α- acarbose voglibose migilitol

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1 C1 α-1-c-alkyl arabinofuranose α- D L n- L α- acarbosevoglibose migilitol Glycosidases and glycosyltransferases are involved in a wide range of anabolic and catabolic process, including digestion, the lysosomal catabolism of glycoconjugates, glycoprotein biosynthesis. ence, modifying or blocking these processes in vivo using inhibitors is a topic of great interest from the therapeutic point of view. Iminosugars are sugars in which the endocyclic oxygen is replaced by a basic nitrogen atom. They are regarded as transition state mimics in certain types of enzyme reactions. This makes the field of iminosugars as carbohydrate mimics an exciting area of research. The asymmetric synthesis of α-1-c-alkyl-arabinoiminofuranoses was achieved by asymmetric allylic alkylation, CM, and egishi cross coupling as key reactions. Surprisingly, the L-forms showed a quite potent inhibitory activity toward rat intestinal maltase, while the activities of the D-forms were much weaker. Some of the prepared L-forms showed potent inhibitory activities towards intestinal maltase, with IC 50 values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity towards intestinal sucrase of α-1-c-l-butylarabinoiminofuranose was quite strong towards intestinal sucrase compared to the above commercial drugs. 2010

2 α-l % 1996 II Glyset TM 2003 Zavesca TM Purine nucleoside phosphorylase (PP) PP Fodosine phaseii BCX-4208 phaseii SF-4, SDD-8, OGT DJ D L DJ D,L β- D L β- (CM)

3 C- α α- α- α-1,4- α- acarbose voglibose miglitol (migilitol),o- C1 C1 L C1 C1 Trost 2

4 D-1 α-1-c--d- (α-1-c-butyl-dab )D-2 (α-1-c-butyl-lab ) L-2 I egishi coupling O O O O D-1 D-2 α- D L C1 n- L L-1 α-1-c--l- (α-1-c-butyl-lab)α- acarbosevoglibosemigilitol α-1-c-alkyl-dab D-2 α-1-c-alkyl-lab L-2 LAB 3 -n-butyl-lab 4 -n-butyl-dj 5 α-1-c-n-alkyl-dj 6 -n-butyl-α-1-c-butyl-lab 7 1,3-C-dibutyl-LAB 8 Table IC 50 Values (µm) for α-1-c-alkyl-lab against Intestinal α- Glucosidases, Compared with α-1-c-alkyl-dj, Acarbose, Voglivose, and α-1-c-butyl-lab 2c migilitol migilitol epg2 MALDI-TOF 2c migilitol ddy 1/10 2c IC 50 (µm) Compounds Maltase Isomaltase Sucrase α-1-c-ethyl-lab (2a) α-1-c-propyl-lab (2b) α-1-c-butyl-lab (2c) α-1-c-pentyl-lab (2d) α-1-c-exyl-lab (2e) α-1-c-eptyl-lab (2f) α-1-c-octyl-lab (2g) α-1-c-onyl-lab (2h) α-1-c-decyl-lab (2i) α-1-c-undecyl-lab (2j) 3.9 I 13 α-1-c-(4-phenylbutyl)-lab (2k) α-1-c-(4-methylpentyl)-lab (2l) LAB (3) butyl-lab (4) butyl-dj(5) α-1-c-butyl-dj (6a) α-1-c-exyl-dj (6b) α-1-c-octyl-dj (6c) Butyl-α-1-C-butyl-LAB (7) 25 I 8.8 1,3-C-Dibutyl-LAB (8) I a I I Acarbose 0.18 I 2.9 Voglivose Miglitol α- 2c D

5 4 YAKUGAKU ZASSI, 135, 2013, Kato, A.; ayashi, E.; Miyauchi, S.; Adachi, I.; Imahori, T.; atori, Y.; Yoshimura, Y.; ash,. J.; Shimaoka,.; akagome, I.; Koseki, J.; irono, S.; Takahata,. α-1-c-butyl-1,4-dideoxy-1,4-imino-l-arabinit ol as a Second- Generation Iminosugar-Based Oral α-glucosidase Inhibitor for Improving Postprandial yperglycemia, J. Med. Chem. 55, 2012, /jm301304e atori, Y.; Kikuchi, S.; Yuichi, Y.; Kato, A.; Adachi, I.; Takahata,. Asymmetric Synthesis of 1-Alkyl-2-deoxyiminofuranoses via The Iridium- catalyzed Intramolecular Cyclization of an Allylic Carbonate, eterocycles, 86, 2012, /COM-12-S()99 atori, Y.; Imahori, T.; Murakami, atori, Y.; Imahori, T.; Murakami, K.; Yoshimura, Y.; akagawa, S.; Kato, A.; Adachi, I.; Takahata,. The synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranoses, a novel class of -glucosidase inhibitors novel class of -glucosidase inhibitors, Bioorg. Med. Chem. Lett. 21, 2011, α-1-c --D C-n--L C14- L α-1-c-alkyl-lab α-1-c-alkyl-lab C14- L L atori, Y.; Yoshimura, Y.; Kato, A.; Adachi, I.; irono, S.; Takahata,. Synthesis of 1-C-Substituted-L-arabinoiminofuranoses and Evaluation of Biological Activities as ovel Class of α-glucosidase Inhibitors, 13th Tetrahedron Symposium Asia Edition, , Taipei, Taiwan atori, Y.; Imahori, T.; Yoshimura, Y.; Takahata,. The Synthesis of 1-C-Alkyl-Larabinoiminofuranoses as ovel Class of α-glucosidase Inhibitors, 13th Belgian Organic Synthesis Symposium, , Leuven, Belgium Isofagomine -glucocerebrosidase

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