Lipophilic prodrugs of 1-deoxynojirimycin derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01229-6

We report a new synthesis of Miglitol, and its conversion to a lipophilic prodrug. The same procedure permits the preparation of a prodrug of 1-desoxynojirimycin and probably of other 1-deoxynojirimycin derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01229-6

Tetrahedron Letters 41 (2000) 7313±7315
Lipophilic prodrugs of 1-deoxynojirimycin derivatives
Sandra Fouacea and Michel Therisodb,*
a
Â
SESNAB, PoÃle Sciences et Technologie, Universite de La Rochelle, 17042 La Rochelle cedex, France
b
Â
LCBB, BaÃt. 420, ICMO, Universite Paris-Sud, 91405 Orsay cedex, France
Received 8 June 2000; accepted 9 July 2000
Abstract
We report a new synthesis of Miglitol, and its conversion to a lipophilic prodrug. The same procedure
permits the preparation of a prodrug of 1-desoxynojirimycin and probably of other 1-deoxynojirimycin
derivatives. # 2000 Elsevier Science Ltd. All rights reserved.
Inhibitors of a-glucosidases are of interest for two possible therapeutic actions:
. Antiviral: as inhibitors of a-glucosidases I and II, they can block the biosynthesis of viral
glycoproteins (e.g. gp 120 of HIV).1
. Antidiabetic: as inhibitors of intestinal sucrase or phosphorylases, they can slow down
the catabolism of sugars and lower the blood content in glucose.2
The latter activity can be a drawback if the drugs are to be used as antivirals, causing diarrhea
and hypoglycaemia.3
Iminosugars, especially 1-deoxynojirimycine (1-dNJ) derivatives, have been shown to inhibit
the development of HIV in vitro.4 As drugs in vivo, however, they show an important hepatic
toxicity, making lipophilic prodrugs promising derivatives. These prodrugs can avoid a rapid
degradation in the liver by travelling as chilomicrons through the lymphatic system.5 Miglitol
(N-(2-hydroxyethyl)-1-deoxynojirimycine) is only available from Bayer (as BAY m1099). Its
synthesis has been patented several times by this company.6 This compound has been extensively
studied, mainly for its antidiabetic potency.7
We report herein a new synthetic route to Miglitol, based on the strategy employed by Ganem
to prepare 1-dNJ8 (Fig. 1).
Our method shortcuts 1-dNJ itself, by introducing the hydroxyethyl group at an early stage.
Two diastereomeric bromomercuric intermediates 1a and 2a are obtained, which can be easily
separated by chromatography before their transformation into 1b and 2b, respectively.10 The
* Corresponding author. Tel: +33-1-69156311; fax: +33-1-69157281; e-mail: therisod@icmo.u-psud.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01229-6

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Figure 1. (a) Zn, HO(CH2)2NH2, NaBH3CN, PrOH/H2O, re¯ux, 3 h; (b) NaH, BnCl, DMF; (c) ClCOOCHClCH3,
toluene/MeOH, re¯ux, 4 h;9 (d) HgOCOCF3, THF, rt, 12 h, then aq. KHCO3/KBr; (e) O2/NaBH4, DMF
amount of the desired stereomer 1b can be signi®cantly improved by transformation of 2b
through the sequence: oxidation (Swern), epimerisation (DBU), reduction (NaBH4). Compound
1b was quantitatively deprotected by hydrogenolysis to give Miglitol.
One free hydroxyl group of the partly protected intermediate 1b obtained, permits an easy
coupling to cholesterol hemisuccinate 3, to give, after hydrogenolysis, a lipophilic conjugate of
Miglitol and cholestanol 4 (Fig. 2).
Figure 2. (a) (1) SOCl2, DMF/toluene, 0ꢀC to rt, 12 h; (2) NEt3, 1b, DCM, 2 h (55%); (b) H2, Pd±C, EtOH (92%)
The same method can be employed for the synthesis of conjugates of 1-dNJ itself. We used the
55:25 diastereoisomeric mixture of protected intermediates 1c and 2c obtained in the Ganem
synthesis. This gave a mixture of conjugates easily separated by chromatography (Fig. 3).
Figure 3. (a) (1) SOCl2, DMF/toluene, 0ꢀC to rt, 12 h; (2) NEt3, 1c+2c, DCM, 2 h (81%); (3) column chromatography;
(b) H2, Pd±C, EtOH (93%)

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The same procedure could most probably be applied to other active derivatives of 1-dNJ and
other iminosugars. The pharmacodynamics of these prodrugs of Miglitol and 1-dNJ will be
estimated in animals.
Acknowledgements
We are grateful to Region Poitou-Charentes for ®nancial support to S.F. We thank Prof. Y.
Letourneux and Prof. L. Elkhiel for useful discussions and help.
References
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2. Scheen, A. J. Drugs 1997, 54, 355±368.
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4. Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de Goede, R. E. Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh,
H. L. Nature 1987, 330, 74±77.
5. Porter, C. J. H. Crit. Rev. Ther. Drug Carrier Systems 1997, 14, 333±393.
6. Kinast, G.; Schedel, M.; Kobernick, W. Eur. Pat. 49858, 1982.
7. Joubert, P. H.; Veuter, C. P.; Joubert, H. F.; Hillebrand, I. Eur. J. Pharmacol. 1985, 28, 705±708.
8. Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985, 26, 1123±1126.
9. Kapnang, H.; Charles, G. Tetrahedron Lett. 1983, 3233±3236.
10. Analytical data. Compound 1b: 1H NMR (400 MHz, CDCl3), ꢀ (ppm) 2.32 (m, 2H, H-1, H-5), 2.49 (td, 1H,
J=14.6, 3.6 Hz, N±CH2±CH2±), 3.03 (m, 1H, N±CH2±CH2±), 3.11 (dd, 1H, J=11.4, 4.5 Hz, H-1), 3.46 (m, 2H,
N±CH2±CH2±), 3.54 (m, 2H, H-2, H-3), 3.62 (t, 1H, H-4, J=9.1 Hz), 3.78 (dd, 1H, J=12.4, 1.4 Hz, H-6), 3.87 (dd,
1H, J=12.4, 2.7 Hz, H-60), 4.48, 4.52, 4.58±4.68, 4.82, 4.93, 4.94 (8H, O±CH2±Ph), 7.29 (m, 20H, Ar); 13C NMR
(100 MHz, CDCl3), ꢀ (ppm) 51.1 (N±CH2±CH2±), 55 (C-1), 57.9 (C-6), 65.5 (C-5), 67.6 (N±CH2±CH2±), 72.9,
73.2, 75.3, 75.5 (O±CH2±Ph), 77.9 (C-4), 78 (C-3), 86.7 (C-2); MS: 568 (M+, 1), 536 (29), 446 (11), 91 (100).
1
Compound 4: H NMR (400 MHz, CD3OD), ꢀ (ppm) 0.69 (s, 3H, CH3-18), 0.85 (s, 3H, CH3-19), 0.87 (d, 3H,
J=6.6 Hz, CH3-27), 0.88 (d, 3H, J=6.6 Hz, CH3-26), 0.92 (d, 3H, J=6.6 Hz, CH3-21), 2.63±2.69 (m, 7H,
NCH2CH2OH, OCOCH2CH2COO, H-1, H-6), 3.02 (m, 2H, NCH2CH2OH, H-10), 3.30±3.63 (m, 5H, H-2, H-3,
H-4, H-6, H-60), 3.9 (m, 2H, NCH2CH2OH), 4.58 (m, 1H, H-3a chol.); IR: 3459, 1737, 2924, 3030±3092. MS
(ESI): 679.1 (M+H)+ (calc. for C39H67NO8: 677.48). Compound 5: 1H NMR (400 MHz, CD3OD), ꢀ (ppm) 0.69 (s,
3H, CH3-18), 0.85 (s, 3H, CH3-19), 0.87 (d, 3H, J=6.7 Hz, CH3-27), 0.88 (d, 3H, J=6.6 Hz, CH3-26), 0.92 (d, 3H,
J=6.6 Hz, CH3-21), 2.64±2.69 (m, 6H, OCOCH2CH2COO, H-1, H-10), 3.38±3.45 (m, 1H, H-5), 3.73 (m, 1H, H-3a
chol.), 3.94 (m, 3H, H-2, H-3, H-4), 4.38 (m, 1H, H-6), 4.43 (dd, 1H, J=12, 4.5 Hz, H-60); 13C NMR (100 MHz,
CD3OD), ꢀ (ppm) 12.5, 12.7, 19.2, 23, 23.2 (CH3-18, CH3-19, CH3-21, CH3-26, CH3-27), 29.7, 29.8
(COCH2CH2COO), 35.1 (C-1), 46 (C-5), 55.6 (C-3a chol.), 63.5 (C-6), 67.6, 68, 69.3 (C-2, C-3, C-4); MS (ESI):
633.8 (M+H)+ (calc. for C37H63NO7: 633.46).