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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 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 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Motesanib (AMG-706)


Motesanib (AMG-706)

Amgen Inc.

 

Motesanib.svg

Motesanib (AMG 706) is an experimental drug candidate originally developed by Amgen[1] but is now being investigated by theTakeda Pharmaceutical Company. It is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of VEGF receptors, platelet-derived growth factor receptors, and stem cell factor receptors.[2] It is used as thephosphatesalt motesanib diphosphate.

Motesanib, also known as AMG-706, is an orally administered multikinase inhibitor that selectively targets VEGF receptors, platelet-derived growth factor receptors, and Kit receptors.

Clinical trials

Motesanib was originally investigated for effectiveness against advanced nonsquamous non-small-cell lung cancer (NSCLC), withPhase II trials indicating an effectiveness comparable to bevacizumab when they were both used in combination withpaclitaxel/carboplatin.[3] However a later and more detailed Phase III trial failed to show any benefit for the treatment of NSCLC.[2][4]A second Phase III trial was started in 2012,[5] which focused on patients from Asian backgrounds (performed on the bases ofsubgroup analysis)[6] however this also failed to meet its primary endpoint.[7]

The drug has undergone a Phase II evaluation as first-line therapy for breast cancer[2] however this study found no evidence to support further investigation.[8] Phase II testing against persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas was also unsuccessful.[9]

There have also been 2 separate Phase II clinical trials for thyroid cancer which have both shown promising results.[10][11][12]

Developed at Amgen, the compound is also being evaluated as both monotherapy and in combination with other agents in the treatment of breast, colorectal, lung, thyroid and ovarian cancers. Clinical trials for the treatment of bladder cancer have been terminated.

The National Cancer Institute had been evaluating the potential of the drug in patients with low-grade neuroendocrine tumors; however, no recent development has been reported for this research. The FDA awarded fast track status to motesanib in 2004. In 2008, the compound was licensed to Takeda in Japan.

AMG-706 is synthesized as follows: 1-Acetyl-3,3-dimethyl-6-nitroindoline (I) is reduced by catalytic hydrogenation over Pd/C, giving the aminoindoline (II), which is then coupled with 2-chloronicotinoyl chloride (III) in the presence of DIEA to yield the corresponding nicotinamide (IV). Subsequent condensation of (IV) with neat 4-(aminomethyl)pyridine (V) at 120 °C affords the 2-aminonicotinamide derivative (VI). The N-acetyl group of (VI) is finally removed by acidic hydrolysis to furnish the title compound (1,2).

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US 2003125339

http://www.google.com/patents/US20030125339

………………………………………………….

US 2003225106

https://www.google.com/patents/US20030225106

EXAMPLE 133

[2295]

Figure US20030225106A1-20031204-C00230

N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

Step A—Preparation of 1-acetyl-6-amino-3,3-dimethylindoline

1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2Cl2 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc’d. for C12H16N2O—204.27.

Step B—Preparation of N-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from 1-acetyl-6-amino-3,3-dimethylindoline (Step A) by the method described in Example 82.

Step C—Preparation of N-(3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from N-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (Step B) by the deacylation method described in Example 993. MS: 374 (M+1). Calc’d. for C22H23N5O—373.45.

…………………….

http://www.google.com/patents/WO2012063085A3?cl=en

Example 133

N- (3, 3-Dimethy1indolin-6-yl) {2- [ (4-pyridylmethyl) amino] (3- pyridyl) }carboxamide Step A – Preparation of l-acetyl-6-amino-3 , 3- dimethylindoline l-Acetyl-3 , 3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20 mL) , the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc :CH2C12 to afford the title compound as a white crystalline material. MS: 205 (M+1). Calc’d. for C12H16N2O-204.27.

Step B – Preparation of N-(l-acetyl- 3 , 3-dimethylindolin-6- yl) (2-[ (4-pyridylmethyl) amino] (3-pyridyl) } carboxamide The titled compound was prepared from l-acetyl-6- amino-3 , 3-dimethylindoline (Step A) by the method described in Example 82.

Step C – Preparation of N- (3 , 3-dimethylindolin-6-yl) {2- [ (4- pyridylmethyl) amino] (3-pyridyl) }carboxamide

The titled compound was prepared from N-(l-acetyl- 3 , 3-dimethylindolin-6-yl) {2- [ (4-pyridylmethyl) amino] (3- pyridyl) } carboxamide (Step B) by the deacylation method described in Example 993. MS: 374 (M+1). Calc’d. for C22H23N50-373.45.

References

  1. Stafford, edited by Rongshi Li, Jeffrey A. (2009). “Chapter 5. Discovery of Motesanib”. Kinase inhibitor drugs. Hoboken, N.J.: Wiley. pp. 113–130. ISBN 978-0-470-27829-1.
  2. “Amgen and Takeda’s NSCLC Drug Fails in Phase III Study”. 30 Mar 2011.
  3. Blumenschein Jr, G. R.; Kabbinavar, F.; Menon, H.; Mok, T. S. K.; Stephenson, J.; Beck, J. T.; Lakshmaiah, K.; Reckamp, K.; Hei, Y.- J.; Kracht, K.; Sun, Y.- N.; Sikorski, R.; Schwartzberg, L. (14 February 2011). “A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer”. Annals of Oncology 22 (9): 2057–2067. doi:10.1093/annonc/mdq731.
  4. Jump up^ Scagliotti, G. V.; Vynnychenko, I.; Park, K.; Ichinose, Y.; Kubota, K.; Blackhall, F.; Pirker, R.; Galiulin, R.; Ciuleanu, T.-E.; Sydorenko, O.; Dediu, M.; Papai-Szekely, Z.; Banaclocha, N. M.; McCoy, S.; Yao, B.; Hei, Y.-j.; Galimi, F.; Spigel, D. R. (2 July 2012). “International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer: MONET1”. Journal of Clinical Oncology 30 (23): 2829–2836. doi:10.1200/JCO.2011.41.4987. PMID 22753922.
  5. “Takeda Initiates Phase 3 Trial of Motesanib in Japan and Additional Asian Countries”. Takeda Pharmaceutical Company Limited. Retrieved 19 February 2015.
  6. Kubota, K.; Ichinose, Y.; Scagliotti, G.; Spigel, D.; Kim, J. H.; Shinkai, T.; Takeda, K.; Kim, S.- W.; Hsia, T.- C.; Li, R. K.; Tiangco, B. J.; Yau, S.; Lim, W.- T.; Yao, B.; Hei, Y.- J.; Park, K. (13 January 2014). “Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis”.Annals of Oncology 25 (2): 529–536. doi:10.1093/annonc/mdt552.
  7. Jump up^ “Takeda Announces Phase 3 MONET-A Study Evaluating Motesanib (AMG 706) in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Does Not Meet Primary Endpoint”. Takeda Pharmaceutical Company Limited. Retrieved 19 February 2015.
  8.  Martin, Miguel; Roche, Henri; Pinter, Tamas; Crown, John; Kennedy, M John; Provencher, Louise; Priou, Frank; Eiermann, Wolfgang; Adrover, Encarna; Lang, Istvan; Ramos, Manuel; Latreille, Jean; Jagiełło-Gruszfeld, Agnieszka; Pienkowski, Tadeusz; Alba, Emilio; Snyder, Raymond; Almel, Sachin; Rolski, Janusz; Munoz, Montserrat; Moroose, Rebecca; Hurvitz, Sara; Baños, Ana; Adewoye, Henry; Hei, Yong-Jiang; Lindsay, Mary-Ann; Rupin, Matthieu; Cabaribere, David; Lemmerick, Yasmin; Mackey, John R (April 2011). “Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study”. The Lancet Oncology 12 (4): 369–376. doi:10.1016/S1470-2045(11)70037-7. PMID 21429799.
  9. Schilder, R.J.; Sill, M.W.; Lankes, H.A.; Gold, M.A.; Mannel, R.S.; Modesitt, S.C.; Hanjani, P.; Bonebrake, A.J.; Sood, A.K.; Godwin, A.K.; Hu, W.; Alpaugh, R.K. (April 2013). “A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: A Gynecologic Oncology Group study”. Gynecologic Oncology 129 (1): 86–91. doi:10.1016/j.ygyno.2013.01.006. PMID 23321064.
  10. Motesanib Diphosphate Provides Anticancer Activity Among Patients with Progressive Thyroid Cancer, CancerConnect.com
  11. Jump up^ Schlumberger, M. J.; Elisei, R.; Bastholt, L.; Wirth, L. J.; Martins, R. G.; Locati, L. D.; Jarzab, B.; Pacini, F.; Daumerie, C.; Droz, J.-P.; Eschenberg, M. J.; Sun, Y.-N.; Juan, T.; Stepan, D. E.; Sherman, S. I. (29 June 2009). “Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer”.Journal of Clinical Oncology 27 (23): 3794–3801. doi:10.1200/JCO.2008.18.7815. PMID 19564535.
  12. Sherman, Steven I.; Wirth, Lori J.; Droz, Jean-Pierre; Hofmann, Michael; Bastholt, Lars; Martins, Renato G.; Licitra, Lisa; Eschenberg, Michael J.; Sun, Yu-Nien; Juan, Todd; Stepan, Daniel E.; Schlumberger, Martin J. (3 July 2008). “Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer”. New England Journal of Medicine 359 (1): 31–42.doi:10.1056/NEJMoa075853. PMID 18596272.

External links

 

 

Motesanib Diphosphate (AMG-706)

857876-30-3 diphosphate
453562-69-1 (free base)

N-(2,3-Dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide diphosphate

3-​Pyridinecarboxamide, N-​(2,​3-​dihydro-​3,​3-​dimethyl-​1H-​indol-​6-​yl)​-​2-​[(4-​pyridinylmethyl)​amino]​-​, phosphate (1:2)

N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide diphosphate

569.4
Formula C22H23N5O.2H3PO4

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TAKEDA, JAPAN

 

TOKYO HO

Takeda Pharmaceutical CEO Yasuchika Hasegawa

Takeda Pharmaceutical Co. President Christophe Weber is interviewed recently in Tokyo.

Christophe Weber (L), the new president of Takeda Pharmaceutical Co., and CEO Yasuchika Hasegawa pose

 

 

Dr. Paul Chapman of Takeda Pharmaceuticals colors in the eye…

Map of osaka japan

 

OSAKA

 

Dotonbori, Osaka, Japan

OSAKA

 

TAK-733……. clinical studies for cancer treatment.


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: 504.23

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.

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

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

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

Full-size image (17 K)

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.

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.

Full-size image (47 K)
Figure 3.

The X-ray co-crystal structure of TAK-733 in the MEK1 allosteric site.

(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

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.

References:

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.

 

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

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.

Information about this agent

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

   

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.

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.

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

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
US20050222177 * Jul 29, 2004 Oct 6, 2005 Irm Llc Diseases with abnormal activation of the Abl, BCR-Abl, Bmx, CSK, TrkB, FGFR3, Fes, Lck, B-RAF, C-RAF, MKK6, alpha and beta SAPK2 kinases; antiproliferative; pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-phenylcarbamoyl-phenyl]-amides and pyrrolo[3,2-c]pyridine analogs

 

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