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Structure of Bafetinib

Bafetinib

4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide, cas 859212-16-1

4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

859212-07-0 (hydrochloride)

  1. bafetinib
  2. INNO-406
  3. NS-187

Bafetinib , previously as INNO-406 , NS-187 and CNS-9 refers is an experimental drug from the substance group ofbenzamides , who as Tyrosinkinasehemmstoff to be used. [2] It was originally developed by the Japanese company Nippon Shinyaku and 2006 Innovive Pharmaceuticals licensed. [3] Innovive was established in June 2008 by the CytRx Corp. adopted. [4]

Bafetinib, also known as INNO-406,  is an orally bioavailable 2-phenylaminopyrimidine derivative with potential antineoplastic activity. Bafetinib specifically binds to and inhibits the Bcr/Abl fusion protein tyrosine kinase, an abnormal enzyme produced by Philadelphia chromosomal translocation associated with chronic myeloid leukemia (CML). This agent also inhibits the Src-family member Lyn tyrosine kinase, upregulated in imatinib-resistant CML cells and in a variety of solid cancer cell types. The inhibitory effect of bafetinib on these specific tyrosine kinases may decrease cellular proliferation and induce apoptosis in tumor cells that overexpress these kinases. CML patients may be refractory to imatinib, which sometimes results from point mutations occurring in the kinase domain of the Bcr/Abl fusion product. Due to its dual inhibitory activity, the use of bafetinib has been shown to overcome this particular drug resistance.

INNO-406 (formerly NS-187) is a potent, orally available, rationally designed, dual Bcr-Abl and Lyn kinase inhibitor that is currently in early clinical studies at CytRx Oncology for the treatment of B-cell chronic lymphocytic leukemia, metastatic prostate cancer and glioblastoma multiforme. CytRx is also conducting phase I clinical studies for the treatment of recurrent high-grade glioma or metastatic disease to the brain that has progressed after treatment with whole brain radiation therapy or stereotactic radiosurgery.

The company is developing INNO-406 in preclinical studies for the prevention of bone loss in multiple myeloma patients. Nippon Shinyaku is also evaluating the compound for the treatment of chronic myeloid leukemia. The compound had been under evaluation for the treatment of certain forms of acute myeloid leukemia (AML) that are refractory or intolerant of other approved treatments; however, no recent development has been reported for this indication.

Based on its mechanisms of action, INNO-406 is expected to be effective in treating Gleevec-resistant CML and may delay or even prevent the onset of resistance in treatment naive CML patients. The ability of INNO-406 to specifically target the Bcr-Abl and Lyn kinases may result in a better side effect profile than compounds that target multiple kinases such as a pan-Src inhibitor.

In 2005, the compound was licensed to Innovive Pharmaceuticals (acquired by CytRx Oncology in 2008) by Nippon Shinyaku on a worldwide basis, with the exception of Japan, for the treatment of CML. Orphan drug designation was assigned to the compound for the treatment of CML in the U.S in 2007 and in the E.U. in 2010.

Pharmacology

Bafetinib is an inhibitor of tyrosine kinases . It affects the formation of the fusion protein Bcr-Abl , as well as that of theenzyme Lyn kinase and should in mice ten times stronger effect than the imported Tyrosinkinasehemmstoff imatinib .[5]

Patent Submitted Granted
Amide Derivative and Medicine [US7728131] 2008-11-27 2010-06-01

Clinical Development 

Bafetinib currently has no indication for an authorization as medicines .

The drug is intended for the treatment of chronic lymphocytic leukemia are developed (CLL). For this indication is Bafetinib is in the development phase II (June 2011). [6]

Bafetinib is also in phase II for the treatment of hormone-refractory prostate cancer . [7]

The US regulatory authority FDA had Bafetinib end of 2006, the status of a drug orphan (orphan drug) awarded. [8]This status could allow an accelerated development and approval.

N-[3-([5,5′-Bipyrimidin]-2-ylamino)-4-methylphenyl]-4-[[(3S)-3-(dimethyl-amino)-1-pyrrolidinyl]methyl]-3-(trifluoromethyl)benzamide

CAS No .:         887650-05-7

MW:  576.62

Formula: C 30 H 31 F 3 N 8 O

Synonym:        INNO-406, NS-187

Synthesis of Bafetinib

Analytical Chemistry Insights 2007:2 93–106
U.S. Patent 7,728,131
Reference Example 31
4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamideStep 1

4-(bromomethyl)-3-trifluoromethylbenzoic acidTo 60.0 g of 4-methyl-3-trifluoromethylbenzoic acid was added 600 ml of isopropyl acetate. Under stirring at room temperature, a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water were added in turn. The mixture was gradually heated from 30° C. up to 50° C. at intervals of 10° C. and stirred until the color of the reaction solution disappeared. The aqueous layer was separated to remove, and to the organic layer were added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and then the mixture was gradually heated up to 60° C. as above. After separation, to the organic layer were further added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and the mixture was gradually heated as above and heated to the temperature the mixture was finally refluxed. After the completion of the reaction, the reaction solution was separated, the organic layer was washed twice with a 5% aqueous sodium thiosulfate solution and twice with 15% saline, dried over anhydrous magnesium sulfate, and, then the solvent was distilled off under reduced pressure. To the residue was added 120 ml of n-heptane, the mixture was stirred, and then the crystals were collected by filtration to obtain 50.0 g of the objective compound as colorless crystals.

Melting point: 140-143° C.

Step 2

4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide7.69 g of 4-(bromomethyl)-3-trifluoromethylbenzoic acid obtained in the step 1 was suspended in 154 ml of anhydrous dichloromethane. Under ice-cool stirring, 6.59 ml of oxalyl chloride and 0.1 ml of anhydrous N,N-dimethylformamide were added dropwise. Under ice cooling, the mixture was further stirred for 3 hours, and then the reaction solution was concentrated under reduced pressure. To the residue was added 70 ml of anhydrous 1,4-dioxane, and then 7.00 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) and 4.18 g of potassium carbonate were added in turn, followed by stirring at room temperature for 18 hours. To the reaction solution was added 175 ml of water, and the mixture was violently stirred for one hour. Then, the deposit was collected by filtration and washed in turn with water, a small amount of acetonitrile, ethyl acetate and diisopropyl ether to obtain 8.10 g of the objective compound as pale yellow crystals.

Melting point: 198-202° C. (with decomposition)

Example 47
4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

To a solution of 6.00 g of 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide (Reference Example 31) in 60 ml of anhydrous N,N-dimethylformamide were added 1.51 g of (S)-(−)-3-(dimethylamino)pyrrolidine and 1.83 g of potassium carbonate, followed by stirring at room temperature for 14 hours. To the reaction solution were added water and an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.57 g of pale yellow crystals.

Melting point: 179-183° C. (with decomposition)

……………………………..
Bioorg Med Chem Lett 2006, 16(5): 1421

A series of 3-substituted benzamide derivatives of STI-571 (imatinib mesylate) was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. Several 3-halogenated and 3-trifluoromethylated compounds, including NS-187, showed excellent potency.

Full-size image (6 K)

 

Full-size image (12 K)Bafetinib

Figure 1.

Chemical structures of STI-571 and NS-187 (9b).

 

Full-size image (32 K)

Scheme 2.

Reagents and conditions: (a) NaBrO3, NaHSO3, EtOAc; (b) (COCl)2, cat. DMF, CH2Cl2, rt; (c) 7, K2CO3, dioxane, rt; (d) cyclic amines, K2CO3, DMF, rt.

 

………………………………

Bioorganic and Medicinal Chemistry Letters, 2007 ,  vol. 17,  10  pg. 2712 – 2717

 

CHEMBL206834.pngBafetinib

References 

  1.  This substance has not yet been rated on their dangerousness either in terms of which a reliable and quotable source for this purpose has not been found.
  2.  A. Quintas-Cardama include: Flying under the radar: the new wave of BCR-ABL inhibitors. In: Nature Reviews Drug Discovery 6/2007, pp 834-848, PMID 17853901 .
  3. Nippon Shinyaku. press release dated January 5, 2006 (s.) , accessed on 25 February 2011th
  4.  Drugs.com: Signs Definitive Agreement Cytrx Corporation to Acquire Innovive Pharmaceuticals, Inc. Retrieved June 17, 2011
  5. H. Naito include: In vivo antiproliferative effect of NS-187, a dual Bcr-Abl / Lyn tyrosine kinase inhibitor, on leukemic cells harbourage ring-Abl kinase domain mutations.In: . Leukemia Research 30/2006, pp 1443-1446, PMID 16546254 .
  6.  ClinicalTrials.gov: Study of Bafetinib as Treatment for relapsed or Refractory Chronic Lymphocytic Leukemia B-Cell (B-CLL). Retrieved on June 17, 2011th
  7. ClinicalTrials.gov: Study of Bafetinib (INNO-406) as Treatment for Patients With Hormone-Refractory Prostate Cancer (PROACT). Retrieved on June 17, 2011th
  8.  Food and Drug Administration: Database summary of 27 December of 2006. Accessed on 16 September, 2009.

Literature 

External links 

References

1: Peter B, Hadzijusufovic E, Blatt K, Gleixner KV, Pickl WF, Thaiwong T, Yuzbasiyan-Gurkan V, Willmann M, Valent P. KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406). Exp Hematol. 2010 Sep;38(9):782-91. doi: 10.1016/j.exphem.2010.05.004. Epub 2010 May 26. PubMed PMID: 20685234.

2: Kantarjian H, le Coutre P, Cortes J, Pinilla-Ibarz J, Nagler A, Hochhaus A, Kimura S, Ottmann O. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010 Jun 1;116(11):2665-72. doi: 10.1002/cncr.25079. PubMed PMID: 20310049; PubMed Central PMCID: PMC2876208.

3: Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia. 2010 Jan;24(1):44-50. doi: 10.1038/leu.2009.228. Epub 2009 Nov 5. PubMed PMID: 19890374.

4: Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008 Nov;15(11):1712-22. doi: 10.1038/cdd.2008.107. Epub 2008 Jul 11. PubMed PMID: 18617896.

5: Morinaga K, Yamauchi T, Kimura S, Maekawa T, Ueda T. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer. 2008 Jun 1;122(11):2621-7. doi: 10.1002/ijc.23435. PubMed PMID: 18338755.

6: Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, Maekawa T. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res. 2008 Jun;32(6):980-3. doi: 10.1016/j.leukres.2007.11.008. Epub 2008 Jan 8. PubMed PMID: 18191450.

7: Pan J, Quintás-Cardama A, Manshouri T, Cortes J, Kantarjian H, Verstovsek S. Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406. Cancer Sci. 2007 Aug;98(8):1223-5. Epub 2007 May 22. PubMed PMID: 17517053.

8: Kuroda J, Kimura S, Strasser A, Andreeff M, O’Reilly LA, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Tabe Y, Taniwaki M, Maekawa T. Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ. 2007 Sep;14(9):1667-77. Epub 2007 May 18. PubMed PMID: 17510658.

9: Maekawa T. [Innovation of clinical trials for anti-cancer drugs in Japan–proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia]. Gan To Kagaku Ryoho. 2007 Feb;34(2):301-4. Japanese. PubMed PMID: 17301549.

10: Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007 Nov 14;2:93-106. PubMed PMID: 19662183; PubMed Central PMCID: PMC2716809.

11: Yokota A, Kimura S, Masuda S, Ashihara E, Kuroda J, Sato K, Kamitsuji Y, Kawata E, Deguchi Y, Urasaki Y, Terui Y, Ruthardt M, Ueda T, Hatake K, Inui K, Maekawa T. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood. 2007 Jan 1;109(1):306-14. Epub 2006 Sep 5. PubMed PMID: 16954504.

Bafetinib

Bafetinib in its binding site


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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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