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New paper on Trelagliptin succinate



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Trelagliptin succinate, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, was approved for the Japanese market on March 26, 2015

Trelagliptin exhibited a better potency against human DPP-4 than alogliptin and sitagliptin, along with its excellent selectivity and slow-binding properties that may partially contribute to its sustained efficacy. In phase III clinical studies, once-weekly oral trelagliptin provided long-term safety and efficacy in both monotherapy and combination with other antidiabetic medicines and was proved to be noninferior to its analogue alogliptin used once daily.

2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile Monosuccinate (1)

white solid
Mp: 186–188 °C (187.1 °C in literature(x)),
[α]D20 = 16.4 (c 1, DMSO, 16.7 in literature(x)),
1H NMR (400 MHz, CD3OD) δ (ppm):7.79–7.82 (m, 1H), 7.15–7.25 (m, 2H), 5.46 (s, 1H), 5.20–5.32 (m, 2H), 3.35–3.37 (m, 2H), 3.22 (s, 3H), 3.03–3.06 (m, 1H), 2.74–2.81 (m, 2H), 2.49 (s, 4H), 2.07–2.11 (m, 1H), 1.82–1.89 (m, 1H), 1.65–1.76 (m, 1H), 1.55–1.59 (m, 1H).
MS (ESI+): m/z, 358.24 ([M + H]+).
Anal. (C22H26FN5O6) calcd: C, 55.57; H, 5.51; N, 14.73; found: C, 55.32; H, 5.46; N, 14.62.

Synthesis of Trelagliptin Succinate

State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, Shanghai 201203, China
Abstract Image

An improved process for the synthesis of antidiabetic drug trelagliptin succinate through unprotected (R)-3-aminopiperidine was described. The impurity profile with different conditions of the key substitution was illustrated, and then the best reaction condition was identified. The optimizations also included the bromination of 4-fluoro-2-methylbenzonitrile so that the process became efficient and concise.

  • 1.
    Zhang, Z.; Wallace, M. B.; Feng, J.; Stafford, J. A.; Skene, R. J.; Shi, L.; Lee, B.; Aertgeerts, K.; Jennings, A.; Xu, R.; Kassel, D. B.; Kaldor, S. W.; Navre, M.; Webb, D. R.; Gwaltney, S. L.J. Med. Chem. 2011, 54, 510524, DOI: 10.1021/jm101016w
  • 2.
    Feng, J.; Gwaltney, S. L.; Dipeptidyl Peptidase Inhibitors. PCT Int. Appl. WO 2005095381, October 13, 2005.
  • 3.

    Grimshaw, C. E.; Jennings, A.; Kamran, R.; Ueno, H.; Nishigaki, N.; Kosaka, T.; Tani, A.; Sano, H.; Kinugawa, Y.; Koumura, E.; Shi, L.; Takeuchi, K. PLoS One 2016, 11, e0157509, DOI: 10.1371/journal.pone.0157509


Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study
Inagaki, Nobuya; Onouchi, Hitoshi; Maezawa, Hideaki; Kuroda, Shingo; Kaku, Kohei
Lancet Diabetes & Endocrinology (2015), 3 (3), 191-197 CODEN: LDEAAS; ISSN:2213-8587. (Elsevier Ltd.)
Trelagliptin is a novel once-weekly oral DPP-4 inhibitor. We assessed the efficacy and safety of trelagliptin vs. the daily oral DPP-4 inhibitor alogliptin in Japanese patients with type 2 diabetes. We did a randomised, double-blind, active-controlled, parallel-group, phase 3, non-inferiority study at 26 sites in Japan.
We included individuals with type 2 diabetes inadequately controlled by diet and exercise. We randomly assigned patients (2:2:1) to receive trelagliptin (100 mg) once per wk, alogliptin (25 mg) once per day, or placebo for 24 wk. Randomisation was done electronically and independently from the study with permuted blocks of ten patients. Patients and clinicians were masked to group assignment.
Patients in the trelagliptin group were given trelagliptin once a week and oral alogliptin placebo every day, whereas patients in the alogliptin group were given oral trelagliptin placebo once a week and oral alogliptin every day (double-dummy design). Patients in the placebo group were given an oral alogliptin placebo once a day and an oral trelagliptin placebo once a week. Our primary outcome was between-groups difference in change in HbA1c concn. from baseline to the end of treatment. The non-inferiority margin was 0·4%. Our anal. included all patients who were randomised and received at least one dose of study drug. The study is registered with, no. NCT01632007.
Between May 26, 2012, and Nov 20, 2012, we enrolled 357 patients. 243 patients were included in the anal. (101 for trelagliptin, 92 for alogliptin, and 50 for placebo). In the primary anal., the least squares mean change in HbA1c concn. was -0·33% in the trelagliptin group (SE 0·059) and -0·45% in the alogliptin group (0·061) based on the ANCOVA model. The least squares mean difference (trelagliptin minus alogliptin) of change from baseline in HbA1c concn. was 0·11% (95% CI -0·054 to 0·281). Trelagliptin was non-inferior to alogliptin. Both active groups had significantly reduced mean HbA1c concns. at end of treatment compared with placebo (p<0·0001). The frequency of adverse events was similar between groups. No hypoglycemia was reported with trelagliptin and the drug was well tolerated.
The once-weekly DPP-4 inhibitor trelagliptin showed similar efficacy and safety to alogliptin once daily in Japanese patients with type 2 diabetes. Trelagliptin could be a useful new antidiabetes drug that needs to be given once a week.Takeda Pharmaceutical Company.
  • 4.

    Inagaki, N.; Onouchi, H.; Maezawa, H.; Kuroda, S.; Kaku, K. Lancet Diabetes Endocrinol.2015, 3, 191197, DOI: 10.1016/S2213-8587(14)70251-7

  • 5.

    Inagaki, N.; Sano, H.; Seki, Y.; Kuroda, S.; Kaku, K. J.Diabetes Investig. 2016, 7, 718726, DOI: 10.1111/jdi.12499


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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, 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...... , 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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