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TAK-733

CAS: 1035555-63-5

Synonym: TAK-733; TAK 733; TAK733.

IUPAC/Chemical name:

(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Chemical Formula: C17H15F2IN4O4

Exact Mass: 504.01060

Molecular Weight: 504.23Image may be NSFW.
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Elemental Analysis: C, 40.49; H, 3.00; F, 7.54; I, 25.17; N, 11.11; O, 12.69

Phase I clinical studies for cancer treatment.Takeda Pharmaceutical,

Solid Tumors Therapy

Description of TAK-733: TAK-733 is an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic activity. MEK inhibitor TAK-733 selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.

Current developer: Millennium Pharmaceuticals, Inc./Takeda Pharmaceutical Company Limited.Image may be NSFW.
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TAK-733 is being developed at Millennium Pharmaceuticals for the treatment of adult patients with advanced non-hematological malignancies. Phase I clinical trials are ongoing for the treatment of advanced metastatic melanoma. In preclinical studies, the compound has been shown to bind to and potently inhibit MEK.

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Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

Qing Dong ^†,
ET AL

Takeda San Diego;10410 Science Center Drive, San Diego, CA 92121, United States

doi:10.1016/j.bmcl.2011.01.071

http://www.sciencedirect.com/science/article/pii/S0960894X11000941

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Scheme 3.

Synthesis of compounds 26 and 27 (Route 4). Reagents and conditions: (a) 1-chloro-2,4-dinitrobenzene, K₂CO₃, DMF; (b) (R)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine or 2,2-dimethyl-1,3-dioxan-5-amine, K₂CO₃ or Cs₂CO₃, DMF; (c) HCl, THF; (d) Selectfluor, CH₃CN,DMF.

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TAK-733 exhibited potent enzymatic and cell activity with an IC₅₀ of 3.2 nM against constitutively active MEK enzyme and an EC₅₀ of 1.9 nM against ERK phosphorylation in cells. TAK-733 did not inhibit any other kinases, receptors or ion channels that were tested with inhibitor concentrations up to 10 μM. TAK-733 was found to bind plasma protein moderately (ca. 97% for human and 96% for mouse), and exhibit high permeability and high microsomal stability across species. It did not inhibit P450s up to 30 μM.

The co-crystal structure of TAK-733 in the MEK1 allosteric site has been solved (Fig. 3). As predicted, the pyridone oxygen makes a hydrogen bond with the backbone NH of Ser212. The 2-fluoro-4-iodoaniline moeity sits in the deep lipophilic pocket. The pyrimidinone oxygen makes a hydrogen bond with Lys97, and the propanediol terminal hydroxyl interacts with both Lys97 and the ADP phosphate.

Image may be NSFW. Clik here to view.: Figure 3.
The X-ray co-crystal structure of TAK-733 in the MEK1 allosteric site.

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(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Molecular Weight:	504.23
TAK-733 Formula:	C₁₇H₁₅F₂IN₄O₄

CAS Number:	1035555-63-5

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Biological Activity of TAK-733:

TAK-733 is an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic activity. MEK inhibitor TAK-733 selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.Image may be NSFW.
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References:Image may be NSFW.
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BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors.
Dahlman et al. Cancer Discov. 2012 Jul 13. PMID: 22798288.Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer.
Dong et al. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9. PMID: 21310613.

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Zhao Y * et al. Takeda California, San Diego, Millenium Pharmaceuticals Inc., Cambridge and IRIX Pharmaceuticals, Greenville, USA

Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor.Org. Process Res. Dev. 2012;
16: 1652-1659

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Clik here to view.MEK kinases regulate the pathway that mediates proliferative and anti-apoptotic signaling factors that promote tumor growth and metastasis. TAK-733 is an MEK kinase inhibitor that entered phase I clinical trials for the treatment of cancer. A noteworthy feature of this short synthesis (25% yield overall) is the one-pot, three-step synthesis of the fluoropyridone D, in which the fluorine atom is present at the outset.
The reaction of F with the nosylate G gave a mixture of N- and O-alkylation products (8:1) from which the desired N-alkylation product was isolated by crystallization. The mixture of N-methyl pyrrolidine (NMP) and methanol used in the final deprotection step, helped to ensure formation of the desired polymorph. The nine-step discovery synthesis (3% overall yield) is also presented.
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WO2008079814A2 Image may be NSFW.
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http://www.google.com/patents/WO2008079814A2?cl=en

Example 18: (i?)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3/f,8H)-dione

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[0364] To a solution of (i?)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)- 8-methylpyrido[2,3-d]pyrimidine-4,7(3/f,8H)-dione (example 6) (1 g, 2.06 mmol, 1 eq) in DMF (19 mL) was added dropwise a mixture of Selectfluor (801 mg, 2.26 mmol, 1.1 eq) in acetonitrile (9 niL) and DMF (5 niL) at ambient temperature while stirring under nitrogen. The reaction mixture was stirred for 10 minutes at ambient temperature and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH₃CN in H₂O) to give (i?)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 18) as an off-white solid. The recovered starting material was subjected to the same reaction conditions to produce a second crop of product. The total yield of product was 347 mg (33% yield). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.36 – 3.40 (m, 1 H) 3.43 – 3.50 (m, 1 H) 3.58 (s, 3 H) 3.61 – 3.72 (m, 1 H) 3.72 – 3.82 (m, 1 H) 4.27 – 4.37 (m, 1 H) 4.78 – 4.87 (m, 1 H) 5.14 (d, J=5.81 Hz, 1 H) 6.93 – 7.03 (m, 1 H) 7.53 (d, J=8.84 Hz, 1 H) 7.65 – 7.74 (m, 1 H) 8.52 (s, 1 H) 10.25 (d, J=LOl Hz, 1 H). [M+H] calc’d for Ci₇Hi₅F₂IN₄O₄, 505; found, 505.

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Example 19: (5)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3/f,8H)-dione

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[0365] To a solution of (5)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)- 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 5) (1.25 g, 2.58 mmol, 1 eq) in DMF (26 mL) was added a mixture of Selectfluor (1.187 g, 3.35 mmol, 1.3 eq) in acetonitrile (26 mL). The reaction mixture was irradiated with microwave at 82 ⁰C for 10 minutes and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH₃CN in H₂O) to give (5)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3-d]pyrimidine-4,7(3/f,8H)-dione (example 19) as an off-white solid (331 mg, 25% yield). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 3.36 – 3.42 (m, 1 H) 3.42 – 3.51 (m, 1 H) 3.59 (s, 3 H) 3.63 – 3.72 (m, 1 H) 3.73 – 3.81 (m, 1 H) 4.32 (dd, J=13.14, 3.03 Hz, 1 H) 4.79 (br. s., 1 H) 5.10 (br. s., 1 H) 6.98 (td, J=8.46, 5.31 Hz, 1 H) 7.52 (dd, J=8.46, 1.14 Hz, 1 H) 7.68 (dd, J=10.36, 1.77 Hz, 1 H) 8.51 (s, 1 H) 10.24 (d, J=2.27 Hz, 1 H). [M+H] calc’d for Ci₇Hi₅F₂IN₄O₄, 505; found, 505.Image may be NSFW.
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US8436200 Image may be NSFW.
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http://www.google.com/patents/US8436200?cl=en

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The synthetic process of the present invention allows for the preparation of (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione while avoiding the use of a fluorinating reagent in the last step. That is, the present invention provides a valuable process for making (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione characterized by the reaction of a compound of formula (8) with 2-fluoro-4-iodoaniline to give a compound of formula (9). Such a process avoids the use of costly and possible hazardous fluorinating regents in later steps which has significant advantages in large-scale manufacture.Image may be NSFW.
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Example 8.1(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Combine (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (24.75 g, 45.58 mmol) and ethanol (250 mL). Add aqueous 9N sulfuric acid (50 mL) over 5 minutes. Heat to 75° C. After 2 hour, cool to ambient temperature and then cool in an ice bath to give a solid. Collect the solid by filtration, rinse with ethanol (3×30 mL), and dry to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ10.24 (s, 1H), 8.52 (s, 1H), 7.69 (dd, 1H, J=10.4, 1.8 Hz), 7.52 (d, 1H, J=8.6 Hz), 6.98 (m, 1H), 5.14 (brs, 1H), 4.83 (brs, 1H), 4.32 (dd, 1H, J=12.9, 2.5 Hz), 3.76 (m, 1H), 3.67 (dd, 1H, J=13.1, 12.9 Hz), 3.58 (s, 3H), 3.46 (ddd, 1H, J=10.9, 5.3, 5.1 Hz), 3.38 (m, 1H); ¹³C NMR (100 MHz, DMSO-d6) δ161.3 (d, J=4.0 Hz), 155.6 (d, J=22.8 Hz), 154.6 (d, J=250 Hz), 152.0, 150.6, 134.3 (d, J=231 Hz), 133.8 (d, J=7.1 Hz), 133.1 (d, J=3.0 Hz), 127.8 (d, J=10.3 Hz), 125.3 (d, J=7.0 Hz), 123.9 (d, J=21.5 Hz), 95.0 (d, J=4.0 Hz), 87.1 (d, J=7.8 Hz), 68.0, 63.8, 50.1, 28.8; ¹⁹F NMR (376 MHz, DMSO-d6) δ-124.4, −149.8; MS (M+H)+m/z calcd 505.0. found 505.0.

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ANTHONY MELVIN CRASTO

Information about this agent

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TAK-733 is currently in Phase I clinical trials and is being developed by Millennium Pharmaceuticals, Inc. (a part of Takeda Pharmaceutical Company Limited).

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References

1: Acquaviva J, Smith DL, Jimenez JP, Zhang C, Sequeira M, He S, Sang J, Bates RC, Proia DA. Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Mol Cancer Ther. 2014 Feb;13(2):353-63. doi: 10.1158/1535-7163.MCT-13-0481. Epub 2014 Jan 7. PubMed PMID: 24398428.

2: Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X. Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep. 2014 Jan;9(1):83-90. doi: 10.3892/mmr.2013.1781. Epub 2013 Nov 7. PubMed PMID: 24213221.

3: Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E, Galvin K, Okaniwa M, Ishikawa T, Yoshida S. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res. 2013 Dec 1;73(23):7043-55. doi: 10.1158/0008-5472.CAN-13-1825. Epub 2013 Oct 11. PubMed PMID: 24121489.Image may be NSFW.
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4: Garraway LA, Baselga J. Whole-genome sequencing and cancer therapy: is too much ever enough? Cancer Discov. 2012 Sep;2(9):766-8. doi: 10.1158/2159-8290.CD-12-0359. PubMed PMID: 22969114.

5: Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones CL, Sosman JA, Ribas A, Zhao Z, Pao W. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012 Sep;2(9):791-7. Epub 2012 Jul 13. PubMed PMID: 22798288; PubMed Central PMCID: PMC3449158.Image may be NSFW.
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6: von Euw E, Atefi M, Attar N, Chu C, Zachariah S, Burgess BL, Mok S, Ng C, Wong DJ, Chmielowski B, Lichter DI, Koya RC, McCannel TA, Izmailova E, Ribas A. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines. Mol Cancer. 2012 Apr 19;11:22. PubMed PMID: 22515704; PubMed Central PMCID: PMC3444881.

7: Dong Q, Dougan DR, Gong X, Halkowycz P, Jin B, Kanouni T, O’Connell SM, Scorah N, Shi L, Wallace MB, Zhou F. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9. doi: 10.1016/j.bmcl.2011.01.071. Epub 2011 Jan 22. PubMed PMID: 21310613.

US8030317	Dec 18, 2007	Oct 4, 2011	Takeda Pharmaceutical Company Limited	MAPK/ERK kinase inhibitors
US20080255160	Dec 18, 2007	Oct 16, 2008	Qing Dong	Mapk/erk kinase inhibitors
WO2008000020A1	Jun 27, 2007	Jan 3, 2008	Gary L Corino	Improved process

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EP1894932A1	Jun 10, 2005	Mar 5, 2008	Japan Tobacco, Inc.	5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer
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