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Ensartinib

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Ensartinib

X396, X 396

  • 1370651-20-9
  • C26H27Cl2FN6O3,
    561.4 g/mol
  • SMA5ZS5B22

6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3R,5S)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide

FDA 12/18/2024, Ensacove, To treat non-small cell lung cancer

Ensartinib, sold under the brand name Ensacove, is an anti-cancer medication used for the treatment of non-small cell lung cancer.[1] Ensartinib is an Anaplastic lymphoma kinase (ALK) inhibitor used as the salt ensartinib hydrochloride.[1] It is taken by mouth.[1]

The most common adverse reactions include rash, musculoskeletal pain, constipation, cough, pruritis, nausea, edema, pyrexia, and fatigue.[2]

Ensartinib was approved for medical use in the United States in December 2024.[1][2][3][4]

PATENT

US9126947, 18

https://patentscope.wipo.int/search/en/detail.jsf?docId=US90227390&_cid=P11-M9JBTT-36001-1

Synthesis of 6-[bis(tert-butoxycarbonyl)amino]-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylic acid (B)

   Step 1: To a solution of A5 (219 g, 1.05 mol) in 1,2-dichloroethane (3500 mL) was added Boc-D-Pro (141 g, 0.65 mol) followed by EDCI (163 g, 0.85 mol) and DMAP (21.57 g, 0.18 mol) at 0° C. The resulting mixture was stirred at r.t. overnight and then water (3500 mL) was added and separated, the water phase was extracted with DCM(1500 mL×3), dried over MgSO 4, concentrated and purified by column chromatography to (PE:EA=30:1) to give B1 (55.96 g, yield: 51.1%)
      Step 2: To a solution of B1 (59.96 g, 268 mmol) in THF (1200 mL) was added 60% NaH (10.71 g, 268 mmol) at 0° C., the resulting mixture was stirred at that temperature for 30 min, was then added A3 (55.82 g, 268 mmol) quickly. The resulting mixture was heated under reflux overnight and evaporated. The residue was purified by column chromatography (PE:EA=4:1) to provide the advanced intermediate B2 (33.95 g, 37.7%). 1H-NMR (300 MHz, CDCl 3): δ=1.87 (d, 3H), 5.08 (s, 2H), 6.03-6.09 (m, 1H), 6.42 (s, 1H), 7.14 (t, 1H), 7.35 (dd, 1H). LC-MS [M+H] +: 336.0.
      Step 3: To a solution of B2 (33.95 g, 101 mmol) in DMF (400 mL) was added BOC 2O (39.59 g, 182 mmol) and DMAP (2.46 g, 20.2 mmol). The mixture was stirred at r.t. overnight and evaporated. The residue was purified by column chromatography (PE:EA=10:1) and the residue was treated with PE:EA=10:1 to afford B3 (46.9 g, 86.7%).
      Step 4: Sodium acetate (14.34 g, 175 mmol) was added to a solution of B3 (46.9 g, 87.4 mmol) in ethanol/DMF [(5:1) (480 mL)]. The mixture was degassed, then added Pd(dppf)Cl 2.CH 2Cl 2 (7.14 g, 8.74 mmol). The resulting mixture was heated at CO atmosphere at 90° C. overnight, then evaporated. The residue was purified by column chromatography (PE:EA=4:1) to afford B4 (47.1 g, 94.0%). 1H-NMR (300 MHz, CDCl 3): δ=1.38 (s, 18H), 1.46 (t, 3H), 1.88 (d, 3H), 4.45-4.53 (m, 2H), 6.18 (q, 1H), 7.13 (t, 1H), 7.34 (dd, 1H), 7.57 (s, 1H). LC-MS [M+H] +: 574.0.
      Step 5: To the solution of B4 (47.1 g, 82.1 mmol) in THF (400 mL) was added 1N LiOH aq. (98.5 mL). The resulting mixture was stirred at r.t. over weekend, then acidified by 2N HCl to pH=5, extracted with ethyl acetate (400 mL×3). The combined organic phase was dried over Na 2SO 4, filtrated and concentrated to give B (45.94 g, ˜100%).

Synthesis of 6-[bis(tert-butoxycarbonyl)amino]-5-[(1S)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylic acid (C)

Step 1: To a solution of A5 (41.8 g, 200 mmol) in 1,2-dichloroethane (800 mL) was added Boc-L-Pro (26.9 g, 125 mmol) followed by EDCI (31.1 g, 163 mmol) and DMAP (4.12 g, 33.8 mmol) at 0° C. The resulting mixture was stirred at r.t. overnight and then water (350 mL) was added and separated, the water phase was extracted with DCM(150 mL×3), dried over MgSO 4, concentrated and purified by column chromatography to (PE:EA=30:1) to give C1 (13.72 g, yield: 65.6%).
      Step 2: The procedure from C1 to C was similar to that of B1 to B (9.46 g, yield: 26.4% from C1).
Synthesis of {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide
  Step 1: The mixture of B (10.92 g, 20.0 mmol)), HATU (9.12 g, 24.0 mmol) and DIEA (3.87 g, 30.0 mmol) in DMF (100 mL) was stirred at room temperature for 0.5 h, then was added 1a (5.26 g, 24.0 mmol). The resulting mixture was stirred at room temperature for 0.5 h and evaporated. The residue was purified by column chromatography (EA:MeOH=5:1) to provide 1b (12.43 g, 83.2%).
      Step 2: 1b (12.43 g, 16.7 mmol) was dissolved in a mixture of DCM (90 mL) and TFA (30 mL), stirred at r.t. for 2 hours and evaporated. The residue was adjusted by sat. Na 2CO 3 to pH=8 and extracted with DCM (150 mL×5). The combined organic phase was dried over MgSO 4 and concentrated. The residue was triturated with methanol and filtered, then the solid was dissolved in DCM and a solution of HCl in Et 2O was added, the mixture was stirred at r.t. overnight, then concentrated and dried over oil pump to afford 1 (8.31 g, 80.5%). 1H-NMR (300 MHz, DMSO-d 6): δ=1.84 (d, 3H), 2.76 (d, 3H), 3.02-3.10 (m, 2H), 3.37-3.53 (m, 5H), 3.40-4.26 (m, 1H), 6.27 (q, 1H), 7.11 (s, 1H), 7.42-7.51 (m, 3H), 7.58-7.62 (m, 1H), 7.86-7.88 (m, 2H). LC-MS [M+H] +:547.2.

Medical uses

Ensartinib is indicated for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer who have not previously received an ALK-inhibitor.[1][2]

History

Efficacy was evaluated in eXALT3 (NCT02767804), an open-label, randomized, active-controlled, multicenter trial in 290 participants with locally advanced or metastatic ALK-positive non-small cell lung cancer who had not previously received an ALK-targeted therapy.[2] Participants were randomized 1:1 to receive ensartinib or crizotinib.[2]

Society and culture

Ensartinib was approved for medical use in the United States in December 2024.[2][3][5]

Name

Ensartinib is the international nonproprietary name.[6]

Ensartinib is sold under the brand name Ensacove.[1][2][3]

References

  1. ^ Jump up to:a b c d e f g “Ensacove (ensartinib) capsules, for oral use” (PDF). Xcovery Holdings, Inc. U.S. Food and Drug Administration. December 2024.
  2. ^ Jump up to:a b c d e f g “FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 18 December 2024. Retrieved 20 December 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ Jump up to:a b c “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
  4. ^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
  5. ^ “FDA Approval of Ensartinib for ALK-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)” (Press release). Xcovery Holdings. 19 December 2024. Retrieved 20 December 2024 – via Business Wire.
  6. ^ World Health Organization (2017). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77”. WHO Drug Information. 31 (1). hdl:10665/330984.

  1. Horn L, Infante JR, Reckamp KL, Blumenschein GR, Leal TA, Waqar SN, Gitlitz BJ, Sanborn RE, Whisenant JG, Du L, Neal JW, Gockerman JP, Dukart G, Harrow K, Liang C, Gibbons JJ, Holzhausen A, Lovly CM, Wakelee HA: Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study. Clin Cancer Res. 2018 Jun 15;24(12):2771-2779. doi: 10.1158/1078-0432.CCR-17-2398. Epub 2018 Mar 21. [Article]
  2. FDA Approved Drug Products: ENSACOVETM (ensartinib) capsules, for oral use (Dec 2024) [Link]
  3. NCI Formulary: Ensartinib (X-396) [Link]
Clinical data
Trade namesEnsacove
Other namesX-396
License dataUS DailyMed: Ensartinib
Routes of
administration		By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only[1]
Identifiers
CAS Number1370651-20-9
PubChem CID56960363
DrugBankDB14860
ChemSpider58828042
UNIISMA5ZS5B22
KEGGD11346
ChEMBLChEMBL4113131
ECHA InfoCard100.306.918 
Chemical and physical data
FormulaC26H27Cl2FN6O3
Molar mass561.44 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

\/////////Ensartinib, FDA 2024, APPROVALS 2024, Ensacove, X396, X 396, GLXC-15836, BCP26265, EX-A2941, NSC793150, s8230

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DR ANTHONY CRASTO

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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, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India 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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