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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 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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TUCATINIB


Tucatinib.svg

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 ,

Ripretinib


Ripretinib skeletal.svg

Ripretinib

リプレチニブ;

FormulaC24H21BrFN5O2
CAS1442472-39-0
Mol weight510.3582

Antineoplastic, Receptor tyrosine kinase inhibitor

US FDA APPROVED 2020/5/15 QUINLOCK

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
QinlockTablet50 mgOralDeciphera Pharmaceuticals. LlcNot applicableNot applicableCanada flag 
QinlockTablet50 mg/1OralDeciphera Pharmaceuticals, LLC2020-05-15Not applicableUS flag 

SYN

Ripretinib, sold under the brand name Qinlock, is a medication for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract.[3] It is taken by mouth.[3] Ripretinib is a kinase inhibitor, meaning it works by blocking a type of enzyme called a kinase, which helps keep the cancer cells from growing.[3]

The most common side effects include alopecia (hair loss), fatigue, nausea, abdominal pain, constipation, myalgia (muscle pain), diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.[3][4] Alopecia is a unique side effect to ripretinib, which is not seen with other tyrosine kinase inhibitors used to treat GISTs.

Ripretinib was approved for medical use in the United States in May 2020,[3] and in Australia in July 2020.[1] Ripretinib is the first new drug specifically approved in the United States as a fourth-line treatment for advanced gastrointestinal stromal tumor (GIST).

Medical uses

Ripretinib is indicated for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract, who have received prior treatment with three or more kinase inhibitor therapies, including imatinib.[3] GIST is type of stomach, bowel, or esophagus tumor.[4]

Adverse effects

The most common side effects include alopecia (hair loss), fatigue, nausea, abdominal pain, constipation, myalgia (muscle pain), diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.[3][4]

Ripretinib can also cause serious side effects including skin cancer, hypertension (high blood pressure) and cardiac dysfunction manifested as ejection fraction decrease (when the muscle of the left ventricle of the heart is not pumping as well as normal).[3][4]

Ripretinib may cause harm to a developing fetus or a newborn baby.[3][4]

History

Ripretinib was approved for medical use in the United States in May 2020.[3][5][6][4]

The approval of ripretinib was based on the results of an international, multi-center, randomized, double-blind, placebo-controlled clinical trial (INVICTUS/NCT03353753) that enrolled 129 participants with advanced gastrointestinal stromal tumor (GIST) who had received prior treatment with imatinibsunitinib, and regorafenib.[3][7] The trial compared participants who were randomized to receive ripretinib to participants who were randomized to receive placebo, to determine whether progression free survival (PFS) – the time from initial treatment in the clinical trial to growth of the cancer or death – was longer in the ripretinib group compared to the placebo group.[3] During treatment in the trial, participants received ripretinib 150 mg or placebo once a day in 28-day cycles, repeated until tumor growth was found (disease progression), or the participant experienced intolerable side effects.[3][7] After disease progression, participants who were randomized to placebo were given the option of switching to ripretinib.[3][7] The trial was conducted at 29 sites in the United States, Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Poland, Singapore, Spain, and the United Kingdom.[4]

The major efficacy outcome measure was progression-free survival (PFS) based on assessment by blinded independent central review (BICR) using modified RECIST 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression.[7] Additional efficacy outcome measures included overall response rate (ORR) by BICR and overall survival (OS).[7] The trial demonstrated a statistically significant improvement in PFS for participants in the ripretinib arm compared with those in the placebo arm (HR 0.15; 95% CI: 0.09, 0.25; p<0.0001).[7]

The U.S. Food and Drug Administration (FDA) granted the application for ripretinib priority review and fast track designations, as well as breakthrough therapy designation and orphan drug designation.[3][8] The FDA granted approval of Qinlock to Deciphera Pharmaceuticals, Inc.[3]

The FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada on the review of the application as part of Project Orbis.[3][7] The FDA approved ripretinib three months ahead of schedule.[3][7] As of May 2020, the review of the applications was ongoing for the Australian TGA and for Health Canada.[3][7]

Names

Ripretinib is the International nonproprietary name (INN) and the United States Adopted Name (USAN).[9][10]

PATENT NUMBERPEDIATRIC EXTENSIONAPPROVEDEXPIRES (ESTIMATED) 
US8940756No2012-06-072032-06-07US flag
US8461179No2012-06-072032-06-07US flag
US8188113No2010-07-272030-07-27US flag

PATENT

US 8461179

PATENT

WO 2013184119

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013184119

[0125] Example A13: A mixture of Example C5 (2.191 g, 7.94 mmol), Example Bl (1.538 g, 8.33 mmol) and KF on alumina (40 wt%) (9.22 g, 63.5 mmol) in DMA (40 mL) was sonicated for 2 h. The mixture was filtered through a shallow bed of silica gel and rinsed well with EtOAc. The filtrate was washed with satd. NaHC03 (lx), 5% LiCl (2x), then brine (lx), dried (MgS04), and concentrated to dryness to afford 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-l -ethyl- l,6-naphthyridin-2(lH)-one (2.793 g, 89% yield) as a brown solid. 1H NMR (400 MHz, DMSO-<¾): δ 8.77 (s, 1 H), 8.00 (s, 1 H), 7.74 (s, 1 H), 7.37 (d, 1 H), 6.77 (d, 1 H), 5.45 (s, 2 H), 4.27 (q, 2 H), 1.20 (t, 3 H); MS (ESI) m z: 398.0 [M+H]+.

[0126] Example A14: A suspension of Example A13 (1.50 g, 3.78 mmol) in dioxane (15 mL) was treated with methylamine (40% in water) (26.4 mL, 303 mmol) in a pressure tube and heated to 100°C overnight. The mixture was cooled to RT, treated with a large amount of brine, then diluted with EtOAc until all of the solids dissolved. The layers were separated, the aqueous layer extracted with additional EtOAc (lx) and the combined organics were washed with satd. NaHC03 (lx), dried (MgS04) and concentrated to dryness. The resulting solid was suspended in MeCN/H20, frozen and lyophilized to afford 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (1.32g, 89% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-<¾): δ 8.37 (s, 1 H), 7.62 (s, 1 H), 7.30 (d, 1 H), 6.99 (q, 1 H), 6.73 (d, 1 H), 6.21 (s, 1 H), 5.33 (s, 2 H), 4.11 (q, 2 H), 2.84 (d, 3 H), 1.19 (t, 3 H); MS (ESI) m/z: 393.0 [M+H]+.

[0263] Example 31: A mixture of Example A14 (0.120 g, 0.307 mmol) and TEA (0.043 mL, 0.307 mmol) in THF (3.0 mL) was treated with phenyl isocyanate (0.040 g, 0.337 mmol) and stirred at RT for 4 h. Over the course of the next 4 days the mixture was treated with additional phenyl isocyanate (0.056 mL) and stirred at RT. The resulting solid was filtered, rinsed with THF, then triturated with MeOH to afford l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo- 1 ,2-dihydro- 1 ,6-naphthyridin-3 -yl)-2-fluorophenyl)-3 -phenylurea (101 mg, 64.5% yield) as a bright white solid. 1H NMR (400 MHz, DMSO-<¾): δ 9.09 (s, 1 H), 8.68 (s, 1 H), 8.41 (s, 1 H), 8.17 (d, 1 H), 7.70 (s, 1 H), 7.65 (d, 1 H), 7.41 (d, 2 H), 7.27 (m, 2 H), 7.03 (m, 1 H), 6.96 (t, 1 H), 6.23 (s, 1 H), 4.13 (q, 2 H), 2.86 (d, 3 H), 1.20 (t, 3 H); MS (ESI) m/z: 510.1 [M+H]+.

References

  1. Jump up to:a b c “Qinlock Australian Prescription Medicine Decision Summary”Therapeutic Goods Administration (TGA). 21 July 2020. Retrieved 17 August 2020.
  2. ^ “Ripretinib (Qinlock) Use During Pregnancy”Drugs.com. 10 August 2020. Retrieved 17 August 2020.
  3. Jump up to:a b c d e f g h i j k l m n o p q r s t “FDA Approves First Drug for Fourth-Line Treatment of Advanced Gastrointestinal Stromal Tumors”U.S. Food and Drug Administration (FDA) (Press release). 15 May 2020. Retrieved 15 May 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b c d e f g “Drug Trial Snapshot: Qinlock”U.S. Food and Drug Administration (FDA). 15 May 2020. Retrieved 2 June 2020.  This article incorporates text from this source, which is in the public domain.
  5. ^ “FDA Grants Full Approval of Deciphera Pharmaceuticals’ Qinlock (ripretinib) for the Treatment of Fourth-Line Gastrointestinal Stromal Tumor”Deciphera Pharmaceuticals, Inc. (Press release). 15 May 2020. Retrieved 15 May 2020.
  6. ^ “Qinlock: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 15 May 2020.
  7. Jump up to:a b c d e f g h i “FDA approves ripretinib for advanced gastrointestinal stromal tumor”U.S. Food and Drug Administration (FDA). 15 May 2020. Retrieved 18 May 2020.  This article incorporates text from this source, which is in the public domain.
  8. ^ “Ripretinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 2 October 2014. Retrieved 15 May 2020.
  9. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1): 106. hdl:10665/330896. License: CC BY-NC-SA 3.0 IGO.
  10. ^ “Ripretinib” (PDF). United States Adopted Name (USAN) Drug Finder. Retrieved 17 May 2020.

Further reading

External links

Clinical data
Pronunciationrip re’ ti nib
Trade namesQinlock
Other namesDCC-2618
AHFS/Drugs.comMonograph
MedlinePlusa620035
License dataUS DailyMedRipretinib
Pregnancy
category
AU: D[1]US: N (Not classified yet)[2]Use should be avoided
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusAU: S4 (Prescription only) [1]US: ℞-only [3]
Identifiers
IUPAC name[show]
CAS Number1442472-39-0
PubChem CID71584930
DrugBankDB14840
ChemSpider67886378
UNII9XW757O13D
KEGGD11353
ChEMBLChEMBL4216467
Chemical and physical data
FormulaC24H21BrFN5O2
Molar mass510.367 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CCN1C(=O)C(=CC2=C1C=C(NC)N=C2)C1=C(Br)C=C(F)C(NC(=O)NC2=CC=CC=C2)=C1
InChI[hide]InChI=1S/C24H21BrFN5O2/c1-3-31-21-12-22(27-2)28-13-14(21)9-17(23(31)32)16-10-20(19(26)11-18(16)25)30-24(33)29-15-7-5-4-6-8-15/h4-13H,3H2,1-2H3,(H,27,28)(H2,29,30,33)Key:CEFJVGZHQAGLHS-UHFFFAOYSA-N

////////////Ripretinib, QINLOCK, リプレチニブ , 2020 APPROVALS, FDA 2020

Triheptanoin


Skeletal formula of triheptanoin

Triheptanoin

Approved US FDA 30/6/2020 Dojolvi UX 007

Triheptanoin is a source of heptanoate fatty acids, which can be metabolized without the enzymes of long chain fatty acid oxidation.4 In clinical trials, patients with long chain fatty acid oxidation disorders (lc-FAODs) treated with triheptanoin are less likely to develop hypoglycemia, cardiomyopathy, rhabdomyolysis, and hepatomegaly.1,2 Complications in lc-FAOD patients are reduced from approximately 60% to approximately 10% with the addition of triheptanoin.2

Triheptanoin was granted FDA approval on 30 June 2020.4

Triheptanoin, sold under the brand name Dojolvi, is a medication for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).[1][2][3]

The most common adverse reactions include abdominal pain, diarrhea, vomiting, and nausea.[1][2][3]

Triheptanoin was approved for medical use in the United States in June 2020.[4][2][3]

Triheptanoin is a triglyceride that is composed of three seven-carbon (C7:0) fatty acids. These odd-carbon fatty acids are able to provide anaplerotic substrates for the TCA cycle. Triheptanoin is used clinically in humans to treat inherited metabolic diseases, such as pyruvate carboxylase deficiency and carnitine palmitoyltransferase II deficiency. It also appears to increase the efficacy of the ketogenic diet as a treatment for epilepsy.

Since triheptanoin is composed of odd-carbon fatty acids, it can produce ketone bodies with five carbon atoms, as opposed to even-carbon fatty acids which are metabolized to ketone bodies with four carbon atoms. The five-carbon ketones produced from triheptanoin are beta-ketopentanoate and beta-hydroxypentanoate. Each of these ketone bodies easily crosses the blood–brain barrier and enters the brain.

Medical uses

Dojolvi is indicated as a source of calories and fatty acids for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).[1][2]

History

Triheptanoin was designated an orphan drug by the U.S. Food and Drug Administration (FDA) in 2006, 2008, 2014, and 2015.[5][6][7][8] Triheptanoin was also designated an orphan drug by the European Medicines Agency (EMA).[9][10][11][12][13][14][15][16]

Triheptanoin was approved for medical use in the United States in June 2020.[4][2]

The FDA approved triheptanoin based on evidence from three clinical trials (Trial 1/NCT018863, Trial 2/NCT022141 and Trial 3/NCT01379625).[3] The trials enrolled children and adults with LC-FAOD.[3] Trials 1 and 2 were conducted at 11 sites in the United States and the United Kingdom, and Trial 3 was conducted at two sites in the United States.[3]

Trial 1 and Trial 2 were used to evaluate the side effects of triheptanoin.[3] Both trials enrolled children and adults diagnosed with LC-FAOD.[3] In Trial 1, participants received triheptanoin for 78 weeks.[3] Trial 2 enrolled participants from other trials who were already treated with triheptanoin (including those from Trial 1) as well as participants who were never treated with triheptanoin before.[3] Trial 2 is still ongoing and is planned to last up to five years.[3]

The benefit of triheptanoin was evaluated in Trial 3 which enrolled enrolled children and adults with LC-FAOD.[3] Half of the participants received triheptanoin and half received trioctanoin for four months.[3] Neither the participants nor the investigators knew which treatment was given until the end of the trial.[3] The benefit of triheptanoin in comparison to trioctanoin was assessed by measuring the changes in heart and muscle function.[3]

Names

Triheptanoin is the international nonproprietary name.[17]

SYN

https://onlinelibrary.wiley.com/doi/abs/10.1002/ejlt.201100425

Synthesis of triheptanoin and formulation as a solid diet for rodents -  Semak - 2012 - European Journal of Lipid Science and Technology - Wiley  Online Library

References

  1. Jump up to:a b c d “Dojolvi- triheptanoin liquid”DailyMed. 30 June 2020. Retrieved 24 September2020.
  2. Jump up to:a b c d e “Ultragenyx Announces U.S. FDA Approval of Dojolvi (UX007/triheptanoin), the First FDA-Approved Therapy for the Treatment of Long-chain Fatty Acid Oxidation Disorders”. Ultragenyx Pharmaceutical. 30 June 2020. Retrieved 30 June 2020 – via GlobeNewswire.
  3. Jump up to:a b c d e f g h i j k l m n o “Drug Trials Snapshots: Dojolvi”U.S. Food and Drug Administration. 30 June 2020. Retrieved 16 July 2020.
  4. Jump up to:a b “Dojolvi: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 30 June 2020.
  5. ^ “Triheptanoin Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 26 May 2006. Retrieved 30 June 2020.
  6. ^ “Triheptanoin Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 1 February 2008. Retrieved 30 June 2020.
  7. ^ “Triheptanoin Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 21 October 2014. Retrieved 30 June 2020.
  8. ^ “Triheptanoin Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 15 April 2015. Retrieved 30 June 2020.
  9. ^ “EU/3/12/1081”European Medicines Agency (EMA). Retrieved 30 June 2020.
  10. ^ “EU/3/12/1082”European Medicines Agency (EMA). Retrieved 30 June 2020.
  11. ^ “EU/3/15/1495”European Medicines Agency (EMA). Retrieved 30 June 2020.
  12. ^ “EU/3/15/1508”European Medicines Agency (EMA). Retrieved 30 June 2020.
  13. ^ “EU/3/15/1524”European Medicines Agency (EMA). Retrieved 30 June 2020.
  14. ^ “EU/3/15/1525”European Medicines Agency (EMA). Retrieved 30 June 2020.
  15. ^ “EU/3/15/1526”European Medicines Agency (EMA). Retrieved 30 June 2020.
  16. ^ “EU/3/16/1710”European Medicines Agency (EMA). Retrieved 30 June 2020.
  17. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information33 (3): 694. hdl:10665/330879. License: CC BY-NC-SA 3.0 IGO.

Further reading

External links

  • “Triheptanoin”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT01379625 for “Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorder (Triheptanoin)” at ClinicalTrials.gov
Clinical data
Trade namesDojolvi
Other namesUX007
AHFS/Drugs.comProfessional Drug Facts
License dataUS DailyMedTriheptanoin
Pregnancy
category
US: N (Not classified yet)
Routes of
administration
By mouth
Drug classGlycerolipids
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
IUPAC name[show]
CAS Number620-67-7 
PubChem CID69286
DrugBankDB11677
ChemSpider62497 
UNII2P6O7CFW5K
KEGGD11465
ChEMBLChEMBL4297585
CompTox Dashboard (EPA)DTXSID40862306 
ECHA InfoCard100.009.681 
Chemical and physical data
FormulaC24H44O6
Molar mass428.610 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CCCCCCC(=O)OCC(COC(=O)CCCCCC)OC(=O)CCCCCC
InChI[hide]InChI=1S/C24H44O6/c1-4-7-10-13-16-22(25)28-19-21(30-24(27)18-15-12-9-6-3)20-29-23(26)17-14-11-8-5-2/h21H,4-20H2,1-3H3 Key:PJHKBYALYHRYSK-UHFFFAOYSA-N 

//////////Triheptanoin, Dojolvi,  UX 007, FDA 2020, 2020 APPROVALS

Prescription Products

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
DojolviLiquid0.96 g/1mLOralUltragenyx Pharmaceutical Inc.2020-07-01Not applicableUS flag

Cetuximab sarotalocan sodium


Cetuximab Sarotalocan Sodium (Genetical Recombination)



Cetuximab Sarotalocan Sodium is an antibody-drug-conjugate (molecular weight: 156,000-158,000) consisting of tetrasodium salt of Sarotalocan (6-({[3-({(OC-6-13)-bis({3-[bis(3-sulfopropyl)(3-sulfonatopropyl)azaniumyl]propyl}dimethylsilanolato-κOO‘)[(phtalocyaninato(2-)κN29N30N31N32)-1-yl]silicon}oxy)propoxy]carbonyl}amino)hexanoyl (C70H96N11O24S6Si3; molecular weight: 1,752.22)) attached to an average of 2-3 Lys residues of Cetuximab.

[2166339-33-7 , Cetuximab sarotalocan]

Cetuximab sarotalocan sodium

Enarodustat


Enarodustat (JAN).png
Enarodustat Chemical Structure

Enarodustat

エナロデュスタット

JTZ 951

FormulaC17H16N4O4
CAS1262132-81-9
Mol weight340.3333

PMDA 2020/9/25 APPROVED ENAROY

Anti-anemic, Hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitor

Originator Japan Tobacco
Developer Japan Tobacco; JW Pharmaceutical
Class Acetic acids; Amides; Antianaemics; Pyridones; Small molecules; Triazoles
Mechanism of Action Hypoxia-inducible factor-proline dioxygenase inhibitors

Preregistration Anaemia

27 Dec 2019 Japan Tobacco and SalubrisBio enter into a development and marketing agreement for enarodustat (JTZ 951) in China, Hong Kong, Macau and Taiwan for Anaemia
29 Nov 2019 Preregistration for Anaemia in Japan (PO)
31 Oct 2019 Phase I development in Anaemia is ongoing in USA

Enarodustat is a potent and orally active factor prolyl hydroxylase inhibitor, with an EC50 of 0.22 μM. Enarodustat has the potential for renal anemia treatment

PATENT

WO 2011007856

PAPER

ACS Medicinal Chemistry Letters (2017), 8(12), 1320-1325

https://pubs.acs.org/doi/10.1021/acsmedchemlett.7b00404

Abstract

Abstract Image

Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π–π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.

(7-Hydroxy-5-phenethyl-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl)glycine (14)

To a solution of SI-5 (2.28 g, 6.19 mmol) in EtOH (9.1 mL) was added 2N NaOH aq. (12.4 mL, 24.8 mmol) at room temperature. After stirring at 90 °C for 2 h, 6N HCl aq. (4.1 mL, 24.6 mmol). This was allowed to gradually cool with stirring and crystals were precipitated. The crystals were collected by filtration to give the title compound 14 (2.16 g, 103% yield). 1H NMR (400 MHz, DMSO-D6) δ: 14.22 (s, 1H), 12.98 (br s, 1H), 9.84 (t, J = 5.6 Hz, 1H), 8.58 (s, 1H), 7.33– 7.18 (m, 5H), 6.80 (s, 1H), 4.22 (d, J = 5.6 Hz, 2H), 3.40 (t, J = 7.7 Hz, 2H), 3.12 (t, J = 7.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ: 170.28, 167.70, 165.32, 152.95, 148.53, 146.49, 140.05, 128.33, 128.20, 126.17, 106.72, 95.56, 41.00, 31.95, 31.72. HRMS m/z: [M+H]+ calcd for C17H17N4O4, 341.1244; found, 341.1243. Anal. (C17H16N4O4) calcd C 59.99%, H 4.74%, N 16.46%; found C 60.02%, H, 4.78%, N, 16.42%. Melting point: 186 °C Purity: 100.0%.

PATENT

 WO 2018097254

PATENT

US 20200017492

/////////////Enarodustat, 2020 APPROVALS, JAPAN 2020, エナロデュスタット  , JTZ 951, ENAROY, 2020 APPROVALS, 

Abametapir アバメタピル , абаметапир , أباميتابير , 阿巴甲吡 ,


Abametapir skeletal.svg

Abametapir

アバアバメタピル , абаметапир , أباميتابير 阿巴甲吡 ,

5,5′-dimethyl-2,2′-bipyridine, 6,6′-Bi-3-picoline

  • BRN 0123183
  • HA 44
  • HA-44
  • HA44
Formula
C12H12N2
CAS
1762-34-1
Mol weight
184.2371

Xeglyze, FD APPROVED 24/7/2020

Pediculicide, Metalloproteinase inhibitor
  Disease
Head lice infestation
  • Originator Hatchtech
  • DeveloperDr Reddys Laboratories; Hatchtech
  • ClassAntiparasitics; Heterocyclic compounds; Pyridines; Small molecules
  • Mechanism of ActionChelating agents; Metalloprotease inhibitors
  • Registered Pediculosis
  • 27 Jul 2020Registered for Pediculosis (In adolescents, In children, In infants, In adults) in USA (Topical)
  • 18 Jun 2020FDA assigns PDUFA action date of 12/08/2020 for Abametapir for Pediculosis (Dr Reddy’s Laboratories website, June 2020)
  • 31 Mar 2019Abametapir is still in preregistration phase for Pediculosis in USA

Abametapir is a novel pediculicidal metalloproteinase inhibitor used to treat infestations of head lice.4 The life cycle of head lice (Pediculus capitis) is approximately 30 days, seven to twelve of which are spent as eggs laid on hair shafts near the scalp.2 Topical pediculicides generally lack adequate ovicidal activity,2 including standard-of-care treatments such as permethrin, and many require a second administration 7-10 days following the first to kill newly hatched lice that resisted the initial treatment. The necessity for follow-up treatment may lead to challenges with patient adherence, and resistance to agents like permethrin and pyrethrins/piperonyl butoxide may be significant in some areas.3

Investigations into novel ovicidal treatments revealed that several metalloproteinase enzymes were critical to the egg hatching and survival of head lice, and these enzymes were therefore identified as a potential therapeutic target.1 Abemetapir is an inhibitor of these metalloproteinase enzymes, and the first topical pediculicide to take advantage of this novel target. The improved ovicidal activity (90-100% in vitro) of abemetapir allows for a single administration, in contrast to many other topical treatments, and its novel and relatively non-specific mechanism may help to curb the development of resistance to this agent.1

Abametapir was first approved for use in the United States under the brand name Xeglyze on July 27, 2020.6

Abametapir, sold under the brand name Xeglyze, is a medication used for the treatment of head lice infestation in people six months of age and older.[1][2]

The most common side effects include skin redness, rash, skin burning sensation, skin inflammation, vomiting, eye irritation, skin itching, and hair color changes.[2]

Abametapir is a metalloproteinase inhibitor.[1] Abametapir was approved for medical use in the United States in July 2020.[1][3]

Medical uses

Abametapir is indicated for the topical treatment of head lice infestation in people six months of age and older.[1][2]

History

The U.S. Food and Drug Administration (FDA) approved abametapir based on evidence from two identical clinical trials of 699 participants with head lice.[2] The trials were conducted at fourteen sites in the United States.[2]

The benefit and side effects of abametapir were evaluated in two clinical trials that enrolled participants with head lice who were at least six months old.[2]

About half of all enrolled participants was randomly assigned to abametapir and the other half to placebo.[2] Abametapir lotion or placebo lotion were applied once as a ten-minute treatment to infested hair.[2] The benefit of abametapir in comparison to placebo was assessed after 1, 7 and 14 days by comparing the counts of participants in each group who were free of live lice.[2]

SYN

Ronald Harding, Lewis David Schulz, Vernon Morrison Bowles, “Pediculicidal composition.” WIPO Patent WO2015107384A2, published July, 2015.

References

  1. Jump up to:a b c d e “Xeglyze (abametapir) lotion, for topical use” (PDF)U.S. Food and Drug Administration (FDA). Dr. Reddy’s Laboratories. Inc. Retrieved 25 July 2020.
  2. Jump up to:a b c d e f g h i “Drug Trial Snapshot: Xeglyze”U.S. Food and Drug Administration (FDA). 24 July 2020. Retrieved 6 August 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ “Abametapir: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 25 July 2020.

Further reading

External links

  • “Abametapir”Drug Information Portal. U.S. National Library of Medicine.
Abametapir
Abametapir skeletal.svg
Clinical data
Trade names Xeglyze
Other names Ha44
AHFS/Drugs.com Professional Drug Facts
License data
Pregnancy
category
  • US: N (Not classified yet)
Routes of
administration
Topical
Drug class PediculicideMetalloproteinase inhibitor
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.157.434 Edit this at Wikidata
Chemical and physical data
Formula C12H12N2
Molar mass 184.242 g·mol−1
3D model (JSmol)

///////Abametapir, 2020 APPROVALS, FDA 2020, Xeglyze, アバメタピル , абаметапир , أباميتابير 阿巴甲吡 , BRN 0123183, HA 44, head lice

CC1=CC=C(N=C1)C1=CC=C(C)C=N1

Bulevirtide acetate


Bulevirtide acetate

(N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt.

molecular formula C248H355N65O72,

molecular mass is 5398.9 g/mol

ブレビルチド酢酸塩;

APROVED 2020/7/31, EU, Hepcludex

MYR GmbH

Antiviral, Entry inhibitor
  Disease
Hepatitis delta virus infection

Bulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/mol

Bulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.

Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.

The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.

https://www.ema.europa.eu/en/documents/assessment-report/hepcludex-epar-public-assessment-report_en.pdf

Hepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.

HDV is an ‘incomplete’ virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.

HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.

Hepcludex contains the active substance bulevirtide.

Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).[2]

The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.[2]

Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.[2] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.[2]

Bulevirtide was approved for medical use in the European Union in July 2020.[2]

Medical uses

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.[2][3]

Pharmacology

Mechanism of action

Bulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.[4]

The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1[5][6] that can also dock to NTCP, blocking the virus’s entry mechanism.[7]

The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.[7]

References

  1. ^ Deterding, K.; Wedemeyer, H. (2019). “Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta”. Aids Reviews21 (3): 126–134. doi:10.24875/AIDSRev.19000080PMID 31532397.
  2. Jump up to:a b c d e f g “Hepcludex EPAR”European Medicines Agency (EMA). 26 May 2020. Retrieved 12 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ^ “Summary of opinion: Hepcludex” (PDF)European Medicines Agency. 28 May 2020.
  4. ^ Francisco, Estela Miranda (29 May 2020). “Hepcludex”European Medicines Agency. Retrieved 6 August 2020.
  5. ^ Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). “The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus”. Journal of Hepatology58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008PMID 23246506.
  6. ^ Abbas Z, Abbas M (August 2015). “Management of hepatitis delta: Need for novel therapeutic options”World Journal of Gastroenterology21 (32): 9461–5. doi:10.3748/wjg.v21.i32.9461PMC 4548107PMID 26327754.
  7. Jump up to:a b Spreitzer H (14 September 2015). “Neue Wirkstoffe – Myrcludex B”. Österreichische Apothekerzeitung (in German) (19/2015): 12.

External links

Bulevirtide
Clinical data
Trade names Hepcludex
Other names MyrB, Myrcludex-B[1]
License data
Routes of
administration
Subcutaneous injection
ATC code
  • None
Legal status
Legal status
  • EU: Rx-only [2]
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL

/////////Bulevirtide acetate, ブレビルチド酢酸塩 , orphan designation, MYR GmbH, PEPTIDE, EU 2020, 2020 APPROVALS

Nifurtimox


Nifurtimox.svg

Nifurtimox

Formula
C10H13N3O5S
CAS
23256-30-6
Mol weight
287.2923

FDA APPROVED, 2020/8/6, LAMPIT

Antiprotozoal
  Disease
Chagas disease

IUPAC Name

3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dione

SMILES

CC1CS(=O)(=O)CCN1\N=C\C1=CC=C(O1)[N+]([O-])=O
SYN
Danong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1
  • OriginatorBayer
  • ClassAntiprotozoals; Nitrofurans; Small molecules; Thiamorpholines; Thiazines
  • Mechanism of ActionDNA damage modulators
  • RegisteredChagas disease
  • 07 Aug 2020Registered for Chagas disease (In adolescents, In children, In infants) in USA (PO)
  • 31 Jan 2020Preregistration for Chagas disease (In infants, In children, In adolescents) in USA (PO)
  • 29 Jan 2020Bayer completes a phase I trial in Chagas disease in Argentina (PO) (NCT03334838)
Title: Nifurtimox
CAS Registry Number: 23256-30-6
CAS Name: 3-Methyl-N-[(5-nitro-2-furanyl)methylene]-4-thiomorpholinamine 1,1-dioxide
Additional Names: 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide; tetrahydro-3-methyl-4-[(5-nitrofurfurylidene)amino]-2H-1,4-thiazine 1,1-dioxide; 1-[(5-nitrofurfurylidene)amino]-2-methyltetrahydro-1,4-thiazine 4,4-dioxide
Manufacturers’ Codes: Bay 2502
Trademarks: Lampit (Bayer)
Molecular Formula: C10H13N3O5S
Molecular Weight: 287.29
Percent Composition: C 41.81%, H 4.56%, N 14.63%, O 27.85%, S 11.16%
Literature References: Prepn from 5-nitrofurfural and 4-amino-3-methyltetrahydro-1,4-thiazine 1,1-dioxide: Herlinger et al., DE 1170957 corresp to US 3262930 (1964 and 1966 to Bayer). Series of articles on pharmacology and clinical findings: Arzneim.-Forsch. 22, 1563-1642 (1972). Toxicity data: K. Hoffmann, ibid. 1590.
Properties: Orange-red crystals from dil acetic acid, mp 180-182°. LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann).
Melting point: mp 180-182°
Toxicity data: LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann)
Therap-Cat: Antiprotozoal (Trypanosoma).
Keywords: Antiprotozoal (Trypanosoma).

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness.[1][4] For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment.[4] In Chagas disease it is a second-line option to benznidazole.[5] It is given by mouth.[1]

Common side effects include abdominal pain, headache, nausea, and weight loss.[1] There are concerns from animal studies that it may increase the risk of cancer but these concerns have not be found in human trials.[5] Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems.[5] It is a type of nitrofuran.[5]

Nifurtimox came into medication use in 1965.[5] It is on the World Health Organization’s List of Essential Medicines.[4] It is not available commercially in Canada.[1] It was approved for medical use in the United States in August 2020.[3] In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO).[6]

Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11

The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11

Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer’s formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10

Medical uses

Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.[7][8] However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.[8][9] Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.[5][9]

In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.[2]

Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse,[10] but the combination of melarsoprol with nifurtimox appears to be efficacious.[11] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[12]

Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis.[13]

Pregnancy and breastfeeding

Use of nifurtimox should be avoided in pregnant women due to limited use.[5][8][14] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.[15] Other authors do not consider breastfeeding a contraindication during nifurtimox use.[15]

Side effects

Side effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.[8]

Contraindications

Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders.[5][16][20]

Mechanism of action

Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA.[8] Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalaseglutathioneperoxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]

Manufacturing and availability

A bottle of nifurtimox

Nifurtimox is sold under the brand name Lampit by Bayer.[3] It was previously known as Bayer 2502.

Nifurtimox is only licensed for use in Argentina and Germany,[citation needed] where it is sold as 120-mg tablets. It was approved for medical use in the United States in August 2020.[3]

Research

Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma.[21]

SYN

Nifurtimox

Synthesis of Essential Drugs

2006, Pages 559-582

Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine (37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul-fide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox [58,59].

58. H. Herlinger, K.H. Heinz, S. Petersen, M.Bock, Ger. Pat. 1.170.957 (1964).

59. H. Herlinger, K.H. Heinz, S. Petersen, M. Bock, U.S. Pat. 3.262.930 (1966)

References

  1. Jump up to:a b c d e f “Nifurtimox (Systemic)”Drugs.com. 1995. Archived from the original on 20 December 2016. Retrieved 3 December 2016.
  2. Jump up to:a b “Lampit (nifurtimox) tablets, for oral use” (PDF)U.S. Food and Drug Administration(FDA). Bayer HealthCare Pharmaceuticals Inc. Retrieved 6 August 2020.
  3. Jump up to:a b c d “Lampit: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.
  4. Jump up to:a b c World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. Jump up to:a b c d e f g h Bern, Caryn; Montgomery, Susan P.; Herwaldt, Barbara L.; Rassi, Anis; Marin-Neto, Jose Antonio; Dantas, Roberto O.; Maguire, James H.; Acquatella, Harry; Morillo, Carlos (2007-11-14). “Evaluation and Treatment of Chagas Disease in the United States”JAMA298 (18): 2171–81. doi:10.1001/jama.298.18.2171ISSN 0098-7484PMID 18000201.
  6. ^ “Trypanosomiasis, human African (sleeping sickness)”World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.
  7. ^ Coura JR, de Castro SL (2002). “A critical review of Chagas disease chemotherapy”Mem Inst Oswaldo Cruz97 (1): 3–24. doi:10.1590/S0074-02762002000100001PMID 11992141.
  8. Jump up to:a b c d e f g h “Nifurtimox Drug Information, Professional”http://www.drugs.comArchivedfrom the original on 2016-11-08. Retrieved 2016-11-09.
  9. Jump up to:a b Jackson, Yves; Alirol, Emilie; Getaz, Laurent; Wolff, Hans; Combescure, Christophe; Chappuis, François (2010-11-15). “Tolerance and Safety of Nifurtimox in Patients with Chronic Chagas Disease”Clinical Infectious Diseases51 (10): e69–e75. doi:10.1086/656917ISSN 1058-4838PMID 20932171.
  10. ^ Pepin J, Milord F, Mpia B, et al. (1989). “An open clinical trial of nifurtimox for arseno-resistant T. b. gambiense sleeping sickness in central Zaire”. Trans R Soc Trop Med Hyg83(4): 514–7. doi:10.1016/0035-9203(89)90270-8PMID 2694491.
  11. ^ Bisser S, N’Siesi FX, Lejon V, et al. (2007). “Equivalence Trial of Melarsoprol and Nifurtimox Monotherapy and Combination Therapy for the Treatment of Second-Stage Trypanosoma brucei gambiense Sleeping Sickness”J Infect Dis195 (3): 322–329. doi:10.1086/510534PMID 17205469.
  12. ^ Pepin J (2007). “Combination Therapy for Sleeping Sickness: A Wake-Up Call”J Infect Dis195 (3): 311–13. doi:10.1086/510540PMID 17205466.
  13. ^ Priotto G, Kasparian S, Mutombo W, et al. (July 2009). “Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiensetrypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial”. Lancet374(9683): 56–64. doi:10.1016/S0140-6736(09)61117-Xhdl:10144/72797PMID 19559476.
  14. ^ Schaefer, Christof; Peters, Paul W. J.; Miller, Richard K. (2014-09-17). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. Academic Press. ISBN 9780124079014Archived from the original on 2017-09-08.
  15. Jump up to:a b “Nifurtimox use while Breastfeeding | Drugs.com”http://www.drugs.comArchived from the original on 2016-11-08. Retrieved 2016-11-07.
  16. Jump up to:a b c “Parasites – American Trypanosomiasis (also known as Chagas Disease)”U.S. Centers for Disease Control and Prevention (CDC)Archived from the original on 2016-11-06. Retrieved 2016-11-09.
  17. Jump up to:a b Forsyth, Colin J.; Hernandez, Salvador; Olmedo, Wilman; Abuhamidah, Adieb; Traina, Mahmoud I.; Sanchez, Daniel R.; Soverow, Jonathan; Meymandi, Sheba K. (2016-10-15). “Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States”Clinical Infectious Diseases63 (8): 1056–1062. doi:10.1093/cid/ciw477ISSN 1537-6591PMC 5036918PMID 27432838.
  18. ^ Castro, José A.; de Mecca, Maria Montalto; Bartel, Laura C. (2006-08-01). “Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis)”. Human & Experimental Toxicology25 (8): 471–479. doi:10.1191/0960327106het653oaISSN 0960-3271PMID 16937919.
  19. Jump up to:a b Estani, Sergio Sosa; Segura, Elsa Leonor (1999-09-01). “Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina”Memórias do Instituto Oswaldo Cruz94: 363–365. doi:10.1590/S0074-02761999000700070ISSN 0074-0276PMID 10677756.
  20. ^ “Chagas disease”World Health OrganizationArchived from the original on 2014-02-27. Retrieved 2016-11-08.
  21. ^ Clinical trial number NCT00601003 for “Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma” at ClinicalTrials.gov. Retrieved on July 10, 2009.

External links

  • “Nifurtimox”Drug Information Portal. U.S. National Library of Medicine.
Nifurtimox
Nifurtimox.svg
Nifurtimox 3D.png
Clinical data
Trade names Lampit[1]
Other names Bayer 2502[1]
AHFS/Drugs.com Drugs.com archive
Lampit
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Low
Metabolism Liver (Cytochrome P450 oxidase (CYP) involved)
Elimination half-life 2.95 ± 1.19 hours
Excretion Kidney, very low
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.377 Edit this at Wikidata
Chemical and physical data
Formula C10H13N3O5S
Molar mass 287.29 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 180 to 182 °C (356 to 360 °F)

///////////Nifurtimox, LAMPIT, 2020 APPROVALS, FDA 2020, ニフルチモックス, CHAGAS DISEASE, ANTI PROTOZOAL

Imlifidase


MDSFSANQEI RYSEVTPYHV TSVWTKGVTP PANFTQGEDV FHAPYVANQG WYDITKTFNG
KDDLLCGAAT AGNMLHWWFD QNKDQIKRYL EEHPEKQKIN FNGEQMFDVK EAIDTKNHQL
DSKLFEYFKE KAFPYLSTKH LGVFPDHVID MFINGYRLSL TNHGPTPVKE GSKDPRGGIF
DAVFTRGDQS KLLTSRHDFK EKNLKEISDL IKKELTEGKA LGLSHTYANV RINHVINLWG
ADFDSNGNLK AIYVTDSDSN ASIGMKKYFV GVNSAGKVAI SAKEIKEDNI GAQVLGLFTL
STGQDSWNQT N

Imlifidase

イムリフィダーゼ;

Formula
C1575H2400N422O477S6
CAS
1947415-68-0
Mol weight
35070.8397

EMA APPROVED, 2020/8/25, Idefirix

Pre-transplant treatment to make patients with donor specific IgG eligible for kidney transplantation
Immunosuppressant, Immunoglobulin modulator (enzyme)

Imlifidase is under investigation in clinical trial NCT02854059 (IdeS in Asymptomatic Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients).

Imlifidase, brand name Idefirix, is a medication for the desensitization of highly sensitized adults needing kidney transplantation, but unlikely to receive a compatible transplant.[1]

Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus pyogenes.[1] It cleaves the heavy chains of all human IgG subclasses (but no other immunoglobulins), eliminating Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC).[1] Thus, imlifidase reduces the level of donor specific antibodies, enabling transplantation.[1]

The benefits with imlifidase are its ability to convert a positive crossmatch to a negative one in highly sensitized people to allow renal transplantation.[1] The most common side effects are infections and infusion related reactions.[1]

In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Imlifidase.[1][2]

Medical uses

Per the CHMP recommendation, imlifidase will be indicated for desensitization treatment of highly sensitized adult kidney transplant people with positive crossmatch against an available deceased donor.[1] The use of imlifidase should be reserved for people unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized people.[1]

History

Imlifidase was granted orphan drug designations by the European Commission in January 2017, and November 2018,[3][4] and by the U.S. Food and Drug Administration (FDA) in both February and July 2018.[5][6]

In February 2019, Hansa Medical AB changed its name to Hansa Biopharma AB.[4]

References

  1. Jump up to:a b c d e f g h i “Imlifidase: Pending EC decision”European Medicines Agency (EMA). 25 June 2020. Retrieved 26 June 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “New treatment to enable kidney transplant in highly sensitised patients”European Medicines Agency (Press release). 26 June 2020. Retrieved 26 June 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ “EU/3/16/1826”European Medicines Agency (EMA). 12 January 2017. Retrieved 27 June 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “EU/3/18/2096”European Medicines Agency (EMA). 13 February 2019. Retrieved 27 June 2020.  This article incorporates text from this source, which is in the public domain.
  5. ^ “Imlifidase Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 3 July 2018. Retrieved 27 June 2020.
  6. ^ “Imlifidase Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 14 February 2018. Retrieved 27 June 2020.

Further reading

External links

  • “Imlifidase”Drug Information Portal. U.S. National Library of Medicine.
Imlifidase
Clinical data
Pronunciation im lif’ i dase
Trade names Idefirix
Other names HMED-IdeS
Routes of
administration
Intravenous
ATC code
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C1575H2400N422O477S6
Molar mass 35071.36 g·mol−1

//////////Imlifidase, Idefirix, PEPTIDE, イムリフィダーゼ , 2020 APPROVALS, EMA 2020, EU 2020

Pralsetinib


Pralsetinib.png

ChemSpider 2D Image | trans-N-{(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl}cyclohexanecarboxamide | C27H32FN9O2

Pralsetinib

Formula
C27H32FN9O2
CAS
2097132-94-8
Mol weight
533.6005
Cyclohexanecarboxamide, N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, cis
2097132-94-8 [RN]
BLU-667
BS-15942

Other Names

  • cis-N-[(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]cyclohexanecarboxamide
  • BLU 123244
  • BLU 667
  • Pralsetinib
  • X 581238
  • cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide

N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide

FDA APPROVED GAVRETO, 2020/9/4

Pralsetinib, sold under the brand name Gavreto, is a medication for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC).[1] Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.[1]

The most common adverse reactions include increased aspartate aminotransferase (AST), decreased hemoglobin, decreased lymphocytes, decreased neutrophils, increased alanine aminotransferase (ALT), increased creatinine, increased alkaline phosphatase, fatigue, constipation, musculoskeletal pain, decreased calcium, hypertension, decreased sodium, decreased phosphate, and decreased platelets.[1]

Pralsetinib was approved for medical use in the United States in September 2020.[1][2][3][4]

Medical uses

Pralsetinib is indicated for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.[1][4]

History

Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385) with 220 participants aged 26-87 whose tumors had RET alterations.[1][4] Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, fluorescence in situ hybridization, or other tests.[1] The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.[1] The trial was conducted at sites in the United States, Europe and Asia.[4]

Efficacy for RET fusion-positive NSCLC was evaluated in 87 participants previously treated with platinum chemotherapy.[1] The ORR was 57% (95% CI: 46%, 68%); 80% of responding participants had responses lasting 6 months or longer.[1] Efficacy was also evaluated in 27 participants who never received systemic treatment.[1] The ORR for these participants was 70% (95% CI: 50%, 86%); 58% of responding participants had responses lasting 6 months or longer.[1]

The US Food and Drug Administration (FDA) granted the application for pralsetinib priority revieworphan drug, and breakthrough therapy designations[1]and granted approval of Gavreto to Blueprint Medicines.[1]

PATENT

US 20170121312

https://patents.google.com/patent/US20170121312A1/en

    • Step 7: Synthesis of (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (Compound 129) and (1S,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (Compound 130)

    • [0194]
      Figure US20170121312A1-20170504-C00094
    • [0195]
      The title compounds were prepared from methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 2.5 mL injections, 70 mL/min). Peak 1 was concentrated to give (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid. Peak 2 was concentrated to give (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (130 mg, 46%) as a white solid.

Example 6. Synthesis of Compound 149Step 1: Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate

    • [0196]
      Figure US20170121312A1-20170504-C00095
    • [0197]
      Methyl 4-iodo-1-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N2. Rieke Zinc (17.7 mL of a 50 mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of Nand 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl2dppf (826 mg, 1.13 mmol). The vessel was capped and heated to 80° C. for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H2O (3×), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (74 mg, 2.2%) as a colorless oil. MS (ES+) C14H19ClN2Orequires: 298, found: 299 [M+H]+.

Step 2: Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate

    • [0198]
      Figure US20170121312A1-20170504-C00096
    • [0199]
      Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd2(dba)(21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added. The reaction mixture was heated to 115° C. for 2 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated onto silica gel, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-hexanes) to give tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (48 mg, 44%) as a yellow oil. MS (ES+) C23H33N5Orequires: 459, found: 460 [M+H]+.

Step 3: Synthesis of 1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid

    • [0200]
      Figure US20170121312A1-20170504-C00097
    • [0201]
      Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H2O (17:1:1, 1.8 mL). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and concentrated to give crude 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, crude) which was used in the subsequent amide coupling without any further purification. MS (ES+) C17H23N5Orequires: 345, found: 346 [M+H]+.

Step 4: Synthesis of (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (Compound 149)

    • [0202]
      Figure US20170121312A1-20170504-C00098
    • [0203]
      The title compound was prepared from 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (36 mg), which was then dissolved in 6 mL methanol-DCM (1:1) and purified by SFC (ChiralPak IC-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 1.0 mL injections, 70 mL/min). Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (1 s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (13.4 mg, 24%) as a white solid.

Synthesis of IntermediatesExample 7. Synthesis of Ketone and Boronate IntermediatesA. Methyl 1-methoxy-4-oxocyclohexane-1-carboxylate

    • [0204]
      Figure US20170121312A1-20170504-C00099
    • [0205]
      The title compound was prepared as described in WO 2014/130810 A1 page 86.

B. Ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate

    • [0206]
      Figure US20170121312A1-20170504-C00100

Step 1: Synthesis of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate

    • [0207]
      A solution of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol) in CHBr(3234 g, 1280 mmol) was cooled to 0° C. and potassium hydroxide (57.5 g, 1024 mmol) in EtOH (300 mL) was added dropwise over 2.5 hrs. After stirring the mixture for 23 h, the mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography on silica gel (gradient elution, PE:EA=15:1 to 10:1) to obtain the title compound (18.0 g).

Step 2: Synthesis of ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate

    • [0208]
      To a solution of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 43 mmol) in 1,4-dioxane (250 mL) was added aqueous HCl (6 M, 92.5 mL), and the mixture was stirred for 23 h at ambient temperature. The mixture was then diluted with H2O and extracted with EtOAc.
    • [0209]
      The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (PE:EA=15:1) to obtain the product (8.0 g). 1H NMR (400 MHz, DMSO) δ 4.20-4.13 (m, 2H), 3.43 (q, J=6.9 Hz, 1H), 2.48-2.39 (m, 1H), 2.24-2.12 (m, 2H), 2.10-2.01 (m, 1H), 1.22 (t, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 2H).

C. Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0210]
      Figure US20170121312A1-20170504-C00101

Step 1: Synthesis of ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate

    • [0211]
      A solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0° C. The mixture was stirred for 30 min at 0° C. and then cooled to −78° C. The solution of ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between −40° C. to −20° C. for 2 h, then was warmed to ambient temperature for 16 h. The reaction mixture was carefully added to a saturated solution of ammonium chloride. The aqueous layer was extracted twice with diethyl ether, and the organic layers were combined. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA=10:1) to give ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g).

Step 2: Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

    • [0212]
      Ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45° C. for 10 minutes. Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45° C. for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2×40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1 g).

Step 3: Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0213]
      Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.03 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.15 g, 4.54 mmol), Pd(dppf)Cl(73.5 mg, 0.09 mmol) and potassium acetate (891 mg, 9.08 mmol) were suspended in 1,4-dioxane (20 mL). The reaction mixture was flushed with nitrogen, then heated to 100° C. for 2 h. The mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (618 mg).

D. Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0214]
      Figure US20170121312A1-20170504-C00102
    • [0215]
      Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate was prepared using the same synthetic protocol as described above using ethyl 2-methyl-4-oxocyclohexane-1-carboxylate as the starting material.

E. Methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate

    • [0216]
      Figure US20170121312A1-20170504-C00103

Step 1: Synthesis of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate

    • [0217]
      A mixture of acrylaldehyde (120 g, 2.14 mol), methyl methacrylate (200 g, 2.00 mol) and hydroquinone (2.2 g, 20 mmol) were heated in a sealed steel vessel at 180° C. for one h. The mixture was then cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=100:1 to 80:1) to give methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (70 g, 22% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 6.38 (d, J=6.4 Hz, 1H), 4.73-4.70 (m, 1H), 3.76 (s, 3H), 2.25-2.22 (m, 1H), 1.99-1.96 (m, 2H), 1.79-1.77 (m, 1H), 1.49 (s, 3H).

Step 2: Synthesis of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate

    • [0218]
      To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in tetrahydrofuran) dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 hours. This reaction was monitored by TLC. The mixture was quenched by a solution of sodium acetate (10.5 g, 128 mmol) in water (15 mL). Then the mixture was treated with 30% hydrogen peroxide solution (23.6 g, 208.2 mmol) slowly at 0° C. and stirred at 30° C. for 3 h. The mixture was then partitioned between saturated sodium sulfite solution and tetrahydrofuran. The aqueous layer was further extracted with tetrahydrofuran (2×). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=10:1 to 1:1) to give crude methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18 g, crude) as a pale yellow oil, which used directly for next step.

Step 3: Synthesis of methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate

    • [0219]
      To a solution of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18.0 g, 103 mmol) in anhydrous dichloromethane (200 mL) was added PCC (45.0 g, 209 mmol) in portions. The reaction mixture was stirred at ambient temperature until TLC indicated the reaction was completed. Petroleum ether (500 mL) was then added and the mixture was filtered. The filter cake was washed with petroleum ether (100 mL), and the filtrate was concentrated under vacuum to give methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (15 g, 84% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 4.25 (d, J=17.6 Hz, 1H), 4.07 (d, J=17.6 Hz, 1H), 3.81 (s, 3H), 2.52-2.44 (m, 3H), 2.11-2.04 (m, 1H), 1.53 (s, 3H).

Example 8. Synthesis of Iodide IntermediatesA. Methyl 1-methoxy-4-iodocyclohexane-1-carboxylate

    • [0220]
      Figure US20170121312A1-20170504-C00104

Step 1: Synthesis of methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate

    • [0221]
      Methyl 1-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved in methanol (100 mL) and the solution was cooled to 0° C. Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH4Cl solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a residue that was purified by flash-column chromatography on silica gel (gradient elution, 5% to 100% ethyl acetate-hexanes) to afford methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 49.5%) as a colorless oil. MS (ES+) C9H16Orequires: 188, found: 211 [M+Na]+.

Step 2: Synthesis of methyl 1-methoxy-4-iodocyclohexane-1-carboxylate

    • [0222]
      Methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0° C., and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was triturated with hexane (40 mL, stir for 20 min). The mixture was filtered, and the filtrate was evaporated to provide a residue that was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate-hexanes) to give the title compound (2.37 g, 75%) as a pale yellow oil. MS (ES+) C9H15IOrequires: 298, found: 299 [M+H]+.

B. Ethyl 1-ethoxy-4-iodocyclohexane-1-carboxylate

    • [0223]
      Figure US20170121312A1-20170504-C00105
    • [0224]
      The title compound was prepared as described above using ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate as a starting material. C11H19IOrequires: 326, found: 327 [M+H].

Example 9. Synthesis of Amine IntermediatesA. (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

    • [0225]
      Figure US20170121312A1-20170504-C00106

Step 1: Synthesis of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one

    • [0226]
      4-Fluoro-1H-pyrazole (4.73 g, 55 mmol) and potassium carbonate (17.27 g, 125 mmol) were combined and stirred in N,N-dimethylformamide (41.7 mL) for 10 minutes in an open sealed tube before addition of 2-bromo-5-acetylpyridine (10 g, 50 mmol). The reaction tube was sealed and stirred for 20 hours at 100° C. The reaction mixture was then cooled to room temperature and poured into water (˜700 mL). The mixture was sonicated and stirred for 20 minutes, after which a beige solid was isolated by filtration, washed with small amounts of water, and dried to yield 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.81 g, 96% yield). MS: M+1=206.0.

Step 2: Synthesis of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

    • [0227]
      To a stirred room temperature solution of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.806 g, 47.8 mmol) in THF (96 mL) was added (R)-(+)-t-Butylsulfinamide (5.79 g, 47.8 mmol) followed by titanium (IV) ethoxide (21.8 g, 96 mmol). The solution was stirred at 75° C. on an oil bath for 15 hours. The reaction solution was cooled to room temperature and then to −78° C. (external temperature) before the next step. To the −78° C. solution was added dropwise over nearly 55 minutes L-Selectride (143 mL of 1N in THF, 143 mmol). During addition, some bubbling was observed. The reaction was then stirred after the addition was completed for 15 minutes at −78° C. before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to −50° C. and quenched slowly with methanol (˜10 mL), then poured into water (600 mL) and stirred. An off-white precipitate was removed by filtration, with ethyl acetate used for washes. The filtrate was diluted with ethyl acetate (800 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography to yield (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.5 g, 99% purity, 70.3% yield) as a light yellow solid. MS: M+1=311.1.

Step 3: Synthesis of (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

  • [0228]
    A solution of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.53 g, 33.9 mmol)) in methanol (79 mmol) and 4N HCl/dioxane (85 mL, 339 mmol) was stirred for 2.5 hours, at which point LC-MS showed reaction was complete. The reaction solution was poured into diethyl ether (300 mL) and a sticky solid was formed. The mixture was treated with ethyl acetate (200 mL) and sonicated. The solvents were decanted, and the sticky solid was treated with more ethyl acetate (˜200 mL), sonicated and stirred. The bulk of the sticky solid was converted to a suspension. A light yellow solid was isolated by filtration, washed with smaller amounts of ethyl acetate, and dried to yield (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (7.419 g, 78% yield). LC-MS confirmed desired product in high purity. MS: M+1=207.1.

PATENT

CN 111440151

PATENT

CN 111362923

References

  1. Jump up to:a b c d e f g h i j k l m n “FDA approves pralsetinib for lung cancer with RET gene fusions”U.S. Food and Drug Administration (FDA). 4 September 2020. Retrieved 8 September 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “Blueprint Medicines Announces FDA Approval of Gavreto (pralsetinib) for the Treatment of Adults with Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer” (Press release). Blueprint Medicines. 4 September 2020. Retrieved 8 September 2020 – via PR Newswire.
  3. ^ “Roche announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer”Roche (Press release). 7 September 2020. Retrieved 8 September 2020.
  4. Jump up to:a b c d “Drug Trial Snapshot: Gavreto”U.S. Food and Drug Administration. 4 September 2020. Retrieved 16 September 2020.  This article incorporates text from this source, which is in the public domain.

External links

Pralsetinib
Clinical data
Trade names Gavreto
Other names BLU-667
License data
Pregnancy
category
  • US: N (Not classified yet)
Routes of
administration
By mouth
Drug class Tyrosine kinase inhibitor
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C27H32FN9O2
Molar mass 533.612 g·mol−1
3D model (JSmol)

Roche buys into Blueprint’s RET inhibitor

The deal positions pralsetinib to compete against Lilly’s Retevmo

by Lisa M. Jarvis
JULY 18, 2020 | APPEARED IN VOLUME 98, ISSUE 28
09828-buscon2-pral.jpg

Roche is investing $775 million in cash and equity for access to Blueprint Medicines’ oncology drug candidate pralsetinib, which is under review by the US Food and Drug Administration.

Pralsetinib is a small-molecule inhibitor of RET alterations—rare genetic fusions or mutations that occur at low levels across lung, thyroid, and many other cancers.

The drug will go up against Eli Lilly and Company’s Retevmo, an RET inhibitor that received FDA approval in May for certain lung and thyroid cancers. Lilly acquired Retevmo in its $8 billion purchase of Loxo Oncology in 2019, a deal to obtain Loxo’s pipeline of small molecules for genetically defined tumors.

But SVB Leerink analyst Andrew Berens points out that Retevmo has side effects: it can cause an irregular heart rhythm called QT prolongation and hemorrhagic events. That leaves room for pralsetinib, which Roche will be better able to get in front of oncologists, Berens argues. In addition to a vast commercial network, Roche brings diagnostic tools to help identify cancer patients whose tumors feature RET alterations.

The FDA has a deadline of Nov. 23 to decide on approving the drug for lung cancer.

Roche’s move lowers the likelihood of a takeover of Blueprint, which had appeared on many investors’ short lists of acquisition targets. “We were surprised by the profuse language framing this deal as ensuring Blueprint’s independence,” Piper Sandler stock analyst Christopher J. Raymond told investors in a note.

//////////Pralsetinib, GAVRETO, 2020 APPROVALS, FDA 2020

CC1=CC(=NN1)NC2=NC(=NC(=C2)C)C3CCC(CC3)(C(=O)NC(C)C4=CN=C(C=C4)N5C=C(C=N5)F)OC

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