Tivozanib

Target :  VEGFRs 1-3.

Synthesis of Tivozanib

Synthesis of Sunitinib

Synthesis of key intermediate

Sun, L.; Liang, C; Shirazian, S.; Zhou, Y.; Miller, T.; Cui, J.; Fukuda, J. Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T. C; Tang, F.; Wei, J.; Tang C. J. Med. Chem. 2003, 46, 1116-1119
Tang, P. C; Miller, T.; Li, X.; Sun, L.; Wei, C. C; Shirazian, S.; Liang, C; Vojkovsky, T.; Nematalla, A. S.; WO 01/060814,2001.
First metod

Other methods

Manley, J. M.; Kaiman, M. J.; Conway, B. G.; Ball, C. C; Havens, J. L.;
Vaidyanathan, R. J. Org. Chem. 2003, 68, 6447-6450.

Vaidyanathan, R. In Process Chemistry in the Pharmaceutical Industry, Ed.
Braish, T. and Gadamasetti, K. CRC Press, Boca Raton, Fl, 2008, 49-63.

Havens, J. L.; Vaidyanathan, R. U.S. Pat. 06/0009510, 2006.

 

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Beilstein J. Org. Chem. 2011, 7, 442–495.

Synthesis of Gefinitib

D'Souza, N., Castañer, J., Levin, M., Iressa. Drugs Fut 2002, 27, 4, 339.

Gibson K.H., Quinazoline derivs.. EP 0823900; JP 1999504033; US 5770599; WO 9633980 .

Gibson K.H., Grundy W., Barker A.J. et al.; Studies leading to the identification of ZD1839 (Iressa): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001, 11, 14, 1911.

Molecules 2006, 11, 286-297



Synthesis of Gefitinib from Methyl 3-Hydroxy-4-methoxy-benzoate

Foretinib

Foretinib (synonim - GSK1363089) is a new MET and VEGFR2/KDR inhibitor (IC50 of 0.4 and 0.8 nM,respectively. Foretinib inhibits HGF receptor family tyrosine kinases - Ron (IC50 of 3 nM). Foretinib inhibits KDR, Flt-1, Flt-4 and KDR (IC50 of 6.8,2.8 nM and 0.9, respectively). In addition, foretinib inhibits members of PDGF family and the angiopoietin-1 receptor Tie-2. Foretinib exhibits modest activity against FGFR-1 and epidermal GFR and is inactive against 50 serinе/threonine kinases, including cyclin-dеpendent kinasеs and protеin kinase C isoforms. To dеlinеate the cеllular effect of foretinib, VEGF - inducеd extracellular signal- regulated kinasе phosphorylation was used to assess the effect of the compound on phosphorylation of KDR in umbilical vein endothelial cells that resulted in an IC50 of 16 nM. Foretinib is the first orally available inhibitor of Met. Anticancer activity has been observed and Foretinib may represent for patients with renal-cell carcinoma.

Anti-Cancer Agents in Medicinal Chemistry, 2010, 10, 7-27

oretinib (GSK1363089, XL880) является новмй мультикиназным МЕТ и VEGFR2/KDR ингибитором (IC50 0.4 и 0.8 нМ, соответственно). Foretinib ингибирует HGF рецепторов тирозинкиназы HGF (IC50 3 нм для Rон). Foretinib ингибирует Flt-1, Flt-4 и KDR (IC50 6.8, 2.8 b 0.9 нм соответственно). Кроме того, он ингибирует семейство тромбоцитарного рецептор фактора роста и ангиопоэтина-1 рецептор Tie-2. Foretinib имеет небольшую активность в отношении фактора роста фибробластов рецептора 1 и рецептора эпидермального фактора роста и неактивен в отношении 50 серин/треонин киназ, в том числе циклин-зависимых киназ и протеинкиназы С изоформ. 

Foretinib является первым представителем малых молекул ингибиторов МET. Противораковая активность Foretinib может использована для лечения пациентов с диагнозом почечно-клеточный рак.

Foretinib is a small-molecule inhibitor of HGF and VEGF receptor tyrosine kinases with single-digit nanomolar IC50 values. It also inhibits KIT, Flt-3, PDGFR-beta and Tie-2. Foretinib exerted cytotoxicity against a broad panel of cancer cell lines. It also reduced tumor cell migration, invasion, and tumor-induced angiogenesis.

catalogue number: F166
synonyms: EXEL-2880, XL880, GSK1363089
CAS: 849217-64-7
MW: 632.65 g/mol

References
Cancer Res. 2009 Oct 15;69(20):8009-16.
Structure of the kinase domain of c-Met/HGFR bound to foretinib PDB: 3LQ8

Synthesis of Gefitinib from Methyl 3-Hydroxy-4-methoxybenzoate

Статья описывает все существующие варианты синтеза Gefinitib и предлагает новый.
Report describes all existing variants of synthesis Gefinitib and offers the new method.
http://www.mdpi.org/molecules/papers/12030673.pdf

Palladia (toceranib)

Palladia

Pfizer announced Palladia a new drug developed to treate cancer in dogs

Пфайзер аннонсировал Палладию, как новое лекарственное средство для лечения рака у собак

Synthesis of Imatinib

(a) Zimmermann, J. EP Patent 564,409, 1993.

(b) Zimmermann, J. U.S. Patent 5,521,184, 1996.

(c) Zimmermann, J.; Buchdunger, E.;Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Bioorg. Med. Chem.Lett. 1996, 11, 1221.

Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H. M.; Meisenbach, M.; Schmitz, B.; Sedelmeier, G. W.O.Patent 03/066,613, 2003.

Organic Process Research & Development  2008, 12, 490–495 

United States Patent 7674901

Process for preparation of imatinib base

An improved process for the preparation of imatinib base and its pharmaceutically acceptable acid addition salts by (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-(chloromethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; and (g) condensing 4-(chloromethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; and adding water or a mixture of water and an organic solvent; and isolating said imatinib base. The process allows for using simple starting materials, while simultaneously avoiding a laborious isolation and purification of intermediates and the final product, thereby facilitating scale-up.

The synthesis of Bcr-Abl inhibiting anticancer
pharmaceutical agents imatinib, nilotinib and dasatinib
Benjamin J. Deadman,a Mark D. Hopkin,a Ian R. Baxendaleb and Steven V. Ley*a
 

Org. Biomol. Chem., 2013, Advance Article