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TUCATINIB

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Tucatinib

ツカチニブ;

N6-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-N4-(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)quinazoline-4,6-diamine

FormulaC26H24N8O2
CAS937263-43-9
Mol weight480.5212

To treat advanced unresectable or metastatic HER2-positive breast cancer
Drug Trials Snapshot

FDA APPROVED 4/17/2020 Tukysa

  • ARRY 380
  • ARRY-380
  • ONT 380
  • ONT-380

Tucatinib (INN),[1] sold under the brand name Tukysa, is a small molecule inhibitor of HER2 for the treatment of HER2-positive breast cancer.[2][3] It was developed by Array BioPharma and licensed to Cascadian Therapeutics (formerly Oncothyreon, subsequently part of Seattle Genetics).[4]

Common side effects are diarrhea, palmar-plantar erythrodysesthesia (burning or tingling discomfort in the hands and feet), nausea, fatigue, hepatotoxicity (liver damage), vomiting, stomatitis (inflammation of the mouth and lips), decreased appetite, abdominal pain, headache, anemia and rash.[5][6] Pregnant or breastfeeding women should not take Tucatinib because it may cause harm to a developing fetus or newborn baby.[5]

Tucatinib was approved for medical use in Australia in August 2020.[7]

Medical uses

Tucatinib is a kinase inhibitor indicated in combination with trastuzumab and capecitabine for treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.[8]

Clinical trials

Two early stage clinical trials have reported encouraging results, both of which had options to enroll subjects with central nervous system (CNS) metastases.[2][9][10][11][12][10] HER2CLIMB is a Phase 2 randomized, double-blinded, placebo-controlled study of tucatinib in combination with trastuzumab and capecitabine in patients with pretreated, unresectable locally advanced or metastatic HER2-positive breast cancer.[13]

History

In April 2020, the U.S. Food and Drug Administration (FDA) approved tucatinib in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adults with advanced forms of HER2-positive breast cancer that can’t be removed with surgery, or has spread to other parts of the body, including the brain, and who have received one or more prior treatments.[5][6][14]

The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health CanadaHealth Sciences Authority (HSA, Singapore) and Swissmedic (SMC, Switzerland) on the review.[5] This was the first Project Orbis partnership between the FDA, HSA and Swissmedic.[5] As of 17 April 2020, the application is still under review at the other agencies.[5]

Tucatinib is a kinase inhibitor meaning it blocks a type of enzyme (kinase) and helps prevent the cancer cells from growing.[5] Tucatinib is approved for treatment after adults have taken one or more anti-HER2-based regimens in the metastatic setting.[5] The FDA approved tucatinib based on the results of the HER2CLIMB trial (NCT02614794) enrolling 612 subjects who had HER2-positive advanced unresectable or metastatic breast cancer and had prior treatment with trastuzumabpertuzumab and ado-trastuzumab emtansine (T-DM1).[5][6] Subjects with previously treated and stable brain metastases, as well as those with previously treated and growing or untreated brain metastases, were eligible for the clinical trial, and 48% of enrolled subjects had brain metastases at the start of the trial.[5]

Subjects received either tucatinib 300 mg twice daily plus trastuzumab and capecitabine (tucatinib arm, n=410) or placebo plus trastuzumab and capecitabine (control arm, n=202).[6] The primary endpoint was progression-free survival (PFS), or the amount of time when there was no growth of the tumor, assessed by a blinded independent central review, evaluated in the initial 480 randomized patients.[5][6] The median PFS in subjects who received tucatinib, trastuzumab, and capecitabine was 7.8 months (95% CI: 7.5, 9.6) compared to 5.6 months (95% CI: 4.2, 7.1) in those subjects who received placebo, trastuzumab, and capecitabine (HR 0.54; 95% CI: 0.42, 0.71; p<0.00001).[5][6] Overall survival and PFS in subjects with brain metastases at baseline were key secondary endpoints.[5] The median overall survival in subjects who received tucatinib, trastuzumab, and capecitabine was 21.9 months (95% CI: 18.3, 31.0) compared to 17.4 months (95% CI: 13.6, 19.9) in subjects who received placebo, trastuzumab, and capecitabine (HR: 0.66; 95% CI: 0.50, 0.87; p=0.00480).[5][6] The median PFS in subjects with brain metastases at baseline who received tucatinib, trastuzumab and capecitabine was 7.6 months (95% CI: 6.2, 9.5) compared to 5.4 months (95% CI: 4.1, 5.7) in subjects who received placebo, trastuzumab and capecitabine (HR: 0.48; 0.34, 0.69; p<0.00001).[5][6]

The FDA granted the application for tucatinib priority reviewbreakthrough therapyfast track, and orphan drug designations.[5][6][15] The FDA granted approval of Tukysa to Seattle Genetics, Inc.[5]

SYN

Recently, the Mao team reported a new route for the efficient synthesis of Tucatinib.

The results were published on Synthesis (DOI: 10.1055/s-0037-1610706).

Previously, the synthesis report route of Tucatinib was published by Array BioPharma in a patent document (WO 2007059257, 2007). The synthetic route reported in the patent is shown in the figure below:

New synthetic route of Tucatinib, a new anti-breast cancer drug

Using 4-nitro-2-cyanoaniline as the raw material, the first step is to condense with DMF-DMA to prepare imine 3 (yield 87%); subsequent catalytic hydrogenation of palladium on carbon to reduce the nitro group to obtain the amine 4 (90% yield); followed by 1,1&39;-thiocarbonyldiimidazole (TCDI) and The amino alcohol undergoes condensation to prepare the thiourea derivative 5 (yield is only 34%); further with the intermediate 6 to undergo ring-closure reaction to obtain the key intermediate 7 (yield 62%) ; Finally, under the action of p-toluenesulfonic acid, intramolecular dehydration and ring closure to form oxazoline, complete the synthesis of the target compound tucatinib.

Reverse synthesis analysis

New synthetic route of Tucatinib, a new anti-breast cancer drug

The author broke the bond of Tucatinib from two points a and b and split them into three fragments. : Thioether oxazoline 17, nitrobenzene 3 and the key fragment of the original research route 6.

Preparation of key fragment 6

New synthetic route of Tucatinib, a new anti-breast cancer drug

4-nitro-3-methylphenol 8 as a starting point The material, with pyridine derivative 9, undergoes aromatic affinity substitution reaction to prepare aryl ether 10 (yield 64%); then it is condensed with DMF-DMA, and then treated with hydroxylamine hydrochloride. The step yield was 81% to obtain the oxime derivative 12; subsequently, the ring was closed under the treatment of trifluoroacetic anhydride, the mostAfter palladium-catalyzed hydrogenation to reduce the nitro group, the key aniline triazole 6 was successfully prepared, with a total yield of 32.8%.

aromatic ring skeleton construction

fragment 3 was synthesized according to the method reported in the literature. The estimated aromatic ring fragment was then constructed with the aniline triazole 6 prepared above:

New synthetic route of Tucatinib, a new anti-breast cancer drug

Compound 6 and fragment 3 were cyclized in acetic acid , 14 was successfully prepared, and finally the nitro group was reduced by palladium-catalyzed hydrogenation to obtain the key arylamine 15 with a two-step yield of 76.4%.

Fragment 17 and Tucatinib synthesis

New synthetic route of Tucatinib, a new anti-breast cancer drug

amino alcohol and 1,1&39;-thiocarbonyl diimidazole (TCDI) The ring is closed to obtain 16, which is then treated with methyl trifluoromethanesulfonate to obtain oxazoline 17, with a total yield of 67.23% in the two steps.

oxazoline17 and arylamine 15 in the presence of cesium carbonate, heated in DMF for 20 hours, and finally completed the synthesis of Tucatinib with a yield of 76%.

Comparison of the new route and the patent route

The yield of the last step of the patent is unknown, starting with key intermediates 3 and 6, total income The rate is less than 19%.

The overview of the new route is as follows:

New synthetic route of Tucatinib, a new anti-breast cancer drug

Correspondingly, starting from the intermediate 3 and 6, the total yield of the new route There is a significant improvement to 39%. Moreover, the purity of the product and other aspects also meet the requirements of API.

Comment

Tucatinib (Tukysa) Tucatinib/Tucatinib as a small-molecule oral tyrosine kinase (TKI) inhibitor for HER2 Positive breast cancer has highly specific targeting selectivity. The study of the new synthetic route

effectively improves the production efficiency in terms of ensuring the purity of the compound, and the raw materials used are relatively simple and easy to obtain.

Medicinal chemists have completed the research and development and synthesis of compounds (from 0 to 1), while process chemists have optimized the synthetic routes and processes, so that the compounds can be prepared more simply, efficiently, economically and environmentally.

SYN PATENT

CN 111825604

PAPER

Synthesis (2019), 51(13), 2660-2664

Abstract

A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over five steps and 99% purity. Next, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.

References

  1. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 161. hdl:10665/331046.
  2. Jump up to:a b “ONT-380 Active Against CNS Mets in HER2-Positive Breast Cancer”Cancer Network. 15 December 2015. Retrieved 17 April 2020.
  3. ^ Martin M, López-Tarruella S (October 2018). “Emerging Therapeutic Options for HER2-Positive Breast Cancer”American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting35 (36): e64–70. doi:10.1200/EDBK_159167PMID 27249772.
  4. ^ “Tucatinib” (PDF). Statement on a Nonproprietary Name Adopted by the USAN Council.
  5. Jump up to:a b c d e f g h i j k l m n o p q “FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer”U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Retrieved 17 April 2020.  This article incorporates text from this source, which is in the public domain.
  6. Jump up to:a b c d e f g h i “FDA approves tucatinib for patients with HER2-positive metastatic brea”U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ “Tukysa”Therapeutic Goods Administration (TGA). 21 August 2020. Retrieved 22 September 2020.
  8. ^ “Tukysa (tucatinib) tablets, for oral use” (PDF). Seattle Genetics. Retrieved 17 April2020.
  9. ^ “Oncothyreon Inc. Announces Data For ONT-380 In HER2-Positive Breast Cancer Patients With And Without Brain Metastases At The San Antonio Breast Cancer Symposium”BioSpace (Press release). 9 December 2015. Retrieved 18 April 2020.
  10. Jump up to:a b Borges VF, Ferrario C, Aucoin N, Falkson CI, Khan QJ, Krop IE, et al. “Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases”Journal of Clinical Oncology. 2016 ASCO Annual Meeting.
  11. ^ “SABCS15: Promising phase 1 results lead to phase 2 for ONT-380 in HER2+ breast cancer”Colorado Cancer Blogs. Retrieved 10 June 2016.
  12. ^ “A Study of Tucatinib (ONT-380) Combined With Capecitabine and/or Trastuzumab in Patients With HER2+ Metastatic Breast Cancer”ClinicalTrials.gov. 31 December 2013. Retrieved 18 April 2020.
  13. ^ “A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB)”ClinicalTrials.gov. Retrieved 18 April 2020.
  14. ^ “Tukysa: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 20 April 2020.
  15. ^ “Tucatinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration(FDA). 24 December 1999. Retrieved 20 April 2020.

External links

  • “Tucatinib”Drug Information Portal. U.S. National Library of Medicine.
  • “Tucatinib”National Cancer Institute.
  • Clinical trial number NCT02614794 for “A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB)” at ClinicalTrials.gov
Clinical data
Trade namesTukysa
Other namesONT-380, ARRY-380
AHFS/Drugs.comMonograph
MedlinePlusa620032
License dataUS DailyMedTucatinib
Pregnancy
category
AU: DUS: N (Not classified yet)
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusAU: S4 (Prescription only)US: ℞-only
Identifiers
CAS Number937263-43-9
PubChem CID51039094
DrugBankDB11652
ChemSpider34995558
UNII234248D0HH
KEGGD11141
ChEMBLChEMBL3989868
Chemical and physical data
FormulaC26H24N8O2
Molar mass480.532 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CC1=C(C=CC(=C1)NC2=NC=NC3=C2C=C(C=C3)NC4=NC(CO4)(C)C)OC5=CC6=NC=NN6C=C5
InChI[hide]InChI=1S/C26H24N8O2/c1-16-10-17(5-7-22(16)36-19-8-9-34-23(12-19)28-15-30-34)31-24-20-11-18(4-6-21(20)27-14-29-24)32-25-33-26(2,3)13-35-25/h4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31)Key:SDEAXTCZPQIFQM-UHFFFAOYSA-N
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
TukysaTablet150 mg/1OralSeattle Genetics, Inc.2020-04-17Not applicableUS flag 
TukysaTablet150 mgOralSeattle Genetics, Inc.2020-08-27Not applicableCanada flag 
TukysaTablet50 mg/1OralSeattle Genetics, Inc.2020-04-17Not applicableUS flag 
TukysaTablet50 mgOralSeattle Genetics, Inc.2020-10-08Not applicableCanada flag 

Showing 1 to 4 of 4 entries

///////tucatinib, FDA 2020, TUKSYA, 2020 APROVALS, ARRY 380, ONT 380, ツカチニブ ,


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

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