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Mini-Reviews in Medicinal Chemistry

Author(s): Amit Kumar, Ankit Siwach and Prabhakar Verma*

DOI: 10.2174/1389557521666211008153329

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An Overview of the Synthetic Route to the Marketed Formulations of Pyrimidine: A Review

Page: [884 - 903] Pages: 20

  • * (Excluding Mailing and Handling)

Abstract

Pyrimidine and its derivatives are a very important class of heterocyclic compounds that show interesting applications in the field of medicinal chemistry. Pyrimidine not only plays an important role as an organic reaction intermediate but also has a wide range of interesting biological activities viz. antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal activities, etc. Numerous methods are available for the formation of pyrimidine derivatives that have been reported in the literature. The advantage of pyrimidine as a starting material for different therapeutically potent derivatives has given momentum to this research. This review aims to report the new work on the synthesis of marketed drugs which consist pyrimidine moiety.

Keywords: Pyrimidine, heterocyclic compounds, marketed drugs, antimicrobial, anticancer, antiviral.

Graphical Abstract

[1]
Patel, A.A.; Mehta, A.G. Synthesis of novel heterocyclic compounds and their biological evaluation. Pharma Chem., 2010, 2(1), 215-223.
[2]
Narwal, S.; Kumar, S.; Verma, P.K. Design, synthesis and antimicrobial evaluation of pyrimidin-2-ol/thiol/amine analogues. Chem. Cent. J., 2017, 11(1), 52.
[http://dx.doi.org/10.1186/s13065-017-0284-2] [PMID: 29086852]
[3]
Kogon, I.C.; Minin, R.; Overberger, C.G. 2‐Chloropyrimidine: Pyrimidine, 2‐chloro‐. Org. Synth., 2003, 35, 34.
[http://dx.doi.org/10.15227/orgsyn.035.0034]
[4]
Overberger, C.G.; Kogon, I.C.; Minin, R. 2‐(Dimethylamino) pyrimidine: Pyrimidine, 2‐dimethylamino. Org. Synth., 2003, 35, 58-58.
[5]
Brown, D.J.; Evans, R.F.; Cowden, W.B.; Fenn, M.D. The Pyrimidines. J. Wiley & Sons Inc , 1994; 24, p. 472.
[6]
Foster, H.M.; Snyder, H.R. 4-Methyl-6-hydroxypyrimidine. Org. Synth., 2003, 35, 80.
[http://dx.doi.org/10.15227/orgsyn.035.0080]
[7]
Bredereck, H. 4-methylpyrimidine‐. Org. Synth., 1963, 43, 77.
[http://dx.doi.org/10.15227/orgsyn.043.0077]
[8]
Mallikarjunaswamy, C.; Mallesha, L.; Bhadregowda, D.G.; Pinto, O. Studies on synthesis of pyrimidine derivatives and their antimicrobial activity. Arab. J. Chem., 2017, 10, S484-S490.
[http://dx.doi.org/10.1016/j.arabjc.2012.10.008]
[9]
Bhalgat, C.M.; Ramesh, B. Synthesis, antimicrobial screening, and structure-activity relationship of novel pyrimidines and their thioethers. Bull. Fac. Pharm. Cairo Univ., 2014, 52, 259-267.
[http://dx.doi.org/10.1016/j.bfopcu.2014.08.001]
[10]
Mohamed Ahmed, M.S.; Farghaly, T.A. Antimicrobial activity of [1, 2, 4] triazolo [4, 3-a] pyrimidine and new pyrido [3, 2-f][1, 4] thiazepine derivatives. Lett. Org. Chem., 2018, 15(3), 183-190.
[http://dx.doi.org/10.2174/1570178614666171010161751]
[11]
Kulkarni, R.; Kompalli, K.; Gaddam, N.; Chandrashekar, V.; Darna, B.; Garlapati, A.; Machha, B. Synthesis, characterization, antitubercular and anti-inflammatory activity of new pyrazolo [3, 4-d] pyrimidines. Comb. Chem. High T. Scr., 2020.
[http://dx.doi.org/10.2174/1386207323999200918114905]
[12]
Mavrova, A.; Dimov, S.; Vuchev, D.; Anichina, K.; Yancheva, D. Antihelminthic activity of Some 2-substituted thieno [2, 3-d] pyrimidin-4-ones. Lett. Drug Des. Discov., 2018, 15(8), 887-894.
[http://dx.doi.org/10.2174/1570180814666171027161555]
[13]
Kumar, S.; Deep, A.; Narasimhan, B. A review on synthesis, anticancer and antiviral potentials of pyrimidine derivatives. Curr. Bioact. Compd., 2019, 15(3), 289-303.
[http://dx.doi.org/10.2174/1573407214666180124160405]
[14]
Kumar, S.; Narasimhan, B.; Lim, S.M.; Ramasamy, K.; Mani, V.; Shah, S.A.A. Design, synthesis and biological potential of 5-(2-amino-6-(3/4-bromophenyl) pyrimidin-4-yl) benzene-1, 3-diol scaffolds as promising antimicrobial and anticancer agents. Mini Rev. Med. Chem., 2019, 19(10), 851-864.
[http://dx.doi.org/10.2174/1389557518666181009141924] [PMID: 30306864]
[15]
Chiacchio, M.A.; Iannazzo, D.; Romeo, R.; Giofr, A". S.V.; Legnani, L. Pyridine and pyrimidine derivatives as privileged scaffolds in biologically active agents. Curr. Med. Chem., 2019, 26(40), 7166-7195.
[http://dx.doi.org/10.2174/0929867325666180904125400] [PMID: 30182842]
[16]
Matada, G.S.; Abbas, N.; Dhiwar, P.S.; Basu, R.; Devasahayam, G. Design, synthesis, in silico, and in vitro evaluation of novel pyrimidine derivatives as EGFR inhibitors. Anticancer. Agents Med. Chem., 2020.
[http://dx.doi.org/10.2174/1871520620666200721102726] [PMID: 32698735]
[17]
Hosny, M.A.; Zaki, Y.H.; Mokbel, W.A.; Abdelhamid, A.O. Synthesis, characterization, antimicrobial activity and anticancer of some new pyrazolo [1, 5-a] pyrimidines and pyrazolo [5, 1-c] 1, 2, 4-triazines. Med. Chem., 2019.
[http://dx.doi.org/10.2174/1573406415666190620144404] [PMID: 31218963]
[18]
Tripathi, M.; Taylor, D.; Khan, S.I.; Tekwani, B.L.; Ponnan, P.; Das, U.S.; Velpandian, T.; Rawat, D.S. Hybridization of fluoro-amodiaquine (FAQ) with pyrimidines: Synthesis and antimalarial efficacy of FAQ–pyrimidines. ACS Med. Chem. Lett., 2019, 10(5), 714-719.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00496] [PMID: 31097988]
[19]
Sharma, P.; Rane, N.; Pandey, P. Synthesis and evaluation of antimicrobial activity of novel hydrazino and N-benzylidinehydrazino-substituted 4,8-dihydro-1H,3H-pyrimido[4,5-d]pyrimidin-2,7-dithiones. Arch. Pharm. (Weinheim), 2006, 339(10), 572-578.
[http://dx.doi.org/10.1002/ardp.200600067] [PMID: 17009302]
[20]
Filian, H.; Kohzadian, A.; Mohammadi, M.; Ghorbani‐Choghamarani, A.; Karami, A. Pd (0)‐guanidine@ MCM‐41: A very effective catalyst for rapid production of bis (pyrazolyl) methanes. Appl. Organomet. Chem., 2020, 34(6), e5579.
[http://dx.doi.org/10.1002/aoc.5579]
[21]
Nikoorazm, M.; Khanmoradi, M.; Mohammadi, M. Guanine‐La complex supported onto SBA‐15: A novel efficient heterogeneous mesoporous nanocatalyst for one‐pot, multi‐component Tandem Knoevenagel condensation–Michael addition–cyclization Reactions. Appl. Organomet. Chem., 2020, 34(4), e5504.
[http://dx.doi.org/10.1002/aoc.5504]
[22]
Tamoradi, T.; Mousavi, S.M.; Mohammadi, M. Praseodymium (iii) anchored on CoFe 2 O 4 MNPs: an efficient heterogeneous magnetic nanocatalyst for one-pot, multi-component domino synthesis of polyhydroquinoline and 2, 3-dihydroquinazolin-4 (1 H)-one derivatives. New J. Chem., 2020, 44(7), 3012-3020.
[http://dx.doi.org/10.1039/C9NJ05468E]
[23]
Kazemi, M.; Mohammadi, M. Magnetically recoverable catalysts: catalysis in synthesis of polyhydroquinolines. Appl. Organomet. Chem., 2020, 34(3), e5400.
[http://dx.doi.org/10.1002/aoc.5400]
[24]
Tamoradi, T.; Mousavi, S.M.; Mohammadi, M. Synthesis of a new Ni complex supported on CoFe 2 O 4 and its application as an efficient and green catalyst for the synthesis of bis (pyrazolyl) methane and polyhydroquinoline derivatives. New J. Chem., 2020, 44(20), 8289-8302.
[http://dx.doi.org/10.1039/D0NJ00223B]
[25]
Ghorbani‐Choghamarani, A.; Aghavandi, H.; Mohammadi, M. Boehmite@ SiO2@ Tris (hydroxymethyl) aminomethane‐Cu (I): A novel, highly efficient and reusable nanocatalyst for the C‐C bond formation and the synthesis of 5‐substituted 1H‐tetrazoles in green media. Appl. Organomet. Chem., 2020, 34(10), e5804.
[http://dx.doi.org/10.1002/aoc.5804]
[26]
Nikoorazm, M.; Mohammadi, M.; Khanmoradi, M. Zirconium@ guanine@ MCM‐41 nanoparticles: An efficient heterogeneous mesoporous nanocatalyst for one‐pot, multi‐component tandem Knoevenagel condensation–Michael addition–cyclization Reactions. Appl. Organomet. Chem., 2020.
[http://dx.doi.org/10.1002/aoc.5704]
[27]
Esam, Z.; Akhavan, M.; Bekhradnia, A.; Mohammadi, M.; Tourani, S. A novel magnetic immobilized para-aminobenzoic acid-Cu (II) complex: A green, efficient and reusable catalyst for aldol condensation reactions in green media. Catal. Lett., 2020, 1-20.
[http://dx.doi.org/10.1007/s10562-020-03216-w]
[28]
Rossi, A.; Vecchio, E.; Pizzocaro, R.; Bedeschi, A. Process of Preparation of Abacavir. Eur. Patent EP 1857458A1 2007.
[29]
Fier, P.S.; Hartwig, J.F. Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution. J. Am. Chem. Soc., 2014, 136(28), 10139-10147.
[http://dx.doi.org/10.1021/ja5049303] [PMID: 24918484]
[30]
Martin, M.A.; Kroetz, D.L. Abacavir pharmacogenetics–from initial reports to standard of care. Pharmacotherapy. J. Human Pharm. Drug Ther., 2013, 33, 765-775.
[http://dx.doi.org/10.1002/phar.1278] [PMID: 23649914]
[31]
Abacavir. Available from: https://www.webmd.com/drugs/2/drug-16830/abacavir-oral/details (last access on 03-07-2020)
[32]
Kar, A. Medicinal Chemistry.New Age International (P) Limited, 2007.
[33]
Pacher, P.; Nivorozhkin, A. SzabA3, C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., 2006, 58(1), 87-114.
[http://dx.doi.org/10.1124/pr.58.1.6] [PMID: 16507884]
[34]
Cameron, J.S.; Moro, F.; Simmonds, H.A. Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr. Nephrol., 1993, 7(1), 105-118.
[http://dx.doi.org/10.1007/BF00861588] [PMID: 8439471]
[35]
Allopurinol. Available from: https://www.medicinenet.com/allopurinol-oral/article.htm (last access on 03-07-2020)
[36]
Perry, M. J. The Chemotherapy sourcebook; Wolters Kluwer Health/Lippincott Williams & Wilkins: Philadelphia, 2008, p. 80.
[37]
Cytarabine. Available from: http://chemocare.com/chemotherapy/drug-info/cytarabine.aspx (last access on 03-07-2020)
[38]
Ramesh, C.; Reddy, R.B.; Reddy, G.M. An improved one-pot synthesis of N-(2, 3-dihydrobenzo [1, 4] dioxin-2-carbonyl) piperazine useful intermediate for anti-hypertensive drug doxazosin. Heterocycl. Commun., 2006, 12, 373-376.
[http://dx.doi.org/10.1515/HC.2006.12.5.373]
[39]
Chung, M.; Vashi, V.; Puente, J.; Sweeney, M.; Meredith, P. Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation. Br. J. Clin. Pharmacol., 1999, 48(5), 678-687.
[http://dx.doi.org/10.1046/j.1365-2125.1999.00067.x] [PMID: 10594469]
[40]
Doxazosin. Available from: https://www.rxlist.com/consumer_doxazosin_cardura/drugs-condition. htm (last access on 03-07-2020).
[41]
Chandregowda, V.; Rao, G.V.; Reddy, G.C. Improved synthesis of gefitinib and erlotinib hydrochloride‐ Anticancer agents. Synth. Commun., 2007, 37, 3409-3415.
[http://dx.doi.org/10.1080/00397910701483761]
[42]
Raymond, E.; Faivre, S.; Armand, J.P. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs, 2000, 60(1)(Suppl. 1), 15-23.
[http://dx.doi.org/10.2165/00003495-200060001-00002] [PMID: 11129168]
[43]
Erlotinib. Available from: https://reference.medscape.com/drug/tarceva-erlotinib-342270 (last access on 03-07-2020).
[44]
Feng, D.; Wei, F.; Wang, Z.; Kang, D.; Zhan, P.; Liu, X. Development of a practical synthesis of etravirine via a microwave-promoted amination. Chem. Cent. J., 2018, 12(1), 144.
[http://dx.doi.org/10.1186/s13065-018-0504-4] [PMID: 30569261]
[45]
Joshi, S.; Maikap, G.C.; Titirmare, S.; Chaudhari, A.; Gurjar, M.K. An improved synthesis of etravirine. Org. Process Res. Dev., 2010, 14(3), 657-660.
[http://dx.doi.org/10.1021/op9003289]
[46]
Das, K.; Clark, A.D., Jr; Lewi, P.J.; Heeres, J.; De Jonge, M.R.; Koymans, L.M.; Vinkers, H.M.; Daeyaert, F.; Ludovici, D.W.; Kukla, M.J.; De Corte, B.; Kavash, R.W.; Ho, C.Y.; Ye, H.; Lichtenstein, M.A.; Andries, K.; Pauwels, R. De BA(c)thune, M.P.; Boyer, P.L.; Clark, P.; Hughes, S.H.; Janssen, P.A.; Arnold, E. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem., 2004, 47(10), 2550-2560.
[http://dx.doi.org/10.1021/jm030558s] [PMID: 15115397]
[47]
Berma, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. Theprotein data bank, 2000.
[48]
Kang, D.; Ruiz, F.X.; Feng, D.; Pilch, A.; Zhao, T.; Wei, F.; Wang, Z.; Sun, Y.; Fang, Z.; De Clercq, E.; Pannecouque, C.; Arnold, E.; Liu, X.; Zhan, P. Discovery and characterization of fluorine-substituted diarylpyrimidine derivatives as novel HIV-1 NNRTIs with highly improved resistance profiles and low activity for the hERG ion channel. J. Med. Chem., 2020, 63(3), 1298-1312.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01769] [PMID: 31935327]
[49]
Szczepek, W.; Luniewski, W.; Kaczmarek, L.; Zagrodzki, B.; Samson-Lazinska, D.; Szelejewski, W.; Skarzynski, M. Process for preparation of imatinib base. U.S. Patent 7,674,901 B2, 2010.
[50]
Imatinib. Available from: https://en.wikipedia.org/wiki/Imatinib#Mechanism_of_action (last access on 03-07-2020).
[51]
Imatinib. Available from: http://chemocare.com/chemotherapy/drug-info/imatinib-mesylate
[52]
Smith, C.J. Iglesias-SigA1/4enza, F.J.; Baxendale, I.R.; Ley, S.V. Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines. Org. Biomol. Chem., 2007, 5(17), 2758-2761.
[http://dx.doi.org/10.1039/b709043a] [PMID: 17700841]
[53]
Petroski, R.E.; Pomeroy, J.E.; Das, R.; Bowman, H.; Yang, W.; Chen, A.P.; Foster, A.C. Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J. Pharmacol. Exp. Ther., 2006, 317(1), 369-377.
[http://dx.doi.org/10.1124/jpet.105.096701] [PMID: 16399882]
[54]
Lankford, A. Indiplon in the treatment of sleep disorders. Neuropsychiatr. Dis. Treat., 2007, 3(6), 765-773.
[PMID: 19300612]
[55]
Jin, H.; Siddiqui, M.A.; Evans, C.A.; Tse, H.L.A.; Mansour, T.S.; Goodyear, M.D.; Ravenscroft, P.; Beels, C.D.J. Diastereoselective synthesis of the potent antiviral agent (-)-2'-Deoxy-3'-thiacytidine and its enantiomer. Org. Chem., 1995, 60, 2621-2623.
[http://dx.doi.org/10.1021/jo00113a050]
[56]
Lamivudine. Available from: https://en.wikipedia.org/wiki/Lamivudine/mechanism (last access on 03-07-2020).
[57]
Lamivudine. Available from: https://aidsinfo.nih.gov/drugs/126/lamivudine/0/patient/ (last access on 03-07-2020).
[58]
Nishino, S.; Hirotsu, K.; Shima, H.; Harada, T.; Oda, H. Process for producing 4-aminoquinazoline compounds. Eur. Patent EP 1 481 971 B1, 2011.
[59]
Wood, E.R.; Truesdale, A.T.; McDonald, O.B.; Yuan, D.; Hassell, A.; Dickerson, S.H.; Ellis, B.; Pennisi, C.; Horne, E.; Lackey, K.; Alligood, K.J.; Rusnak, D.W.; Gilmer, T.M.; Shewchuk, L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): Relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res., 2004, 64(18), 6652-6659.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1168] [PMID: 15374980]
[60]
Oakman, C.; Pestrin, M.; Zafarana, E.; Cantisani, E.; Di Leo, A. Role of lapatinib in the first-line treatment of patients with metastatic breast cancer. Cancer Manag. Res., 2010, 2, 13-25.
[PMID: 21188093]
[61]
Anthony, W.C.; Ursprung, J.J. 6-amino-1, 2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines. U.S. Patent No. 3,382,247, 1968.
[62]
Freire, P.C.B.; Riera, R.; Martimbianco, A.L.C.; Petri, V.; Atallah, A.N. Minoxidil for patchy alopecia areata: Systematic review and meta-analysis. J. Eur. Acad. Dermatol. Venereol., 2019, 33(9), 1792-1799.
[http://dx.doi.org/10.1111/jdv.15545] [PMID: 30835901]
[63]
Lippa, A.S.; Chen, Z.; Skolnick, P. Salts and co-crystals of pyrazolopyrimidine compounds, compositions thereof, and methods for their production and use. U. S. Patent 2008/0045547 A1, 2008.
[64]
Lippa, A.; Czobor, P.; Stark, J.; Beer, B.; Kostakis, E.; Gravielle, M.; Bandyopadhyay, S.; Russek, S.J.; Gibbs, T.T.; Farb, D.H.; Skolnick, P. Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator. Proc. Natl. Acad. Sci. USA, 2005, 102(20), 7380-7385.
[http://dx.doi.org/10.1073/pnas.0502579102] [PMID: 15870187]
[65]
Belyk, K.M.; Morrison, H.G.; Jones, P.; Summa, V. Potassium salt of an HIV-integrase inhibitor. WO Patent 2006/060712 A2, 2006.
[66]
Caputo, F.; Corbetta, S.; Piccolo, O.; Vigo, D. Seeking for selectivity and efficiency: New approaches in the synthesis of raltegravir. Org. Process Res. Dev., 2020, 24(6), 1149-1156.
[http://dx.doi.org/10.1021/acs.oprd.0c00155]
[67]
Raltegravir. Available from: https://aidsinfo.nih.gov/drugs/420/raltegravir/13/professional#S12.4 (last access on 03-07-2020).
[68]
Ramkumar, K.; Neamati, N. Raltegravir: The evidence of its therapeutic value in HIV-1 infection. Core Evid., 2010, 4, 131-147.
[PMID: 20694070]
[69]
Istvan, E.S.; Deisenhofer, J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science, 2001, 292(5519), 1160-1164.
[http://dx.doi.org/10.1126/science.1059344] [PMID: 11349148]
[70]
Liao, J.K.; Laufs, U. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 89-118.
[http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095748] [PMID: 15822172]
[71]
Baxendale, I.R.; Ley, S.V. Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil. Bioorg. Med. Chem. Lett., 2000, 10(17), 1983-1986.
[http://dx.doi.org/10.1016/S0960-894X(00)00383-8] [PMID: 10987432]
[72]
Gong, B.; Ma, M.; Xie, W.; Yang, X.; Huang, Y.; Sun, T.; Luo, Y.; Huang, J. Direct comparison of tadalafil with sildenafil for the treatment of erectile dysfunction: A systematic review and meta-analysis. Int. Urol. Nephrol., 2017, 49(10), 1731-1740.
[http://dx.doi.org/10.1007/s11255-017-1644-5] [PMID: 28741090]
[73]
Stober, H.; DeWitte, W. Sulfadiazine. In: Analytical profiles of drug substances; Academic Press , 1982; 11, pp. 523-551.
[74]
Sulfadiazine. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/sulfadiazine (last access on 03-07-2020).
[75]
Woolfenden, R.D. Sulphamerazine. In: Analytical profiles of drug substances; Academic Press, , 1977; 6, pp. 515-577.
[76]
Sulfamerazine. Available from: https://www.pharmacompass.com/chemistry-chemical-name/ (last access on 03-07-2020).
[77]
Zhang, Q.; Ma, B.W.; Wang, Q.Q.; Wang, X.X.; Hu, X.; Xie, M.S.; Qu, G.R.; Guo, H.M. The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation. Org. Lett., 2014, 16(7), 2014-2017.
[http://dx.doi.org/10.1021/ol500583d] [PMID: 24650095]
[78]
Ray, A.S.; Fordyce, M.W.; Hitchcock, M.J. Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res., 2016, 125, 63-70.
[http://dx.doi.org/10.1016/j.antiviral.2015.11.009] [PMID: 26640223]
[79]
Ebbens, M.M.; Verster, J.C. Clinical evaluation of zaleplon in the treatment of insomnia. Nat. Sci. Sleep, 2010, 2, 115-126.
[PMID: 23616704]
[80]
Granito, A.; Marinelli, S.; Terzi, E.; Piscaglia, F.; Renzulli, M.; Venerandi, L.; Benevento, F.; Bolondi, L. Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure. Dig. Liver Dis., 2015, 47(6), 518-522.
[http://dx.doi.org/10.1016/j.dld.2015.03.010] [PMID: 25861840]
[81]
Marinelli, S.; Granito, A.; Piscaglia, F.; Renzulli, M.; Stagni, A.; Bolondi, L. Metronomic capecitabine in patients with hepatocellular carcinoma unresponsive to or ineligible for sorafenib treatment: Report of two cases. Hepat. Mon., 2013, 13(9), e11721.
[http://dx.doi.org/10.5812/hepatmon.11721] [PMID: 24282421]
[82]
Trevisani, F.; Brandi, G.; Garuti, F.; Barbera, M.A.; Tortora, R.; Casadei Gardini, A.; Granito, A.; Tovoli, F.; De Lorenzo, S.; Inghilesi, A.L.; Foschi, F.G.; Bernardi, M.; Marra, F.; Sacco, R.; Di Costanzo, G.G. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. J. Cancer Res. Clin. Oncol., 2018, 144(2), 403-414.
[http://dx.doi.org/10.1007/s00432-017-2556-6] [PMID: 29249005]