirsevimab, sold under the brand name Beyfortus, is a human recombinant monoclonal antibody with activity against respiratory syncytial virus, or RSV for infants.[2][3] It is under development by AstraZeneca and Sanofi.[2][3] Nirsevimab is designed to bind to the fusion protein on the surface of the RSV virus.[4][5]

The most common side effects reported for nirsevimab are rash, pyrexia (fever) and injection site reactions (such as redness, swelling and pain where the injection is given).[6]

Nirsevimab was approved for medical use in the European Union in November 2022.[1][7]

Nirsevimab (MEDI8897) is a recombinant human immunoglobulin G1 kappa (IgG1ĸ) monoclonal antibody used to prevent respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants.6 It binds to the prefusion conformation of the RSV F protein, a glycoprotein involved in the membrane fusion step of the viral entry process, and neutralizes several RSV A and B strains.6,1 Compared to palivizumab, another anti-RSV antibody, nirsevimab shows greater potency at reducing pulmonary viral loads in animal models. In addition, nirsevimab was developed as a single-dose treatment for all infants experiencing their first RSV season, whereas palivizumab requires five monthly doses to cover an RSV season.5 This is due to a modification in the Fc region of nirsevimab that grants it a longer half-time compared to typical monoclonal antibodies.1,6

On November 2022, nirsevimab was approved by the EMA for the prevention of RSV lower respiratory tract disease in newborns and infants during their first RSV season.6

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

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetF protein of RSV
Clinical data
Trade namesBeyfortus
Other namesMED-18897, MEDI8897
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusEU: Rx-only [1]
Identifiers
CAS Number1989556-22-0
PubChem SID384585358
DrugBankDB16258
UNIIVRN8S9CW5V
KEGGD11380
ChEMBLChEMBL4297575
Chemical and physical data
FormulaC6494H10060N1708O2050S46
Molar mass146336.58 g·mol−1

Adverse effects

No major hypersensitivity reactions have been reported, and adverse events of grade 3 or higher were only reported in 8% (77 of 968) of participants in clinical trial NCT02878330.[8][4]

Pharmacology

Mechanism of action

Nirsevimab binds to the prefusion conformation of the RSV fusion protein, i.e. it binds to the site at which the virus would attach to a cell; effectively rendering it useless. It has a modified Fc region, extending the half-life of the drug in order for it to last the whole RSV season.[4]

History

The opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) is based on data from two randomized, double-blind, placebo-controlled multicenter clinical trials that investigated the efficacy and safety of nirsevimab in healthy preterm (premature) and full-term infants entering their first respiratory syncytial virus (RSV) season.[6] These studies demonstrated that nirsevimab prevents lower respiratory tract infection caused by RSV requiring medical attention (such as bronchiolitis and pneumonia) in term and preterm infants during their first RSV season.[6]

The safety of nirsevimab was also evaluated in a phase II/III, randomized, double‑blind, multicenter trial in infants who were born five or more weeks prematurely (less than 35 weeks gestation) at higher risk for severe RSV disease and infants with chronic lung disease of prematurity (i.e. long-term respiratory problems faced by babies born prematurely) or congenital heart disease.[6] The results of this study showed that nirsevimab had a similar safety profile compared to palivizumab (Synagis).[6]

Society and culture

Legal status

On 15 September 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Beyfortus, intended for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants.[9][6] Beyfortus was reviewed under EMA’s accelerated assessment program.[9] The applicant for this medicinal product is AstraZeneca AB.[9] Nirsevimab was approved for medical use in the European Union in November 2022.[1][7]

Research

Nirsevimab is being investigated as an experimental vaccine against respiratory syncytial virus, RSV, in the general infant population.[2][3] The MELODY study is an ongoing, randomized, double-blind, placebo-controlled to evaluate the safety and efficacy of nirsevimab in late preterm and term infants. Initial results have been promising, with nirsevimab reducing LRTI (lower respiratory tract infections) by 74.5% compared to placebo in infants born at term or late preterm.[5][10][11]

Ongoing trials for nirsevimab are:

References

  1. Jump up to:a b c “Beyfortus”Union Register of medicinal products. 3 November 2022. Retrieved 6 November 2022.
  2. Jump up to:a b c “Nirsevimab demonstrated protection against respiratory syncytial virus disease in healthy infants in Phase 3 trial” (Press release). Sanofi. 26 April 2021. Archived from the original on 27 December 2021. Retrieved 27 December 2021.
  3. Jump up to:a b c “Nirsevimab MELODY Phase III trial met primary endpoint of reducing RSV lower respiratory tract infections in healthy infants” (Press release). AstraZeneca. 26 April 2021. Archived from the original on 26 December 2021. Retrieved 27 December 2021.
  4. Jump up to:a b c Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, et al. (Nirsevimab Study Group) (July 2020). “Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants”The New England Journal of Medicine383 (5): 415–425. doi:10.1056/NEJMoa1913556PMID 32726528S2CID 220876651.
  5. Jump up to:a b Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. (March 2022). “Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants”The New England Journal of Medicine386 (9): 837–846. doi:10.1056/NEJMoa2110275PMID 35235726S2CID 247220023.
  6. Jump up to:a b c d e f “New medicine to protect babies and infants from respiratory syncytial virus (RSV) infection”European Medicines Agency (EMA) (Press release). 16 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. Jump up to:a b “Beyfortus approved in the EU for the prevention of RSV lower respiratory tract disease in infants”AstraZeneca (Press release). 4 November 2022. Retrieved 6 November 2022.
  8. ^ Clinical trial number NCT02878330 at ClinicalTrials.gov
  9. Jump up to:a b c “Beyfortus: Pending EC decision”European Medicines Agency (EMA). 15 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. ^ Zacks Equity Research (25 March 2022). “Pfizer’s (PFE) RSV Jab Gets Another Breakthrough Therapy Tag”NasdaqArchived from the original on 8 April 2022. Retrieved 8 April 2022.
  11. ^ “Nirsevimab significantly protected infants against RSV disease in Phase III MELODY trial”AstraZeneca (Press release). 3 March 2022. Retrieved 6 November 2022.

////////////Nirsevimab, EU 2022, APPROVALS 2022, PEPTIDE, Monoclonal antibody, respiratory syncytial virus infection, ANTIVIRAL, 1989556-22-0, MED-18897, MEDI8897, AstraZeneca AB

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Olutasidenib


Olutasidenib.svg

Olutasidenib

  • FT-2102
  • FT2102

C18H15ClN4O2

354.79

CAS1887014-12-1

Rezlidhia (Forma Therapeutics)

SYN Caravella JA, et al. Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor. J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub 2020 Feb 12.

FDA 12/1/2022, To treat adults with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, Rezlidhia

Olutasidenib, sold under the brand name Rezlidhia, is an anticancer medication used to treat relapsed or refractory acute myeloid leukemia.[1][2] Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor.[1] It is taken by mouth.[1]

Olutasidenib was approved for medical use in the United States in December 2022.[1][2][3][4]

Medical uses

Olutasidenib is indicated for the treatment of adults with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.[1][2]

Society and culture

Names

Olutasidenib is the international nonproprietary name.[5]

Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.

Olutasidenib (FT-2102) is a selective and potent isocitrate dehydrogenase-1 (IDH1) inhibitor approved by the FDA in December 2022.5,6 It is indicated for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients with a susceptible IDH1 mutation as determined by an FDA-approved test.5 IDH1 mutations are common in different types of cancer, such as gliomas, AML, intrahepatic cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndromes (MDS), and they lead to an increase in 2-hydroxyglutarate (2-HG), a metabolite that participates in tumerogenesis.1,2 Olutasidenib inhibits the mutated IDH1 specifically, and provides a therapeutic benefit in IDH1-mutated cancers.1,5

Other IDH1 inhibitors, such as ivosidenib, have also been approved for the treatment of relapsed or refractory AML.3,4 Olutasidenib is orally bioavailable and capable of penetrating the blood-brain barrier, and is also being evaluated for the treatment of myelodysplastic syndrome (MDS), as well as solid tumors and gliomas (NCT03684811).4

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01423

a Reagents and conditions: (a) DIEA, DMSO, 80−110 °C, 16 h, 67%; (b) (R)-2-methylpropane-2-sulfinamide, CuSO4, 55 °C, DCE, 16 h, 81%; (c) MeMgBr, DCM, −50 to −60 °C, 3 h, 63%; (d) 1 N HCl, dioxane, reflux, 16 h, >98%, 98.4% ee; (e) m-CPBA, CHCl3, reflux, 4 days, 52%; (f) Ac2O, reflux, 3 days, 60%; (g) K2CO3, MeOH, 4 h, 92%; (h) MeI, K2CO3, DMF, 45 min, 67%.


1H NMR (300 MHz,
DMSO-d6) δ 12.07 (s, 1 H), 7.71−7.76 (m, 2 H), 7.51 (dd, J = 8.79,
2.35 Hz, 1 H), 7.31 (d, J = 8.79 Hz, 1 H), 6.97 (d, J = 7.92 Hz, 1 H),
6.93 (d, J = 7.92 Hz, 1 H), 5.95 (d, J = 7.92 Hz, 1 H), 4.62−4.75 (m,
1 H), 3.58 (s, 3 H), 1.50 (d, J = 6.74 Hz, 3 H); 13C NMR (75 MHz,
DMSO-d6) δ 161.0, 155.9, 141.4, 136.6, 135.0, 133.4, 129.8, 126.7,
125.8, 120.1, 119.4, 116.7, 115.1, 104.5, 103.7, 47.4, 34.0, 20.3; LCMS
(method 2) >95% purity; tR 10.18 min; m/z 355, 357 [M + H]+
;
HRMS (ESI) calcd for C18H16ClN4O2 [M + H]+ 355.0962 found
356.0956.

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Clinical data
Trade namesRezlidhia
Other namesFT-2102
License dataUS DailyMedOlutasidenib
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1887014-12-1
PubChem CID118955396
IUPHAR/BPS10319
DrugBankDB16267
ChemSpider72380144
UNII0T4IMT8S5Z
KEGGD12483
ChEMBLChEMBL4297610
PDB ligandPWV (PDBeRCSB PDB)
Chemical and physical data
FormulaC18H15ClN4O2
Molar mass354.79 g·mol−1
3D model (JSmol)Interactive image
showSMILES

References

  1. Jump up to:a b c d e f https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf
  2. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/215814Orig1s000ltr.pdf Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “Rigel Announces U.S. FDA Approval of Rezlidhia (olutasidenib) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with a Susceptible IDH1 Mutation”Rigel Pharmaceuticals, Inc. (Press release). 1 December 2022. Retrieved 2 December 2022.
  4. ^ “Rigel Announces U.S. FDA Approval of Rezlidhia (olutasidenib) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with a Susceptible IDH1 Mutation” (Press release). Rigel Pharmaceuticals. 1 December 2022. Retrieved 2 December 2022 – via PR Newswire.
  5. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information33 (3). hdl:10665/330879.

Further reading

External links

  • “Olutasidenib”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02719574 for “Open-label Study of FT-2102 With or Without Azacitidine or Cytarabine in Patients With AML or MDS With an IDH1 Mutation” at ClinicalTrials.gov

/////////////Olutasidenib, FDA 2022, APPROVALS 2022, Rezlidhia, FT-2102, FT 2102

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Mirvetuximab soravtansine-gynx


STR1

Mirvetuximab soravtansine-gynx

FDA 11/14/2022,To treat patients with recurrent ovarian cancer that is resistant to platinum therapy

Elahere

FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer

https://www.biochempeg.com/article/315.html

4846-85a8-48171ab38275

FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer

November 15, 2022

Kristi Rosa

The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere) for the treatment of select patients with folate receptor α–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere) for the treatment of adult patients with folate receptor α (Frα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens.1-3

The regulatory agency also gave the green light to the VENTANA FOLR1 (FOLR-2.1) RxDx Assay for use as a companion diagnostic device to identify patients who are eligible to receive the agent. Testing can be done on fresh or archived tissue. Newly diagnosed patients can be tested at diagnosis to determine whether this agent will be an option for them at the time of progression to platinum resistance.

The decision was supported by findings from the phase 3 SORAYA trial (NCT04296890), in which mirvetuximab soravtansine elicited a confirmed investigator-assessed objective response rate (ORR) of 31.7% (95% CI, 22.9%-41.6%); this included a complete response rate of 4.8% and a partial response rate of 26.9%. Moreover, the median duration of response (DOR) was 6.9 months (95% CI, 5.6-9.7) per investigator assessment.

“The approval of Elahere is significant for patients with FRα-positive platinum-resistant ovarian cancer, which is characterized by limited treatment options and poor outcomes,” Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, professor of medicine at the Harvard Medical School, and SORAYA co-principal investigator, stated in a press release. “Elahere impressive anti-tumor activity, durability of response, and overall tolerability observed in SORAYA demonstrate the benefit of this new therapeutic option, and I look forward to treating patients with Elahere.”

The global, single-arm SORAYA trial enrolled a total of 106 patients with platinum-resistant ovarian cancer whose tumors expressed high levels of FRα. Patients were allowed to have received up to 3 prior lines of systemic treatment, and all were required to have received bevacizumab (Avastin).

If patients had corneal disorders, ocular conditions in need of ongoing treatment, peripheral neuropathy that was greater than grade 1 in severity, or noninfectious interstitial lung disease, they were excluded.

Study participants received intravenous mirvetuximab soravtansine at 6 mg/kg once every 3 weeks until progressive disease or unacceptable toxicity. Investigators conducted tumor response assessments every 6 weeks for the first 36 weeks, and every 12 weeks thereafter.

Confirmed investigator-assessed ORR served as the primary end point for the research, and the key secondary end point was DOR by RECIST v1.1 criteria.

In the efficacy-evaluable population (n = 104), the median age was 62 years (range, 35-85). Ninety-six percent of patients were White, 2% were Asian, and 2% did not have their race information reported; 2% of patients were Hispanic or Latino. Regarding ECOG performance status, 57% of patients had a status of 0 and the remaining 43% had a status of 1.

Ten percent of patients received 1 prior line of systemic treatment, 39% received 2 prior lines, and 50% received 3 or more prior lines. All patients previously received bevacizumab, as required, and 47% previously received a PARP inhibitor.

The safety of mirvetuximab soravtansine was evaluated in all 106 patients. The median duration of treatment with the agent was 4.2 months (range, 0.7-13.3).

The all-grade toxicities most commonly experienced with mirvetuximab soravtansine included vision impairment (50%), fatigue (49%), increased aspartate aminotransferase (50%), nausea (40%), increased alanine aminotransferase (39%), keratopathy (37%), abdominal pain (36%), decreased lymphocytes (35%), peripheral neuropathy (33%), diarrhea (31%), decreased albumin (31%), constipation (30%), increased alkaline phosphatase (30%), dry eye (27%), decreased magnesium (27%), decreased leukocytes (26%), decreased neutrophils (26%), and decreased hemoglobin (25%).

Thirty-one percent of patients experienced serious adverse reactions with the agent, which included intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Toxicities proved to be fatalfor 2% of patients, and these included small intestinal obstruction (1%) and pneumonitis (1%).

Twenty percent of patients required dose reductions due to toxicities. Eleven percent of patients discontinued treatment with mirvetuximab soravtansine because of adverse reactions. Toxicities that resulted in more than 2% of patients discontinuing treatment included intestinal obstruction (2%) and thrombocytopenia (2%). One patient discontinued because of visual impairment.

References

  1. ImmunoGen announces FDA accelered approval of Elahere (mirvetuximab soravtansine-gynx) for the treatment of platinum-resistant ovarian cancer. News release. ImmunoGen Inc. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3GgrCwL
  2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. News release. FDA. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3UP742w
  3. Elahere (mirvetuximab soravtansine-gynx). Prescribing information; ImmunoGen Inc; 2022. Accessed November 14, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761310s000lbl.pdf
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//////////Mirvetuximab soravtansine-gynx, FDA 2022, APPROVALS 2022,  recurrent ovarian cancer, 

Elahere

Tremelimumab


(Light chain)
DIQMTQSPSS LSASVGDRVT ITCRASQSIN SYLDWYQQKP GKAPKLLIYA ASSLQSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YYSTPFTFGP GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV IWYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDP RGATLYYYYY GMDVWGQGTT
VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSN FGTQTYTCNV DHKPSNTKVD KTVERKCCVE CPPCPAPPVA
GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF
NSTFRVVSVL TVVHQDWLNG KEYKCKVSNK GLPAPIEKTI SKTKGQPREP QVYTLPPSRE
EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP MLDSDGSFFL YSKLTVDKSR
WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K
(Disulfide bridge: L23-L88, L134-L194, L214-H139, H22-H96, H152-H208, H265-H325, H371-H429, H227-H’227, H228-H’228, H231-H’231, H234-H’234)

Tremelimumab 5GGV.png

Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV.

Tremelimumab

FormulaC6500H9974N1726O2026S52
CAS745013-59-6
Mol weight146380.4722

FDA APPROVED2022/10/21, Imjudo

PEPTIDE, CP 675206

Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody
  DiseaseHepatocellular carcinoma

Tremelimumab (formerly ticilimumabCP-675,206) is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer,[1] it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.[2] It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer

PUBLISHED24 October 2022

https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html

24 October 2022 07:00 BST
 

Approval based on HIMALAYA Phase III trial results which showed single priming dose of Imjudo added to Imfinzi reduced risk of death by 22% vs. sorafenib
 

AstraZeneca’s Imjudo (tremelimumab) in combination with Imfinzi (durvalumab) has been approved in the US for the treatment of adult patients with unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer. The novel dose and schedule of the combination, which includes a single dose of the anti-CTLA-4 antibody Imjudo 300mg added to the anti-PD-L1 antibody Imfinzi 1500mg followed by Imfinzi every four weeks, is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the HIMALAYA Phase III trial. In this trial, patients treated with the combination of Imjudo and Imfinzi experienced a 22% reduction in the risk of death versus sorafenib (based on a hazard ratio [HR] of 0.78, 95% confidence interval [CI] 0.66-0.92 p=0.0035).1 Results were also published in the New England Journal of Medicine Evidence showing that an estimated 31% of patients treated with the combination were still alive after three years, with 20% of patients treated with sorafenib still alive at the same duration of follow-up.2

Liver cancer is the third-leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide.3,4 It is the fastest rising cause of cancer-related deaths in the US, with approximately 36,000 new diagnoses each year.5,6

Ghassan Abou-Alfa, MD, MBA, Attending Physician at Memorial Sloan Kettering Cancer Center (MSK), and principal investigator in the HIMALAYA Phase III trial, said: “Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival. In addition to this regimen demonstrating a favourable three-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “With this first regulatory approval for Imjudo, patients with unresectable liver cancer in the US now have an approved dual immunotherapy treatment regimen that harnesses the potential of CTLA-4 inhibition in a unique combination with a PD-L1 inhibitor to enhance the immune response against their cancer.”

Andrea Wilson Woods, President & Founder, Blue Faery: The Adrienne Wilson Liver Cancer Foundation, said: “In the past, patients living with liver cancer had few treatment options and faced poor prognoses. With today’s approval, we are grateful and optimistic for new, innovative, therapeutic options. These new treatments can improve long-term survival for those living with unresectable hepatocellular carcinoma, the most common form of liver cancer. We appreciate the patients, their families, and the broader liver cancer community who continue to fight for new treatments and advocate for others.”

The safety profiles of the combination of Imjudo added to Imfinzi and for Imfinzi alone were consistent with the known profiles of each medicine, and no new safety signals were identified.

Regulatory applications for Imjudo in combination with Imfinzi are currently under review in Europe, Japan and several other countries for the treatment of patients with advanced liver cancer based on the HIMALAYA results.

Notes

Liver cancer
About 75% of all primary liver cancers in adults are HCC.3 Between 80-90% of all patients with HCC also have cirrhosis.Chronic liver diseases are associated with inflammation that over time can lead to the development of HCC.7

More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.8 A critical unmet need exists for patients with HCC who face limited treatment options.8 The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC.8

HIMALAYA
HIMALAYA was a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and a regimen comprising a single priming dose of Imjudo 300mg added to Imfinzi 1500mg followed by Imfinzi every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.

The trial included a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue).

The trial was conducted in 181 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint was overall survival (OS) for the combination versus sorafenib and key secondary endpoints included OS for Imfinzi versus sorafenib, objective response rate and progression-free survival (PFS) for the combination and for Imfinzi alone.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi was recently approved to treat patients with advanced biliary tract cancer in the US based on results from the TOPAZ-1 Phase III trial. It is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy and is the global standard of care in this setting based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer, and other solid tumours.

Imfinzi combinations have also demonstrated clinical benefit in metastatic NSCLC in the POSEIDON Phase III trial.

Imjudo
Imjudo (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Imjudo blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond HIMALAYA, Imjudo is being tested in combination with Imfinzi across multiple tumour types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE).

Imjudo is also under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON Phase III trial, which showed the addition of a short course of Imjudo to Imfinzi plus chemotherapy improved both overall and progression-free survival compared to chemotherapy alone.

AstraZeneca in GI cancers
AstraZeneca has a broad development programme for the treatment of GI cancers across several medicines spanning a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new diagnoses leading to approximately 3.6 million deaths.9

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic, and colorectal cancers.

Imfinzi (durvalumab) is being assessed in combinations in oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

The Company aims to understand the potential of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib) is a first-in-class PARP inhibitor with a broad and advanced clinical trial programme across multiple GI tumour types including pancreatic and colorectal cancers. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in immuno-oncology (IO)
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s immuno-oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumour immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical trial programme that includes Imfinzi as a single treatment and in combination with Imjudo (tremelimumab) and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

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Mechanism of action

Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.[3] This is immune checkpoint blockade.

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.[4][5]

Clinical trials

Melanoma

Phase 1 and 2 clinical studies in metastatic melanoma showed some responses.[6] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.[1][7]

However, within a year, the survival curves showed separation of the treatment and control groups.[8] The conventional Response Evaluation Criteria in Solid Tumors (RECIST) may underrepresent the merits of immunotherapies. Subsequent immunotherapy trials (e.g. ipilimumab) have used the Immune-Related Response Criteria (irRC) instead.

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma,[9] tremelimumab failed to improve lifespan in the phase IIb DETERMINE trial, which assessed the drug as a second or third-line treatment for unresectable malignant mesothelioma.[10][11]

Non-small cell lung cancer

In a phase III trial, AstraZeneca paired tremelimumab with a PD-L1 inhibitor, durvalumab, for the first-line treatment of non-small cell lung cancer.[12] The trial was conducted across 17 countries, and in July 2017, AstraZeneca announced that it had failed to meet its primary endpoint of progression-free survival.[13]

References

  1. Jump up to:a b “Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma”. Pfizer.com. 1 April 2008. Retrieved 5 December 2015.
  2. ^ Mechanism of Pathway: CTLA-4 Inhibition[permanent dead link]
  3. ^ Antoni Ribas (28 June 2012). “Tumor immunotherapy directed at PD-1”. New England Journal of Medicine366 (26): 2517–9. doi:10.1056/nejme1205943PMID 22658126.
  4. ^ Tomillero A, Moral MA (October 2008). “Gateways to clinical trials”. Methods Find Exp Clin Pharmacol30 (8): 643–72. doi:10.1358/mf.2008.30.5.1236622PMID 19088949.
  5. ^ Poust J (December 2008). “Targeting metastatic melanoma”. Am J Health Syst Pharm65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461PMID 19052265.
  6. ^ Reuben, JM; et al. (1 Jun 2006). “Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma”Cancer106 (11): 2437–44. doi:10.1002/cncr.21854PMID 16615096S2CID 751366.
  7. ^ A. Ribas, A. Hauschild, R. Kefford, C. J. Punt, J. B. Haanen, M. Marmol, C. Garbe, J. Gomez-Navarro, D. Pavlov and M. Marsha (May 20, 2008). “Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma”Journal of Clinical Oncology26 (15S): LBA9011. doi:10.1200/jco.2008.26.15_suppl.lba9011.[permanent dead link]
  8. ^ M.A. Marshall, A. Ribas, B. Huang (May 2010). “Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma”Journal of Clinical Oncology28 (15S): 2609. doi:10.1200/jco.2010.28.15_suppl.2609.[permanent dead link]
  9. ^ FDA Grants AstraZeneca’s Tremelimumab Orphan Drug Status for Mesothelioma [1]
  10. ^ “Tremelimumab Fails Mesothelioma Drug Trial”. Archived from the original on 2016-03-06. Retrieved 2016-03-06.
  11. ^ AZ’ tremelimumab fails in mesothelioma trial
  12. ^ “AstraZeneca’s immuno-oncology combo fails crucial Mystic trial in lung cancer | FierceBiotech”.
  13. ^ “AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer”.

///////////Tremelimumab, Imjudo, APPROVALS 2022, FDA 2022, PEPTIDE, CP 675206, Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody

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Daxibotulinumtoxin A


FDA Approves Botox Challenger Daxxify for Frown Lines

Daxibotulinumtoxin A

FDA APPROVED 2022 2022/9/7, Daxxify

FormulaC6708H10359N1729O1995S32
CAS93384-43-1
Mol weight148171.4934

Daxibotulinumtoxin A-lanm

Treatment of galbellar lines, cervical dystonia, lateral canthal lines, migraine headaches and hyperhidrosis

  • DeveloperRevance Therapeutics; Shanghai Fosun Pharmaceutical
  • ClassAnalgesics; Anti-inflammatories; Antiarrhythmics; Antidepressants; Antimigraines; Antipruritics; Antispasmodics; Bacterial proteins; Bacterial toxins; Botulinum toxins; Eye disorder therapies; Foot disorder therapies; Muscle relaxants; Skin disorder therapies; Urologics; Vascular disorder therapies
  • Mechanism of ActionAcetylcholine inhibitors; Glutamate antagonists; Membrane transport protein modulators; Neuromuscular blocking agents
  • Orphan Drug StatusYes – Torticollis
  • RegisteredGlabellar lines
  • Phase IIITorticollis
  • Phase IIMuscle spasticity
  • No development reportedSkin disorders
  • DiscontinuedPlantar fasciitis
  • 19 Sep 2022Efficacy data from a phase IIa FHL trials in Glabellar-lines (crow’s feet) released by Revance
  • 19 Sep 2022Updated efficacy and safety data from the phase III SAKURA 1, SAKURA 2 and SAKURA 3 trials in Glabellar lines released by Revance Therapeutics
  • 18 Sep 2022Updated efficacy and safety data from the phase III SAKURA 1, SAKURA 2 and SAKURA 3 trials in Glabellar lines released by Revance Therapeutics

////////

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DAXI Impresses; Approaches FDA Approval

March 2, 2021

Lisette Hilton

Dermatology Times, Dermatology Times, February 2021 (Vol. 42, No. 2), Volume 42, Issue 2

The investigational neuromodulator, evaluated in clinical trials as a treatment for glabellar lines and as a combined therapy for glabellar, dynamic forehead, and lateral canthal lines, is quickly nearing an approval by the FDA.

The long-awaited, longer-lasting neuromodulator drug candidate DaxibotulinumtoxinA for Injection (DAXI), a botulinum toxin type A formulated with a novel peptide excipient, may be nearing FDA approval.

In mid-December 2020, Revance Therapeutics shared results from its phase 2 upper facial lines study (NCT04259086),1 in which investigators looked at DAXI for combined treatment of glabellar, dynamic forehead, and lateral canthal lines.

The authors reported on a multicenter study of 48 patients enrolled to receive 40, 32, and 48 U of DAXI for injection in the glabellar complex, forehead, and lateral canthal areas, respectively. At week 4, nearly 92% of patients achieved an Investigator Global Assessment (IGA) score indicating no or mild wrinkle severity with maximum contraction on their lateral canthal lines. Nearly 96% achieved similar results on their forehead and glabellar lines at week 4.

Wrinkle severity returned to baseline at a median of 7.6 months post treatment, according to the phase 2 study findings.

The treatment was well tolerated in all upper facial regions. The most common adverse event (AE) was injection site erythema, which occurred in 6.3% of patients. The authors reported no eyelid or brow ptosis.

This was Revance’s first DAXI study on not just glabellar lines but also on forehead and periocular lines, or crow’s-feet, according to Jeffrey S. Dover, MD, FRCPC, a phase 2 study investigator and a dermatologist at SkinCare Physicians in Chestnut Hill, Massachusetts. “I think this is yet more evidence that the Revance neuromodulator produces an impressive effect on lines of negative facial expression and lasts longer than any of the other neuromodulators approved by the FDA thus far,” said Dover.

Dermatologic Surgery published 2 papers on the investigational neuromodulator in January 2021. In one study,2 investigators evaluated the use of up to 3 DAXI treatments for moderate or severe glabellar lines. They focused on data from SAKURA 1 and 2 (NCT03014622 and NCT03014635), two identical phase 3, open label, multicenter studies in which investigators evaluated single and repeat treatment of the glabellar lines with 40 U of DAXI.

The authors reported on safety results for nearly 2700 patients, including 882 who received a second treatment and 568 who got DAXI a third time. Treatment-related AEs, which were generally mild and resolved, occurred in 17.8% of patients. Eyelid ptosis occurred in 0.9% of treatments.

Investigators of 2 other studies3,4 focused on DAXI efficacy among nearly 2700 subjects enrolled in Revance’s preceding pivotal trials. Participants received repeat treatments when they returned to baseline on the IGA–Frown Wrinkle Severity (FWS) and IGA–Patient Frown Winkle Severity (PFWS) scales at 12 weeks and up to 36 weeks after treatment.

More than 96% of patients achieved no or mild severity in glabellar wrinkles on the IGA- FWS scale after each of the 3 treatments, with peak responses between weeks 2 to 4, and about one-third or more saw no or mild severity at week 24. Response rates reached highs of 92% or more at weeks 2 to 4 on the IGA-PFWS scale.

“The median duration for return to moderate or severe severity was 24 weeks,” the authors said. “If approved, I believe daxibotulinumtoxinA will change the landscape of neuromodulators significantly. The approved ones all last 3 months. They all give nice results and have few adverse effects,” Dover said.

He and other investigators have seen no rise in AEs, and those that did occur lasted no longer than those of Botox, he said.

Revance appears to be preparing for approval. The company announced on December 22, 2020, that it has a strategic commercial manufacturing agreement with Ajinomoto Bio- Pharma Services for the supply of DAXI.5

As of November 24, 2020, the FDA had deferred a decision on the neuromodulator because the required factory inspection could not be conducted due to travel restrictions related to coronavirus disease 2019.6 The FDA did not indicate any other issues.

References:

  1. Green JB, Mariwalla K, Coleman K, et al. A large, open-label, phase 3 safety study of DaxibotulinumtoxinA for Injection in glabellar lines: a focus on safety from the SAKURA 3 study. Derm Surg. 2021;47(1):42-46. doi:10.1097/DSS.0000000000002463
  2. Carruthers JD, Jean D, Fagien S, et al; SAKURA 1 and SAKURA 2 Investigator Group. DaxibotulinumtoxinA for Injection for the treatment of glabellar lines: results from each of two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2).Plast Reconstr Surg. 2020;1(145):45-58.doi: 10.1097/PRS.0000000000006327
  3. Fabi SG, Cohen JL, Green LJ, et al. DaxibotulinumtoxinA for Injection for the treatment of glabellar lines: efficacy results from SAKURA 3, a large, open-label, phase 3 safety study. Derm Surg. 2021;47(1):48-54. doi:10.1097/DSS.0000000000002531
  4. https://investors.revance.com/news-releases/news-release-details/ajinomoto-bio-pharma-services-and-revance-therapeutics-announce. December 22, 2020. Accessed January 15, 2021.
  5. FDA defers approval of DaxibotulinumtoxinA for Injection in glabellar lines due to COVID-19 related travel restrictions impacting manufacturing site inspection. News release. Revance Therapeutics, Inc. November 25, 2020. Accessed January 13, 2021. https://www.businesswire.com/news/home/20201125005462/en/FDA-Defers-Approval-DaxibotulinumtoxinA-Injection-Glabellar-Lines

///////////Daxibotulinumtoxin A, FDA 2022, APPROVALS 2022, DAXI, Daxibotulinumtoxin-A, DaxibotulinumtoxinA for Injection, daxibotulinumtoxinA-lanm, DAXXIFY, RT-002, Orphan Drug

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Ozoralizumab



Ozoralizumab

FormulaC1682H2608N472O538S12
CAS 1167985-17-2
Mol weight38434.3245 

PMDA JAPAN  APPROVED 2022 2022/9/26 Nanozora

anti-TNFα Nanobody®; ATN-103; Nanozora; PF-5230896; TS-152

Ozoralizumab is a humanized monoclonal antibody designed for the treatment of inflammatory diseases.[1]

Ozoralizumab was developed by Pfizer Inc, and now belongs to Ablynx NV. Ablynx has licensed the rights to the antibody in China to Eddingpharm.

Ozoralizumab has been used in trials studying the treatment of Rheumatoid Arthritis and Active Rheumatoid Arthritis.

Ozoralizumab is a 38 kDa humanized trivalent bispecific construct consisting of two anti-TNFα NANOBODIES® and anti-HSA NANOBODY® that was generated at Ablynx by a previously described method (23). Llamas were immunized with human TNFα and human muscle extract, which is rich in HSA, to induce the formation of anti-TNFα VHH and anti-HSA VHH. Both the anti-TNFα VHH and anti-HSA VHH were humanized by a complementary determining regions (CDR) grafting approach in which the CDR of the gene encoding llama VHH was grafted onto the most homologous human VHH framework sequence. Since binding to serum albumin prolongs the half-life of VHH (23, 26, 27), an anti-HSA VHH which efficiently binds murine serum albumin as well was incorporated into the two anti-TNFα VHHs. The three components were fused using a flexible Gly-Ser linker.

////////

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

Monoclonal antibody
TypeWhole antibody
SourceHumanized
Clinical data
ATC codenone
Identifiers
CAS Number1167985-17-2 
ChemSpidernone
UNII05ZCK72TXZ
KEGGD09944
Chemical and physical data
FormulaC1682H2608N472O538S12
Molar mass38434.85 g·mol−1
  • OriginatorAblynx
  • DeveloperAblynx; Eddingpharm; Pfizer; Taisho Pharmaceutical
  • ClassAnti-inflammatories; Antirheumatics; Monoclonal antibodies; Proteins
  • Mechanism of ActionTumour necrosis factor alpha inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes
  • RegisteredRheumatoid arthritis
  • DiscontinuedAnkylosing spondylitis; Crohn’s disease; Psoriatic arthritis
  • 05 Oct 2022Sanofi’s affiliate Ablynx has worldwide patent pending for Nanobodies® (Sanofi website, October 2022)
  • 05 Oct 2022Sanofi’s affiliate Ablynx has worldwide patent protection for Nanobodies® (Sanofi website, October 2022)
  • 26 Sep 2022First global approval – Registered for Rheumatoid arthritis in Japan (SC)

References

  1. ^ Kratz F, Elsadek B (July 2012). “Clinical impact of serum proteins on drug delivery”. J Control Release161 (2): 429–45. doi:10.1016/j.jconrel.2011.11.028PMID 22155554.

////////Ozoralizumab, Nanozora, Monoclonal antibody, nanobody, Treatment inflammation, ATN 103, APPROVALS 2022, JAPAN 2022

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Futibatinib


Futibatinib (JAN/USAN/INN).png
img

Futibatinib

フチバチニブ

FormulaC22H22N6O3
CAS1448169-71-8
Mol weight418.4485

2022/9/30 FDA APPROVED, Lytgobi

Antineoplastic, Receptor tyrosine kinase inhibitor
  DiseaseCholangiocarcinoma (FGFR2 gene fusion)

1-[(3S)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one

TAS-120, TAS 120, TAS120; Futibatinib

Futibatinib, also known as TAS-120 is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. FGFR inhibitor TAS-120 selectively and irreversibly binds to and inhibits FGFR, which may result in the inhibition of both the FGFR-mediated signal transduction pathway and tumor cell proliferation, and increased cell death in FGFR-overexpressing tumor cells. FGFR is a receptor tyrosine kinase essential to tumor cell proliferation, differentiation and survival and its expression is upregulated in many tumor cell types.

SYN

Patent Document 1: International Publication WO 2007/087395 pamphlet
Patent Document 2: International Publication WO 2008/121742 pamphlet
Patent Document 3: International Publication WO 2010/043865 pamphlet
Patent Document 4: International Publication WO 2011/115937 pamphlet

 

Unlicensed Document 1 : J. Clin. Oncol. 24, 3664-3671 (2006)
Non-licensed Document 2: Mol. Cancer Res. 3, 655-667 (2005)
Non-licensed Document 3: Cancer Res. 70, 2085-2094 (2010)
Non-licensed Document 4: Clin. Cancer Res. 17, 6130-6139 (2011)
Non-licensed Document 5: Nat. Med. 1, 27-31 (1995)

WO2020095452

WO2020096042

WO2020096050

WO2019034075

WO2015008844

WO2015008839

WO2013108809

SYN

US9108973

SYN

Reference Example 1: WXR1

Compound WXR1 was synthesized according to the route reported in patent WO2015008844. 1 H NMR(400MHz, DMSO-d 6 )δ8.40(d,J=3.0Hz,1H),6.93(d,J=2.5Hz,2H),6.74-6.52(m,2H),6.20-6.16( m,1H), 5.74-5.69(m,1H), 5.45-5.61(m,1H), 4.12-3.90(m,2H), 3.90-3.79(m,8H), 2.47-2.30(m,2H). MS m/z: 419.1[M+H] +

PAPER

Bioorg Med Chem, March 2013, Vol.21, No.5, pp.1180-1189

SYN

WO2015008844

PATENT

////////

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

Clinical data
Trade namesLytgobi
Other namesTAS-120
License dataUS DailyMedFutibatinib
Routes of
administration
By mouth
Drug classAntineoplastic
ATC codeL01EN04 (WHO)
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number1448169-71-8
PubChem CID71621331
IUPHAR/BPS9786
DrugBankDB15149
ChemSpider58877816
UNII4B93MGE4AL
KEGGD11725
ChEMBLChEMBL3701238
PDB ligandTZ0 (PDBeRCSB PDB)
Chemical and physical data
FormulaC22H22N6O3
Molar mass418.457 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

Futibatinib, sold under the brand name Lytgobi, is a medication used for the treatment of cholangiocarcinoma (bile duct cancer).[1][2] It is a kinase inhibitor.[1][3] It is taken by mouth.[1]

Futibatinib was approved for medical use in the United States in September 2022.[1][2][4]

Medical uses

Futibatinib is indicated for the treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.[1][2]

Names

Futibatinib is the international nonproprietary name (INN).[5]

References

  1. Jump up to:a b c d e f “Lytgobi (futibatinib) tablets, for oral use” (PDF). Archived (PDF) from the original on 4 October 2022. Retrieved 4 October 2022.
  2. Jump up to:a b c https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/214801Orig1s000ltr.pdf Archived 4 October 2022 at the Wayback Machine Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “Lytgobi (Futibatinib) FDA Approval History”Archived from the original on 4 October 2022. Retrieved 4 October 2022.
  4. ^ “FDA Approves Taiho’s Lytgobi (futibatinib) Tablets for Previously Treated, Unresectable, Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma” (Press release). Taiho Oncology. 30 September 2022. Archived from the original on 4 October 2022. Retrieved 4 October 2022 – via PR Newswire.
  5. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1). hdl:10665/330896.

External links

//////////Futibatinib, Lytgobi, FDA 2022, APPROVALS 2022, フチバチニブ , ANTINEOPLASTIC, TAS 120

C=CC(N1C[C@@H](N2N=C(C#CC3=CC(OC)=CC(OC)=C3)C4=C(N)N=CN=C42)CC1)=O

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Lutetium (177Lu) chloride


Lutetium (177Lu) chloride.png
LuCl3structure.jpg

Lutetium (177Lu) chloride

塩化ルテチウム (177Lu)

FormulaLu. 3Cl
CAS16434-14-3
Mol weight281.326

2022/9/15 EMA 2022, Illuzyce

EndolucinBeta

(177Lu)lutetium(3+) trichloride

Diagnostic aid, Radioactive agent

Lutetium 177 is an isotope of a rare-earth lanthanide metal lutetium. Radioactive decay of Lu 177 produces electrons with low energies making the isotope suitable for treatment of metastatic disease. A complex of Lu177 and somatostatin analog DOTA-TATE was approved by the FDA for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults. It is marketed under a tradename Lutathera. Lutetium in the complex with other carriers – phosphonates and monoclonal antibodies – was investigated in clinical trials as radiotherapy to prostate, ovarian, renal and other types of cancer.Lutetium (177Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy (medical imaging).[5][6] It is an isotopomer of lutetium(III) chloride containing the radioactive isotope 177Lu, which undergoes beta decay with a half-life of 6.65 days.

Medical uses

Lutetium (177Lu) chloride is a radiopharmaceutical precursor and is not intended for direct use in patients.[5] It is used for the radiolabeling of carrier molecules specifically developed for reaching certain target tissues or organs in the body. The molecules labeled in this way are used as cancer therapeutics or for scintigraphy, a form of medical imaging.[5] 177Lu has been used with both small molecule therapeutic agents (such as 177Lu-DOTATATE) and antibodies for targeted cancer therapy[8][9]

////////

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

Clinical data
Trade namesLumark, EndolucinBeta, Illuzyce
AHFS/Drugs.comLumark UK Drug Information
EndolucinBeta UK Drug Information
License dataEU EMAby INN
Pregnancy
category
AU: X (High risk)[1][2]
ATC codeNone
Legal status
Legal statusAU: Unscheduled [3][4]EU: Rx-only [5][6][7]In general: ℞ (Prescription only)
Identifiers
showIUPAC name
CAS Number16434-14-3
PubChem CID71587001
DrugBankDBSALT002634
ChemSpider32700269
UNII1U477369SN
KEGGD10828
CompTox Dashboard (EPA)DTXSID20167745 
Chemical and physical data
FormulaCl3Lu
Molar mass281.32 g·mol−1
3D model (JSmol)Interactive image
hideSMILES[Cl-].[Cl-].[Cl-].[177Lu+3]

Contraindications

Medicines radiolabeled with lutetium (177Lu) chloride must not be used in women unless pregnancy has been ruled out.[5]

Adverse effects

The most common side effects are anaemia (low red blood cell counts), thrombocytopenia (low blood platelet counts), leucopenia (low white blood cell counts), lymphopenia (low levels of lymphocytes, a particular type of white blood cell), nausea (feeling sick), vomiting and mild and temporary hair loss.[5]

Society and culture

Legal status

Lutetium (177Lu) chloride (Lumark) was approved for use in the European Union in June 2015.[5] Lutetium (177Lu) chloride (EndolucinBeta) was approved for use in the European Union in July 2016.[6]

On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Illuzyce, a radiopharmaceutical precursor.[10] Illuzyce is not intended for direct use in patients and must be used only for the radiolabelling of carrier medicines that have been specifically developed and authorized for radiolabelling with lutetium (177Lu) chloride.[10] The applicant for this medicinal product is Billev Pharma ApS.[10] Illuzyce was approved for medical use in the European Union in September 2022.[7]

References

  1. ^ “Lutetium (177Lu) Chloride”Therapeutic Goods Administration (TGA). 21 January 2022. Archived from the original on 5 February 2022. Retrieved 5 February 2022.
  2. ^ “Updates to the Prescribing Medicines in Pregnancy database”Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  3. ^ “TGA eBS – Product and Consumer Medicine Information Licence”Archived from the original on 5 February 2022. Retrieved 5 February 2022.
  4. ^ http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=1C7A40803A3A3F94CA2587D4003CE48A&agid=(PrintDetailsPublic)&actionid=1 Archived 30 July 2022 at the Wayback Machine[bare URL PDF]
  5. Jump up to:a b c d e f g “Lumark EPAR”European Medicines Agency (EMA)Archived from the original on 25 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. Jump up to:a b c “EndolucinBeta EPAR”European Medicines Agency (EMA)Archived from the original on 28 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. Jump up to:a b “Illuzyce EPAR”European Medicines Agency (EMA). 18 July 2022. Archived from the original on 22 September 2022. Retrieved 21 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ^ Lundsten S, Spiegelberg D, Stenerlöw B, Nestor M (December 2019). “The HSP90 inhibitor onalespib potentiates 177Lu‑DOTATATE therapy in neuroendocrine tumor cells”International Journal of Oncology55 (6): 1287–1295. doi:10.3892/ijo.2019.4888PMC 6831206PMID 31638190.
  9. ^ Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ (April 2005). “177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo”. Nuclear Medicine and Biology32 (3): 269–78. doi:10.1016/j.nucmedbio.2005.01.003PMID 15820762.
  10. Jump up to:a b c “Illuzyce: Pending EC decision”European Medicines Agency. 21 July 2022. Archived from the original on 30 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

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Valemetostat tosilate


Valemetostat tosilate (JAN).png
2D chemical structure of 1809336-93-3

Valemetostat tosilate

バレメトスタットトシル酸塩

FormulaC26H34ClN3O4. C7H8O3S
CAS1809336-93-3
Mol weight660.2205

PMDA JAPAN approved 2022/9/26, Ezharmia

  • 1,3-Benzodioxole-5-carboxamide, 7-chloro-N-((1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-, (2R)-, compd. with 4-methylbenzenesulfonate (1:1)

Antineoplastic, histone methyltransferase inhibitor

1809336-39-7 (free base). 1809336-93-3 (tosylate)   1809336-92-2 (mesylate)   1809336-94-4 (fumarate)   1809336-95-5 (tarate)

Synonym: Valemetostat; DS-3201; DS 3201; DS3201; DS-3201b

日本医薬品一般的名称(JAN)データベース

(2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide mono(4-methylbenzenesulfonate)

C26H34ClN3O4▪C7H8O3S : 660.22
[1809336-93-3]

STR1
img

1809336-39-7 (free base)
Chemical Formula: C26H34ClN3O4
Exact Mass: 487.2238
Molecular Weight: 488.02

(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide

 Valemetostat, also known as DS-3201 is a potent, selective and orally active EZH1/2 inhibitor. DS-3201 selectively inhibits the activity of both wild-type and mutated forms of EZH1 and EZH2. Inhibition of EZH1/2 specifically prevents the methylation of lysine 27 on histone H3 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways, enhances transcription of certain target genes, and results in decreased proliferation of EZH1/2-expressing cancer cells.

  • OriginatorDaiichi Sankyo Inc
  • DeveloperCALYM Carnot Institute; Daiichi Sankyo Inc; Lymphoma Academic Research Organisation; Lymphoma Study Association; University of Texas M. D. Anderson Cancer Center
  • ClassAmides; Amines; Antineoplastics; Benzodioxoles; Chlorinated hydrocarbons; Cyclohexanes; Pyridones; Small molecules
  • Mechanism of ActionEnhancer of zeste homolog 1 protein inhibitors; Enhancer of zeste homolog 2 protein inhibitors
  • Orphan Drug StatusYes – Adult T-cell leukaemia-lymphoma; Peripheral T-cell lymphoma
  • New Molecular EntityYes
  • RegisteredAdult T-cell leukaemia-lymphoma
  • Phase IIB-cell lymphoma; Peripheral T-cell lymphoma
  • Phase I/IISmall cell lung cancer
  • Phase INon-Hodgkin’s lymphoma; Prostate cancer; Renal cell carcinoma; Urogenital cancer
  • PreclinicalDiffuse large B cell lymphoma
  • No development reportedAcute myeloid leukaemia; Precursor cell lymphoblastic leukaemia-lymphoma
  • 26 Sep 2022First global approval – Registered for Adult T-cell leukaemia-lymphoma (Monotherapy, Second-line therapy or greater) in Japan (PO)
  • 26 Sep 2022Updated efficacy and adverse events data from a phase II trial in Adult T-cell leukaemia-lymphoma released by Daiichi Sankyo
  • 28 Dec 2021Preregistration for Adult T-cell leukaemia-lymphoma (Monotherapy, Second-line therapy or greater) in Japan (PO
Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure–Activity Relationships Insights and Evolution Prospects | Journal of Medicinal Chemistry

PATENT

WO 2015141616

 Watson, W. D. J. Org. Chem. 1985, 50, 2145.
 Lengyel, I. ; Cesare, V. ; Stephani, R. Synth. Common. 1998, 28, 1891.

PATENT

WO2022009911

The equipment and measurement conditions for the powder X-ray diffraction measurement in the examples are as follows.
Model: Rigaku Rint TTR-III
Specimen: Appropriate
X-ray generation conditions: 50 kV, 300 mA
Wavelength: 1.54 Å (Copper Kα ray)
Measurement temperature: Room temperature
Scanning speed: 20°/min
Scanning range: 2 to 40°
Sampling width: 0.02°

[0043]

(Reference Example 1) Production of ethyl trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

[0044]

[hua 6]

[0045]

 Under a nitrogen atmosphere, ethanol (624 L) and ethyl trans-4-aminocyclohexanecarboxylate monohydrochloride (138.7 kg, 667.8 mol) were added to a reaction vessel and cooled. Triethylamine (151.2 kg, 1495 .5 mol) and di-tert-butyl dicarbonate (160.9 kg, 737.2 mol) were added dropwise while maintaining the temperature below 20°C. After stirring at 20-25°C for 4 hours, water (1526 kg) was added dropwise at 25°C or lower, and the mixture was further stirred for 2 hours. The precipitated solid was collected by filtration, washed with a mixture of ethanol:water 1:4 (500 L), and dried under reduced pressure at 40°C to obtain 169.2 kg of the title compound (yield 93.4%). .
1 H NMR (500 MHz, CDCl 3 ): δ 4.37 (br, 1H), 4.11 (q, J = 2.8 Hz, 2H), 3.41 (br, 1H), 2.20 (tt, J = 4.8, 1.4 Hz, 1H),2.07(m,2H),2.00(m,2H),1.52(dq,J=4.6,1.4Hz,2H),1.44(s,9H),1.24(t,J=2.8Hz,3H), 1.11(dq,J=4.6,1.4Hz,2H)

[0046]

(Reference Example 2) Production of tert-butyl = [trans-4-(hydroxymethyl)cyclohexyl]carbamate

[0047]

[hua 7]

[0048]

 Under a nitrogen atmosphere, tetrahydrofuran (968 kg), ethyl = trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate (110 kg, 405.4 mol), lithium chloride (27.5 kg, 648 kg) were placed in a reaction vessel. .6 mol), potassium borohydride (32.8 kg, 608.1 mol), and water (2.9 L, 162.2 mol) were added, the temperature was slowly raised to 50°C, and the mixture was further stirred for 6 hours. Cooled to 0-5°C. Acetone (66 L) and 9 wt % ammonium chloride aqueous solution (1210 kg) were added dropwise while maintaining the temperature at 20° C. or lower, and the mixture was stirred at 20-25° C. for 1 hour. Additional ethyl acetate (550 L) was added, the aqueous layer was discarded and the organic layer was concentrated to 550 L. Ethyl acetate (1650 L) and 9 wt% aqueous ammonium chloride solution (605 kg) were added to the residue, and the aqueous layer was discarded after stirring. Washed sequentially with water (550 L). The organic layer was concentrated to 880 L, ethyl acetate (660 L) was added to the residue, and the mixture was concentrated to 880 L while maintaining the internal temperature at 40-50°C. The residue was cooled to 0-5° C. and stirred for 1 hour, petroleum ether (1760 L) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The precipitated solid was collected by filtration, washed with a petroleum ether:ethyl acetate 3:1 mixture (220 L) cooled to 0-5°C, and dried at 40°C under reduced pressure to give 86.0 kg of the title compound (yield: obtained at a rate of 92.3%).
1 H NMR (500 MHz, CDCl 3 ): δ 4.37 (br, 1H), 3.45 (d, J = 2.2 Hz, 2H), 3.38 (br, 1H), 2.04 (m, 2H),
1.84(m,2H),1.44(m,10H),1.28-1.31(m,1H),1.00-1.13(m,4H)

[0049]

(Reference Example 3) Production of tert-butyl = [trans-4-(2,2-dibromoethenyl)cyclohexyl]carbamate

[0050]

[hua 8]

[0051]

(Step 1)
 Under a nitrogen atmosphere, ethyl acetate (50 L), tert-butyl = [trans-4-(hydroxymethyl)cyclohexyl]carbamate (2.5 kg, 10.90 mol), potassium bromide ( 39.3 g, 0.33 mol), 2,2,6,6-tetramethylpiperidine 1-oxyl (51.1 g, 0.33 mol), 4.8% aqueous sodium hydrogen carbonate solution (26.25 kg ) was added and cooled to 0-5°C, 9.9% sodium hypochlorite (8.62 kg, 11.45 mol) was added at 5°C or lower, and the mixture was further stirred at 0°C for 4 hours. Sodium sulfite (250 g) was added to the mixture and stirred at 0-5°C for 30 minutes before warming to 20-25°C. Thereafter, the aqueous layer was discarded and washed with a 20% aqueous sodium chloride solution (12.5 kg), then the organic layer was dried over sodium sulfate and concentrated to 7.5 L. Ethyl acetate (12.5 L) was added to the residue, the mixture was concentrated again to 7.5 L, and used in the next reaction as a tert-butyl=(trans-4-formylcyclohexyl)carbamate solution.

[0052]

(Step 2)
Under a nitrogen atmosphere, tetrahydrofuran (30 L) and triphenylphosphine (5.72 kg, 21.8 mol) were added to a reaction vessel, heated to 40°C, and stirred for 5 minutes. Carbon tetrabromide (3.61 kg, 10.9 mol) was added over 30 minutes and stirred at 40-45° C. for another 30 minutes. A mixture of tert-butyl (trans-4-formylcyclohexyl)carbamate solution and triethylamine (2.54 kg, 25.1 mol) was added below 45°C over 20 minutes and stirred at 40°C for an additional 15 hours. After cooling the reaction solution to 0° C., water (0.2 L) was added at 10° C. or lower, and water (25 L) was added. After heating to 20-25° C., the aqueous layer was discarded, ethyl acetate (4.5 kg) and 10% aqueous sodium chloride solution (25 kg) were added, and after stirring, the aqueous layer was discarded again. After the obtained organic layer was concentrated to 15 L, 2-propanol (19.65 kg) was added and concentrated to 17.5 L. 2-Propanol (11.78 kg) and 5 mol/L hydrochloric acid (151.6 g) were added to the residue, and the mixture was stirred at 25-35°C for 2.5 hours. Water (16.8 L) was added dropwise to the resulting solution, and the mixture was stirred at 20-25°C for 30 minutes and then stirred at 0°C for 2 hours. The precipitated solid was collected by filtration, washed with a mixture (11 kg) of acetonitrile:water 60:40 cooled to 0-5°C, and dried at 40°C under reduced pressure to give 3.05 kg of the title compound (yield 73%). .0%).
1 H NMR (500 MHz, CDCl3):δ6.20(d,J=3.6Hz,1H),4.37(br,1H),3.38(br,1H),2.21(dtt,J=3.6,4.6,1.4Hz,1H),2.05-2.00(m,2H),1.80-1.83(m,2H),1.44(s,9H),1.23(ddd,J=9.9,5.3,1.2 Hz,2H), 1.13(ddt,J=4.6,1.4,5.2 Hz,2H)

[0053]

(Reference Example 4) Production of tert-butyl = (trans-4-ethynylcyclohexyl) carbamate

[0054]

[Chemical 9]

[0055]

Under a nitrogen atmosphere, toluene (1436 kg), tert-butyl = [trans-4-(2,2-dibromoethenyl)cyclohexyl]carbamate (110 kg, 287.1 mol), and N,N,N ‘,N’-Tetramethylethane-1,2-diamine (106.7 kg, 918.8 mol) was added and cooled to -10°C. An isopropylmagnesium chloride-tetrahydrofuran solution (2.0 mol/L, 418 kg, 863 mol) was added dropwise at -5°C or lower, and stirred at -10°C for 30 minutes. After the reaction, 5 mol/L hydrochloric acid (465 kg) was added at 5°C or lower, heated to 20-25°C, and further 5 mol/L hydrochloric acid (41.8 kg) was used to adjust the pH to 5.0-. adjusted to 6.0. After discarding the aqueous layer, the organic layer was washed twice with water (550 L) and concentrated to 550 L. 2-Propanol (1296 kg) was added to the concentrate and concentrated to 550 L again. Further, 2-propanol (1296 kg) was added to the residue, and after concentrating to 550 L, water (770 L) was added dropwise in 4 portions. At that time, it was stirred for 30 minutes after each addition. After the addition, the mixture was stirred for 1 hour and further stirred at 0° C. for 1 hour. The precipitated solid was collected by filtration, washed with a 5:7 mixture of 2-propanol:water (550 L) cooled to 0-5°C, and dried at 40°C under reduced pressure to yield 57.8 kg of the title compound. obtained at a rate of 90.2%).
1 H NMR (500 MHz, CDCl 3 ): δ 4.36 (br, 1H), 3.43 (br, 1H), 2.18-2.23 (m, 1H), 1.97-2.04 (m, 5H), 1.44-1.56 (m, 11H ),1.06-1.14(m,2H)

[0056]

(Reference Example 5) Production of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0057]

[Chemical 10]

[0058]

Under a nitrogen atmosphere, water (300 L), 2-cyanoacetamide (20 kg, 238 mol), 1-pentane-2-4-dione (26.2 kg, 262 mol), potassium carbonate (3.29 mol) were added to a reaction vessel. kg, 23.8 mol) was added and stirred at room temperature for 6 hours or longer. After the reaction, the precipitated solid was collected by filtration, washed with water (60 L), further washed with a mixture of methanol (40 L) and water (40 L), and dried under reduced pressure at 40°C to give the title compound as 34 Obtained in .3 kg (97.3% yield).
1 H NMR (500 MHz, DMSO-d 6 ): δ 2.22 (s, 3H), 2.30 (s, 3H), 6.16 (s, 1H), 12.3 (brs, 1H)

[0059]

(Reference Example 6) Production of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one monohydrochloride

[0060]

[Chemical 11]

[0061]

 Under a nitrogen atmosphere, water (171 L), methanol (171 L), 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17.1 kg, 116 mol), concentrated After adding hydrochloric acid (15.8 kg, 152 mol) and 5% palladium carbon (55% wet) (3.82 kg), the inside of the reaction vessel was replaced with hydrogen. Then, the mixture was pressurized with hydrogen and stirred overnight at 30°C. After the reaction, the reaction vessel was purged with nitrogen, the palladium on carbon was removed by filtration, and the palladium on carbon was washed with a 70% aqueous solution of 2-propanol (51 L). Activated carbon (0.86 kg) was added to the filtrate and stirred for 30 minutes. Activated carbon was removed by filtration and washed with 70% aqueous 2-propanol solution (51 L). The filtrate was concentrated under reduced pressure until the liquid volume became 103 L, and 2-propanol (171 L) was added. The mixture was again concentrated under reduced pressure until the liquid volume reached 103 L, then 2-propanol (171 L) was added, and the mixture was stirred for 1 hour or longer. Precipitation of a solid was confirmed, and the solution was concentrated to a volume of 103 L. Further, 2-propanol (51 L) was added, and after concentration under reduced pressure until the liquid volume reached 103 L, the mixture was stirred at 50° C. for 30 minutes. After adding acetone (171 L) over 1 hour while keeping the internal temperature at 40° C. or higher, the mixture was stirred at 40 to 45° C. for 30 minutes. The solution was cooled to 25°C and stirred for 2 hours or longer, and the precipitated solid was collected by filtration, washed with acetone (86 L) and dried under reduced pressure at 40°C to give 19.7 kg of the title compound (yield 90.4%). ).
1 H NMR (500 MHz, methanol-d 4 ): δ 2.27 (s, 3H), 2.30 (s, 3H), 4.02 (s, 2H), 6.16 (s, 1H)

[0062]

(Example 1-1) Production of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate

[0063]

[Chemical 12]

[0064]

 Under a nitrogen atmosphere, water (420 L), toluene (420 L), acetonitrile (420 L), and methyl 3,4-dihydroxy-2-methylbenzoate (1) (60 kg, 329 mol) were added to the reactor and cooled. After that, sulfuryl chloride (133.4 kg, 988 mol) was added dropwise while maintaining the temperature at 20°C or lower. After the reaction, the mixture was separated into an organic layer 1 and an aqueous layer, acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer, and the mixture was stirred. Water (420 L) and acetonitrile (210 L) were added to the organic layer 1, and after cooling, sulfuryl chloride (88.9 kg, 659 mol) was added dropwise at 20°C or lower, and sulfuryl chloride (53.2 kg, 394 mol) was added. ) was added in portions. After the reaction, the mixture was separated into an organic layer 3 and an aqueous layer, and the organic layer 2 was added to the aqueous layer and stirred. Water (420 L), acetonitrile (210 L) were added to the combined organic layer, sulfuryl chloride (44.5 kg, 329 mol) was added dropwise below 20°C, and sulfuryl chloride (106.4 kg, 788 mol) was added. ) was added in portions. After the reaction, the organic layer 4 and the aqueous layer were separated, acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer, and the mixture was stirred. The combined organic layers were washed three times with 20 wt % aqueous sodium chloride solution (300 L) and then concentrated under reduced pressure to 600 L. After repeating the operation of adding toluene (300 L) and concentrating under reduced pressure to 600 L again twice, the mixture was heated and stirred at 60° C. for 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with toluene (120 L), and dried under reduced pressure at 40°C to give 52.1 kg of the crude title compound (2) (yield: 73.0%). ).

[0065]

 Under a nitrogen atmosphere, toluene (782 L) and crude title compound (52.1 kg, 241 mol) were added to a reactor and heated to 80°C. After confirming that the crystals were completely dissolved, they were filtered and washed with heated toluene (261 L). The mixture was cooled to 60° C. and stirred for 0.5 hours after crystallization. After cooling to 10°C, the precipitated solid was collected by filtration, washed with toluene (156 L), and dried under reduced pressure at 40°C to give 47.9 kg of the title compound (2) (yield 91.9%). Acquired.
1 H NMR (500 MHz, methanol-d 4 ): δ 2.41 (s, 3H), 3.82 (s, 3H), 7.41 (s, 1H)

[0066]

(Example 1-2) Examination of chlorination conditions 1 Since
it is difficult to remove compound (1), which is the starting material, and compound (4), which is a by-product of the reaction, even in subsequent steps, need to control. Therefore, chlorination was investigated in the same manner as in Example 1-1 using compound (1) as a starting material. Table 1 shows the results.

[0067]

[Chemical 13]

[0068]

[Table 1]

[0069]

HPLC condition
detection: 220 nm
column: ACQUITY UPLC BEH C18 (2.1 mm ID x 50 mm, 1.7 μm, Waters)
column temperature: 40 ° C
 mobile phase: A: 0.1 vol% trifluoroacetic acid aqueous solution, B: acetonitrile
Gradient conditions:

[0070]

[Table 2]

[0071]

Flow rate: 1.0 mL/min
Injection volume: 1 μL
Sample solution: acetonitrile/water (1:1)
wash solution: acetonitrile/water (1:1)
purge solution: acetonitrile/water (1:1)
seal wash solution : Acetonitrile/water (1:1)
Sample cooler temperature: None
Measurement time: 5 minutes
Area measurement time: about 0.5 minutes – 4.0 minutes
Comp. 1: 1.11 min, Comp. 2: 1.55 min,
Comp. 3: 1.44 min, Comp. 4: 1.70 min

[0072]

(Example 1-3) Examination of chlorination conditions 2
Compound (1) was used as a starting material, sulfuryl chloride was used as a chlorination reagent, and chlorination in various solvents was examined. Table 3 shows the results.

[0073]

[table 3]

[0074]

(Example 2) Methyl (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5- Manufacture of carboxylates

[0075]

[Chemical 14]

[0076]

 Toluene (9.0 L), tert-butyl = (trans-4-ethynylcyclohexyl) carbamate (2.23 kg, 9.99 mol), methyl = 5-chloro-3,4- were added to a reaction vessel under a nitrogen atmosphere. Dihydroxy-2-methylbenzoate (1.80 kg, 8.31 mol), tri(o-tolyl)phosphine (76.0 g, 250 mmol), triruthenium dodecacarbonyl (53.0 g, 82.9 mmol) ) was added, and the mixture was heated and stirred at 80 to 90° C. for 7 hours under an oxygen-containing nitrogen stream. The reaction solution was cooled to room temperature to obtain a toluene solution of the title compound.

[0077]

(Example 3) (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carvone acid production

[0078]

[Chemical 15]

[0079]

Methyl = (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole obtained in Example 2 -5-carboxylate toluene solution (13 L, equivalent to 7.83 mol), methanol (9.0 L), 1,2-dimethoxyethane (3.6 L), 5 mol / L sodium hydroxide aqueous solution ( 2.50 L, 12.5 mol) was added and stirred at 55-65° C. for 3 hours. After adding water (5.4 L), the mixture was allowed to stand and separated into an organic layer and an aqueous layer. After cooling to room temperature, 1,2-dimethoxyethane (16.2 L) was added to the aqueous layer, and after adjusting the pH to 4.0 to 4.5 with 3 mol/L hydrochloric acid, toluene (5.4 L) was added. added. After heating to 50-60° C., the organic layer and aqueous layer were separated, and the organic layer was washed with a 20 wt % sodium chloride aqueous solution (7.2 L). Then, 1,2-dimethoxyethane (21.6 L) was added to the organic layer, and after concentration under reduced pressure to 9 L, 1,2-dimethoxyethane (21.6 L) was added and heated to 50-60°C. After that, filtration was performed to remove inorganic substances. Then, after washing with 1,2-dimethoxyethane (1.8 L), the 1,2-dimethoxyethane solution of the title compound (quantitative value 89.6% (Example 2 total yield from ), corresponding to 7.45 mol).

[0080]

(Example 4) (1S)-1-phenylethanaminium (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1, Preparation of 3-benzodioxole-5-carboxylate

[0081]

[Chemical 16]

[0082]

(2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5 obtained in Example 3 – A solution of carboxylic acid in dimethoxyethane (21.6 L, corresponding to 7.45 mol) was heated to 75-80°C, and then (1S)-1-phenylethanamine (1.02 kg, 8.42 mmol). was added and stirred for 4 hours. A mixture of 1,2-dimethoxyethane (9.2 L) and water (3.4 L) heated to 50-60° C. was added, stirred, and then cooled to room temperature. The precipitated solid was collected by filtration and washed with 1,2-dimethoxyethane (9 L) to give a crude title compound (1.75 kg (converted to dry matter), yield 38.5% (Example 2 total yield from ) and an optical purity of 93.8% ee).

[0083]

 Under a nitrogen atmosphere, a 1,2-dimethoxyethane aqueous solution (13.6 L) was placed in a reaction vessel, and (1S)-1-phenylethanaminium obtained in step 1 (2R)-2-{trans-4-[(tert -Butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate crude (1.70 kg equivalent, 3.11 mol) was added. After that, 5 mol/L hydrochloric acid (0.56 L, 2.8 mol) was added dropwise. After stirring at room temperature for 10 minutes or longer, the mixture was heated to 75° C. or higher, and (1S)-1-phenylethanamine (360 g, 2.97 mmol) was dissolved in 1,2-dimethoxyethane (2.6 L). The solution was added dropwise over 1 hour. It was then washed with 1,2-dimethoxyethane (0.9 L), stirred for 2 hours and cooled to 0-5°C. The slurry was collected by filtration and washed with 1,2-dimethoxyethane (5.1 L) cooled to 0-5° C. to give the title compound (1.56 kg, yield 91.9%, obtained with an optical purity of 99.5% ee).
1 H NMR (500 MHz, methanol-d 4 ): δ 1.15-1.23(m,2H), 1.28-1.35(m,2H), 1.42(s,9H),
1.59(s,3H), 1.60-1.61(d ,3H,J=7.0Hz,3H),1.80-1.86(dt,J=12.0,3.0Hz,1H),1.95-1.96(m,4H),2.27(s,3H),3.24-3.28(m,1H ),4.39-4.43(q,J=7.0Hz,1H),7.07(s,1H),7.37-7.45(m,5H)

[0084]

(Example 5) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride Manufacturing A

[0085]

[Chemical 17]

[0086]

(Step 1)
Under a nitrogen atmosphere, 1,2-dimethoxyethane (200 L) and (1S)-1-phenylethanaminium (2R)-2-{trans-4-[(tert-butoxycarbonyl) were placed in a reaction vessel. Amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (equivalent to 87.64 kg, 160 mol), 35% hydrochloric acid (16.7 kg, 160 mol) was added and heated to 45-55° C., 35% hydrochloric acid (36.7 kg, 352 mol) was added dropwise in 7 portions and stirred for 3 hours after dropping. After cooling to room temperature, the reaction solution was added to a mixture of water (982 L) and 5 mol/L sodium hydroxide (166.34 kg, 702 mol). 3 mol/L hydrochloric acid (22.4 kg) was added dropwise to the resulting solution at 30°C, crystal precipitation was confirmed, and the mixture was stirred for 30 minutes or more, cooled to 10°C, and further stirred for 2 hours. After stirring, 3 mol/L hydrochloric acid (95.1 kg) was added dropwise at 10°C to adjust the pH to 7.0. The slurry liquid was collected by filtration, washed with water (293 L) cooled to 10° C., and (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3- Benzodioxol-5-carboxylic acid trihydrate was obtained (57.63 kg (converted to dry matter), yield 94.7%).
1 H NMR (500 MHz, methanol- d4 + D2O): 1.32-1.44 ( m, 4H), 1.61 (s, 3H), 1.89-1.94 (m, 1H), 2.01-2.13 (m, 4H) ,2.27(s,3H),2.99-3.07(m,1H),7.06(s,3H)

[0087]

(Step 2)
Under nitrogen atmosphere, 1,2-dimethoxyethane (115 L), (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3 -benzodioxole-5-carboxylic acid trihydrate (57.63 kg equivalent, 152 mmol), formic acid (34.92 kg, 759 mol), 37% formaldehyde aqueous solution (93.59 kg, 1153 mol) was added and stirred at 55-65°C for 2 hours. Cool to room temperature, add 2-propanol (864 L) and concentrate to 576 L under reduced pressure. 2-Propanol (231 L) was added thereto and concentrated under reduced pressure to 576 L. Further, 2-propanol (231 L) was added and concentrated under reduced pressure to 576 L. After concentration, 35% hydrochloric acid (20.40 kg, 196 mol) was added dropwise over 2 hours and stirred at room temperature for 30 minutes. Ethyl acetate (576 L) was added to the resulting slurry over 30 minutes and concentrated to 692 L. Ethyl acetate (461 L) was added followed by further concentration to 519 L. Ethyl acetate (634 L) was added to the residue and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with ethyl acetate (491 L) and dried under reduced pressure at 40°C to give the title compound (51. 56 kg, 87.1% yield).
1 H NMR (500 MHz, methanol-d 4 ): δ 1.38-1.47 (m, 2H), 1.53-1.61 (m, 2H), 1.67 (s, 3H), 1.99-2.05 (m, 1H), 2.13 -2.18(m,4H),2.38(s,3H),2.84(s,6H),3.19-3.25(dt,J=12.5,3.5Hz,1H),
7.53(s,1H)

[0088]

(Example 6) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride Manufacturing B

[0089]

[Chemical 18]

[0090]

 Under a nitrogen atmosphere, formic acid (20 mL), 37% formaldehyde aqueous solution (15 mL), dimethoxyethane (10 mL), (1S)-1-phenylethanaminium (2R)-2-{trans-4- [(tert-Butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (10 g, 18.3 mmol) was added and Stirred for 10 hours. After cooling to room temperature and filtering the insolubles, 2-propanol (100 mL) was added and the mixture was concentrated under reduced pressure until the liquid volume became 30 mL. While stirring at room temperature, ethyl acetate (120 mL) and concentrated hydrochloric acid (6.1 mL) were added to form a slurry. This was concentrated under reduced pressure to 30 mL, ethyl acetate (120 mL) was added, and then concentrated under reduced pressure to 30 mL again. After adding ethyl acetate (120 mL), the precipitated solid was collected by filtration, washed with ethyl acetate (50 mL) and dried under reduced pressure at 40°C to give 6.56 g of the title compound (yield 92.0%). Acquired.

[0091]

(Example 7) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ) Preparation of methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate

[0092]

[Chemical 19]

[0093]

 Under nitrogen atmosphere, acetone (6.5 L), purified water (1.3 L), (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4- Dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride (650.4 g, 1.67 mol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one Monohydrochloride (330.1 g, 1.75 mol) and triethylamine (337 g, 3.33 mol) were added and stirred at room temperature for 30 minutes. After that, 1-hydroxybenzotriazole monohydrate (255 g, 1.67 mol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (383 g, 2.00 mmol) were added, and the mixture was stirred overnight at room temperature. Stirred. After adjusting the pH to 11 with 5 mol/L sodium hydroxide, toluene (9.8 L) was added, and after stirring, the mixture was separated into an organic layer 1 and an aqueous layer. Toluene (3.3 L) was added to the aqueous layer, and after stirring, the aqueous layer was discarded, and the obtained organic layer was combined with the previous organic layer 1. The combined organic layers were concentrated under reduced pressure to 9.75 L, toluene (6.5 L) was added and washed twice with purified water (3.25 L). The resulting organic layer was concentrated under reduced pressure to 4.875 L and 2-propanol (1.625 L) was added. A solution of p-toluenesulfonic acid monohydrate (0.12 kg, 0.631 mol) dissolved in 4-methyl-2-pentanone (1.14 L) was added to the organic layer heated to 68°C. The mixture was added dropwise over 5 hours and stirred at 68°C for 30 minutes. Furthermore, a solution of p-toluenesulfonic acid monohydrate (0.215 kg, 1.13 mol) dissolved in 4-methyl-2-pentanone (2.11 L) was added dropwise over 3.5 hours, Stirred at 68° C. for 30 minutes. After that, 4-methyl-2-pentanone (6.5 L) was added dropwise over 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with 4-methyl-2-pentanone (3.25 L) and dried under reduced pressure at 40°C to give 1.035 kg of the crude title compound (yield 94%). .2%).

[0094]

Under a nitrogen atmosphere, 2-propanol (6.65 L) and the obtained crude title compound (950 g) were added to the reactor and stirred. Purified water (0.23 L) was added to completely dissolve the solid at 68° C., filtered, and washed with warm 2-propanol (0.95 L). After confirming that the solid was completely dissolved at an internal temperature of 68°C, the solution was cooled to 50°C. After cooling, seed crystals* (9.5 g, 0.01 wt) were added and stirred at 50° C. overnight. tert-Butyl methyl ether (11.4 L) was added dropwise thereto in 4 portions over 30 minutes each. At that time, it was stirred for 30 minutes after each addition. After cooling to room temperature, the precipitated solid was collected by filtration, washed with a mixture of 2-propanol (0.38 L) and tert-butyl methyl ether (3.42 L), and further treated with tert-butyl methyl ether (4.75 L). ) and dried under reduced pressure at 40° C. to obtain the title compound (915.6 g, yield 96.4%).
1 H NMR (500 MHz, methanol-d 4 ): δ 1.35-1.43 (m, 2H), 1.49-1.57 (m, 2H), 1.62 (s, 3H),
1.94-2.00 (dt, J = 12.5, 3.0Hz ,1H),2.09-2.13(m,4H),2.17(s,3H),2.24(s,3H),2.35(s,3H),2.36(s,3H),2.82(s,6H),3.16- 3.22(dt,J=12.0,3.5Hz,1H),4.42(s,2H),
6.10(s,1H),6.89(s,1H),7.22-7.24(d,J=8.0Hz,2H),7.69 -7.71(dt,J=8.0,1.5 Hz,2H)
*Seed crystal preparation method
Under a nitrogen atmosphere, 2-propanol (79.0 L) and the obtained crude title compound (7.90 kg) were added to a reactor and stirred. Purified water (7.9 L) was added to completely dissolve the solid, and activated carbon (0.40 kg) was added and stirred. After filtering the activated carbon, it was washed with 2-propanol (79.0 L) and concentrated to 58 L. 2-Propanol (5 L) was added to the residue, and after heating to 64° C., tert-butyl methyl ether (19.8 L) was added, and after crystal precipitation was confirmed, tert-butyl methyl ether (75. 1 L) was added in three portions. At that time, it was stirred for 30 minutes after each addition. After cooling to room temperature, the precipitated solid was collected by filtration, washed with a mixture of 2-propanol (7.9 L) and tert-butyl methyl ether (15.8 L), and dried under reduced pressure at 40°C to obtain seed crystals. The title compound was obtained (7.08 kg, 89.6% yield).

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