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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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RELACORILANT


Relacorilant.svg
Relacorilant.png

Relacorilant

  • Molecular FormulaC27H22F4N6O3S
  • Average mass586.561 Da

CAS 1496510-51-0

Phase III

UNII-2158753C7E

2158753C7E

[(4aR)-1-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinolin-4a-yl]-[4-(trifluoromethyl)pyridin-2-yl]methanone

[(4aR)-1-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinolin-4a-yl]-[4-(trifluoromethyl)pyridin-2-yl]methanone

Methanone, [(4aR)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-6-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl][4-(trifluoromethyl)-2-pyridinyl]-

Methanone, ((4aR)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4ah-pyrazolo(3,4-g)isoquinolin-4a-yl)(4-(trifluoromethyl)-2-pyridinyl)-

релакорилант[Russian][INN]

ريلاكوريلانت[Arabic][INN]

瑞拉可兰[Chinese][INN]

  • OriginatorCorcept Therapeutics
  • ClassAntineoplastics; Fluorine compounds; Isoquinolines; Ketones; Organic sulfur compounds; Pyrazoles; Pyridines; Small molecules
  • Mechanism of ActionGlucocorticoid receptor antagonists
  • Orphan Drug StatusYes – Pancreatic cancer; Cushing syndrome
  • Phase IIICushing syndrome; Ovarian cancer; Pancreatic cancer
  • Phase IIFallopian tube cancer; Peritoneal cancer; Prostate cancer
  • Phase I/IISolid tumours
  • Phase IAdrenocortical carcinoma

Most Recent Events

  • 09 Sep 2022Subgroup analysis efficacy data from a phase-II trial in Ovarian cancer presented at the 47th European Society for Medical Oncology Congress (ESMO-2022)
  • 29 Jun 2022Phase-III clinical trials in Ovarian cancer (Combination therapy, Recurrent, Second-line therapy or greater) in USA (PO)
  • 06 Jun 2022Corcept Therapeutics announces intentions to submit a NDA for Ovarian cancer

Relacorilant (developmental code name CORT-125134) is an antiglucocorticoid which is under development by Corcept Therapeutics for the treatment of Cushing’s syndrome.[1] It is also under development for the treatment of solid tumors and alcoholism.[1][2] The drug is a nonsteroidal compound and acts as an antagonist of the glucocorticoid receptor.[1] As of December 2017, it is in phase II clinical trials for Cushing’s syndrome and phase I/II clinical studies for solid tumors, while the clinical phase for alcoholism is unknown.[1]

Relacorilant is an orally available antagonist of the glucocorticoid receptor (GR), with potential antineoplastic activity. Upon administration, relacorilant competitively binds to and blocks GRs. This inhibits the activity of GRs, and prevents both the translocation of the ligand-GR complexes to the nucleus and gene expression of GR-associated genes. This decreases the negative effects that result from excess levels of endogenous glucocorticoids, like those seen when tumors overproduce glucocorticoids. In addition, by binding to GRs and preventing their activity, inhibition with CORT125134 also inhibits the proliferation of GR-overexpressing cancer cells. GRs are overexpressed in certain tumor cell types and promote tumor cell proliferation.

CLIP

https://europepmc.org/article/pmc/pmc8175224

Relacorilant (CORT125134)118) is being developed by Corcept Therapeutics, Inc. It is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that may benefit from the modulation of cortisol activity. In structural optimization, the introduction of a trifluoromethyl group to the 4-position on the pyridyl moiety was found to increase HepG2 tyrosine amino transferase assay potency by a factor of four. Relacorilant is currently being evaluated in a phase II clinical study in patients with Cushing’s syndrome.119)

2-Bromo-4-(trifluoromethyl)pyridine (17) prepared from (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one is employed as a key intermediate for the preparation of relacorilant as shown in Scheme 31.120)

An external file that holds a picture, illustration, etc. Object name is jps-46-2-D21-012-scheme31.jpg

Scheme31. Synthesis of relacorilant.118)

118) H. Hunt, T. Johnson, N. Ray and I. Walters (Corcept Therapeutics, Inc.): PCT Int. Appl. WO2013/177559 (2013).

119) H. J. Hunt, J. K. Belanoff, I. Walters, B. Gourdet, J. Thomas, N. Barton, J. Unitt, T. Phillips, D. Swift and E. Eaton: Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist. J. Med. Chem. 60, 3405–3421 (2017). [Abstract] [Google Scholar]

120) B. Lehnemann, J. Jung and A. Meudt (Archimica GmbH): PCT Int. Appl. WO 2007/000249 (2007).

PAPER

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b00162

The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing’s syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushing’s syndrome.

Abstract Image

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013177559

SYN

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Cushing’s syndrome (CS) is a metabolic disorder caused by chronic hypercortisolism. CS is associated with cardiovascular, metabolic, skeletal and psychological dysfunctions and can be fatal if left untreated. The first-line treatment for all forms of CS is a surgery. However, medical therapy has to be chosen if surgical resection is not an option or is deemed ineffective. Currently available therapeutics are either not selective and have side effects or are only available as an injection (pasireotide).

References

  1. Jump up to:a b c d “Relacorilant – Corcept Therapeutics – AdisInsight”.
  2. ^ Veneris JT, Darcy KM, Mhawech-Fauceglia P, Tian C, Lengyel E, Lastra RR, Pejovic T, Conzen SD, Fleming GF (2017). “High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer”Gynecol. Oncol146 (1): 153–160. doi:10.1016/j.ygyno.2017.04.012PMC 5955699PMID 28456378.

External links

Clinical data
Other namesCORT-125134
Routes of
administration
By mouth
Drug classAntiglucocorticoid
Identifiers
showIUPAC name
CAS Number1496510-51-0
PubChem CID73051463
ChemSpider57617720
UNII2158753C7E
KEGGD11336
Chemical and physical data
FormulaC27H22F4N6O3S
Molar mass586.57 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

//////////////Relacorilant, Phase III , Orphan Drug, Cushing syndrome, Ovarian cancer, Pancreatic cancer, релакорилант , ريلاكوريلانت , 瑞拉可兰 , 

CN1C=C(C=N1)S(=O)(=O)N2CCC3=CC4=C(CC3(C2)C(=O)C5=NC=CC(=C5)C(F)(F)F)C=NN4C6=CC=C(C=C6)F

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ELRAGLUSIB


STR1
3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-1H-pyrrole-2,5-dione.png

ELRAGLUSIB

RN: 1034895-42-5
UNII: ND1SOF0DLU, WHO 11553,  9-ING-41

  • 1H-Pyrrole-2,5-dione, 3-(5-fluoro-3-benzofuranyl)-4-(5-methyl-5H-1,3-dioxolo(4,5-F)indol-7-yl)-
  • 3-(5-Fluoro-benzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-F)indol-7-yl)-pyrrole-2,5-dioneAntineoplastic

Molecular Formula

  • C22-H13-F-N2-O5

Molecular Weight

  • 404.3517
  • OriginatorNorthwestern University; University of Illinois at Chicago
  • DeveloperActuate Therapeutics; Incyte Corporation; Levine Cancer Institute; University of Kansas Medical Center
  • ClassAntineoplastics; Benzofurans; Dioxolanes; Indoles; Pyrroles; Small molecules
  • Mechanism of ActionGlycogen synthase kinase 3 beta inhibitors
  • Orphan Drug StatusYes – Glioblastoma; Neuroblastoma
  • Phase IIAdenoid cystic carcinoma; Myelofibrosis; Neuroblastoma; Pancreatic cancer; Salivary gland cancer
  • Phase I/IICancer
  • PreclinicalBrain cancer; Chronic lymphocytic leukaemia; Colorectal cancer
  • 20 Sep 2022Elraglusib – Actuate Therapeutics receives Fast Track designation for Pancreatic cancer [IV] (Combination therapy, First-line therapy, Late-stage disease, Metastatic disease, Recurrent) in USA
  • 03 Jun 2022Efficacy and safety data from a phase I trial in cancer presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022)
  • 08 Apr 2022Preclinical trials in Brain cancer in USA (unspecified route)

9-ING-41 is under investigation in clinical trial NCT04218071 (Actuate 1901: 9-ING-41 in Myelofibrosis).

STR1

SYN

WO2019079299

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019079299

3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[l,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione (“9-ING-41”) has the following chemical structure:

[0004] 9-ING-41 has been reported as being useful for the treatment of cancers, including brain, lung, breast, ovarian, bladder, neuroblastoma, renal, and pancreatic cancers, as well as for treatment of traumatic brain injury.

[0005] The structure, properties, and/or biological activity of 9-ING-41 are set forth in U.S. Patent Number 8,207,216; Gaisina et al., From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863; and Hilliard, et al., Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth, Anti-Cancer Drugs 2011, 22:978-985.

Example 1: Preparation of 9-ING-41

[0056] Crude 9-ING-41 can be obtained by the general methods described in U.S. Patent Number 8,207,216, and in Gaisina et al., From a Natural Product Lead to the

Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863.

Example 2: Preparation of 9-ING-41 Crystalline Form I

[0057] Crystalline Form I of 9-ING-41 may also be prepared as follows.

Synthesis of Intermediate 1

[0058] Into a 3-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 6-nitro-2H-l,3-benzodioxole-5-carbaldehyde (200 g, 1.02 mol, 1.00 equiv), ammonium acetate (200 g, 2.59 mol, 2.53 equiv), acetic acid (2 L), and nitromethane (313 g, 5.13 mol, 5.00 equiv). The solution was stirred for 12 h at lOOoC. The reaction repeated three times. The solutions were combined and diluted with 20 L of water. The resulting solution was extracted with 3×10 L of ethyl acetate and the organic layers were combined. The mixture was washed with 3×10 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 450 g (crude) of 5-nitro-6-[(E)-2-nitroethenyl]-2H-l,3-benzodioxole (1) as a dark green solid.

Synthesis of Intermediate 2

[0059] Fe (120 g, 2.14 mol, 17.01 equiv) was slowly added in portions into a suspension of 5-nitro-6-[(Z)-2-nitroethenyl]-2H-l,3-benzodioxole (30 g, 125.97 mmol, 1.00 equiv), silica gel (120 g) in acetic acid (300 mL), toluene (200 mL), and cyclohexane (400 mL) at 80oC under nitrogen. The resulting black mixture was stirred for 8h at 80oC.The reaction repeated ten times. The reaction mixtures were combined. The solids were filtrated out. The filtrate was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). The collected fractions were combined and concentrated under vacuum to give 67.3 g (33%) of 2H, 5H-[1, 3] dioxolo [4, 5-f] indole (2) as an off-white solid.

Synthesis of Intermediate 3

[0060] Sodium hydride (19.9 g, 497.50 mmol, 1.18 equiv, 60%) was added in portions into a solution of 2H,3H,5H-furo[2,3-f]indole (67.3 g, 422.78 mmol, 1.00 equiv) in N,N-

dimethylformamide (1.3 L) at 0°C under nitrogen. The mixture was stirred for lh at 0°C and CH3I (70.9 g, 499.51 mmol, 1.18 equiv) was added dropwise. The resulting solution was stirred for 3 h at room temperature. The solution was quenched by added 1 L of ice water. The resulting solution was extracted with 3×1 L of ethyl acetate and the organic layers were combined. The mixture was washed with 3×1 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). The collected fractions were combined and concentrated under vacuum to give 71 g (97%) of 5-methyl-2H,3H,5H-furo[2,3-f]indole (3) as a light yellow solid.

Synthesis of Int rmediate 4

[0061] Ethyl 2-chloro-2-oxoacetate (220 g, 1.61 mol, 3.96 equiv) was added dropwise into a solution of 5-methyl-2H,3H,5H-furo[2,3-f]indole (70.4 g, 406.44 mmol, 1.00 equiv) in ethyl ether (1.6 L) at OoC under nitrogen. The resulting solution was warmed to room temperature and stirred for 4 h. The reaction was quenched slowly by the addition of 2 L of ice water and the pH value of the resulting solution was adjusted to 9 by Na2C03. The resulted mixture was extracted with 3×1.5 L of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 92.8 g (84%) of ethyl 2-[5-methyl-2H,3H,5H-furo[2,3-f]indol-7-yl]-2-oxoacetate (4) as a light yellow solid.

[0062] 1H MR (300 MHz, DMSO-d6): δ 8.28 (s, 4H), 7.56 (s, 4H), 7.27 (s, 4H), 6.17 (s, 1H), 6.08 (s, 8H), 4.35 (q, J = 7.1 Hz, 7H), 3.85 (s, 11H), 3.35 (s, 2H), 1.35 (t, J = 7.1 Hz, 11H), 1.25 (s, 2H).

Synthesis of Intermediate 5

5

[0063] Into a 10-L 4-necked round-bottom flask was placed 2-bromo-4-fluorophenol (500 g, 2.62 mol, 1.00 equiv), N,N-dimethylformamide (5 L), potassium carbonate (1253 g, 9.07 mol, 3.46 equiv), and ethyl (2E)-4-bromobut-2-enoate (1010 g, 5.23 mol, 2.00 equiv). The resulting solution was stirred for 12 h at room temperature. The solids were collected by filtration. The reaction was then quenched by the addition of 15 L of water and extracted with 3×10 L of ethyl acetate. The organic layers were combined and washed with 4×20 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20). The collected fractions were combined and concentrated under vacuum to give 500 g (63%) of ethyl (2E)-4-(2-bromo-4-fluorophenoxy)but-2-enoate (5) as a white solid.

Synthesis of Intermediate 6

[0064] Into a 2-L 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-4-(2-bromo-4-fluorophenoxy)but-2-enoate (125 g, 412.37 mmol, 1.00 equiv), benzyltri ethyl azanium chloride (99 g, 434.64 mmol, 1.05 equiv), sodium formate dihydrate (45.1 g), Pd(OAc)2 (2.9 g, 12.92 mmol, 0.03 equiv), sodium carbonate (92 g, 868.01 mmol, 2.10 equiv), and N,N-dimethylformamide (1.25 L). The resulting solution was stirred for 12 h at 80°C. The reaction repeated four times. The reaction mixtures were combined and the solids were filtrated out. The filtrate was diluted with 10 L of brine and extracted with 3×5 L of ethyl acetate. The organic layers were combined and washed with 4×6 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20). The collected fractions were combined and concentrated under vacuum. This resulted in 258 g (crude) of ethyl 2-(5-fluoro-l-benzofuran-3-yl)acetate (6) as light yellow oil.

Synthesis of Intermediate 7

7

[0065] Into a 5-L round-bottom flask was placed ethyl 2-(5-fluoro-l-benzofuran-3-yl)acetate (147 g, 661.53 mmol, 1.00 equiv), methanol (1 L), tetrahydrofuran (1 L), water (1 L), and Li OH (47.7 g, 1.99 mol, 3.01 equiv). The resulting solution was stirred for 3 h at room temperature. The reaction repeated twice. The mixture was concentrated under vacuum and then extracted with 1 L of dichloromethane. The aqueous layer was collected and the pH of the layer was adjust to 1-3 by hydrogen chloride (1 mol/L). The resulting solution was extracted with 3×1 L of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 160 g (62%) of 2-(5-fluoro-l-benzofuran-3-yl)acetic acid (7) as a white solid.

Synthesis of Intermediate 8

[0066] Into a 10-L round-bottom flask was placed 2-(5-fluoro-l-benzofuran-3-yl) acetic acid (160 g, 824.1 mmol, 1.00 equiv), H4C1 (436 g, 8.16 mol, 9.89 equiv), N,N-dimethylformamide (6L), DIEA (1064 g, 8.24 mol, 9.99 equiv), and HATU (376 g, 988.88 mmol, 1.20 equiv). The resulting solution was stirred for 12 h at room temperature. The resulting solution was diluted with 10 L of water. The solids were collected by filtration to give in 126 g (78%) of 2-(5-fluoro-l-benzofuran-3-yl) acetamide (8) as a white solid.

Synthesis of 9-ING-41 in cr stalline Form I

8 9-ING-41

[0067] t-BuOK (1200 mL, 1 mol/L in THF) was added dropwise into a solution of ethyl 2-[5-methyl-2H,3H,5H-furo[2,3-f]indol-7-yl]-2-oxoacetate (100 g, 365.9 mmol, 1.00 equiv), 2-(5-fluoro-l-benzofuran-3-yl)acetamide (72 g, 372.7 mmol, 1.02 equiv) in tetrahydrofuran (3 L) at 0°C under nitrogen. The reaction was stirred for 2h at room temperature. The reaction was cooled to 0°C and poured into of 2 L of H4C1 (saturated solution in water) and extracted with 4×2 L of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/dichloromethane/petroleum ether (1/1/5). The collected fractions were combined and concentrated under vacuum to give 107.9 g (74%) of 3-(5-fluoro-l-benzofuran-3-yl)-4-[5-methyl-2H,5H-[l,3]dioxolo[4,5-f]indol-7-yl]-2,5-dihydro-lH-pyrrole-2,5-dione as a red solid. This red solid is 9-ING-41 crystalline Form I. MS-ESI: [M+H]+ = 405.

PATENT

WO2019032958

PATENT

US20100004308

REF

Journal of Medicinal Chemistry (2009), 52(7), 1853-1863

PATENT

WO2008077138

////////

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Elraglusib is a maleimide-based, small molecule inhibitor of glycogen synthase kinase-3 (GSK-3; serine/threonine-protein kinase GSK3) with potential antineoplastic activity. Upon intravenous administration, elraglusib binds to and competitively inhibits GSK-3, which may lead to downregulation of nuclear factor kappa B (NF-kappaB) and decreased expression of NF-kappaB target genes including cyclin D1, B-cell lymphoma 2 (Bcl-2), anti-apoptotic protein XIAP, and B-cell lymphoma extra-large (Bcl-XL). This may inhibit NF-kappaB-mediated survival and chemoresistance in certain tumor types. GSK-3, a constitutively active serine/threonine kinase that plays a role in numerous pathways involved in protein synthesis, cellular proliferation, differentiation, and metabolism, is aberrantly overexpressed in certain tumor types and may promote tumor cell survival and resistance to chemotherapy and radiotherapy.

Actuate Therapeutics Announces Initiation of a Multicenter Randomized Trial of Elraglusib Plus FOLFIRINOX As First Line Therapy for Advanced Pancreatic Cancer

https://www.biospace.com/article/releases/actuate-therapeutics-announces-initiation-of-a-multicenter-randomized-trial-of-elraglusib-plus-folfirinox-as-first-line-therapy-for-advanced-pancreatic-cancer/

Published: Feb 07, 2022

CHICAGO and FORT WORTH, Texas, Feb. 07, 2022 (GLOBE NEWSWIRE) — Actuate Therapeutics (Actuate), a clinical stage biopharmaceutical company, today announced the opening of a randomized study of elraglusib (9-ING-41) plus FOLFIRINOX alone or with Losartan for patients with advanced pancreatic cancer in the first-line setting (NCT05077800). Elraglusib is Actuate’s proprietary small molecule glycogen synthase kinase-3 beta (GSK-3β) inhibitor which is being developed for adults and children with advanced refractory cancers. This multicenter investigator-initiated study, which is receiving substantial support from the Lustgarten Foundation for Pancreatic Cancer Research, is being led by Colin D. Weekes MD at the Massachusetts General Hospital and will also enroll patients at the University of Washington, University of Colorado Denver, and Johns Hopkins University.

“Novel approaches for patients with advanced pancreatic cancer are urgently required,” said Dr Weekes. “The pre-clinical and clinical data being generated with elraglusib in a spectrum of cancers, including pancreatic cancer, is extremely encouraging and we are delighted to have initiated this study with elraglusib. Elraglusib is the first clinically relevant specific GSK-3β inhibitor that we can thoroughly investigate. In preclinical models, elraglusib has multiple biologic effects relevant to targeting pancreatic cancer including direct cytotoxicity, reversal of chemoresistance, reversal of pathologic fibrosis, and there is increasing evidence of its immune-modulatory activity. In our study, we are particularly focused on elraglusib’s potential to synergize with TGF-β suppression mediated by Losartan. This study builds on the work of our investigative teams demonstrating the roles of TGF-β and GSK-3β in acquired chemotherapy resistance. This study uniquely attempts to harness the mechanisms that pancreatic cancer utilizes to combat the effects of chemotherapy as an Achilles heel for therapeutic intent. We believe that a multi-pronged attack as represented by elraglusib plus Losartan is a potentially sophisticated approach to a complex, often lethal, situation. It is an honour to lead this multicenter collaboration with my clinical and pre-clinical colleagues across the US and Europe. We are very grateful for the critical support of this program by the Lustgarten Foundation.”

“At the Lustgarten Foundation, we understand time is everything for patients and their families,” said Andrew Rakeman, PhD, VP of Research. “Dr. Weekes’ study will help us understand and address a critical issue in pancreatic cancer treatment—acquired chemotherapy resistance. This trial builds on exciting observations from previous preclinical and clinical research. The Foundation established the Clinical Accelerator Initiative for projects like this; bringing more trials based on the best science to the clinic and expanding our understanding of pancreatic cancer biology and treatment. We believe Dr. Weekes’ trial and others like it have the potential to change the way we think about treating pancreatic cancer, ultimately transforming it into a curable disease.”

“We are honored and excited to collaborate with Dr. Weekes, his colleagues at world-leading cancer research centers, and the Lustgarten Foundation on this important trial, which will advance the development of elraglusib for treating patients with one of the most challenging types of cancer,” said Daniel Schmitt, Actuate’s President & CEO. “The results we have seen to date with elraglusib combined with chemotherapy in pancreatic cancer are very promising, and this Phase 2 trial in combination with FOLFIRINOX leverages significant positive preclinical and clinical experience for potentially better outcomes for patients.”

Based on positive data from a prior Phase 2 open-label single arm study of elraglusib plus gemcitabine/nab-paclitaxel, Actuate has also recently initiated an international randomized controlled study of elraglusib in combination with gemcitabine/nab-paclitaxel, in patients with advanced pancreatic cancer in the first-line setting (NCT03678883, EudraCT#:2018-003739-32). Actuate is also conducting studies in pediatric patients with refractory tumors in preparation for a neuroblastoma-specific clinical program (NCT04239092). Actuate is also collaborating with investigators at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital on a Phase 2 study focused on elraglusib combined with cytotoxic therapy for patients with advanced salivary gland carcinomas (NCT05010629).

About Actuate Therapeutics, Inc.
Actuate is a clinical stage pharmaceutical company focused on the development and commercialization of novel therapeutics for cancers and inflammatory diseases. For additional information, please visit the Company’s website at http://www.actuatetherapeutics.com.

///////////ELRAGLUSIB, WHO 11553, 9-ING-41, Orphan Drug

Cn1cc(C2=C(C(=O)NC2=O)c3coc4ccc(F)cc34)c5cc6OCOc6cc15

wdt-7

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Valemetostat tosilate


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

Valemetostat tosilate

バレメトスタットトシル酸塩

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

PMDA JAPAN approved 2022/9/26, Ezharmia

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

Antineoplastic, histone methyltransferase inhibitor

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

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

日本医薬品一般的名称(JAN)データベース

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

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

STR1
img

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

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

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

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

PATENT

WO 2015141616

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

PATENT

WO2022009911

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

[0043]

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

[0044]

[hua 6]

[0045]

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

[0046]

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

[0047]

[hua 7]

[0048]

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

[0049]

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

[0050]

[hua 8]

[0051]

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

[0052]

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

[0053]

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

[0054]

[Chemical 9]

[0055]

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

[0056]

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

[0057]

[Chemical 10]

[0058]

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

[0059]

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

[0060]

[Chemical 11]

[0061]

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

[0062]

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

[0063]

[Chemical 12]

[0064]

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

[0065]

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

[0066]

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

[0067]

[Chemical 13]

[0068]

[Table 1]

[0069]

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

[0070]

[Table 2]

[0071]

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

[0072]

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

[0073]

[table 3]

[0074]

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

[0075]

[Chemical 14]

[0076]

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

[0077]

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

[0078]

[Chemical 15]

[0079]

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

[0080]

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

[0081]

[Chemical 16]

[0082]

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

[0083]

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

[0084]

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

[0085]

[Chemical 17]

[0086]

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

[0087]

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

[0088]

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

[0089]

[Chemical 18]

[0090]

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

[0091]

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

[0092]

[Chemical 19]

[0093]

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

[0094]

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

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///////Valemetostat tosilate, japan 2022, approvals 2022, Ezharmia, バレメトスタットトシル酸塩 , DS-3201, DS 3201, DS3201, DS-3201b, Orphan Drug

CN(C)[C@@H]1CC[C@H](CC1)[C@]2(C)Oc3c(C)c(cc(Cl)c3O2)C(=O)NCC4=C(C)C=C(C)NC4=O

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Danavorexton, TAK 925


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Danavorexton Structure.svg

Danavorexton,  TAK 925

2114324-48-8

  • Molecular FormulaC21H32N2O5S
  • Average mass424.554 Da

1-Piperidinecarboxylic acid, 3-[(methylsulfonyl)amino]-2-[[(cis-4-phenylcyclohexyl)oxy]methyl]-, methyl ester, (2R,3S)-

Methyl (2R,3S)-3-[(methylsulfonyl)amino]-2-[[(cis-4-phenylcyclohexyl)oxy]methyl]-1-piperidinecarboxylate

  • OriginatorTakeda
  • ClassCyclohexanes; Esters; Ethers; Piperidines; Sleep disorder therapies; Small molecules; Sulfonamides
  • Mechanism of ActionOrexin receptor type 2 agonists
  • Orphan Drug StatusYes – Narcolepsy
  • Phase IHypersomnia; Narcolepsy; Respiration disorders; Sleep apnoea syndrome
  • 01 Jun 2022Takeda Pharmaceuticals completes a phase I clinical trials in Respiratory disorder (In adults) in Netherlands (IV) (ISRCTN63027076)
  • 02 Apr 2022Efficacy and safety data from phase a Ib trial in Hypersomnia presented at the 74th Annual Meeting of the American Academy of Neurology 2022 (AAN-2022)
  • 10 Mar 2022Phase-I clinical trials in Sleep apnoea syndrome in Australia (IV) (NCT05180890)

Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist.[1] It is a small-molecule compound and is administered intravenously.[1][2] The compound was found to dose-dependently produce wakefulness to a similar degree as modafinil in a phase 1 clinical trial.[1][3] As of March 2021, danavorexton is under development for the treatment of narcolepsyidiopathic hypersomnia, and sleep apnea.[2][1][4] It is related to another orexin receptor agonist known as TAK-994, the development of which was discontinued for safety reasons in October 2021.[1][5]

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00626

TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16], was identified through the optimization of compound 2, which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

aReagents and conditions: (a) chiral column separation; (b) RCOCl, Et3N, THF, rt (for 15 and 16); (c) ethyl chlorocarbonate, DIEA, THF, rt (for 17); (d) isocyanatoethane, Et3N, THF, 0 °C−rt (for 18).

Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (16) To a mixture of 14 (58 mg, 0.16 mmol) and Et3N (0.044 mL, 0.32 mmol) in THF (3 mL) was added methyl chlorocarbonate (0.024 mL, 0.32 mmol) at rt. The mixture was stirred at rt overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc, 1:1 to 0:100) to give 16 (64 mg, 0.15 mmol, 95%) as a colorless oil. Crystallization of 16 (1.8 g, 4.1 mmol) from EtOH-H2O gave 16 (1.7 g, 3.9 mmol, 95%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 1.40−1.55 (5H, m), 1.56−1.73 (5H, m), 1.87 (1H, brd, J = 13.2 Hz), 1.96 (1H, brd, J = 13.6 Hz), 2.44−2.57 (1H, m), 2.83 (1H, brs), 2.95 (3H, s), 3.40 (1H, brs), 3.53−3.62 (5H, m), 3.73 (1H, brt, J = 9.7 Hz), 3.84 (1H, brs), 4.47 (1H, brs), 7.15 (1H, brt, J = 7.2 Hz), 7.18 (1H, brs), 7.19 (2H, brd, J = 8.1 Hz), 7.27 (2H, brt, J = 7.4 Hz). 13C NMR (151 MHz, DMSO-d6, the minor rotamer’s signals are marked with an asterisk) δ24.05, 24.39*, 26.00, 26.17*, 27.60*, 27.79, 28.68, 30.15*, 37.54, 38.13*, 39.91, 42.99, 51.01, 52.07, 53.90*, 54.49, 61.48, 61.89*, 71.68, 125.68, 126.51, 128.14, 147.34, 155.27*, 156.08. MS (ESI/APCI) mass calculated for [M + H]+ (C21H33N2O5S) requires m/z 424.6, found m/z 425.2. mp 113 °C. Anal. Calcd for C21H32N2O5S: C, 59.41; H, 7.60; N, 6.60. Found: C, 59.45; H, 7.59; N, 6.55. [α] 20 D +16.3 (c 0.1, CHCl3

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Clinical data
Other namesTAK-925
Routes of
administration
Intravenous[1][2]
Drug classOrexin receptor agonist
Identifiers
showIUPAC name
CAS Number2114324-48-8
PubChem CID130310079
ChemSpider68011464
UNII1QMD83K4YN
ChEMBLChEMBL4650341
Chemical and physical data
FormulaC21H32N2O5S
Molar mass424.56 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

References

  1. Jump up to:a b c d e f Jacobson LH, Hoyer D, de Lecea L (January 2022). “Hypocretins (orexins): The ultimate translational neuropeptides”. J Intern Meddoi:10.1111/joim.13406PMID 35043499.
  2. Jump up to:a b c “Danavorexton – Takeda”Adis Insight. Springer Nature Switzerland AG. Retrieved 7 March 2021.
  3. ^ Evans, R., Hazel, J., Faessel, H., Wu, J., Hang, Y., Alexander, R., … & Hartman, D. (2019). Results of a phase 1, 4-period crossover, placebo-controlled, randomized, single dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-925, a novel orexin 2 receptor agonist, in sleep-deprived healthy adults, utilizing modafinil as an active comparator. Sleep Medicine, 64, S106. https://scholar.google.com/scholar?cluster=10933819770107034612
  4. ^ Evans R, Tanaka S, Tanaka S, Touno S, Shimizu K, Sakui S, et al. (December 2019). “A Phase 1 single ascending dose study of a novel orexin 2 receptor agonist, TAK-925, in healthy volunteers (HV) and subjects with narcolepsy type 1 (NT1) to assess safety, tolerability, pharmacokinetics, and pharmacodynamic outcomes”. Sleep Medicine64: S105–S106. doi:10.1016/j.sleep.2019.11.290.
  5. ^ Tong A (6 October 2021). “Takeda flashes red light on ‘breakthrough’ narcolepsy drug after PhII trials turned up mysterious safety signal”Endpoints News.

External links

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Darinaparsin


69819-86-9.png
img
2D chemical structure of 69819-86-9
SVG Image
IUPAC CondensedH-gGlu-Cys(Unk)-Gly-OH
SequenceXXG

Darinaparsin

ダリナパルシン , Darvias

JAPAN 2022 APPROVED, PMDA 2022/6/20

(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-dimethylarsanylsulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid

(S)-2-amino-5-(((R)-1-((carboxymethyl)amino)-3-((dimethylarsino)thio)-1-oxopropan-2-yl)amino)-5-oxopentanoic acid

Glycine, L-gamma-glutaMyl-S-(diMethylarsino)-L-cysteinyl-

FormulaC12H22AsN3O6S
CAS69819-86-9
Mol weight411.3062
EfficacyAntineoplastic
Commentorganic arsenical

Zinapar, ZIO-101, DMAs(III)G, clarinaparsinUNII-9XX54M675GSP-02L

  • OriginatorTexas A&M University; University of Texas M. D. Anderson Cancer Center
  • DeveloperSolasia Pharma; ZIOPHARM Oncology
  • ClassAmines; Antineoplastics; Arsenicals; Oligopeptides; Pentanoic acids; Small molecules; Sulfides
  • Mechanism of ActionApoptosis stimulants; Cell cycle inhibitors; Reactive oxygen species stimulants
  • Orphan Drug StatusYes – Peripheral T-cell lymphoma
  • PreregistrationPeripheral T-cell lymphoma
  • DiscontinuedLiver cancer; Lymphoma; Multiple myeloma; Non-Hodgkin’s lymphoma; Solid tumours
  • 28 Mar 2022No recent reports of development identified for phase-I development in Peripheral-T-cell-lymphoma in China (IV, Injection)
  • 26 Jan 2022ZIOPHARM Oncology is now called Alaunos Therapeutics
  • 11 Dec 2021Safety and efficacy data from a phase II trial in Peripheral T-cell lymphoma presented at the 63rd American Society of Hematology Annual Meeting and Exposition (ASH-2021)

Darinaparsin is a small-molecule organic arsenical with potential antineoplastic activity. Although the exact mechanism of action is unclear, darinaparsin, a highly toxic metabolic intermediate of inorganic arsenicals (iAs) that occurs in vivo, appears to generate volatile cytotoxic arsenic compounds when glutathione (GSH) concentrations are low. The arsenic compounds generated from darinaparsin disrupt mitochondrial bioenergetics, producing reactive oxygen species (ROS) and inducing ROS-mediated tumor cell apoptosis; in addition, this agent or its byproducts may initiate cell death by interrupting the G2/M phase of the cell cycle and may exhibit antiangiogenic effects. Compared to inorganic arsenic compounds such as arsenic trioxide (As2O3), darinaparsin appears to exhibit a wide therapeutic window.

Darinaparsin, also know as ZIO-101 and SP-02, is a small-molecule organic arsenical with potential antineoplastic activity. Although the exact mechanism of action is unclear, darinaparsin, a highly toxic metabolic intermediate of inorganic arsenicals (iAs) that occurs in vivo, appears to generate volatile cytotoxic arsenic compounds when glutathione (GSH) concentrations are low. The arsenic compounds generated from darinaparsin disrupt mitochondrial bioenergetics, producing reactive oxygen species (ROS) and inducing ROS-mediated tumor cell apoptosis; in addition, this agent or its byproducts may initiate cell death by interrupting the G2/M phase of the cell cycle and may exhibit antiangiogenic effects.

Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and is being investigated for antitumor properties in vitro and in vivo. While other arsenicals, including arsenic trioxide, have been used clinically, none have shown significant activity in malignancies outside of acute promyelocytic leukemia. Darinaparsin has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models. Here, we review the literature describing the signaling pathways and mechanisms of action of darinaparsin and compare them to mechanisms of cell death induced by arsenic trioxide. Darinaparsin has overlapping, but distinct, signaling mechanisms. We also review the current results of clinical trials with darinaparsin (both intravenous and oral formulations) that demonstrate significant antitumor activity.

PAPER

 Biochemical Pharmacology (Amsterdam, Netherlands), 126, 79-86; 2017

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PATENT

WO 2015085208

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015085208

Preparation of Darinaparsin

[0071] Sterile water (15.5 L) and ethyl alcohol (200 proof, 15.5 L) were charged in a reaction flask prior to the addition of L-glutathione (3.10 kg). While being stirred, the reaction mixture was cooled to 0-5 °C prior to the addition of triethylamine (1.71 L). Stirring was continued until most of the solids were dissolved and the solution was filtered. After filtration, the reaction mixture was cooled to 0-5 °C prior to the addition of chlorodimethylarsine (1.89 kg) over 115 minutes while maintaining the temperature at 0-5 °C. Stirring continued at 0-5 °C for 4 hours before acetone (30.6 L) was added over 54 minutes while maintaining the temperature at 0-5 °C. The suspension was stored at 0-5°C overnight prior to filtration. The solid was collected in a filter funnel, washed successively with ethyl alcohol (200 proof, 13.5 L) and acetone (13.5 L) and dried in suction for 23 minutes. A second similar run was performed and the collected solids from both runs were combined. Ethyl alcohol (200 proof, 124 L) and the combined solids (11.08 kg) were charged in a vessel. The slurry was stirred at ambient temperature for 2 hours before filtration, washing successively with ethyl alcohol (200 proof, 27 L) and acetone (27 L) and dried in suction for 60 minutes. The resulting solid was transferred to drying trays and dried in a vacuum oven at ambient temperature for 66 hours to provide darinaparsin as a solid with the differential scanning calorimetry (DSC) thermogram of Figure 1, with an extrapolated onset temperature at about 191.36° C and a peak temperature at about 195.65° C.

PATENT

WO 2010021928

Step 1

Dimethylchloroarsine. Dimethylarsinic acid, (CH3)2As(O)OH was supplied by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was accompanied by a statement of its purity and was supplied as 99.7% pure. The dimethylarsinic acid was dissolved in water-hydrochloric acid to pH 3. A stream of sulfur dioxide was passed through this solution for about one hour. Dimethylchloroarsine separated as a heavy, colorless oil. The two liquid phases, water/(CH3)2AsCl were separated using a separatory funnel. The chlorodimethylarsine was extracted into diethylether and the ether solution was dried over anhydrous sodium sulfate. The dried solution was transferred to a distillation flask which was heated slowly to evaporate the ether. The remaining liquid, dimethylchloroarsine was purified by distillation. The fraction boiling at 106-109°C was collected. The product, a colorless oil. 1H NMR resonance at 1.65 ppm.

Step 2

SGLU-1: Glutathione (14.0 g, 45.6 mmol) was stirred rapidly in glyme while dimethylchoroarsine (6.5 g, 45.6 mmol) was added dropwise. Pyridine (6.9 g, 91.2 mmol) was then added to the slurry and the mixture was subsequently heated to reflux. The heat was removed immediately and the mixture stirred at room temperature for 4 h. Isolation of the resultant insoluble solid and recrystallization from ethanol afforded 4 as the pyridine hydrochloride complex (75% yield). mp 115-118°C; NMR (D20) δ1.35 (s, 6H), 1.9-4.1 (m’s, 10H), 7.8-9.0 (m, 5H); mass spectrum (m/e) 140, 125, 110, 105, 79, 52, 45, 36.

PATENT

WO 2009075870

Step 1

Example 1. Preparation of Dimethylchloroarsine (DMCA). A 3-neck round-bottom flask (500 mL) equipped with mechanical stirrer, inlet for nitrogen, thermometer, and an ice bath was charged with cacodylic acid (33 g, 0.23 mol) and cone. hydrochloric acid (67 mL). In a separate flask, a solution of SnCl2·2H2O (54 g, 0.239 mol) in cone. hydrochloric acid (10 mL) was prepared. The SnCl2·2 H2O solution was added to the cacodylic acid in HCl solution under nitrogen while maintaining the temperature between 5 °C and 10 °C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was transferred to a separatory funnel and the upper layer (organic) collected. The bottom layer was extracted with dichloromethane (DCM) (2 × 25 mL). The combined organic extract was washed with 1 N HCl (2 × 10 mL) and water (2 × 20 mL). The organic extract was dried over MgSO4 and DCM was removed by rotary evaporation (bath temperature 80 °C, under nitrogen, atmospheric pressure). The residue was further distilled under nitrogen. Two tractions of DMCA were collected. The first fraction contained some DCM and the second fraction was of suitable quality (8.5 g, 26% yield). The GC analysis confirmed the identity and purity of the product.

Step 2

Example 3. Preparation of S-Dimethylarsinoglutathione (SGLU-1). In a 3 L three-neck flask equipped with a mechanic stirrer, dropping funnel and thermometer under an inert atmosphere was prepared a suspension of glutathione (114.5 g, 0.37 mol) in a 1:1 (v/v) mixture of water/ethanol (1140 mL) and cooled to below 5 °C. The mixture was treated slowly (over 15 min) with triethylamine (63.6 mL, 0.46 mol) while maintaining the temperature below 20 °C. The mixture was cooled to 4 °C and stirred for 15 min and then the traces of undissolved material removed by filtration. The filtrate was transferred in a clean 3 L three-neck flask equipped with a mechanic stirrer, dropping funnel, nitrogen inlet, and thermometer and DMCA (70 g, 0.49 mol) (lot # 543-07-01-44) was added slowly while maintaining the temperature at 3-4°C. The reaction mixture was stirred at 1-4°C for 4 h, and acetone (1.2 L) was added over a period of 1 h. The mixture was stirred for 90 min between 2 and 3°C and the resulting solid was isolated by filtration. The product was washed with ethanol (2 × 250 mL) and acetone (2 × 250 mL) and the wet solids were suspended in ethanol 200 Proof (2000 mL). The product was isolated by filtration, washed with ethanol (2 × 250 mL) and acetone (2 × 250 mL) and dried in vacuum for 2 days at RT to give 115 g (75%) of SGLU-1, HPLC purity > 99.5% (in process testing).

PATENT

WO 2007027344

Example 2 Preparation of S-Dimethylarsinoglutathione A 5 L, three necked round bottom flask was equipped with a mechanical stirrer assembly, thermometer, addition funnel, nitrogen inlet, and a drying tube was placed in a cooling bath. A polyethylene crock was charged with glutathione-reduced (200 g) and deionized water (2 L) and stirred under a nitrogen atmosphere to dissolve all solids. The mixture was filtered to remove any insoluble material and the filtrate was transferred to the 5 L flask. While stirring, ethanol, 200 proof (2 L) was added and the clear solution was cooled to 0-5° C. using an ice/methanol bath. Pyridine (120 g) was added followed by a dropwise addition of Me2AsCl (120 g) over a minimum of 1 hour. The reaction mixture was stirred at 0-5° C. for a minimum of 2 hours prior to removal of the cooling bath and allowing the mixture to warm to room temperature under a nitrogen atmosphere with stirring. The reaction mixture was stirred overnight (>15 hrs) at room temperature under a nitrogen atmosphere at which time a white solid may precipitate. The reaction mixture was concentrated to a slurry (liquid and solid) at 35-45° C. using oil pump vacuum to provide a white solid residue. As much water as possible is removed, followed by two coevaporations with ethanol to azeotrope the last traces of water. The white solid residue was slurried in ethanol, 200 pf. (5 L) under a nitrogen atmosphere at room temperature overnight. The white solid was filtered and washed with ethanol, 200 pf. (2×500 mL) followed by acetone, ACS (2×500 mL). The resulting solid was transferred to drying trays and vacuum oven dried overnight at 25-35° C. using oil pump vacuum to provide pyridinium hydrochloride-free S-dimethylarsinoglutathione as a white solid. melting point of 189-190° C.

PATENT

WO 20060128682

Step 1

Dimethylchloroarsine. Dimethylarsinic acid, (CH3)2As(O)OH was supplied by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was accompanied by a statement of its purity and was supplied as 99.7% pure. The dimethylarsinic acid was dissolved in water-hydrochloric acid to pH 3. A stream of sulfur dioxide was passed through this solution for about one hour. Dimethylchloroarsine separated as a heavy, colorless oil. The two liquid phases, water/(CH3)2AsCl were separated using a separatory funnel. The chlorodimethylarsine was extracted into diethylether and the ether solution was dried over anhydrous sodium sulfate. The dried solution was transferred to a distillation flask which was heated slowly to evaporate the ether. The remaining liquid, dimethylchloroarsine was purified by distillation. The fraction boiling at 106-109° C. was collected. The product, a colorless oil. 1H NMR resonance at 1.65 ppm.

Step 2

Pyridine Hydrochloride Free Synthesis of S-Dimethylarsinoglutathione (GLU) Dimethylarsinoglutathione is made using an adapted of Chen (Chen, G. C., et al. Carbohydrate Res. (1976) 50: 53-62) the contents of which are hereby incorporated by reference in their entirety. Briefly, dithiobis(dimethylarsinoglutamine) is dissolved in dichloromethane under nitrogen. Tetramethyldiarsine is added dropwise to the solution and the reaction is stirred overnight at room temperature under nitrogen and then exposed to air for 1 h. The mixture is then evaporated to dryness and the residue is washed with water and dried to give a crude solid that is recrystallized from methanol to give S-dimethylarsinoglutathione.

//////////

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Solasia Announces Submission of New Drug Application for Anti-cancer Drug DARINAPARSIN for Peripheral T-Cell Lymphoma in Japan

Solasia Pharma K.K. (TSE: 4597, Headquarters: Tokyo, Japan, President & CEO: Yoshihiro Arai, hereinafter “Solasia”) today announced submission of a New Drug Application (NDA) for its new anti-cancer drug darinaparsin (generic name, development code: SP-02) as a treatment for relapsed or refractory peripheral T-cell lymphoma to the Ministry of Health, Labour and Welfare (MHLW). Based on positive results of R&D on darinaparsin, centered primarily on the results of the Asian Multinational Phase 2 Study (study results released in June 2020), Solasia filed an NDA for the drug with the regulatory authority in Japan ahead of anywhere else in the world.

Solasia expects to obtain regulatory approval in 2022 and to also launch in the same year. If approved and launched, darinaparsin would be the third drug Solasia successfully developed and brought to market since its founding and is expected to contribute to the treatment of PTCL.

Mr. Yoshihiro Arai, President and CEO of Solasia, commented as follows:
“No standard treatment has been established for relapsed or refractory PTCL as of yet. I firmly believe that darinaparsin, with its novel mechanism of action that differs from those of already approved drugs, will contribute to patients and healthcare providers at clinical sites as a new treatment option for relapsed or refractory PTCL. Since founding, Solasia has conducted R&D on five pipeline drugs. Of the five, we have successfully developed and brought to market two drugs, i.e., began providing them to patients, and today, we submitted an NDA for our first anti-cancer drug. Under our mission to provide patients with ‘Better Medicine for a Brighter Tomorrow’, we will continue aiming to contribute to patients’ treatment and enhanced quality of life. ”

About darinaparsin (SP-02)
Darinaparsin, an organoarsenic compound with anticancer activity, is a novel mitochondrial-targeted agent being developed for the treatment of various hematologic and solid tumors. The proposed mechanism of action of the drug involves the disruption of mitochondrial function, increased production of reactive oxygen species, and modulation of intracellular signal transduction pathways. Darinaparsin is believed to exert anticancer effect by inducing cell cycle arrest and apoptosis. Darinaparsin has been granted orphan drug designation in the US and EU.
For more information, please visit at https://solasia.co.jp/en/pipeline/sp-02.html

About Asian Multinational Phase 2 Study
The Asian Multinational Phase 2 Study was a multinational, multicenter, single-arm, open-label, non-randomized study to evaluate the efficacy and safety of darinaparsin monotherapy in patients with relapsed or refractory PTCL conducted in Japan, Korea, Taiwan, and Hong Kong. (CT.gov Identifier: NCT02653976).
Solasia plans to present the results of the study at an international academic conference to be held in the near future.

About peripheral T-cell lymphoma (PTCL)
Please visit at https://solasia.co.jp/en/pipeline/sp-02.html

About Solasia
Please visit at https://solasia.co.jp/en/

/////////////Darinaparsin, Darvias, JAPAN 2022,  APPROVALS 2022, PMDA, ダリナパルシン  , Zinapar, ZIO-101, DMAs(III)G, clarinaparsinUNII-9XX54M675GSP-02LOrphan Drug

C[As](C)SCC(C(=O)NCC(=O)O)NC(=O)CCC(C(=O)O)N

Olipudase alfa


HPLSPQGHPA RLHRIVPRLR DVFGWGNLTC PICKGLFTAI NLGLKKEPNV ARVGSVAIKL
CNLLKIAPPA VCQSIVHLFE DDMVEVWRRS VLSPSEACGL LLGSTCGHWD IFSSWNISLP
TVPKPPPKPP SPPAPGAPVS RILFLTDLHW DHDYLEGTDP DCADPLCCRR GSGLPPASRP
GAGYWGEYSK CDLPLRTLES LLSGLGPAGP FDMVYWTGDI PAHDVWHQTR QDQLRALTTV
TALVRKFLGP VPVYPAVGNH ESTPVNSFPP PFIEGNHSSR WLYEAMAKAW EPWLPAEALR
TLRIGGFYAL SPYPGLRLIS LNMNFCSREN FWLLINSTDP AGQLQWLVGE LQAAEDRGDK
VHIIGHIPPG HCLKSWSWNY YRIVARYENT LAAQFFGHTH VDEFEVFYDE ETLSRPLAVA
FLAPSATTYI GLNPGYRVYQ IDGNYSGSSH VVLDHETYIL NLTQANIPGA IPHWQLLYRA
RETYGLPNTL PTAWHNLVYR MRGDMQLFQT FWFLYHKGHP PSEPCGTPCR LATLCAQLSA
RADSPALCRH LMPDGSLPEA QSLWPRPLFC
(Disulfide bridge: 43-119, 46-111, 74-85, 175-180, 181-204, 339-385, 538-542, 548-561)

Olipudase alfa

Xenpozyme, Japan 2022, APPROVALS 2022, 2022/3/28

PEPTIDE, オリプダーゼアルファ (遺伝子組換え)

Alternative Names: Acid sphingomyelinase Niemann Pick disease type B – Sanofi; Acid-sphingomyelinase – Sanofi; GZ-402665; Recombinant human acid sphingomyelinase – Sanofi; rhASM – Sanofi; Sphingomyelinase-C (synthetic human) – Sanofi; Synthetic human sphingomyelinase-C – Sanofi; Xenpozyme

FormulaC2900H4373N783O791S24
CAS927883-84-9
Mol weight63631.0831
EfficacyLysosomal storage disease treatment, Enzyme replacement (acid sphingomyelinase)
CommentEnzyme replacement therapy product
Treatment of Niemann-Pick disease type A/B
  • OriginatorGenzyme Corporation
  • DeveloperSanofi
  • ClassRecombinant proteins; Sphingomyelin phosphodiesterases
  • Mechanism of ActionSphingomyelin-phosphodiesterase replacements
  • Orphan Drug StatusYes – Niemann-Pick diseases
  • RegisteredNiemann-Pick diseases
  • 28 Mar 2022Registered for Niemann-Pick diseases (In adolescents, In children, In adults) in Japan (IV) – First global approval
  • 09 Feb 2022FDA assigns PDUFA action date of (03/07/2022) for Olipudase alfa (In children, In adults) for Niemann-Pick diseases
  • 09 Feb 2022Adverse e

//////////

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Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

https://www.empr.com/home/mpr-first-report/worldsymposium-2021/olipudase-alfa-chronic-visceral-acid-sphingomyelinase-efficacy/embed/#?secret=x9Jl0tjBl4#?secret=4RmoWVLWaQ

Olipudase alfa was associated with significant improvements in clinically relevant disease end points among patients with chronic visceral acid sphingomyelinase (ASM) deficiency (ASMD), according to results from the phase 2/3 ASCEND trial presented at the 17th Annual WORLDSymposium.

ASMD is a rare, debilitating lysosomal storage disease characterized by a deficiency of the enzyme acid sphingomyelinase, which results in the accumulation of sphingomyelin in various tissues of the body. Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM.

The multicenter, randomized, double-blind, placebo-controlled ASCEND trial evaluated the efficacy and safety of olipudase alfa in 36 adults with chronic visceral ASMD. Patients were randomly assigned 1:1 to receive olipudase alfa 3mg/kg intravenously every 2 weeks or placebo for 52 weeks. The coprimary end points were the percent change in spleen volume and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO).

At week 52, treatment with olipudase alfa resulted in a 39.45% reduction in spleen volume, compared with a 0.5% increase for placebo (P <.0001). A decrease in spleen volume of at least 30% was observed in 17 patients (94%) treated with olipudase afla compared with no patients treated with placebo. Additionally, olipudase alfa significantly improved lung function by 22% from baseline compared with 3% for patients receiving placebo (P =.0004), as measured by percent predicted DLCO.

Olipudase alfa also met key secondary end points including a 31.7% reduction in liver volume (vs a 1.4% reduction for placebo; P <.0001) and a 16.8% improvement in mean platelet counts (vs 2.5% with placebo; P =.019) at week 52. Significant improvements in HDL, LDL, AST, ALT, chitotriosidase (54% vs 12% with placebo; P =.0003), and lyso-sphingomyelin (78% vs 6% with placebo) were also observed in the olipudase alfa group at week 52.

With regard to Splenomegaly Related Score, a patient-reported outcome measurement that evaluates patient symptoms associated with an enlarged spleen, findings showed no meaningful difference between olipudase alfa and placebo (-8 point vs -9.3 points, respectively).

As for safety, olipudase alfa was well tolerated with most adverse events being mild to moderate in severity. There were no treatment-related serious adverse events and no adverse event-related discontinuations.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Wasserstein M, Arash-Kaps L, Barbato A, et al. Adults with chronic acid sphingomyelinase deficiency show significant visceral, pulmonary, and hematologic improvements after enzyme replacement therapy with olipudase-alfa: 1-year results of the ASCEND placebo-controlled trial. Presented at: 17th Annual WORLDSymposium; February 8-12, 2021. Abstract 265.

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https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-06-14-00-00-2346501

EMA accepts regulatory submission for olipudase alfa, the first potential therapy for ASMD

  • Olipudase alfa has been granted PRIority MEdicines (PRIME) designation in Europe, Breakthrough Therapy designation in the United States, and SAKIGAKE designation in Japan
  • European regulatory decision anticipated second half of 2022

DECEMBER 6, 2021

The European Medicines Agency (EMA) has accepted for review under an accelerated assessment procedure the Marketing Authorization Application (MAA) for olipudase alfa, Sanofi’s investigational enzyme replacement therapy which is being evaluated for the treatment of acid sphingomyelinase deficiency (ASMD). Historically referred to as Niemann-Pick disease (NPD) type A and type B, ASMD is a rare, progressive, and potentially life-threatening disease for which no treatments are currently approved. The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan. If approved, olipudase alfa will become the first and only therapy for the treatment of ASMD.

Today’s milestone has been decades in the making and our gratitude goes to the ASMD community who has stood by us with endless patience while olipudase alfa advanced through clinical development,” said Alaa Hamed, MD, MPH, MBA, Global Head of Medical Affairs, Rare Diseases, Sanofi. “Olipudase alfa represents the kind of potentially life-changing innovation that is possible when industry, medical professionals and the patient community work together toward a common goal.”

The MAA is based on positive results from two separate clinical trials (ASCEND and ASCEND-Peds) evaluating olipudase alfa in adult and pediatric patients with non-central nervous system (CNS) manifestations of ASMD type A/B and ASMD type B.

Olipudase alfa has received special designations from regulatory agencies worldwide, recognizing the innovation potential of the investigational therapy.

“Scientific innovation is the greatest source of hope for people living with diseases like ASMD where there are no approved treatments and is a critical component for ensuring a viable healthcare ecosystem,” said Bill Sibold, Executive Vice President of Sanofi GenzymeAt Sanofi, we have a long history of pioneering scientific innovation, and we remain committed to finding solutions to address unmet medical needs, including those of the rare disease community.”

The EMA awarded olipudase alfa the PRIority MEdicines designation, also known as PRIME, intended to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to olipudase alfa. This designation is intended to expedite the development and review of drugs intended to treat serious or life-threatening diseases and conditions. The criteria for granting Breakthrough Therapy designation include preliminary clinical evidence indicating that the molecule may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

In Japan, olipudase alfa was awarded the SAKIGAKE designation, which is intended to promote research and development in Japan for innovative new medical products that satisfy certain criteria, such as the severity of the intended indication. In September, Sanofi filed the J-NDA submission for olipudase alfa.

About ASMD

ASMD results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to disease-causing variants in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan.

ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum sometimes referred to as ASMD type A and ASMD type B. ASMD type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to central nervous system complications. ASMD type B is a serious and potentially life-threatening disease that predominantly impacts the lungs, liver, and spleen, as well as other organs. ASMD type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Patients with ASMD type A/B or ASMD type B were studied in the ASCEND trial program. Another type of NPD is NPD type C, which is unrelated to ASMD.

About olipudase alfa

Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat non-CNS manifestations of ASMD. Olipudase alfa has not been studied in ASMD type A patients. Olipudase alfa is an investigational agent and the safety and efficacy have not been evaluated by the FDA, EMA, or any other regulatory authority worldwide.

About Sanofi

Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.

With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.

///////Olipudase alfa,  japan 2022, APPROVALS 2022, Xenpozyme, PEPTIDE, オリプダーゼアルファ (遺伝子組換え) , ORPHAN DRUG, GZ-402665 , GZ 402665

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Efgartigimod alfa-fcab


DKTHTCPPCP APELLGGPSV FLFPPKPKDT LYITREPEVT CVVVDVSHED PEVKFNWYVD
GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK
GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS
DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALKFHYTQKS LSLSPGK
(Disulfide bridge: 6-6′, 9-9′, 41-101, 147-205, 41′-101′, 147′-205′)

Efgartigimod alfa-fcab

FormulaC2310H3554N602O692S14
CAS1821402-21-4
Mol weight51279.464

US FDA APPROVED 12/17/2021, To treat generalized myasthenia gravis
Press ReleaseVyvgart BLA 761195

エフガルチギモドアルファ (遺伝子組換え)

PEPTIDE

Treatment of IgG-driven autoimmune diseases

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https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis

FDA Approves New Treatment for Myasthenia Gravis

Approval is the First of a New Class of Medication for this Rare, Chronic, Autoimmune, Neuromuscular DiseaseFor Immediate Release:December 17, 2021

The U.S. Food and Drug Administration today approved Vyvgart (efgartigimod) for the treatment of generalized myasthenia gravis (gMG) in adults who test positive for the anti-acetylcholine receptor (AChR) antibody.

Myasthenia gravis is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles (also called voluntary muscles) that worsens after periods of activity and improves after periods of rest. Myasthenia gravis affects voluntary muscles, especially those that are responsible for controlling the eyes, face, mouth, throat, and limbs. In myasthenia gravis, the immune system produces AChR antibodies that interfere with communication between nerves and muscles, resulting in weakness. Severe attacks of weakness can cause breathing and swallowing problems that can be life-threatening.

“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases.”

Vyvgart is the first approval of a new class of medication. It is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing FcRn from recycling immunoglobulin G (IgG) back into the blood. The medication causes a reduction in overall levels of IgG, including the abnormal AChR antibodies that are present in myasthenia gravis.

The safety and efficacy of Vyvgart were evaluated in a 26-week clinical study of 167 patients with myasthenia gravis who were randomized to receive either Vyvgart or placebo. The study showed that more patients with myasthenia gravis with antibodies responded to treatment during the first cycle of Vyvgart (68%) compared to those who received placebo (30%) on a measure that assesses the impact of myasthenia gravis on daily function. More patients receiving Vyvgart also demonstrated response on a measure of muscle weakness compared to placebo.

The most common side effects associated with the use of Vyvgart include respiratory tract infections, headache, and urinary tract infections. As Vyvgart causes a reduction in IgG levels, the risk of infections may increase. Hypersensitivity reactions such as eyelid swelling, shortness of breath, and rash have occurred. If a hypersensitivity reaction occurs, discontinue the infusion and institute appropriate therapy. Patients using Vyvgart should monitor for signs and symptoms of infections during treatment. Health care professionals should administer appropriate treatment and consider delaying administration of Vyvgart to patients with an active infection until the infection is resolved.

The FDA granted this application Fast Track and Orphan Drug designations. The FDA granted the approval of Vyvgart to argenx BV.

///////////efgartigimod alfa-fcab, Vyvgart, FDA 2021,APPROVALS 2021, myasthenia gravis, argenx BV, Fast Track,  Orphan Drug, PEPTIDE,

エフガルチギモドアルファ (遺伝子組換え)
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Vosoritide


PGQEHPNARK YKGANKKGLS KGCFGLKLDR IGSMSGLGC
(Disulfide bridge: 23-39)
ChemSpider 2D Image | vosoritide | C176H290N56O51S3
Vosoritide.png
SVG Image

H-Pro-Gly-Gln-Glu-His-Pro-Asn-Ala-Arg-Lys-Tyr-Lys-Gly-Ala-Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys(1)-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys(1)-OH

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
H-PGQEHPNARKYKGANKKGLSKGC(1)FGLKLDRIGSMSGLGC(1)-OH

PEPTIDE1{P.G.Q.E.H.P.N.A.R.K.Y.K.G.A.N.K.K.G.L.S.K.G.C.F.G.L.K.L.D.R.I.G.S.M.S.G.L.G.C}$PEPTIDE1,PEPTIDE1,23:R3-39:R3$$$

L-prolyl-glycyl-L-glutaminyl-L-alpha-glutamyl-L-histidyl-L-prolyl-L-asparagyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysyl-glycyl-L-alanyl-L-asparagyl-L-lysyl-L-lysyl-glycyl-L-leucyl-L-seryl-L-lysyl-glycyl-L-cysteinyl-L-phenylalanyl-glycyl-L-leucyl-L-lysyl-L-leucyl-L-alpha-aspartyl-L-arginyl-L-isoleucyl-glycyl-L-seryl-L-methionyl-L-seryl-glycyl-L-leucyl-glycyl-L-cysteine (23->39)-disulfide

(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-5-oxo-2-[[2-[[(2S)-pyrrolidine-2-carbonyl]amino]acetyl]amino]pentanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]acetyl]amino]-40-(4-aminobutyl)-49-benzyl-28-[(2S)-butan-2-yl]-31-(3-carbamimidamidopropyl)-34-(carboxymethyl)-16,22-bis(hydroxymethyl)-10,37,43-tris(2-methylpropyl)-19-(2-methylsulfanylethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecazacyclotripentacontane-4-carboxylic acid

Vosoritide

Formula C176H290N56O51S3
CAS 1480724-61-5
Mol weight 4102.7254

1480724-61-5[RN]BMN 111L-Cysteine, L-prolylglycyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-, cyclic (23→39)-disulfideL-prolylglycyl-(human C-type natriuretic peptide-(17-53)-peptide (CNP-37)), cyclic-(23-39)-disulfideUNII:7SE5582Q2Pвосоритид [Russian] [INN]فوسوريتيد [Arabic] [INN]伏索利肽 [Chinese] [INN]

Voxzogo, 2021/8/26 EU APPROVED

Product details
Name Voxzogo
Agency product number EMEA/H/C/005475
Active substance Vosoritide
International non-proprietary name (INN) or common name vosoritide
Therapeutic area (MeSH) Achondroplasia
Anatomical therapeutic chemical (ATC) code M05BX
OrphanOrphan This medicine was designated an orphan medicine. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. For more information, see Orphan designation.
Publication details
Marketing-authorisation holder BioMarin International Limited
Date of issue of marketing authorisation valid throughout the European Union 26/08/2021

On 24 January 2013, orphan designation (EU/3/12/1094) was granted by the European Commission to BioMarin Europe Ltd, United Kingdom, for modified recombinant human C-type natriuretic peptide for the treatment of achondroplasia.

The sponsorship was transferred to BioMarin International Limited, Ireland, in February 2019.

This medicine is now known as Vosoritide.

The medicinal product has been authorised in the EU as Voxzogo since 26 August 2021.

PEPTIDE

Treatment of Achondroplasia
modified recombinant human C-type natriuretic peptide (CNP)

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.[1]

The most common side effects include injection site reactions (such as swelling, redness, itching or pain), vomiting and decreased blood pressure.[1]

Vosoritide was approved for medical use in the European Union in August 2021.[1][2]

Voxzogo is a medicine for treating achondroplasia in patients aged 2 years and older whose bones are still growing.

Achondroplasia is an inherited disease caused by a mutation (change) in a gene called fibroblast growth-factor receptor 3 (FGFR3). The mutation affects growth of almost all bones in the body including the skull, spine, arms and legs resulting in very short stature with a characteristic appearance.

Achondroplasia is rare, and Voxzogo was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 24 January 2013. Further information on the orphan designation can be found here: ema.europa.eu/medicines/human/orphan-designations/EU3121094.

Voxzogo contains the active substance vosoritide.

Achondroplasia Posters | Fine Art America

Medical uses

Vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.[1]

Mechanism of action

AChondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway
B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein.[3]

Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3).[1] FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth.[3]

The protein C-type natriuretic peptide (CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life,[3] allowing for once-daily administration.[4]

Chemistry

 

Vosoritide is an analogue of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence isPGQEHPNARKYKGANKKGLS KGCFGLKLDIGSMSGLGC

with a disulfide bridge between positions 23 and 39 (underlined).[5] The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken by mouth.

History

Vosoritide is being developed by BioMarin Pharmaceutical and, being the only available causal treatment for this condition, has orphan drug status in the US as well as the European Union.[1][2][6] As of September 2015, it is in Phase II clinical trials.[7][4]

Society and culture

Controversy

Some people with achondroplasia, as well as parents of children with this condition, have reacted to vosoritide’s study results by saying that dwarfism is not a disease and consequently does not need treatment.[8]

Research

Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01).[9] The body proportions, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.[7][10]

As of September 2015, it is not known whether the effect of the drug will last long enough to result in normal body heights,[10] or whether it will reduce the occurrence of achondroplasia associated problems such as ear infections, sleep apnea or hydrocephalus. This, together with the safety of higher doses, is to be determined in further studies.[4]

References

  1. Jump up to:a b c d e f g “Voxzogo EPAR”European Medicines Agency. 23 June 2021. Retrieved 9 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. Jump up to:a b “European Commission Approves BioMarin’s Voxzogo (vosoritide) for the Treatment of Children with Achondroplasia from Age 2 Until Growth Plates Close”BioMarin Pharmaceutical Inc. (Press release). 27 August 2021. Retrieved 9 September 2021.
  3. Jump up to:a b c Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. (December 2012). “Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia”American Journal of Human Genetics91 (6): 1108–14. doi:10.1016/j.ajhg.2012.10.014PMC 3516592PMID 23200862.
  4. Jump up to:a b c Clinical trial number NCT02055157 for “A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)” at ClinicalTrials.gov
  5. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN): List 112” (PDF). WHO Drug Information28 (4): 539. 2014.
  6. ^ “Food and Drug Administration Accepts BioMarin’s New Drug Application for Vosoritide to Treat Children with Achondroplasia” (Press release). BioMarin Pharmaceutical. 2 November 2020. Retrieved 9 September 2021 – via PR Newswire.
  7. Jump up to:a b Spreitzer H (6 July 2015). “Neue Wirkstoffe – Vosoritid”. Österreichische Apothekerzeitung (in German) (14/2015): 28.
  8. ^ Pollack A (17 June 2015). “Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says”The New York Times.
  9. ^ “BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study”. BioMarin. 17 June 2015.
  10. Jump up to:a b “Vosoritid” (in German). Arznei-News.de. 20 June 2015.

External links

  • “Vosoritide”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Trade names Voxzogo
Other names BMN-111
Routes of
administration
Subcutaneous injection
ATC code None
Legal status
Legal status EU: Rx-only [1]
Identifiers
CAS Number 1480724-61-5
DrugBank DB11928
ChemSpider 44210446
UNII 7SE5582Q2P
KEGG D11190
Chemical and physical data
Formula C176H290N56O51S3
Molar mass 4102.78 g·mol−1
3D model (JSmol) Interactive image
showSMILES
showInChI

/////////Vosoritide, Voxzogo, PEPTIDE, ボソリチド (遺伝子組換え) , восоритид , فوسوريتيد , 伏索利肽 , APPROVALS 2021, EU 2021, BMN 111, ORPHAN DRUG

CCC(C)C1C(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NCC(=O)NC(CSSCC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCNC(=N)N)CC(=O)O)CC(C)C)CCCCN)CC(C)C)CC2=CC=CC=C2)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)C(CC(=O)N)NC(=O)C(C)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC3=CC=C(C=C3)O)NC(=O)C(CCCCN)NC(=O)C(CCCNC(=N)N)NC(=O)C(C)NC(=O)C(CC(=O)N)NC(=O)C4CCCN4C(=O)C(CC5=CN=CN5)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C6CCCN6)C(=O)O)CC(C)C)CO)CCSC)CO

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MAX 40279


Thieno(3,2-d)pyrimidin-2-amine, 7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(1-(4-piperidinyl)-1H-pyrazol-4-yl)-.png
2D chemical structure of 2070931-57-4

MAX 40279, EX-A4057

Max 4; MAX-40279; MAX-40279-001; MAX-40279-01

UNII-DL772G3NN7

2070931-57-4

C22H23FN6OS, 438.5

7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-(1-piperidin-4-ylpyrazol-4-yl)thieno[3,2-d]pyrimidin-2-amine

Thieno[3,2-d]pyrimidin-2-amine, 7-(4-fluoro-2-methoxyphenyl)-6-methyl-N-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-

Structure of MAX-40279 HEMIFUMARATE
Unii-JU19P2M2KM.png

7-(4-FLUORO-2-METHOXYPHENYL)-6-METHYL-N-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL) THIENO (3,2-D)PYRIMIDIN-2-AMINE SEMI-FUMARATE CAS 2388506-43-0 

  • 7-(4-Fluoro-2-methoxyphenyl)-6-methyl-N-[1-(4-piperidinyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-2-amine
  • Originator Maxinovel Pharmaceuticals
  • ClassAntineoplastics
  • Mechanism of ActionFibroblast growth factor receptor antagonists; Fms-like tyrosine kinase 3 inhibitors
  • Orphan Drug StatusYes – Acute myeloid leukaemia
  • Phase IAcute myeloid leukaemia; Solid tumours

Most Recent Events

  • 28 Nov 2019Phase-I clinical trials in Solid tumours (Late-stage disease, Metastatic disease) in China (PO) (NCT04183764)
  • 16 Apr 2019Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) (NCT04187495)
  • 23 Jan 2019Guangzhou Maxinovel Pharmaceuticals plans a phase I trial in China (ChiCTR1900020971)
  • MaxiNovel Pharmaceuticals, Inc. Announces FDA Orphan Drug Designation for MAX-40279 for the Treatment of Acute Myeloid Leukemia (AML)
Jobs with Maxinovel Pharmaceuticals

March 29, 2018 11:24 AM Eastern Daylight Timehttps://www.businesswire.com/news/home/20180329005826/en/MaxiNovel-Pharmaceuticals-Inc.-Announces-FDA-Orphan-Drug-Designation-for-MAX-40279-for-the-Treatment-of-Acute-Myeloid-Leukemia-AML

GUANGZHOU, China–(BUSINESS WIRE)–MaxiNovel Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (“FDA”) has granted MaxiNovel Orphan Drug Designation for MAX-40279 in the treatment of Acute Myeloid Leukemia (AML).

AML is the most common acute leukemia which accounts for approximately 25% of all adult leukemias worldwide. Approximately one-third of AML patients have a FLT3 gene mutation. Such mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML. Inhibition of FLT3 mutation is of high importance in combating AML.

In the preclinical testing, MAX-40279 demonstrated potent inhibition of both FLT3 and FGFR with excellent drug concentration in the bone marrow. It is designed to overcome the observed drug resistance of the current FLT3 inhibitors due to the bone marrow FGF/FGFR pathway activation.

“We are very pleased to receive the ODD,” commented MaxiNovel’s Vice President Dr. Elizabeth Ashraf. “Our objective is to bring the best in class medicine to the patients worldwide.”

The FDA Office of Orphan Products Development grants orphan drug designation to novel drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. The designation allows manufacturers to qualify for various incentives including federal grants, tax credits for qualified clinical trials, a waiver of PDUFA filing fees and 7 years of market exclusivity upon regulatory approval.

About MaxiNovel Pharmaceuticals, Inc:

Maxinovel Pharmaceuticals, Inc. is a biotech company focusing on the discovery and development of Immuno-oncology therapy and targeted therapy. It will use its orally active Immuno-oncology product platform to bring effective combo product of multi-components in a single oral pill to the patients worldwide. For more info: www.maxinovel.com

The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signal pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, and it participates in many important biology such as cell proliferation, differentiation, apoptosis and immune regulation. Process (Aaronson, D Set al. Science 2002, 296, 1653-1655; O’Shea, J Jet al. Nat. Rev. Drug Discovery 2004, 3, 555-564). Compared with other signal pathways, the transmission process of this signal pathway is relatively simple. It mainly consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT. JAK (Janus Kinase), a type of molecule in the cell, is rapidly recruited and activated on the receptor after receiving the signal from the upstream receptor molecule. The activated JAK catalyzes the receptor tyrosine phosphorylation, and the phosphorylation of tyrosine on the receptor molecule Amino acid is the recognition and binding site of a kind of signal molecule STAT SH2. Tyrosine phosphorylation occurs after STAT binds to the receptor. Tyrosine phosphorylated STAT forms a dimer and enters the nucleus. As an active transcription factor, dimeric STAT molecules directly affect the expression of related genes, thereby changing the proliferation or differentiation status of target cells.

The JAK-STAT pathway is widely present in various tissues and cells in the body, and has an important role in the differentiation, proliferation, and anti-infection of lymphocytes, and participates in the interaction of various inflammatory factors and signal transduction (Kiesseleva T. et al. . J. Gene, 2002, 285, 1-24). The abnormal activation of this pathway is closely related to a variety of diseases. Finding and screening JAK inhibitors can help in-depth study of the regulatory mechanism of JAK-STAT, thereby providing new drugs and methods for the prevention and treatment of related diseases

The occurrence, growth, invasion and metastasis of tumors are related to the JAK-STAT signal transduction pathway. In normal signal transduction, the activation of STATs is rapid and transient. The continuous activation of STATs is closely related to the process of malignant transformation of cells (Buettner R. et al. Clin. Cancer Res. 2002, 8(4), 945-954). STAT3 is the focus of multiple oncogenic tyrosine kinase signal channels such as EGFR, IL-6/JAK, Src, etc. It is activated in a variety of tumor cells and tissues, such as breast cancer, ovarian cancer, and head and neck squamous cells. Like cell carcinoma, prostate cancer, malignant melanoma, multiple myeloma, lymphoma, brain tumor, non-small cell lung cancer and various leukemias, etc. (Niu G. et al. Oncogene 2002, 21(13), 2000-2008 ). JAK-STAT pathway inhibitors belong to PTK inhibitors, and this enzyme is a member of the oncogene protein and proto-oncoprotein family, and plays an important role in the normal and abnormal cell proliferation. The occurrence and growth of tumors are inseparable from PTK. Therefore, JAK-STAT pathway inhibitors inhibit tumor growth by antagonizing PTK, and have obvious anti-tumor effects (Mora LBet al.J.Cancer Res.2002,62(22) , 6659-6666).

In addition, the latest research shows that: organ transplant rejection, psoriasis, tissue and organ fibrosis, bronchial asthma, ischemic cardiomyopathy, heart failure, myocardial infarction, blood system diseases, and immune system diseases are all related to JAK-STAT signaling. The pathway is closely related. This signaling pathway is not only important for maintaining the normal physiological functions of cells, but also has an important regulatory role for the occurrence and development of diseases.

The Fibroblast Growth Factor Receptor family belongs to a new type of receptor kinase family, which includes four receptor subtypes (FGFR-1,2,3) encoded by four closely related genes. And 4) and some heterogeneous molecules, which form a ternary complex with fibroblast growth factor (FGF) and heparan sulfate, and then trigger a series of signal transduction pathways to participate in the regulation of physiological processes in the organism. FGFR has a wide range of physiological and pathological effects in the body: (1) Embryo development. Studies have shown that during embryonic development, FGFR signal transduction is essential for most organ development and the formation of embryonic patterns. (2) Cell division, migration and differentiation. FGFR stimulates cell proliferation and participates in the regulation of cell transformation in the pathological process. There are many parallel pathways to achieve FGFR-mediated cell division signal transduction, which has been confirmed by many studies (JKWang et al., Oncogene 1997, 14, 1767 -1778.). (3) Bone diseases. The growth and differentiation of bones are also regulated by the FGF family, and mutations in FGFR can cause bone deformities (R. Shang et al., Cell 1994, 78, 335-342.). (4) The occurrence of tumors. FGFR can promote the migration, proliferation and differentiation of endothelial cells, and plays an important role in the regulation of angiogenesis and angiogenesis. Uncontrolled angiogenesis can lead to the occurrence of tumors and the growth of metastases (J.Folkman.Nat.Med.1995) ,1,27-31.).

FMS-like tyrosine kinase 3 (FMS-like tyrosine kinase 3, FLT3) belongs to the type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, it is composed of extracellular domain, intracellular domain and The transmembrane region is composed of 3 parts, which are first expressed in human hematopoietic stem cells. FLT3 interacts with its ligand FL to stimulate or act on stem cells, which is of great significance to the growth and differentiation of stem cells. FLT3 kinase has wild-type FLT3-WT and its main activation mutant FLT3-ITD and FLT3-D835Y. FLT3 is mainly expressed in the precursors of normal myeloid cells, but its abnormal expression is also found in a large part of acute myeloid leukemia (AML) cells. 

In recent years, many large-scale studies have confirmed that activating mutations of FLT3 play a very important pathological role in the occurrence and progression of acute myeloid leukemia. FLT3 has become an important target for the treatment of acute myeloid leukemia.

rc family kinase (SFK) is a family of non-receptor tyrosine kinases, including c-Src, LYN, FYN, LCK, HCK, FGR, BLK, YES and YRK, among which LYN kinase has LYNα and LYNβ Both subtypes, LYN kinase and its two subtypes can cause similar intracellular tyrosine phosphorylation. According to the amino acid sequence, SFK can be divided into two sub-families: one family is c-Src, FYN, YES and FGR, which are widely expressed in different tissues; the other family is LCK, BLK, LYN and HCK, which are closely related to hematopoietic cells. SFK is connected to multiple signal transduction pathways in the body, and can be activated by growth factors, cytokines and immune cell receptors, G protein-coupled receptors, integrins and other cell adhesion molecules, and then activate the corresponding signal transduction pathways , Causing a variety of physiological effects of cells. The activity of SFK mainly includes the regulation of cell morphology, cell movement, cell proliferation and survival. The abnormal activation and expression of these kinases leads to the occurrence and development of a wide range of diseases, such as a large number of solid tumors, various hematological malignancies and some neuronal pathologies. Therefore, looking for SFK inhibitors is a promising research topic in the field of medicinal chemistry.

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Patent

CN106366093A

PATENT

WO 2017012559

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017012559Example 31
N-[7-(4-Fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidin-4-yl)- 1H-pyrazole-4-amine (Compound 31)

Synthesis of compound 31-e
2,4-Dichloro-6-methylthiophene [3,2-d] pyrimidine (10g, 45.6mmol) was dissolved in tetrahydrofuran (100mL) and ethanol (100mL), and the reaction solution was cooled to 0°C and divided Sodium borohydride (12.5 g, 198 mmol) was added in batches. The reaction solution was raised to room temperature and continued to stir for 16 hours, diluted with water (500 mL), and then adjusted to pH=7 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (150 mL×3). The organic phase was washed sequentially with water (100mL×3) and saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 31-e (7.5g, yield: 88%). The product does not require further purification. LC-MS(ESI): m/z=187[M+H] + .[0492]Synthesis of compound 31-d[0493]Compound 31-e (7.5 g, 40 mmol) was dissolved in chloroform (300 mL) at 0°C, active manganese dioxide (35 g, 400 mmol) was added, the reaction solution was raised to room temperature and stirring was continued for 16 hours. The reaction solution was filtered through Celite, and the filter cake was washed with chloroform (100 mL×3). The combined filtrates were concentrated under reduced pressure to obtain white solid 31-d (6.6 g, yield: 89%), which did not require further purification. LC-MS(ESI): m/z=185[M+H]+.[0494]Synthesis of compound 31-c[0495]Compound 31-d (3.1g, 16.8mmol) was dissolved in trifluoroacetic acid (30mL) at 0℃, N-iodosuccinimide (5.7g, 25.3mmol) was added in batches, and the reaction solution was raised to Keep stirring at room temperature for 1 hour. Water (50 mL) was added to the reaction solution to quench the reaction, and it was extracted with dichloromethane (50 mL×3). The organic phase was washed successively with water (50mL×3) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 31-c (4.9g, yield: 94%). The product does not require further purification. LC-MS(ESI): m/z=311[M+H] + .[0496]Synthesis of compound 31-b[0497]Compound 31-c (615mg, 1.98mmol), 2-methoxy-4-fluorophenylboronic acid (405mg, 2.38mmol) and sodium carbonate (630mg, 5.94mmol) were suspended in dioxane (5mL) water (5mL) ), add [1,1′-bis(diphenylphosphorus)ferrocene]dichloropalladium dichloromethane complex (163mg, 0.2mmol). Replace with nitrogen 3 times, and heat to 80°C to react for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was partitioned with dichloromethane (50mL) and water (50mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum Ether: dichloromethane=1:1) to obtain a white solid 31-b (240 mg, yield: 39%). LC-MS(ESI): m/z=309[M+H] + .[0498]Synthesis of compound 31-a[0499]Compound 31-b (240mg, 0.78mmol) and compound 32-c (208mg, 0.78mmol) were dissolved in N,N-dimethylformamide (3mL), potassium carbonate (323mg, 2.34mmol) was added, 2- Dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (112 mg, 0.24 mmol) and tris(dibenzylideneacetone) dipalladium (134 mg, 0.24 mmol). Under the protection of nitrogen, heat to 110°C to react for 16 hours. After cooling to room temperature, the reaction solution was partitioned with dichloromethane (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography preparation plate (petroleum Ether: ethyl acetate = 1:1) to obtain a yellow viscous oil 31-a (190 mg, yield: 45%). LC-MS(ESI): m/z=539[M+H] + .[0500]Synthesis of compound 31[0501]31-a (190 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was layered with ethyl acetate (50mL) and 1N aqueous hydrochloric acid (50mL). The aqueous phase was adjusted to pH=10 with saturated aqueous potassium carbonate solution. 3) Washing and vacuum drying the solid to obtain a light yellow solid 31 (22 mg, yield: 14%). LC-MS(ESI): m/z=439[M+H] + .[0502]1 H-NMR (400MHz, MeOD) δ: 8.78 (d, J = 5Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 7.35 (m, 1H), 7.05 (dd, J = 11Hz) ,J = 2Hz, 1H), 6.91 (m, 1H), 4.10 (m, 1H), 3.79 (s, 3H), 3.22 (m, 2H), 2.77 (m, 2H), 2.47 (s, 3H), 2.03(m,2H),1.73(m,2H)ppm

PATENT

WO 2019228171

Example 1 Preparation of fumarate of fused ring pyrimidine compound as shown in formula 2
Weigh the compound N-[7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-d]pyrimidin-2-yl]-1-(piperidine-4- Base)-1H-pyrazol-4-amine (synthesized according to Example 31 of patent CN106366093A) 100mg (0.228mmol, 1eq) into the vial, add 10mL 88% acetone-water solution, add the vial at about 50°C and stir until dissolved clear. 1.1 mL of fumaric acid with a concentration of 0.25 mol/L in ethanol (0.275 mmol, 1.2 eq) was slowly added dropwise to the free base solution of fused ring pyrimidine compounds, and stirred at 50 ℃ for 1 hour, and then the solution was The rate of 5°C/h was slowly reduced to room temperature, and the solid was collected and dried under vacuum at 40°C overnight.
1 H-NMR (400MHz, DMSO-d 6 ) δ: 9.45 (s, 1H), 8.94 (s, 1H), 7.75 (s, 1H), 7.78-7.33 (m, 2H), 7.15 (d, J = 6.4Hz, 1H), 6.99 (dd, J = 7.6 Hz, J = 7.2 Hz, 1H), 6.42 (s, 1H), 4.10 (m, 1H), 3.73 (s, 3H), 3.17 (d, J = 12.4 Hz, 2H), 2.77 (dd, J = 12.4 Hz, J = 11.6 Hz, 2H), 2.40 (s, 3H), 1.94 (d, J = 11.6 Hz, 2H), 1.73 (m, 2H) ppm.

PATENT

WO2021175155

7-(4-Fluoro-2-methoxyphenyl)-6-methyl-N-(1-piperidin-4-yl)-1hydro-pyrazol-4-yl)thieno[3,2 -D]pyrimidine-2-amino is a strong JAK, FGFR, FLT3 kinase inhibitor, and has a good application prospect in the treatment of tumors, immune system diseases, allergic diseases and cardiovascular diseases. This compound is described in patent CN106366093A and has the following chemical structure:

CN106366093A discloses the preparation method of the compound:

In the above synthetic route, NaBH 4 is sodium borohydride, MnO 2 is manganese dioxide, NIS is N-iodosuccinimide, TFA is trifluoroacetic acid, and Pd(dppf)Cl 2 is [1,1′- Bis(diphenylphosphino)ferrocene]palladium dichloride, DIAD is diisopropyl azodicarboxylate, PPh 3 is triphenylphosphine, Pd/C is palladium on carbon, Pd 2 (dba) 3 is Tris(dibenzylideneacetone)dipalladium, RuPhos is 2-bicyclohexylphosphine-2′,6′-diisopropoxybiphenyl.

However, the above method has the problems of a large number of reaction steps, low yield, and requires column chromatography for separation and purification, and is not suitable for industrial scale-up production. Therefore, it is necessary to improve its preparation method.

The present invention provides a method for preparing a compound represented by formula B, which comprises the following steps: under a protective gas atmosphere, in a solvent, in the presence of a catalyst and a base, a compound represented by formula C is combined with a compound represented by formula K The compound can be subjected to the coupling reaction shown below; the catalyst includes a palladium compound and a phosphine ligand;

The preparation method of the compound represented by formula B may further include the following steps: in an organic solvent, in the presence of a base, the compound represented by formula E and the compound represented by formula D are subjected to the substitution reaction shown below, To obtain the compound represented by formula C;

The present invention provides a method for preparing a compound represented by formula C, which comprises the following steps: in an organic solvent, in the presence of a base, a compound represented by formula E and a compound represented by formula D are subjected to the following steps: Substitution reaction is enough;

Example 1: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
Into a 500L reactor, add 10% palladium on carbon (4.6Kg), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (24.2Kg, 109.5mol), and tetrahydrofuran (150Kg) in sequence And N,N-diisopropylethylamine (17.0Kg, 131.5mol). Fill the kettle with hydrogen, and control the hydrogen pressure at 0.5 MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 120 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (58Kg) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (60Kg) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 360Kg of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was separated out, centrifuged, and the filter cake was vacuum dried to obtain the product 2-chloro-6-methylthieno[3,2-D]pyrimidine 18.94Kg, yield: 93.2%. LC-MS(ESI): m/z=185.1[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.30 (s, 1H), 7.34 (s, 1H), 2.73 (s, 3H). 
Example 2: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
To a 100mL reaction flask, add 10% palladium on carbon (0.17g), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (2g, 9.2mmol), tetrahydrofuran (40mL) and N,N-Diisopropylethylamine (1.412 g, 10.9 mmol). Fill the bottle with hydrogen and control the hydrogen pressure at 0.5MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 20 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (2.1 g) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (2.2g) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 13.3g of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was precipitated, centrifuged, and the filter cake was vacuum dried to obtain 2.4 g of 2-chloro-6-methylthieno[3,2-D]pyrimidine as a product, with a yield of 82%. The LC-MS and 1 H NMR are the same as in Example 1. 
Example 3: 7-Bromo 2-chloro-6-methylthieno[3,2-D]pyrimidine (Compound E) 
Add trifluoroacetic acid (150Kg) and 2-chloro-6-methylthieno[3,2-D]pyrimidine (18.90Kg, 102.4mol) into a 500L enamel reactor. Add N-bromosuccinimide (18.33Kg, 103.0mol) under temperature control at 15±5℃. After the addition, the temperature is controlled at 25±5℃ to react for 2 hours. Sampling to monitor the reaction, there is still a small amount of raw materials remaining. Additional N-bromosuccinimide (1.0 Kg, 5.6 mol) was added, stirring was continued for 1 hour, sampling and monitoring showed that the reaction was complete. Control the temperature at 10±5°C, and add 274Kg of water dropwise. After the addition, stir at 10±5°C for 2 hours. After centrifugation, the solid was vacuum-dried to obtain the product, 7-bromo-2-chloro-6-methylthieno[3,2-D]pyrimidine, 24.68Kg, yield: 91.4%. LC-MS(ESI): m/z=265.0[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.33 (s, 1H), 2.64 (s, 3H). 
Example 4: 4-(p-toluenesulfonyl)-piperidine-1-tert-butyl carbonate (Compound G) 
Add pyridine (176Kg) and N-BOC-4-hydroxypiperidine (36.00Kg, 178.9mol) to a 500L enamel reactor. Add p-toluenesulfonyl chloride (50.5Kg, 264.9mol) in batches under temperature control at 10±10°C. After the addition, the temperature is controlled at 25±5°C to react for 18 hours. The reaction solution was transferred to a 1000L reactor, the temperature was controlled at 15±5°C, and 710Kg of water was added dropwise. After the addition, stir at 15±5°C for 2 hours. After filtration, the solid was washed with water and dried in vacuum to obtain the product 4-(p-methylbenzenesulfonyl)-piperidine-1-carbonate tert-butyl ester, 59.3Kg, yield: 93.3%. LC-MS(ESI): m/z=378.0[M+Na] + . 
Example 5: 4-(4-Nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound F) 
Add N,N-dimethylformamide (252Kg), 4-(p-methylbenzenesulfonyl)-piperidine-1-carbonate tert-butyl ester (59.3Kg, 166.8mol), 4-nitro to the reaction kettle Pyrazole (21.5Kg, 190.1mol), and anhydrous potassium carbonate (34.3Kg, 248.2mol). The temperature was controlled at 80±5°C and the reaction was stirred for 18 hours. Cool down to 15±5°C, add 900Kg of water dropwise, control the dropping rate, and keep the temperature at 15±5°C. After the addition, stir at 5±5°C for 2 hours. After filtering, the solid was washed twice with water and dried in vacuum to obtain the product 4-(4-nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 39.92Kg, yield: 80.8%. LC-MS (ESI): m/z=319.1 [M+Na] + . 
1 H NMR (400MHz, d 6 -DMSO): δ8.96(s,1H), 8.27(s,1H), 4.44-4.51(m,1H), 4.06-4.08(m,2H), 2.75-2.91( m, 2H), 2.04-2.07 (m, 2H), 1.80-1.89 (m, 2H), 1.41 (s, 9H). 
Example 6: 4-(4-Amino-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound D) 
Add 10% palladium-carbon (2.00Kg), 4-(4-nitro-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (39.94Kg, 134.09mol) to the reaction kettle, nothing Water ethanol (314Kg) and ammonia (20.0Kg, 134.09mol). Fill the kettle with hydrogen, and control the hydrogen pressure at 0.2MPa. Turn on the stirring and keep the temperature at 45±5°C to react for 4 hours. Filter, collect the filtrate, and concentrate the filtrate under reduced pressure. Add ethyl acetate (40Kg) and n-heptane (142Kg) to the concentrate, stir at 25±5°C for 1 hour, and then lower the temperature to 5±5°C and stir for 2 hours. After filtration, the solid was vacuum dried to obtain the product 4-(4-amino-1hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 31.85Kg, yield: 88.6%. LC-MS(ESI): m/z=267.2[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ7.06 (s, 1H), 6.91 (s, 1H), 4.08-4.15 (m, 1H), 3.98-4.01 (m, 2H), 3.81 (brs, 2H), 2.83-2.87 (m, 2H), 1.88-1.91 (m, 2H), 1.63-1.72 (m, 2H), 1.41 (s, 9H). 
Example 7: 4-(4-(7-Bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1hydro-pyrazol-1-yl)piperidine-1 -Tert-butyl carbonate (compound C) 
Add n-butanol (117Kg), N,N-diisopropylethylamine (15.00Kg, 116.06mol), 4-(4-amino-1hydro-pyrazol-1-yl)piperidine to the reaction kettle 1-tert-butyl carbonate (32.02Kg, 120.22mol) and 7-bromo-2-chloro-6-methylthieno[3,2-D]pyrimidine (24.68Kg, 93.65mol). Turn on the stirring and keep the temperature at 100±5°C to react for 42 hours. Concentrate under reduced pressure. Methanol was added to the concentrate to be beaten. The solid was filtered and dried under vacuum to obtain the product 4-(4-(7-bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1hydro-pyrazol-1-yl ) Piperidine-1-tert-butyl carbonate 37.26Kg, yield: 80.6%. LC-MS(ESI): m/z=493.1[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.73 (s, 1H), 8.97 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 4.30-4.36 (m, 1H) ,4.01-4.04(m,2H),2.87-2.93(m,2H),2.53(s,3H),2.00-2.03(m,2H),1.70-1.80(m,2H),1.41(s,9H) . 
Example 8: 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino)-1 Hydro-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (Compound B) 
Add purified water (113Kg), dioxane (390Kg), 4-(4-(7-bromo-6-methylthieno[3,2-D]pyrimidin-2-yl)amino) into the reactor -1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate (37.26Kg, 93.65mol), 2-methoxy-4-fluorophenylboronic acid pinacol ester (23.05Kg, 120.22mol) , Anhydrous potassium carbonate (20.95Kg, 151.8mol), palladium acetate (0.18Kg, 0.80mol) and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.90Kg, 1.89mol). Under the protection of nitrogen, the temperature is controlled at 70±5℃ to react for 4 hours. Cool down to 40±5°C, add ammonia water (68Kg), and stir for 8 hours. Cool down to 20±5°C and dilute with water (1110Kg). Dichloromethane extraction twice (244Kg, 170Kg). Combine the organic phases, wash sequentially with water and then with saturated brine. Add 3-mercaptopropyl ethyl sulfide-based silica (4.0Kg, used to remove heavy metal palladium) into the organic phase, and stir at 40±5°C for 20 hours. After filtration, the filtrate was concentrated under reduced pressure. The remainder was slurried sequentially with methyl tert-butyl ether and ethanol. Filter and dry in vacuo to obtain 4-(4-((7-(4-fluoro-2-methoxyphenyl)-6-methylthieno[3,2-D]pyrimidin-2-yl)amino) -1H-pyrazol-1-yl)piperidine-1-tert-butyl carbonate 34.6Kg, yield: 68.6%. LC-MS(ESI): m/z=539.3[M+H] + . 
1 H NMR (400MHz, d 6 -DMSO): δ9.46 (s, 1H), 8.94 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 7.33 to 7.35 (m, 1H) ,7.08-7.11(m,1H),6.91-6.95(m,1H),4.03-4.12(m,3H),3.73(s,3H),2.85-2.89(m,2H),2.39(s,3H) ,1.90-1.93(m,2H),1.55-1.60(m,2H),1.41(s,9H). 
Comparative Example 1: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
Into a 100mL reaction flask, add 10% palladium on carbon (0.1g), 2,4-dichloro-6-methylthieno[3,2-D]pyrimidine (2g, 9.2mmol), methanol (40mL) and N,N-Diisopropylethylamine (1.412 g, 10.9 mmol). Fill the bottle with hydrogen and control the hydrogen pressure at 0.5MPa. Turn on the stirring and keep the temperature at 25±5°C to react for 21 hours. Filter, collect the filtrate, concentrate the filtrate under reduced pressure, add ethanol (2.1 g) to the concentrate, and concentrate again to bring out residual tetrahydrofuran. Add ethanol (2.2g) and stir at 70±5°C until all solids are dissolved. Cool down, control the temperature at 25±5°C, add 13.3g of purified water dropwise to the kettle, control the dropping rate, and keep the temperature at 25±5°C. The solid product was precipitated, centrifuged, and the filter cake was vacuum dried to obtain 1.6 g of 2-chloro-6-methylthieno[3,2-D]pyrimidine as a product, with a yield of 54%. Methoxy substituted impurities in 20% yield.
Comparative Example 2: 2-Chloro-6-methylthieno[3,2-D]pyrimidine (Compound I) 
After replacing the solvent tetrahydrofuran in Example 2 with ethyl acetate, the solubility of 2-chloro-6-methylthieno[3,2-D]pyrimidine in ethyl acetate was poor, and only a small amount of product was formed, which was not calculated Specific yield. 
Comparative example 3: 4-(p-toluenesulfonyl)-piperidine-1-tert-butyl carbonate (Compound G) 
Triethylamine (25mL), N-BOC-4-hydroxypiperidine (5g) were added to a 100mL reaction flask. P-toluenesulfonyl chloride (7.1g) was added in batches while controlling the temperature at 10±10°C. After the addition, the temperature is controlled at 25±5℃ to react for 25 hours. Monitoring by LC-MS showed a large amount of unreacted raw materials and the reaction liquid was black and red. 

Publication Number TitlePriority Date Grant Date
WO-2019228171-A1Salt of fused ring pyrimidine compound, crystal form thereof and preparation method therefor and use thereof2018-05-31 
AU-2016295594-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
AU-2016295594-B2Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212020-04-16
EP-3354653-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
EP-3354653-B1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212019-09-04
Publication Number TitlePriority Date Grant Date
JP-2018520202-AFused ring pyrimidine compounds, intermediates, production methods, compositions and applications thereof2015-07-21 
KR-20180028521-ACondensed ring pyrimidine-based compounds, intermediates, methods for their preparation, compositions and applications2015-07-21 
US-10494378-B2Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-212019-12-03
US-2018208604-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21 
WO-2017012559-A1Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof2015-07-21
CTID TitlePhaseStatusDate
NCT03412292MAX-40279 in Subjects With Acute Myelogenous Leukemia (AML)Phase 1Recruiting2021-05-21

///////////////Orphan Drug, Acute myeloid leukaemia, MAX 40279, EX-A4057, Max 4,  MAX-40279, MAX-40279-001, MAX-40279-01, PHASE 1, Maxinovel Pharmaceuticals

CC1=C(C2=NC(=NC=C2S1)NC3=CN(N=C3)C4CCNCC4)C5=C(C=C(C=C5)F)OC

Nanatinostat


Nanatinostat Chemical Structure
ChemSpider 2D Image | CHR-3996 | C20H19FN6O2
Hdac inhibitor CHR-3996.png

Nanatinostat

Tractinostat

CHR-3996, CHR 3996, VRx 3996,

C20H19FN6O2, 394.41

CAS 1256448-47-1

2-[(1α,5α,6α)-6-[[(6-Fluoro-2-q

2-[(1R,5S,6R)-6-{[(6-fluoroquinolin-2-yl)methyl]amino}-3-azabicyclo[3.1.0]hexan-3-yl]-N-hydroxypyrimidine-5-carboxamide2-[(1R,5S,6s)-6-{[(6-Fluoro-2-quinolinyl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl]-N-hydroxy-5-pyrimidinecarboxamide5-Pyrimidinecarboxamide, 2-[(1R,5S)-6-[[(6-fluoro-2-quinolinyl)methyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-N-hydroxy-Chroma Therapeutics Ltd. (Originator)

  • OriginatorChroma Therapeutics
  • DeveloperChroma Therapeutics; Viracta Therapeutics
  • ClassAmides; Antineoplastics; Pyrimidines; Quinolines; Small molecules
  • Mechanism of ActionHistone deacetylase inhibitors
  • Orphan Drug StatusYes – Post-transplant lymphoproliferative disorder; Plasmablastic lymphoma; T-cell lymphoma
  • Phase IILymphoma
  • Phase I/IIMultiple myeloma
  • Phase ISolid tumours
  • No development reportedGastric cancer; Nasopharyngeal cancer; Post-transplant lymphoproliferative disorder
  • 01 Jun 2021Phase-II clinical trials in Lymphoma (Combination therapy, Second-line therapy or greater) in North America, Europe, Asia (PO)
  • 18 May 2021Ninatinostat is still in phase I trials for Solid tumour in United Kingdom and Netherlands (Viracta Therapeutics pipeline, May 2021)
  • 18 May 2021Virata Therapeutics has patent protection for dose regimen in NAVAL-1 trial in USA

Nanatinostat is under investigation in clinical trial NCT00697879 (Safety Study of the Histone Deacetylase Inhibitor, CHR-3996, in Patients With Advanced Solid Tumours).

Nanatinostat is an orally bioavailable, second-generation hydroxamic acid-based inhibitor of histone deacetylase (HDAC), with potential antineoplastic activity. Nanatinostat targets and inhibits HDAC, resulting in an accumulation of highly acetylated histones, the induction of chromatin remodeling, and the selective transcription of tumor suppressor genes; these events result in the inhibition of tumor cell division and the induction of tumor cell apoptosis. This agent may upregulate HSP70 and downregulate anti-apoptotic Bcl-2 proteins more substantially than some first-generation HDAC inhibitors. HDACs, upregulated in many tumor cell types, are a family of metalloenzymes responsible for the deacetylation of chromatin histone proteins.

Patent

WO2006123121

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006123121

Example 44: N-Hvdroxy 2-(6-fr(6-fluoroαuinolin-2-yl)methvnamino)-3-azabicvclorS.I.OIhex-S-vDpyrimidine-δ-carboxamide

LCMS purity >98%, m/z 395 [M+H]+1H NMR (300 MHz, c/6-DMSO) δ: 2.30 (2H, s), 2.75 (1 H, s), 3.60 (2H, dm, J = 11.7 Hz), 3.88 (2H, d, J = 11.7 Hz), 4.69 (2H, br s), 7.66 (1 H, d, J = 8.4 Hz), 7.75 (1 H, td, J = 8.7, 3.0 Hz), 7.88 (1 H, dd, J = 9.3, 2.7 Hz), 8.48 (1 H, d, J = 8.4 Hz), 8.67 (2H, s), 9.01 (1 H, br s), 9.61 (1 H, br s), 11.09 (1 H, br s).

PATENT

WO-2021113694

Crystalline hydrate form A of N-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide ( nanatinostat ) .

Compound 1 is also known as nanatinostat, VRx-3996, or CHR-3996. It has been previously described in patents and patent applications, e.g. US patent 7,932,246 and US patent application 15/959,482, each of which is incorporated by reference in their entirety.

Compound 1

PATENT

WO2021071809 , claiming dosages for HDAC treatment with reduced side effects.

/////////Nanatinostat, CHR-3996, CHR 3996, VRx 3996, CHROMA, ORPHAN DRUG, Tractinostat, PHASE 2

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wdt-13

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