Synthetic Approaches to Gliflozins: A Comprehensive Overview

Abstract

Diabetes mellitus, commonly referred to as diabetes, is a persistent medical condition that contributes to a significant global mortality rate and various associated complications in individuals. To address the needs of those diagnosed with type 2 diabetes, the pharmaceutical market offers a range of antidiabetic medications. Among these options, gliflozins stand out as highly efficacious therapeutic agents for the management of type 2 diabetes. These medications inhibit the function of sodium–glucose linked transporter (SGLT) enzymes in the kidneys, effectively halting the reabsorption of sugar and leading to a reduction in the overall glucose load within the bloodstream. This review aims at providing a comprehensive overview of the various syntheses for each of the gliflozin drugs reported in the literature and also summarizes the synthetic advancements in this area to date.

1 Introduction

2 Synthesis of Gliflozins

2.1 Canagliflozin

2.2 Dapagliflozin

2.3 Ipragliflozin

2.4 Empagliflozin

2.5 Luseogliflozin

2.6 Tofogliflozin

2.7 Ertugliflozin

2.8 Sotagliflozin

2.9 Licogliflozin

2.10 Remogliflozin

2.11 Henagliflozin

2.12 Bexagliflozin

2.13 Janagliflozin

2.14 Velagliflozin

2.15 Sergliflozin Etabonate

2.16 Enavogliflozin

3 Conclusion

Key words

gliflozins - diabetes mellitus - sodium–glucose co-transporters - SGLT1/2 inhibitors - synthetic methodology

Publication History

Received: 14 August 2023

Accepted after revision: 19 October 2023

Article published online:
09 January 2024

• References

• 1a Alberti KG. M. M, Zimmet PZ. Diabetic Med. 1998; 15: 539
• 1b What is diabetes (accessed Nov 15, 2023): https://www.idf.org/aboutdiabetes/what-is-diabetes.html
• 2 Mealey BL, Ocampo GL. Periodontol. 2007; 44: 127
• 3 Mathers CD, Loncar D. PLOS Med. 2006; 3: e442
• 4 Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D. Diabetes Res. Clin. Pract. 2019; 157: 107843
• 5a The Top 10 Causes of Death, World Health Organization 2020 (accessed Nov 15, 2023): https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
• 5b Reusch JE. B, Manson JE. JAMA 2017; 317: 1015
• 6 World Health Organization. Global Report on Diabetes (accessed Nov 15, 2023): http://www.who.int/diabetes/global-report/en/
• 7 Williams R, Karuranga S, Malanda B, Saeedi P, Basit A, Besançon S, Bommer C, Esteghamati A, Ogurtsova K, Zhang P, Colagiuri S. Diabetes Res. Clin. Pract. 2020; 162
• 8 American Diabetes Association, Diagnosis and Classification of Diabetes Mellitus 2011; 34: S62
• 9 Washburn WN. SGLT2 Inhibitors in Development . In New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches . Jones RM. RSC Drug Discovery Series; Royal Society of Chemistry; Cambridge: 2012: 30-31
• 10 Stadler LK. J, Farooqi IS. Cell 2017; 170: 12
• 11a Agarwal A, Jadhav P, Deshmukh Y. J. Basic Clin. Pharm. 2014; 5: 79
• 11b DeFronzo RA, Norton L, Abdul-Ghani M. Renal Nat. Rev. Nephrol. 2017; 13: 11
• 11c He Z.-X, Zhou Z.-W, Yang Y, Yang T, Pan S.-Y, Qiu J.-X, Zhou S.-F. Clin. Exp. Pharmacol. Physiol. 2015; 42: 125
• 11d Bergenstal RM, Bailey CJ, Kendall DM. Am. J. Med. 2010; 123: 374.e9
• 12 Faillie JL. Pharmacol. Res. 2017; 118: 71
• 13a Vick H, Diedrich DF, Baumann K. Am. J. Physiol. 1973; 224: 552
• 13b Washburn WN. Expert Opin. Ther. Pat. 2009; 19: 1485
• 14 Lorris BA, Drewes LR, Gilboe DD. Biochim. Biophys. Acta Biomembr. 1975; 406: 505
• 15 Ehrenkranz JR. L, Lewis NG, Kahn CR, Roth J. Diabetes Metab. Res. Rev. 2005; 21: 31
• 16 Larson GL. Chem. Today 2015; 567: 635
• 17a Levy DE, Tang C. Introduction . In The Chemistry of C-Glycosides, Vol. 13. Levy DE, Tang C. Tetrahedron Organic Chemistry Series; Elsevier; Oxford: 1995: 1-27
• 17b Satirapoj B. Kidney Dis. 2017; 3: 24
• 18a Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero R.-M, Woerle H.-J, Broedl UC, Johansen OE. Diabetes Vasc. Dis. Res. 2015; 12: 90
• 18b Cai W, Jiang L, Xie Y, Liu Y, Liu W, Zhao G. Med. Chem. (Sharjah, United Arab Emirates) 2015; 11: 317
• 19a Aguillón AR, Mascarello A, Segretti ND, de Azevedo HF. Z, Guimaraes CR. W, Miranda LS. M, de Souza RO. M. A. Org. Process Res. Dev. 2018; 22: 467
• 19b Ragan JA, Nelson JD, Brandt TA, Robinson RP. Synthesis of SGLT-2 Inhibitors. In Chemistry, Molecular Sciences and Chemical Engineering. Elsevier; 2022
• 19c Haider K, Pathak A, Rohilla A, Haider MR, Ahmad K, Shahar YM. Eur. J. Med. Chem. 2019; 184: 111773
• 20a Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M. J. Med. Chem. 2010; 53: 6355
• 20b Filliers WF. M, Broeckx RL. M, Nieste PH. J, Hatsuda M, Yoshinaga M, Yada M. WO2010043682, 2010
• 20c Nomura S, Kawanishi E. US Patent 7943582B2, 2011
• 20d Abdel-Magid AF, Chislom M, Mehrman S, Scott L, Wells KM, Zhang-Plasket F, Nomura S, Hongu M, Koga Y. US Patent 9024009B2, 2011
• 20e Fillers WF. M, Laurent R, Nieste PH. J, Hatsuda M, Yoshinaga M, Yada M. US Patent 2010/0099883, 2010
• 20f Nagda DP, Singh TK, Jayachandra SB. WO2016/016852, 2016
• 20g Eswaraiah S, Nagaraju C, Kodandaramprasad A, Seetharamasarma P, Rajesham B. WO2016/135747, 2016
• 20h Bhirud SB, Naik S, Srivastava S, Deore D, Sinha S. WO2015/181692, 2015
• 20i Vellanki SR. P, Balusu RB, Pilli R, Javvaji RR, Annadasu AN. WO2016/035042, 2016
• 20j Rao DR, Malhotra G, Phull MS, Sawant AA, Hire KR. WO2016/083790, 2016
• 20k Nair R, Ramesan PV, Deshmukh SK, Panandikar AM. WO2016/128995, 2016
• 21a Henschke JP, Wu P.-Y, Lin C.-W, Chen S.-F, Chiang P.-C, Hsiao C.-N. J. Org. Chem. 2015; 80: 2295
• 21b Henschke JP, Lin C.-W, Wu P.-Y, Tsao W.-S, Liao J.-H, Chiang P.-C. J. Org. Chem. 2015; 80: 5189
• 21c Henschke JP, Wu P.-Y, Liao J.-H, Lin C.-W. US Patent 2015/0291569, 2015
• 21d Farina V, Lemaire SF. E, Houpis IN. US Patent 2011/0087017, 2011
• 21e Houpis IN, Lemaire SF. E. WO2012/140120, 2012
• 21f Kadam VT, Saikrishna DhereV. A, Minhas HS, Minhas GS. WO2016/142950, 2016
• 21g Desai SJ, Parihar JA, Patel JM, Suryawanshi US, Bhalala JB. US Patent 2016/0002275, 2016
• 22a Lemaire S, Houpis IN, Xiao T, Li J, Digard E, Gozlan C, Liu R, Gavryushin A, Diène C, Wang Y, Farina V, Knochel P. Org. Lett. 2012; 14: 1480
• 22b Gong H, Gagne MR. J. Am. Chem. Soc. 2008; 130: 12177
• 23a Sasikala ChV. A, Annapragada R, Basu D, Singarapu KK, Aaseef M, Bandichhor R. Org. Lett. 2022; 24: 3450
• 23b Oruganti S, Kandagatla B, Dahanukar VH, Cherukupally P, Mohammad A, Nalivela V, Konakalla M, Basu D, Cheemalapati VA. S. K, Bandichhor R, Andiappan M, Dey A, Kaipu RR, Jose J, Ramakrishnan S, Totad R, Pachore SS, Madavaram S, Bandaru SK, Metil DS, McCormack PJ, Reddy VV. V. IN2014CH06343A, 2016
• 24a Metil DS, Sonawane SP, Pachore SS, Mohammad A, Dahanukar VH, McCormack PJ, Reddy ChV, Bandichhor R. Org. Process Res. Dev. 2018; 22: 27
• 24b Polterauer D, Williams JD, Hone CA, Kappe CO. Tetrahedron Lett. 2021; 82: 153351
• 25 Meng W, Ellsworth BA, Nirschal AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN. J. Med. Chem. 2008; 51: 1145
• 26 Ellsworth B, Washburn WN, Sher PM, Wu G, Meng W. US6515117B2, 2003
• 27 Deshpande PP, Ellsworth BA, Singh J, Denzel T, Lai C, Crispino G, Randazzo ME, Gougoutas JZ. US7375213B2, 2008
• 28 Gougoutas JZ, Lobinger H, Ramakrishnan S, Deshpande PP, Bien JT, Lai C, Wang C, Riebel P, Grosso JA, Nirschl AA, Singh J, Dimarco JD. US7919598, 2011
• 29 Srivasan TR, Sajja E. WO2015132803A2, 2015
• 30 Henschke JP, Lin C, Wu P, Hsiao C, Liao J, Hsiao T. WO2013068850A2, 2013
• 31 Hu L, Zou P, Wei W, Yuan XM, Qiu XL, Gou SH. Synth. Commun. 2019; 49: 3373
• 32 Yu J, Cao Y, Yu H, Wang J. Org. Process Res. Dev. 2019; 23: 1458
• 33 Wang C, Xuan B, Huang C, Yao J, Wu C, Sun T. Org. Process Res. Dev. 2023; in press DOI: 10.1021/acs.oprd.2c00389.
• 34 Gougoutas JZ, Lobinger H, Ramakrishnan S, Deshpande PP, Bien JT, Lai C, Wang CC, Riebel P, Grosso JA, Nirschl AA, Singh J, Dimarco JD. US2008004336A1, 2008
• 35 Poole RM, Dungo RT. Drugs 2014; 74: 611
• 36a Imamura M, Murakami T, Shiraki R, Ikegai K, Sugane T, Iwasaki F, Kurosaki E, Tomiyama H, Noda A, Kitta K, Kobayashi Y.-C. WO2004080990A1, 2004
• 36b Imamura M, Murakami T, Shiraki R, Ikegai K, Sugane T, Iwasaki F, Kurosaki E, Tomiyama H, Noda A, Kitta K, Kobayashi Y.-C. US2007161787A1, 2007
• 37 Imamura M, Nakanishi K, Suzuki T, Ikegai K, Shiraki R, Ogiyama T, Murakami T, Kurosaki E, Noda A, Kobayashi Y, Yokota M, Koide T, Kosakai K, Ohkura Y, Takeuchi M, Tomiyama H, Ohta M. Bioorg. Med. Chem. 2012; 20: 3263
• 38 Imamura M, Nakanishi K, Shiraki R, Onda K, Sasuga D, Yuda M. WO2007114475A1, 2007
• 39 Lin G, Li X, Liu Z, Wang Z, Li Y, Pei Y. CN105481915A, 2016
• 40 Zupancic B, Lovro S, Cusak A, Richter F. WO2015177083A1, 2015
• 41 Ma S, Zhou W. WO2016173551A, 2015
• 42 Ma S, Liu Z, Pan J, Zhang S, Zhou W. Beilstein J. Org. Chem. 2017; 13: 1064
• 43 Eckhardt M, Himmelsbach F, Schmid S, Schuehle M, Martin H.-J. WO2006117359, 2006
• 44a Wang X.-j, Zhang L, Byrne D, Nummy L, Weber D, Krishnamurthy D, Yee N, Senanayake CH. Org. Lett. 2014; 16: 4090
• 44b Weber D, Renner S, Fiedler T, Orlich S. WO2011039107, 2011
• 45 Kaushik VK, Tummanepally JM. C, Pothani J, Dodda R. WO2015101916, 2015
• 46 Hrapchak M, Latli B, Wang XJ, Lee H, Campbell S, Song JJ, Senanayake CH. J. Label. Compd. Radiopharm. 2014; 57: 687
• 47 Markham A, Elkinson S. Drugs 2014; 74: 945
• 48 Kakinuma H, Oi T, Hashimoto-Tsuchiya Y, Arai M, Kawakita Y, Fukasawa Y, Iida I, Hagima N, Takeuchi H, Chino Y, Asami J, Okumura-Kitajima L, Io F, Yamamoto D, Miyata N, Takahashi T, Uchida S, Yamamoto K. J. Med. Chem. 2010; 53: 3247
• 49a Kakinuma H, Hashimoto Y, Oi T, Hirano H. WO2006073197A1, 2006
• 49b Driguez H, Henrissat B. Tetrahedron Lett 1981; 22: 5061
• 49c Ohara K, Matsuda H, Hashimoto M, Miyairi K, Okuno T. Chem. Lett 2002; 31: 626
• 49d Sato M, Kakinuma H, Asanuma H. WO2004014930A1, 2004
• 50 Poole RM, Prossler JE. Drugs 2014; 74: 939
• 51a Kobayashi T, Sato T, Nishimoto M. WO2006080421A1, 2005
• 51b Kobayashi T, Sato T, Nishimoto M. US2009030006, 2005
• 51c Ohtake Y, Sato T, Kobayashi T, Nishimoto M, Taka N, Takano K, Yamamoto K, Ohmori M, Yamaguchi M, Takami K, Yeu SY, Ahn KH, Matsuoka H, Morikawa K, Suzuki M, Hagita H, Ozawa K, Yamaguchi K, Kato M, Ikeda S. J. Med. Chem. 2012; 55: 7828
• 51d Ohtake Y, Emura T, Nishimoto M, Takano K, Yamamoto K, Tsuchiya S, Yeu SY, Kito Y, Kimura N, Takeda S, Tsukazaki M, Murakata M, Sato T. J. Org. Chem. 2016; 81: 2148
• 52a Murakata M, Ikeda T, Kimura N, Kawase A, Nagase M, Yamamoto K, Takata N, Yoshizaki S, Takano K. WO2009154276, 2009
• 52b Murakata M, Ikeda T, Kimura N, Kawase A, Nagase M, Yamamoto K, Takata N, Yoshizaki S, Takano K. EP2308886, 2011
• 53 Yang X.-D, Pan Z.-X, Li D.-J, Wang G, Liu M, Wu R.-G, Wu Y.-H, Gao Y.-C. Org. Process Res. Dev. 2016; 20: 1821
• 54 Fellner C. Pharm. Ther. 2016; 41: 650
• 55a Terra SG, Focht K, Davies M, Frias J, Derosa G, Darekar A, Golm G, Johnson J, Saur D, Lauring B, Dagogo-Jack S. Diabetes Obes. Metab. 2017; 19: 721
• 55b Madhavi K, Reddy DS, Kulkarni SK. Pharm. Sci. Nanotechnol. 2015; 8: 2787
• 56a Mascitti V, Thuma BA, Smith AC, Robinson RP, Brandt T, Kalgutkar AS, Maurer TS, Samas B, Sharma R. MedChemComm 2013; 4: 101
• 56b Mascitti V, Collman BM. US2010056618A1, 2009
• 56c Mascitti V, Maurer TS, Robinson RP, Bian J, Boustany-Kari CM, Brandt T, Collman BM, Kalgutkar AS, Klenotic MK, Leininger MT, Lowe A, Maguire RJ, Masterson VM, Miao Z, Mukaiyama E, Patel JD, Pettersen JC, Préville C, Samas B, She L, Sobol Z, Steppan CM, Stevens BD, Thuma BA, Tugnait M, Zeng D, Zhu T. J. Med. Chem. 2011; 54: 2952
• 56d Bernhardson D, Brandt TA, Hulford CA, Lehner RS, Preston BR, Price K, Sagal JF, St Pierre MJ, Thompson PH, Thuma B. Org. Process Res. Dev. 2014; 18: 57
• 57 Mascitti V, Préville C. Org. Lett. 2010; 12: 2940
• 58a Brenek SJ, Caron S, Nelson JD, Webster ME, Weekly RM. WO2014159151A1, 2013
• 58b Parikh JR, Doering W. vE. J. Am. Chem. Soc. 1967; 89: 5505
• 59a Cariou B, Charbonnel B. Expert Opin. Invest. Drugs 2015; 24: 1647
• 59b Lapuerta P, Zambrowicz B, Strumph P, Sands A. Diabetes Vasc. Dis. Res. 2015; 12: 101
• 60a Zhao MM, De Paul SM, Perlberg A. US8217156B2, 2009
• 60b Zhao M, Zhang H, Limura S, Bednarz M, Song Q.-L, Lim N.-K, Yan J, Wu W, Dai K, Gu X, Wang Y. Org. Process Res. Dev. 2020; 24: 2689
• 61 Harrison SA, Manghi FP, Smith WB, Alpenidze D, Aizenberg D, Klarenbeek N, Chen CY, Zuckerman E, Ravussin E, Charatcharoenwitthaya P, Cheng PN, Katchman H, Klein S, Ari ZB, Mendonza AE, Zhang Y, Martic M, Ma S, Kao S, Tanner S, Pachori A, Badman MK, He YL, Ukomadu C, Sicard E. Nat. Med. 2022; 28: 1432
• 62 Bebernitz GR, Bock MG, Reddy DS, Hajare AK, Vyavahare V, Bhosale BS, Kurhade ES, Salunkhe V, Shaikh N, Bhuniya Palle V, Feng PB, Liang A. US8163704B2, 2012
• 63 Fujikura H, Nishimura T, Katsuno K, Hiratochi M, Iyobe A, Fujioka M, Isaji M. US7056892B2, 2006
• 64 Kasai K, Kobayashi M, Ozawa T, Nishimura M, Tashino Y. JP2011201871A, 2011
• 65 Swamy V, Bhirud BS, Nair R, Khemnar E, Kadam S, Thorat J. WO2019193572A1, 2019
• 66 Kobayashi M, Isawa H, Sonehara J, Kubota M, Ozawa T. Chem. Pharm. Bull. 2016; 64: 1009
• 67 Yang F, Tang PC, Dong Q, Tu W, Fan J, Guan D, Shen G, Wang Y, Yuan J, Zhang L. US8609622B2, 2013
• 68 Chun K, Peng Z, Qichao L, Bo Z, Zhen W, Guorong Z, Yongjun T. CN 112375087A, 2020
• 69 Chen Y, Cheng H, Li S, Wu Y, Feng Y, Lv B, Xu B, Seed B, Hadd MJ, Song Y, Du J, Wang C, Roberge J. US7838499B2, 2010
• 70a Xu B, Lv B, Xu G, Seed B, Roberge J. US 20130267694A1, 2013
• 70b Gharpure M, Sharma SK, Vishwasrao S, Vichare P, Varal D. WO2018207113A1, 2018
• 70c Jason L, Yuelin W, Li S.-B, Xu G. WO2010022313A2, 2010
• 70d Cai M, Liu Q, Xu G, Lv B, Seed B, Roberge J. WO2011153712A1, 2011
• 71a Wu F. US9315438B2, 2016
• 71b Wu F. EP2891654A1, 2014
• 72a Eckhardt M, Himmelsbach F, Eickelmann P, Sauer A, Thomas L. US7776830B2, 2010
• 72b Eckhardt M, Himmelsbach F, Eickelmann P, Sauer A, Thomas L. WO2007128749A1, 2007
• 73a Fujikura H, Fushimi N. US6872706B2, 2005
• 73b Fujikura H, Fushimi N, Nishimura T, Tatani K, Katsuno K, Hiratochi M, Tokutake Y, Isaji M. WO2001068660A1, 2001
• 74a Kobayashi M, Isawa H, Sonehara J, Kubota M. Heterocycles 2016; 92: 1599
• 74b Lee YS, Rho SE, Min KY, Kim TB, Kim HK. J. Carbohydr. Chem. 2001; 20: 503
• 75 Choi S, Song KS, Lee SH, Kim MJ, Seo HJ, Park E.-J, Kong Y, Park SO, Kang H, Jung ME, Lee K, Kim HJ, Lee JS, Lee MW, Kim M.-S, Hong DH, Kang M. US9034921B2, 2015
• 76 Yoon H.-K, Park S.-H, Yoon J.-S, Choi S, Seo HJ, Park E.-J, Kong Y, Song K.-S, Kim MJ, Park SQ. WO2017217792A1, 2017