WO2013061105A2

WO2013061105A2 - Glycogen phosphorylase inhibitors

Info

Publication number: WO2013061105A2
Application number: PCT/HU2012/000116
Authority: WO
Inventors: Somsák László; Bokor Éva; Vágvölgyiné Tóth Marietta; Juhász László; Czifrák Katalin; Kónya Bálint; Kun Sándor; Páhi András; Szőcs Béla; Varga Gergely; Gergely Pál; Docsa Tibor; Kóder Lászlóné; Nagy Károlyné
Original assignee: Debreceni Egyetem
Priority date: 2011-10-28
Filing date: 2012-10-27
Publication date: 2013-05-02
Also published as: WO2013061105A8; WO2013061105A3

Abstract

The invention relates to compounds of formula (I) and stereoisomers, tautomers and pharmaceutically acceptable salts thereof and processes for preparing them. In formula (I) X is -CH= or -N= or -N(R") -; Y is -N= or -N(R") -; R is an alkyl group, an aryl group or a heteroaryl group, which groups are unsubstituted or substituted; R' is hydrogen or PG¹, R" is hydrogen or PG², R"' is hydrogen or R'OCH₂-; n is an integer of 1 to 3. The invention also relates to pharmaceutical compositions containing these compounds. The compounds according to the invention are glycogen phosphorylase inhibitors and can be used e.g. for the treatment of type 2 diabetes, cardiovascular disorders and tumorous growth.˙

Description

GLYCOGEN PHOSPHORYLASE INHIBITORS

TECHNICAL FIELD

The invention relates to new D-glycosyl azole derivatives of formula I having glycogen phosphorylase inhibitor activity and processes for the preparation of these compounds, including new intermediates. The pharmaceutical compositions containing these compounds are usable for the treatment of type 2 diabetes and other diseases associated with glycogen phosphorylase activity. BACKGROUND ART

The end of the 20^th century has witnessed a dramatic increase in the number of patients diagnosed with diabetes worldwide. Diabetes mellitus is characterized by chronically elevated blood glucose levels, and afflicts approximately 6% of the adult population in Western society [Moller, D.E. Nature, 414, 821-827 (2001)]. There is a rapidly increasing incidence of type 2 diabetes which is predicted to reach more than 360 million cases by 2030 [Israili, Z. H. Am. J. Ther., 18, pp. 117-152 (2011)]. This can even be an underestimate due to methodological uncertainties as well as undiagnosed cases [Green, A.; Hirsch, N.C.; Pramming, S. . Diabetes-Metab. Res. Rev., 19, 3-7 (2003)]. The highest increases are expected in the developing countries of Africa, Asia, and South America, while European populations seem to be less affected [Diamond, J. Nature, 423, 599-602 (2003)]. Especially due to its long term complications like retinopathy, neuropathy, and nephropathy, but particularly cardiovascular diseases, diabetes has become one of the largest contributors to mortality [Somsak, L.; Czifrak, .; Toth, M.; Bokor, E.; Chrysina, E. D.; Alexacou, K. M.; Hayes, J. M.; Tiraidis, C; Lazoura, E.; Leonidas, D. D.; Zographos, S. E.; Oikonomakos, N. G., Curr. Med. Chem., 15, 2933-2983 (2008)].

Diabetes mellitus is divided into two main forms: type 1 (T1DM) is an autoimmune disease characterized by a complete insulin deficiency, and can be treated by exogenous insulin; type 2 (T2DM) involves abnormal insulin secretion and/or insulin resistance, and blood glucose levels of patients are controlled mainly by diet, exercise, and oral hypoglycemic agents [Hengesh, E.J. In Principles of Medicinal Chemistry. Foye, W.O.; Lemke, T.L.; Williams, D.A., Eds.; Williams & Wilkins: Baltimore, 581-600 (1995)]. While the ratio of T1DM and T2DM was estimated to be ~25: 75 in the early nineties [Martin, J.L.; Veluraja, K.; Ross, K.; Johnson, L.N.; Fleet, G.W.J.; Ramsden, N.G.; Bruce, I.; Orchard, M.G.; Oikonomakos, N.G.; Papageorgiou, A.C.; Leonidas, D.D.; Tsitoura, H.S. Biochem., 30, 10101-101 16 (1991)], the frequency of the latter has increased to more than 90 % for today [Moller, D.E. Nature, 414, 821-827 (2001); Zimmet, P.; Alberti, K.G.M.M.; Shaw, J. Nature, 414, 782-861 (2001)]. The epidemic of T2DM is in conjunction with genetic susceptibility: evidence for a genetic component to the disease are accumulating, and the potential of these factors in the treatment and prevention of diabetes has been reviewed [Toye, A.; Gauguier, D. Genome Biol, 4, 241 (2003); Barroso, I. Diabetic Med., 22, 517-535 (2005)]. A similarly high contribution to this epidemic may originate from behavioral factors such as sedentary lifestyle, overly rich nutrition diets, and obesity. Recent years have seen the appearance and spreading of the disease among young people including children and this forecasts severe economic and health service burdens in the coming decades [Ehtisham, S.; Barrett, T.G. Ann. Clin. Biochem., 41, 10-16 (2004); Bloomgarden, Z.T. Diabetes Care, 27, 998-1010 (2004); Alberti, G.; Zimmet, P.; Shaw, J.; Bloomgarden, Z.; Kaufman, F.; Silink, M. Diabetes Care, 27, 1798-1811 (2004)].

Although several pathomechanisms [Panunti, B.; Jawa, A.A.; Fonseca, V.A. Drug Discov. Today: Disease Meek, 1, 151-157 (2004); Stumvoll, M.; Goldstein, B.J.; van Haeften, T.W. Lancet, 365, 1333-1346 (2005); Lowell, B.B.; Shulman, G.I. Science, 307, 384-387 (2005)] are under investigation, in the absence of a firm understanding of the molecular origins of the disease several types of oral hypoglycemic drugs (sulfonylureas, biguanides, thiazolidinediones) are in use as symptomatic treatments for T2DM [Cobb, J.; Dukes, I. In Annual Reports in Medicinal Chemistry. Bristol, J.A., Ed.; Academic Press: San Diego, 33, 213-222 (1998); Perfetti, R.; Barnett, P.S.; Mathur, R.; Egan, J.M. Diabetes Metab. Rev., 14, 207-225 (1998); Rose, M.L.; Paulik, M.A.; Lenhard, J.M. Expert Opin. Ther. Patents, 9, 1-14 (1999); Zhang, B.B.; Moller, D.E. Curr. Opin. Chem. Biol., 4, 461-467 (2000); Rendell, M. Drugs, 64, 1339-1358 (2004); Cheng, A.Y.Y.; Fantus, I.G. Can. Med. Assoc. J., 172, 213-226 (2005); Padwal, R.; Majumdar, S.R.; Johnson, J.A.; Varney, J.; McAlister, F.A. Diabetes Care, 28, Ί 6-ΊΑΑ (2005); Krentz, A.J.; Bailey, C.J. Drugs, 65, 385- -411 (2005)]. a-Glucosidase inhibitors (acarbose, miglitol, voglibose) are also widely used [van de Laar, F.A.; Lucassen, P.L.; Akkermans, R.P.; van de Lisdonk, F.H.; Rutten, G.E.; van Weel, C. Diabetes Care, 28, 154-163 (2005)]. These treatments aim to more or less approach the normal physiological regulation of blood glucose levels, however, there are several adverse side effects as well as the danger of causing hypoglycemia [Murata, G.H.; Duckworth, W.C.; Hoffman, R.M.; Wendel, C.S.; Mohler, M.J.; Shah, J.H. Biomed. Pharmacother., 58, 551-559 (2004)]. Furthermore, these drugs are inadequate for 30-40 % of patients [Wagman, A.S.; Nuss, J.M. Curr. Pharm. Design, 7, 417-450 (2001)]. Therefore, other therapeutic possibilities (among these novel insulin secretagogues, insulin sensitizers, glucagon receptor antagonists, inhibitors of hepatic glucose output, combination therapies) have been intensively investigated [Moller, D.E. Nature, 414, 821-827 (2001); Cohen, P. Phil. Trans. R. Soc. Lond. B, 354, 485-495 (1999); Treadway, J.L.; Mendys, P.; Hoover, D.J. Expert Opin. Invest. Drugs, 10, 439-454 (2001); Saltiel, A.R.; ahn, C.R. Nature, 414, 799- -806 (2001); Staehr, P.; Hother-Nielsen, O.; Beck-Nielsen, H. Diabetes Obes. Metab. 4, 215- -223 (2002); Morral, N. Trends Endocrin. Metab., 14, 169-175 (2003); Nourparvar, A.; Bulotta, A.; Di Mario, U.; Perfetti, R. Trends Pharmacol. ScL, 25, 86-91 (2004); Agius, L. Best Pract. Res. Clin. Endocrin. Metab., 21, 587-605 (2007)], with a therapy solely based on nutrition also proposed [McCarty, M.F. Med. Hypoth., 54, 483-487 (2000)].

The liver is the predominant source of blood glucose. Numerous studies have shown that hepatic glucose production is increased in type 2 diabetes in the post-absorptive state, and it is directly correlated to fasting hyperglycemia [Moller, D.E. Nature, 414, 821-827 (2001); Treadway, J.L.; Mendys, P.; Hoover, D.J. Expert Opin. Invest. Drugs, 10, 439-454 (2001); Staehr, P.; Hother-Nielsen, O.; Beck-Nielsen, H. Diabetes Obes.Metab., 4, 215-223 (2002); Bollen, M.; Keppens, S.; Stalmans, W. Biochem. J., 336, 19-31 (1998); Radziuk, J.; Pye, S. Diabetes Metab. Res. Rev., 17, 250-272 (2001)]. Hepatic glucose is produced from two pathways: glycogenolysis (the breakdown of glycogen) and gluconeogenesis (de novo synthesis of glucose). Glycogenolysis may account for more than 70% of the hepatic glucose production, furthermore, a substantial portion of glucose formed by gluconeogenesis [Roden, M.; Bernroider, E. Best Pract. Res. Clin. Endocrin. Metab., 17, 365-383 (2003)] is cycled through the glycogen pool prior to efflux from the liver cells (for references, see [Andersen, B.; Rassov, A.; Westergaard, N.; Lundgren, K. Biochem. J., 342, 545-550 (1999)]).

Hepatic glucose output is regulated by a complex system of enzymes. The main regulatory enzyme of this system is glycogen phosphorylase (GP), and only the phosphorylated form (GPa) has significant activity. GPa releases glucose 1 -phosphate from glycogen suggesting an important role for glycogenolysis in hepatic glucose production. Gluconeogenesis from lactate and other precursor molecules can also contribute to the elevated blood glucose levels, however, it was clearly demonstrated that glucose arising from gluconeogenesis has cycled through glycogen. Therefore the inhibition of hepatic GP could suppress glucose production arising from both glycogenolysis and gluconeogenesis [Treadway, J.L.; Mendys, P.; Hoover, D.J. Expert Opin. Invest. Drugs, 10, 439-454 (2001); Oikonomakos, N.G. Curr. Protein Pept. Sci., 3, 561-586 (2002); McCormack, J.G.; Westergaard, N.; Kristiansen, M.; Brand, C.L.; Lau, J. Curr. Pharm. Design, 7, 1451-1474 (2001)].

GP inhibitors have been considered as effective therapeutic approach in other diseased states such as myocardial ischemia [Tracey, W., Treadway, J., Magee, W., McPherson, R., Levy, C, Wilder, D., Li, Y., Yue, C, Zavadoski, W., Gibbs, E., Smith, A., Flynn, D. & Knight, D. Diabetes, 52, A135-A135 (2003)]. ; Henke, B. R.; Sparks, S. M. Mini-Rev. Med. Chem., 6, 845-857 (2006)], cerebral ischemia [Guan, T.; Qian, Y. S.; Tang, X. Z.; Huang, M. H.; Huang, L. R; Li, Y. M.; Sun, H. B. J. Neurosci. Res., 89, 1829-1839 (2011); Sun, H. & Xu, L. Mini-Rev. Med. Chem., 10, 1 188-1 193 (2010)]. ], and tumors [Lee, W. N. P.; Guo, P.; Lim, S.; Bassilian, S.; Lee, S. T.; Boren, J.; Cascante, M.; Go, V. L. W.; Boros, L. G. Brit. J. Cancer, 91, 2094-2100 (2004); Geschwind, J.-R, Georgiades, C. S., Ko, Y. H. & Pedersen, P. L. Exp. Rev. Anticanc. Ther., 4, 449-457 (2004)]. Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma [Schnier, J. B., Nishi, K., Monks, A., Gorin, F. A. & Bradbury, E. M. Biochem. Biophys. Res. Commun., 309, 126-134 (2003)]. ; Henke, B. R.; Sparks, S. M. Mini-Rev. Med. Chem., 6, 845-857 (2006)], and were claimed to have cardioprotective effect [Tracey, W. R., Treadway, J. L., Magee, W. P., Sutt, J. C, McPherson, R. K., Levy, C. B., Wilder, D. E., Yu, L. J., Chen, Y., Shanker, R. M., Mutchler, A. K., Smith, A. H., Flynn, D. M. & Knight, D. R. Am. J. Physiol.-Heart and Circulatory Physiol, 286, HI 177-H1184 (2004); Treadway, J. L.; Magee, W. P.; Hoover, D. J.; McPherson, R. K.; Martin, W. H.; Zavadoski, W. J.; Gibbs, E. M.; Tracey, W. R. Diabetes, 49, A127-A127 (2000); Baker, D. J.; Greenhaff, P. L.; Timmons, J. A. Exp. Opin. Ther. Patents, 16, 459-466 (2006)].

SUMMARY OF THE INVENTION

The objective of the invention is to discover potent glycogen phosphorylase inhibitors.

These and other objective of the invention, which will become apparent from the following description, have been achieved by the discovery of the glycosyl azole derivatives, stereoisomers, tautomers and pharmaceutically acceptable salts thereof described below, which inhibit the activity of glycogen phophorylase. Pharmaceutical compositions containing such agents are useful in treating and preventing diseases mediated by glycogen phosphorylase activity, such as type 2 diabetes, as well as other diseases, such as early stage cardiovascular diseases, cardiac arrhythmia, ischaemic lesions or tumorous growth.

In general aspects, the invention relates to compounds of formula I:

wherein

X is -CH= or -N= or -N(R") -;

Y is -N= or -N(R") -;

R is a Ci-6 alkyl group, which is unsubstituted or substituted with a substituent selected from the group of hydroxyl, azide, nitro, amino, sulfanyl, alkoxy, alkylthio, carboxyl and halogen; an C_6-io aryl group or heteroaryl group of 5-10 ring atoms which include 1 -3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, which aryl or heteroaryl groups are unsubstituted or substituted with 1-3 substituents selected from the group of Ci_-4 alkyl, halogen, trifluoromethyl, hydroxyl, C alkoxy, carboxyl, unsubstituted or N-(mono or di)substituted carbamoyl, amino and nitro;

R' is hydrogen or PG¹, where

PG¹ is Ci_-6 alkyl, C_3-7 cycloalkyl, (C|_-6 alkyl)carbonyl, (C_3-7 cycloalkyl)carbonyl, tetrahydropyranyl, allyl, (C_6-i₀ aryl)carbonyl, (C _-1o aryl)(Ci_-6 alkyl) optionally carrying one or more substituents selected from the group of halogen, Ci_-4 alkyl, Ci_-6 alkoxy and nitro;

R" is hydrogen or PG², where

PG² is Ci-6 alkyl, C₆.|₀ aryl, (C_6-io aryl)(Ci_-6 alkyl), C|.₆ alkylsulfonyl, C_6-io arylsulfonyl, Ci- alkoxycarbonyl or benzyloxycarbonyl optionally carrying one or more substituents selected from the group of halogen, Ci_-4 alkyl, Ci_-6 alkoxy and nitro;

R'" is hydrogen or R'OCH₂-;

n is an integer of 1 to 3;

in the Gly moiety of formula

each R'O- is attached to a -CH₂-unit of the ring; moiety A of formula / Y includes a heteroaromatic ring which may have only one NR" ring member,

and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.

The invention is also directed to stereoisomers, tautomers and pharmaceutically acceptable salts of the compounds of formula I. Embodiments of the invention relate to compounds of formula I wherein ring A stands for any of formulae i, ii and iii below

i ii iii

wherein

R is methyl, tert-butyl, hydroxymethyl, acetoxymethyl, phenyl, naphthyl, tert-

-butylphenyl, trifluoromethylphenyl, hydroxyphenyl, acetoxyphenyl, carboxyphenyl, benzyloxycarbonylphenyl, mono- or diaminophenyl, mono- or dinitrophenyl, mono-, di- or trimethylphenyl, mono-, di- or trialkoxyphenyl, pyridyl;

R" is hydrogen, benzyl or tosyl;

moiety Gly stands for any of formulae Glc, Xyl and Gal

Glc Xyl Gal wherein

R' is hydrogen, acetyl, benzoyl, or benzyl; and

R'" is as defined above.

Embodiments of the invention also relate to compounds of formula I wherein ring A stands for formula iv or v

iv v

wherein

R is phenyl or naphthyl;

R" is hydrogen or benzyl or tosyl;

moiety Gly stands for any of formulae Glc, Xyl and Gal

Glc yi Gal wherein

R' is hydrogen, acetyl, benzoyl or benzyl; and

R'" is as defined above.

Embodiments of the invention also relate to the following compounds covered by formula I:

5-( -D-glucopyranosyl)-3-phenyl-l ,2,4-triazole,

5-(P-D-glucopyranosyl)-3-(4-methylphenyl)- 1 ,2,4-triazole,

3-(4-aminophenyl)-5-( -D-glucopyranosyl)-l ,2,4-triazole,

5-(p-D-glucopyranosyl)-3-(2-naphthyl)-l,2,4-triazole,

3-(2-naphthyl)-5-( -D-xylopyranosyl)-l ,2,4-triazole,

2-(P-D-glucopyranosyl)-4(5)-phenyl-imidazole,

2-(P-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole,

4(5)-phenyl-2-(P-D-xylopyranosyl)-imidazole, and

4(5)-(2-naphthyl)-2-(P-D-xylopyranosyl)-imidazole.

The inventive compounds show glycogen phosphorylase inhibitor activity.

Methods for preparing the compounds of formula I, are as follow,

(a) To obtain a compound of formula I wherein X is -N= or -N(R") - and Y, R, R', R", R'" and n are as defined in claim 1 ,

(i) a compound of formula 13 is reacted with SOCl₂, and the resulted compound of formula 13'

13'

is reacted with a compound of formula 3

wherein R, PG , PG , R'" and n are as defined in claim 1 , or

(ii) a compound of formula 9

is reacted with RCOCl, wherein R, PG¹, R'" and n are as defined in claim 1, or

(iii) a compound of formula 10

is reacted with a compound of formula 4

wherein R, PG', R'" and n are as defined in claim 1, or

(iv) a compound of formula 11

is reacted with a compound of formula 4

wherein R, PG', R'" and n are as defined in claim 1, or

(v) compound of formula 12

wherein R, PG¹, R'" and n are as defined in claim 1, or

is treated with NH₄OAc,

(vi) compound of formula 12

wherein R, PG', R'" and n are as defined in claim 1 ,

is heated in pyridine; or

(b) to obtain a compound of formula I, wherein X is -CH= and Y, R, R', R", R'" and n are as defined in claim 1,

(i) a compound of formula 5

is reacted with a compound of formula 20

20 wherein R, R", R'", PG¹ and n are as defined in claim 1, or

(ii) a compound of formula 11

is reacted with a compound of formula 21

21

wherein R, R'", PG¹ and n are as defined in claim 1, and if desired, substituent PG and/or PG are removed,

and if desired, a resulted compound being in free basis form or free acid form is converted to a salt, or a compound being in salt form converted to a free basis or a free acid.

The invention also relates to the above compounds of formulae 5, 9 and 11, wherein PG¹, R'" and n are as defined in formula I, and a compounds of formula 12, wherein PG¹, R, R'" and n are as defined in formula I, which compounds are used as intermediates in the processes according to the invention.

The invention also relates to pharmaceutical compositions containing an effective amount of a compound of formula I or stereoisomers, tautomers or pharmaceutically acceptable salts thereof and at least one suitable pharmaceutical carrier or additive.

The pharmaceutical compositions according to the invention are usable for the treatment or prevention of type 2 diabetes or early stage cardiovascular diseases, or in the stabilization of cardiac arrhythmia or in the protection against ischaemic lesions or in the prevention of tumorous growth.

The invention further provides methods of treating or preventing type 2 diabetes, and other diseases, like early stage cardiovascular diseases, cardiac arrhythmia, ischaemic lesions or tumorous growth, which methods comprising administering to a patient suffering from said diseases effective amount of a compound of formula I or stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The inventive compounds of formula I are useful for inhibiting the activity of glycogen phosphorylase, and thus, providing treatments for type 2 diabetes and other diseases, like early stage cardiovascular diseases, or in the stabilization of cardiac arrhythmia or in the protection against ischaemic lesions or in the prevention of tumorous growth.

The definitions of the substituents of formula I are as follow. The term "alkyl" used herein refers to straight- and any branched- chain alkyl groups having one to six carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl (Et), n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), n-pentyl, isopentyl, n-hexyl, isohexyl, and the like.

The term "cycloalkyl" refers to saturated carbocycles having from three to seven carbon atoms. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The terms "aryl" and "heteroaryl" refer to monocyclic and polycyclic aromatic ring structures, with "aryl" referring to those that are carbocycles and "heteroaryl" referring to those that are heterocycles. Examples of aryl ring structures include phenyl and naphthyl. Examples of heteroaryl ring structures include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, and their benzologues where relevant and possible.

The term "alkoxy" is intended to mean the group -O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like.

The term "halogen" represents chlorine, fluorine, bromine or iodine.

"A pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, chlorides, bromides, iodides, acetates, propionates, malonates, succinates, fumarates, maleates, benzoates, sulfonates, citrates, lactates, tartrates and methane-sulfonates.

Some of the inventive compounds may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.

The compounds of formula I exhibit the phenomenon of tautomerism. Accordingly, the compounds of formula I wherein ring A represents a triazole group of formula i, ii or iii are tautomers. Similarly, the compounds of formula I wherein ring A represents an imidazole group of formula iv or v are tautomers. In the compounds of formula I, wherein R" represents H, these tautomer forms may coexist. It is therefore to be understood that within the description the formulae wherein R" is H are intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific tautomeric form depicted by the formula drawings.

Therapeutically effective amounts of the agents of the invention may be used to treat diseases mediated by modulation or regulation of glycogen phosphorylase. An "effective amount" is intended to mean that amount of an agent that, when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease mediated by the activity of glycogen phosphorylase. Thus, e.g., a therapeutically effective amount of a compound of the formula I salt is a quantity sufficient to inhibit the activity of glycogen phosphorylase such that a disease condition which is mediated by that activity is reduced or alleviated.

The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g. weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Procedures for the Synthesis of the Compounds according to the Invention

Preparation of the Intermediates

The preparation of the intermediates used in the syntheses of the compounds of formula I are disclosed in Scheme 1.

The substituents of the formulae included in Scheme 1 are as defined for formula I. As it is shown in Scheme 1 below, the starting compounds for the syntheses of the

C-glycosyl heterocyclic derivatives, such as protected C-(P-D-glycopyranosyl)formamides of formula 1 (e. g. C-(2,3,4,6-tetra-O-benzoyl-p-D-glucopyranosyl)formamide 1-Glc [Somsak, L.; Nagy, V.: Tetrahedron: Asymmetry, 11, 1719-1727, Corrigendum 2247 (2000)]), or protected β-D-glycopyranosyl cyanides of formula 2 (e. g. 2,3,4,6-tetra-O-benzoyl-P-D- -glucopyranosyl cyanide 2-Glc [Somsak, L.; Nagy, V.: Tetrahedron: Asymmetry, 11, 1719- -1727, Corrigendum 2247 (2000)] or 2,3,4-tri-O-benzoyl-p-D-xylopyranosyl cyanide 2-Xyl [Dong, L.; Li, L.; Ma, L.; Zhang, L. Chin. Chem. Lett., 3, 597-600 (1992)], or 2,3,4,6-tetra-O- -acetyl- -D-galactopyranosyl cyanide 2-Gal [Myers, R. W.; Lee, Y. C. Carbohydr. Res., 154, 145-163 (1986)]), or protected 5-(P-D-glycopyranosyl)tetrazoles of formula 3 (e. g. 5- -(2,3,4,6-tetra-O-benzoyl-p-D-glucopyranosyl)tetrazole 3-Glc [Hadady, Z.; Toth, M.; Somsak, L.: Arkivoc (vii), 140-149 (2004); Kun, S.; Nagy, G. Z.; Toth, M.; Czecze, L.; Nguyen van Nhien, A.; Docsa, T.; Gergely, P.; Charavgi, M.-D.; Skourti, P. V.; Chrysina, E. D.; Patonay, T.; Somsak, L.: Carbohydr. Res., 346, 1427-1438 (2011)], or 5-(2,3,4,6-tetra-O- -acetyl- -D-galactopyranosyl)tetrazole 3-GaI [Farkas, I.; Szabo, I. F.; Bognar, R. Carbohydr.

Res., 56, 404-406 (1977)]), or protected C-( -D-glycopyranosyl)formic acids of formula 6 (e. g. C-(2,3,4,6-tetra-O-benzoyl-P-D-glucopyranosyl)formic acid 6-GIc [Czifrak, K.; Szilagyi,

P.; Somsak, L.: Tetrahedron: Asymmetry, 16, 127-141 (2005)]), or protected C- -Ό- -glycopyranosyl)formamidoximes of formula 7 (e. g. C-(2,3,4,6-tetra-0-benzoyl-p-D-

-glucopyranosyl)formamidoxime 7-Glc [Benltifa, M.; Vidal, S.; Fenet, B.; Msaddek, M.;

Goekjian, P. G.; Praly, J-P.; Brunyanszki, A.; Docsa, T.; Gergely, P.: Eur. J. Org. Chem.,

4242-4256 (2006)]), or protected β-D-glycopyranosylcarbonyl chlorides of formula 10 (e. g.

2,3,4,6-tetra-0-benzoyl-P-D-glucopyranosylcarbonyl chloride 10-Glc [Czifrak, K.; Szilagyi, P.; Somsak, L.: Tetrahedron: Asymmetry, 16, 127-141 (2005)]) were obtained by published procedures.

11

Treatment of compounds 1 with Et₃OBF₄ furnished protected ethyl C-β-ϋ-

-glycopyranosyl)formimidates 5, which were reacted with tosylhydrazide to give protected N'-tosyl-C-( -D-glycopyranosyl)formamidrazones 9. Reductive cleavage of the N-O bond in amidoximes 7 gave protected C-( -D-glycopyranosyl)formamidines 11. Nitriles 2 were converted to protected N-[C-(P-D-glycopyranosyl)methylideneamino]arenecarboximid- -amides 8 under reductive conditions (Raney-Ni, NaH₂P0₂) in the presence of arenecarboxamidrazones 4 obtained by literature methods [Case, F. H.: J. Org. Chem., 30, 931-933 (1965)]. Bromination of compounds 8 by N-bromosuccinimide gave protected N- -arenecarboximidoyl-C-( -D-glycopyranosyl)carbohydrazonoyl bromides 12.

Preparation of the Compounds of formula I

formula I wherein X is Ν)

O

Ν

H

The substituents of the formulae included in Scheme 2 are as defined for formula I.

Reaction of tetrazoles 3 with N-benzyl-carboximidoyl chlorides 13' obtained from the corresponding N-benzyl-carboxamides 13 by SOCl₂ (Scheme 2) proved an efficient way to get O-protected 4-benzyl-3-substituted-5-(P-D-glycopyranosyl)-l,2,4-triazoles 14. Deprotection of these derivatives was readily carried out by well known methods (Zemplen conditions to remove the (9-acyl groups yielding compounds 15, and catalytic hydrogenation to cleave benzyl groups, whereby the order of the deprotection steps can be reversed to get compounds 16 first) to give the target 3-substiruted-5-(P-D-glycopyranosyl)-l ,2,4-triazoles 17.

Tosyl-amidrazones 9 were transformed (Scheme 2) by acylation (and concomitant or subsequent removal of the tosyl group by TBAF where necessary) to give protected compounds 16 which were then O-deprotected by using standard methods to yield the target 1 ,2,4-triazoles 17.

Transformations of acid chlorides 10 or amidines 11 with carboxamidrazones 4

(Scheme 2) provided alternative ways to get C-glycosyl triazoles 16 which were deprotected to 17.

Ring closure of protected N-arenecarboximidoyl-C-( -D-glycopyranosyl)carbohydra- -zonoyl bromides 12 to protected 3-substituted-5-(P-D-glycopyranosyl)-l,2,4-triazoles 16 was effected by NH₄OAc (Scheme 2) or by heating in pyridine, and subsequent deprotection yielded the corresponding end-products 17.

In the above Scheme 2 formulae 16 and 17 however depict a specific tautomer, these formulae are intended to represent the other tautomer forms as well, as it was mentioned above.

Preparation of 4(5)-substituted-2-(P-D-glvcopyranosyl)-imidazoles (compounds of formula I wherein X is CH)

Scheme 3

The substituents of the formulae included in Scheme 3 are as defined in formula I. In reactions of imidates 5 with a-aminoketones 20 or, alternatively, in reactions of amidines 11 with a-bromoketones 21 (Scheme 3) protected 4(5)-substituted-2-( -D-glyco- pyranosyl)-imidazoles 18 were obtained from which deprotection gave imidazoles 19.

In the above Scheme 3 formulae 19 however depicts a specific tautomer, this formula is intended to represent the other tautomer form as well, as it was mentioned above.

In addition, the reactions disclosed in Scheme 1 to 3 can also be carried out using protecting groups different from PG and PG defined in formula I. These further protecting groups are well known by a person skilled in the field of organic syntheses and disclosed for example in Green's handbook [T. W. Green, P. G. M. Wuts, Protective Groups in organic Synthesis, Wiley-Interscience, New York, 503-507, 736-739 (1999)].

The pharmaceutical compositions according to the invention are usable in the treatment or prevention of type 2 diabetes or early stage cardiovascular diseases, or in the stabilization of cardiac arrhythmia or in the protection against ischaemic lesions or in the prevention of tumorous growth and other diseases influenced by glycogen phosphorylase.

The active agents of the invention may be formulated in the pharmaceutical composition as described below. The pharmaceutical composition according to the invention comprises an effective amount of compound I and at least one pharmaceutically acceptable carrier or additive.

The pharmaceutical compositions of the invention may be administered in any commonly used pharmaceutical form, such as solid, semisolid or liquid forms. The solid forms are for example tablets, capsules, coated tablets, the semisolid forms are for example ointments, cremes or gels, the liquids are for example solutions, suspensions or emulsions. The pharmaceutical compositions according to the invention may include commonly used carriers and additives corresponding to the given pharmaceutical form.

The solid compositions for oral use are for example tablets, capsules, coated tablets. The liquid compositions for oral use are for example solutions, suspensions and emulsions. The compositions according to the invention may be formulated for veterinary use, such forms are for example powder mixtures used as food additives or solutions admixed in watering solutions.

Parenteral compositions are for example solutions, suspensions and emulsions.

Topical compositions are for example powers, ointments, gels and aqueous solutions, suspensions and emulsions. On mucous membranes semisolid or liquid forms are preferably used. In the preparation of pharmaceutical compositions the active agent is mixed with commonly used non-toxic inert carriers and/or additives.

Commonly used carriers are for example water, gelatin, lactose, starch, magnesium stearate, stearic acid, glycols, alcohols, vegetable oils and the like. In cremes and ointments the carriers can be for example petrolatum, liquid paraffin, lanoline, polyethylene glycols, alcohols and any mixtures thereof. Commonly used pharmaceutical additives are for example preservatives, stabilizers, viscosity increasing agents, osmolarity controlling agents, pH controlling agents, moisteners, emollients, emulsifiers, colorants, flavours, odorants and the like.

Preferably, the pharmaceutical compositions according to the invention are administered orally, especially in the above-mentioned solid and liquid forms.

The preparation of preferred compounds of formula I of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other glycogen phosphorylase inhibitors of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

EXPERIMENTAL PART

General methods

Melting points were measured in open capillary tubes or on a Kofler hot-stage and are uncorrected. Optical rotations were determined with a Perkin-Elmer 241 polarimeter at room temperature. NMR spectra were recorded with Bruker WP 200 SY (200/50 MHz for 'H/^{I 3}C), Bruker AM 360 (360/90 MHz for 'H/¹³C) or Bruker AM 400 (400/100 MHz for ¹H/^{, 3}C) spectrometers. Chemical shifts are referenced to Me₄Si (Ή), or to the residual solvent signals (^1JC). TLC was performed on DC-Alurolle Kieselgel 60 F₂₅₄ (Merck), and the spots were visualized under UV light and by gentle heating. For column chromatography Kieselgel 60 (Merck, particle size 0.063-0.200 mm) was used.

Substituent R of the formulae of the compounds prepared in the examples below are indicated in Table 1. The signs shown in Table 1 are used to identify a specific compound coverd by a general formula I indicated in Schemes 1 to 3. Table 1

Examples

Syntheses of intermediates

Intermediate Example 1

5-(2',3',4'-tri-0-Benzoyl-P-D-xylopyranosyl)-tetrazole (3-Xyl)

2,3,4-Tri-O-benzoyl-P-D-xylopyranosyl cyanide [Dong, L.; Li, L.; Ma, L.; Zhang, L. Chin. Chem. Lett. 3, 597-600 (1992)] (2-Xyl, 2.00 g, 4.24 mmol), trimethylsilyl azide (2.23 mL, 16.96 mmol), Bu₂SnO (0.10 g, 0.42 mmol) was dissolved in anhydrous toluene (60 mL) and heated overnight at 80 °C. Toluene was then removed under reduced pressure, and the residue was crystallized from MeOH to yield 1.98 g (91 %) white solid. Mp: 176-177 °C; [a]_D = -29 (c 1.02, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 14.73 (1H, brs, NH), 7.99-7.19 (15H, m, aromatics), 6.08, 5.87 (2 x 1H, 2 pseudo t, J= 9.5, 9.4 Hz in each, H-2', H-3'), 5.61 (1H, ddd, J = 10.8, 9.7, 5.7 Hz, H-4'), 5.26 (1H, d, J = 9.6 Hz, H-l '), 4.56 (1H, dd, J= 1 1.3, 5.3 Hz, H- -5'a), 3.80 (1H, pseudo t, J= 10.8, 10.8 Hz, H-5'b); ¹³C NMR (CDC1₃) δ (ppm): 165.9, 165.8, 165.5 (CO), 152.3 (tetrazole C-5), 133.7-128.3 (aromatics), 72.9, 72.2, 71.1, 69.7 (C-Γ - C- -4'), 67.4 (C-5').

Intermediate Example 2

Synthesis of arenecarboxamidrazones (4r, 4d, 4q)

Pyridine-2-carboxamidrazone (4r) was prepared according to the literature procedure [Case, F. H. The Preparation of Hydrazidines and os-Triazines Related to Substituted 2-Cyanopyridines. J. Org. Chem., 30, 931-933 (1965)], benzamidrazone (4d) and naphthalene-2-carboxamidrazone (4q) were synthesized from the corresponding carboximidate. An arenecarboximidate [Yadav, V. K.; Babu, K. G. Eur. J. Org. Chem., 452- -456 (2005)] (3.36 mmol) was dissolved in anhydrous MeOH (10 mL), hydrazine acetate (3.36 mmol, 1 equiv.) was added, and the mixture was stirred at rt for 3 hours. The solvent was removed under diminished pressure, and the crude product was used freshly without further purification for the synthesis of 1,2,4-triazole derivatives.

Intermediate Example 3

Ethyl C-(2,3,4,6-tetra-0-benzoyl-P-D-glucopyranosyl)formimidate (5-Glc)

C-(2,3,4,6-Tetra-O-benzoyl-P-D-glucopyranosyl)formamide [Somsak, L.; Nagy, V.

Tetrahedron: Asymmetry, 11, 1719-1727 (2000). Corrigendum 2247] (1-Glc, 1 g, 1.60 mmol) and Et₃OBF₄ (0.91 g, 4.80 mmol) were dissolved in anhydrous CH₂C1₂ (15 mL), the mixture was stirred at rt under Ar, and monitored by TLC (1 :1 EtOAc-hexane). After completion of the reaction (2 days), the mixture was diluted with CH₂C1₂ (30 mL), extracted with satd aq NaHC0₃ solution (30 mL) then with water (30 mL). The organic phase was dried over MgS0₄, filtered, and evaporated. The pale yellow amorphous crude product was used without further purification. Yield: 1.00 g, 96 %, Rf. 0.55 (1 :1 EtOAc-hexane); Ή NMR (CDC1₃) δ (ppm): 8.06-7.25 (21H, m, aromatics, NH), 5.99, 5.72, 5.55 (3 x 1H, 3 pseudo t, J = 10.6, 9.2 Hz in each, H-2, H-3, H-4), 4.70 (1H, dd, J = 1 1.9, 2.6 Hz, H-6a), 4.52 (1 H, dd, J = 1 1.9, 5.3 Hz, H-6b), 4.25 (1H, ddd, J = 9.2, 5.3, 2.6 Hz, H-5), 4.21 (1H, d, J = 9.2 Hz, H-l), 4.12-3.91 (2H, m, CH₂), 0.84 (3H, t, 6.6 Hz, CH₃); ¹³C NMR (CDC1₃) δ (ppm): 167.5, 166.1, 165.7, 165.1 (2) (CO, CNH), 133.5-128.2 (aromatics), 75.8, 74.6, 73.6, 70.7, 69.1 (C-l - C-5), 62.8, 62.1 (C-6, CH₂), 13.4 (CH₃).

General procedure I

for the synthesis of protected N-[C-(P-D-glycopyranosyl)methylideneamino]arene- -carboximidamides (8)

An arenecarboxamidrazone (4, 0.50 mmol) was dissolved in a mixture of pyridine (1.5 mL) and water (0.9 mL) and stirred at rt for 20 minutes. Then acetic acid (0.9 mL), Raney-Ni (0.38 g, from an aqueous suspension, Merck), sodium hypophosphite (0.20 g), and a nitrile (2, (0.25 mmol) were added to the solution. The reaction mixture was vigorously stirred and heated at 40 °C. When the reaction was complete (TLC, eluent: 1 :2 EtOAc-hexane) the insoluble materials were filtered off with suction, and washed with dichloromethane (10 mL). The organic layer of the filtrate was separated, washed with water (2 x 6 mL), dried (MgS0₄), and evaporated under reduced pressure, traces of pyridine were removed by repeated co- -evaporations with toluene. The residue was purified by column chromatography (1 :2 EtOAc- hexane). Intermediate Example 4

N-[C-(2,3,4,6-Tetra-(?-benzoyl-p-D-glucopyranosyl)methylideneamino]benzene- -carboximidamide (8-GIc-d)

The title compound is prepared from 2,3,4,6-tetra-0-benzoyl- -D-glucopyranosyl cyanide [Somsak, L.; Nagy, V.: Tetrahedron: Asymmetry, 11, 1719-1727, Corrigendum 2247 (2000)] (2-GIc, 2.52 g, 4.16 mmol) and benzamidrazone (4d, 1.12 g, 8.31 mmol) according to General procedure I. Purified by column chromatography (1 :2 EtOAc-hexane) to yield 1.45 g (49%) white amorphous solid. Rf. 0.50 (2:3 EtOAc-hexane); [a]_D = + 16 (c 0.40, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.04-7.23 (26 H, m, aromatics, CH=N), 6.06-5.99 (2H, m, H-2 and/or H-3 and/or H-4), 5.80-5.58 (3H, m, H-2 or H-3 or H-4, NH, C=NH), 4.67 (1H, dd, J = 12.3, 2.8 Hz, H-6a), 4.62 (1H, dd, J= 9.4, 2.7 Hz, H-l), 4.50 (1H, dd, J = 12.3, 5.0 Hz, H-6b), 4.26 (1H, ddd, J = 9.2, 5.0, 2.8 Hz, H-5); ¹³C NMR (CDCI3) δ (ppm): 166.0, 165.8, 165.6, 165.1 (CO), 160.6 (C=NH), 151.3 (CH=N), 133.3-126.5 (aromatics), 77.1, 76.1, 74.4, 70.0, 69.5 (C-l - C-5), 63.1 (C-6). Intermediate Example 5

N-[C-(2,3,4,6-Tetra-0-benzoyl-P-D-glucopyranosyl)methylideneamino]naphtha- -lene-2-carboximidamide (8-Glc-q)

The title compound is prepared from 2,3,4,6-tetra-0-benzoyl-P-D-glucopyranosyl cyanide [Somsak, L.; Nagy, V.: Tetrahedron: Asymmetry, 11, 1719-1727, Corrigendum 2247 (2000)] (2-Glc, 1.54 g, 2.55 mmol) and naphthalene-2-carboxamidrazone (4q, 0.96 g, 5.11 mmol) according to General procedure I. Purified by column chromatography (1 :2 EtOAc- -hexane) to yield 1.00 g (51%) white amorphous solid. R_f: 0.44 (1 :2 EtOAc-hexane); [α]ο = + 1 (c 1.10, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.13-7.21 (28 H, m, aromatics, CH=N), 6.09- -6.01 (2H, m, H-2 and/or H-3 and/or H-4), 5.77 (1H, pseudo t, J= 9.6, 9.5 Hz, H-2 or H-3 or H-4), 4.67 (1H, dd, J= 12.2, 2.7 Hz, H-6a), 4.63 (lH, dd, J= 9.1, 4.3 Hz, H-l), 4.51 (1H, dd, J = 12.2, 4.9 Hz, H-6a), 4.24 (1H, ddd, J= 9.5, 4.5, 2.7 Hz, H-5); ^l3C NMR (CDC1₃) δ (ppm): 166.1, 165.9, 165.7, 165.1 (CO), 160.8 (C=NH), 151.4 (CH=N), 134.3-123.7 (aromatics), 77.1, 76.1, 74.4, 70.0, 69.5 (C-l - C-5), 63.1 (C-6).

Intermediate Example 6

N-[C-(2,3,4,6-Tetra-i?-benzoyI-P-D-glucopyranosyl)methylideneamino]pyridine-2- -carboximidamide (8-Glc-r)

The title compound is prepared from 2,3,4,6-tetra-0-benzoyl-P-D-glucopyranosyl cyanide [Somsak, L.; Nagy, V.: Tetrahedron: Asymmetry, 11, 1719-1727, Corrigendum 2247 (2000)] (2-Glc, 2.00 g, 3.31 mmol) and pyridine-2-carboxamidrazone (4r, 0.90 g, 6.61 mmol) according to General procedure I. Purified by column chromatography (1 : 1 EtOAc-hexane) to yield 1.18 g (49%) white amorphous solid. R_f: 0.55 (1 : 1 EtOAc-hexane); [a]_D = +59 (c 0.28, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.45-7.21 (25 H, m, aromatics, CH=N), 6.43 (2H, brs, NH, C=NH), 6.10-6.02 (2H, m, H-2 and/or H-3 and/or H-4), 5.80 (1H, pseudo t, J = 9.6, 9.3 Hz, H-2 or H-3 or H-4), 4.70 (1H, dd, J = 12.2, 3.0 Hz, H-6a), 4.66 (1H, dd, J = 9.6, 4.2 Hz, H-l), 4.54 (1H, dd, J = 12.2, 5.4 Hz, H-6b), 4.30 (1H, ddd, J= 9.9, 5.1, 3.0 Hz, H-5); ¹³C NMR (CDC1₃) δ (ppm): 165.9, 165.7, 165.5, 165.0 (CO), 157.7 (C=NH), 151.5 (CH=N), 149.6 (q), 148.0, 136.3-121.3 (aromatics), 77.1, 76.1, 74.3, 70.0, 69.4 (C-l - C-5), 63.0 (C-6).

Intermediate Example 7

7V¹-Tosyl-C-(2,3,4,6-tetra-0-benzoyl-p-D-glucopyranosyl)formamidrazone (9-Glc)

Ethyl C-(2,3,4,6-tetra-O-benzoyl-P-D-glucopyranosyl)formimidate (5-Glc, 1 g, 1.53 mmol) and p-toluenesulfonhydrazide (0.43 g, 2.3 mmol) were dissolved in 30 mL anhydrous CH₂C1₂, stirred at rt, and monitored by TLC (1 : 1 EtOAc-hexane). After completion of the reaction (3 days) the solvent was removed, and the residue was purified by column chromatography (4:6 EtOAc-hexane) to give colourless oil. Yield: 0.92 g (76 %); R_f: 0.52 (1 :1 EtOAc-hexane); [a]_D = -50 (c 0.21, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.02-6.87 (24H, m, aromatics), 6.30 (1H, s, NH), 5.96 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2 or H-3 or H-4), 5.74 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2 or H-3 or H-4), 5.64-5.59 (3H, m, H-2 or H-3 or H-4, NH₂), 4.62 (1H, dd, J = 1 1.9, 2.6 Hz, H-6a), 4.50 (1H, dd, J = 11.9, 5.3 Hz, H-6b), 4.37 (1H, d, J = 9.2 Hz, H-l), 4.22 (1H, ddd, J = 9.2, 5.3, 2.6 Hz, H-5), 2.21 (3H, s, CH₃); ^l3C NMR (CDC1₃) δ (ppm): 166.1, 165.6, 165.3, 165.1 (CO), 157.0 (CNH), 143.0, 134.6, 133.3-127.6 (aromatics), 76.7, 76.0, 73.5, 70.4, 69.0 (C-l - C-5), 63.0 (C-6), 21.4 (CH₃).

Intermediate Example 8

C-(2,3,4,6-Tetra-0-benzoyl-P-D-glucopyranosyl)formamidine (11-Glc)

C-(2,3,4,6-Tetra- -benzoyl-P-D-glucopyranosyl)formamidoxime [Benltifa, M.; Vidal, S.; Fenet, B.; Msaddek, M.; Goekjian, P. G.; Praly, J.-P.; Brunyanszki, A.; Docsa, T.; Gergely, P. Eur. J. Org. Chem., 4242-4256 (2006)] (7-Glc, 3.19 g, 5.0 mmol) and acetic anhydride (0.52 mL, 5.5 mmol) were stirred in glacial acid (10 mL) at rt for 10 minutes. Potassium formate was prepared in situ from K₂C0₃ (3.46 g, 25 mmol) and formic acid (1.9 mL, 50 mmol) in methanol (7.5 mL), the above solution of the acetylated amidoxime and 0.5 g 10 % Pd(C) were added, stirred at rt and monitored by TLC (1 : 1 EtOAc-hexane and 9: 1 CHCl₃-MeOH). After completion of the reaction (1 hour) the mixture was diluted with MeOH and filtered through a celite pad then the filtrate was concentrated. The residue was dissolved in EtOAc (200 mL), extracted with water (200 ml) then with brine (200 ml). The organic phase was dried over MgS0₄, filtered and evaporated. The crude product was crystallised by a mixture of CHCl₃-hexane to give a white solid. Yield: 1.90 g (61 %). Mp: 153-155 °C; [ ]_D = +53 (c 0.23, DMSO); Ή NMR (DMSO-d₆) δ (ppm): 9.82 (3H, brs, amidine NH, NH₂), 8.06- -7.40 (20H, m, aromatics), 6.09, 5.94, 5.81 (3 x 1H, 3 pseudo t, J = 9.2, 9.2 Hz in each, H-2, H-3, H-4), 4.96 (1H, d, J = 9.2 Hz, H-l), 4.74 (1H, ddd, J = 9.2, 5.3, 2.6 Hz, H-5), 4.61-4.55 (2H, m, H-6a, H-6b); ¹³C NMR (DMSO-d₆) δ (ppm): 165.4, 165.3, 165.0, 164.7, 164.6 (CO, CNH), 134.2-127.8 (aromatics), 74.6, 74.0, 73.6, 70.2, 68.1 (C-l - C-5), 62.4 (C-6). General procedure II

for the synthesis of protected N-arenecarboximidoyl-C-(P-D-glycopyranosyl)carbo- -hydrazonoyl bromides (12)

A protected N-[C-(P-D-glycopyranosyl)methylideneamino]arenecarboximidaniide (8, 0.28 mmol) was dissolved in dichloromethane (4 mL), then N-bromosuccinimide (0. 05 g, 0.28 mmol) was added. The mixture was stirred at rt. When the reaction was complete (TLC, 1 :2 EtOAc-hexane) the solvent was evaporated, and the residue was purified by column chromatography (1 :2 EtOAc-hexane).

Intermediate Example 9

N-Benzenecarboximidoyl-C-(2,3,4,6-tetra-0-benzoyl-P-D-glucopyranosyl)carbo- -hydrazonoyl bromide (12-Glc-d)

The title compound is prepared from 8-Glc-d (0.40 g, 0.55 mmol) and NBS (0.10 g, 0.55 mmol) according to General procedure II. Purified by column chromatography (1 :2 EtOAc-hexane) to yield 0.33 g (74%) white amorphous solid. R_f: 0.30 (1 :2 EtOAc-hexane); [<x]_D = +30 (c 0.15, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.06-7.24 (25H, m, aromatics), 6.30 (brs, NH), 6.24, 5.99, 5.73 (3 x 1H, 3 pseudo t, J = 9.6, 9.6 Hz in each, H-2, H-3, H-4), 4.78 (1H, d, J= 9.6 Hz, H-l), 4.68 (1H, dd, J= 12.2, 2.5 Hz, H-6a), 4.53 (lH, dd, J = 12.2, 5.6 Hz, H-6b), 4.32 (1H, ddd, J = 9.6, 5.6, 2.5 Hz, H-5); ¹³C NMR (CDCI₃) δ (ppm): 166.1, 166.0, 165.8, 165.2 (CO), 161.5 (C=NH), 133.4-127.0 (aromatics), 82.3, 76.5, 74.3, 70.4, 69.6 (C-l - C-5), 63.2 (C-6).

Intermediate Example 10

N-(Naphthalene-2-carboximidoyl)-C-(2,3,4,6-tetra-i?-benzoyl-p-D-glucopyrano- -syl)carbohydrazonoyl bromide (12-Glc-q)

The title compound is prepared from 8-Glc-q (0.30 g, 0.39 mmol) and NBS (0.08 g, 0.39 mmol) according to General procedure II. Purified by column chromatography (1 :2 EtOAc-hexane) to yield 0.23 g (70%) pale yellow amorphous solid. R_f: 0.40 (1 :2 EtOAc- -hexane); [a]_D = +17 (c 0.07, CHCI₃); Ή NMR (CDCI₃) δ (ppm): 8.21-7.21 (27H, m, aromatics), 6.31 (1H, pseudo t, J= 9.7, 9.5 Hz, H-2 or H-3 or H-4), 6.14 (brs, NH), 6.00, 5.76 (2 x 1 H, 2 pseudo t, J= 9.6, 9.8 Hz in each, H-2 and/or H-3 and/or H-4), 4.77 (1H, d, J = 9.8 Hz, H-l), 4.69 (1H, dd, J = 12.2, 2.4 Hz, H-6a), 4.54 (1H, dd, J = 12.2, 5.2 Hz, H-6b), 4.29 (1H, ddd, J = 9.6, 5.2, 2.4 Hz, H-5); ^l3C NMR (CDCI₃) δ (ppm): 166.0, 165.9, 165.8, 165.1 (CO), 161.4 (C=NH), 134.5-123.8 (aromatics), 82.4, 76.3, 74.4, 70.4, 69.5 (C-l - C-5), 63.1 (C-6). ESI-MS (positive mode) m/z: 856.167 [M+H]⁺.

Intermediate Example 11

N-(Pyridine-2-carboximidoyl)-C-(2,3,4,6-tetra-0-benzoyl-p-D-glucopyranosyl)- -carbohydrazonoyl bromide (12-Glc-r)

The title compound is prepared from 8-Glc-r (0.30 g, 0.41 mmol) and NBS (0.09 g, 0.41 mmol) according to General procedure II. Purified by column chromatography (1 :8 EtOAc-toluene) to yield 0.12 g (36%) white amorphous solid. R_f: 0.50 (1 :8 EtOAc-toluene); [a]_D = +55 (c 0.38, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.52-7.25 (24H, m, aromatics), 6.96 (1H, brs, NH), 6.60 (1H, brs, NH) 6.30, 6.00, 5.75 (3 x 1H, 3 pseudo t, J = 9.6, 9.4 Hz in each, H-2, H-3, H-4), 4.76 (1H, d, J = 9.6 Hz, H-l), 4.70 (1 H, dd, J = 12.0, < 1 Hz, H-6a), 4.54 (1H, dd, J = 12.0, 5.3 Hz, H-6b), 4.41-4.18 (1H, m, H-5); ^,3C NMR (CDC1₃) δ (ppm): 166.1, 165.9, 165.8, 165.1 (CO), 158.8 (C=NH), 149.1 (q), 148.2 136.7, 133.4-122.3 (aromatics), 82.4, 76.5, 74.4, 70.4, 69.6 (C-l - C-5), 63.2 (C-6).

Intermediate Example 12

Synthesis of N-benzyl-arenecarboxamides (13)

In a flame dried three necked bottle, equipped with a CaCl₂ tube, benzylamine (1 mL, 9.16 mmol) and TEA (1.53 mL, 1 1 mmol, 1.2 equiv.) was dissolved in the appropriate anhydrous solvent (5 mL, CH₂C1₂, THF or toluene, depending on the solubility of acid chloride). To this stirred mixture a solution (in 5 mL anhydrous CH₂C1₂, THF or toluene) of an acid chloride (9.16 mmol, 1 equiv.) was added dropwise at 0°C. The mixture was slowly allowed to reach rt, stirred for 2 hours, then diluted, and extracted with water. The organic phase was dried over MgS0₄, the solvent was evaporated, and the crude product was crystallised from EtOH.

Syntheses of C-glycosyl heterocycles of formula I

Preparation of 3-substituted-5-(P-D-glvcopyranosyl)-l,2,4-triazoles General procedure III

for the synthesis of protected 4-benzyl-3-substituted-5-(P-D-glycopyranosyl)-l,2,4- -triazoles (14)

An N-benzyl-arenecarboxamide (13, 4.63 mmol) was dissolved in thionyl chloride (20 mL), and refluxed for 2 hours. After distilling off the excess of thionyl chloride under diminished pressure, 20 mL of anhydrous toluene was evaporated from the residue. A tetrazole 3 (1.54 mmol, 1 equiv.) and anhydrous toluene or xylene (20 mL) were added, the mixture was heated to reflux temperature, and the reaction was monitored by TLC (1 : 1 EtOAc-hexane). After total consumption of the tetrazole the solvent was removed and the residue was purified by column chromatography.

Example 1

4-Benzyl-3-phenyl-5-(2',3',4',6'-tetra-0-benzoyl-p-D-glucopyranosyl)-l,2,4-triazole (14-Glc-d)

The title compound is prepared from 3-Glc (2.00 g, 3.08 mmol) and N-

-benzylbenzamide (13d, 1.95 g, 9.25 mmol) in toluene according to General procedure III. Reaction time: 16 hours. Purified by column chromatography (1 : 1 EtOAc-hexane) to yield 2.50 g (69 %) colourless syrup. R_f: 0.15 (1 : 1 EtOAc-hexane); [a]_D = -25 (c 0.50, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.95-6.97 (30H, m aromatics), 5.99-5.96 (2 x 1H, m, H-2' and/or H- -3' and/or H-4'), 5.67 (1H, pseudo t, J = 10.6, 9.3 Hz, H-2' or H-3' or H-4'), 5.63 (1H, d, J = 15.9 Hz, PhCH₂), 5.53 (1H, d, J = 15.9 Hz, PhCH₂), 5.16 (1H, d, J = 9.3 Hz, H-l '), 4.49 (1H, dd, J = 12.2, 2.4 Hz, H-6'a), 4.33 (1H, dd, J = 12.2, 5.4 Hz, H-6'b), 4.19 (1H, ddd, J = 9.6, 5.4, 2.4 Hz, H-5'); ^,3C NMR (CDC1₃) δ (ppm): 165.9, 165.7, 165.1 , 164.8 (CO), 156.7, 149.8 (triazole C-3, C-5), 135.4-126.2 (aromatics), 76.8, 73.8, 73.2, 70.0, 69.1 (C-Γ - C-5'), 62.9 (C-6'), 48.1 (PhCH₂).

Example 2

4-Benzyl-3-(4-methylphenyl)-5-(2',3',4',6'-tetra-0-benzoyI-P-D-glucopyranosyI)- -1,2,4-triazole (14-Glc-e)

The title compound is prepared from 3-Glc (0.50 g, 0.77 mmol) and N-benzyl-4-

-methylbenzamide (13e, 0.52 g, 2.31 mmol) in m-xylene according to General procedure III. Reaction time: 3 hours. Purified by column chromatography (1 :1 EtOAc-hexane) to yield 0.32 g (49 %) brownish foam. Rf. 0.20 (1 :1 EtOAc-hexane); [a]_D = -4 (c 0.50, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.97-6.98 (29H, m, aromatics), 6.04, 5.98, 5.68 (3 x 1H, 3 pseudo t, J = 9.5, 9.5 Hz in each, H-2', H-3', H-4'), 5.50 (1H, d, J = 16.5 Hz, PhCH₂), 5.31 (1H, d, J = 16.5 Hz, PhCH₂), 5.13 (1H, d, J = 9.5 Hz, H-l '), 4.48 (1H, dd, J = 12.4, 2.6 Hz, H-6'a), 4.34 (1H, dd, J = 12.4, 5.4 Hz, H-6'b), 4.20 (1H, ddd, J = 9.8, 5.4, 2.6 Hz, H-5'), 2.24 (1H, s, CH₃); ¹³C NMR (CDC1₃) δ (ppm): 165.8, 165.7, 165.0, 164.6 (CO), 156.7, 149.7 (triazole C- -3, C-5), 140.2 (q), 135.4 (q), 133.4-123.6 (aromatics), 76.6, 73.8, 73.0, 69.9, 69.0 (C-Γ - C- -5'), 62.8 (C-6'), 47.9 (PhCH₂), 21.3 (CH₃).

Example 3

4-Benzyl-3-(4-tert-butylphenyl)-5-(2',3',4',6'-tetra-i?-benzoyl-P-D-gluco- pyranosyl)- 1,2,4- triazole (14-Glc-f)

The title compound is prepared from 3-Glc (0.70 g, 1.08 mmol) and N-benzyl-4-tert- -butylbenzamide (13f, 0.93 g, 3.23 mmol) in m-xylene according to General procedure III. Reaction time: 3 hours. Purified by column chromatography (1 : 1 EtOAc-hexane) to yield 0.57 g (61 %) yellow solid. Mp: 231-233 °C; R_f: 0.28 (1 : 1 EtOAc-hexane); [<x]_D = -43 (c 0.37, CHC1₃);'H NMR (CDC1₃) δ (ppm): 7.97-7.00 (29H, m, aromatics), 6.00, 5.97, 5.65 (3 x 1H, 3 pseudo t, J = 9.6, 9.6 Hz in each, H-2', H-3', H-4'), 5.51 (1H, d, J = 16.5 Hz, PhCH₂), 5.33 (1H, d, J= 16.5 Hz, PhCH₂), 5.1 1 (1H, d, J= 9.6 Hz, H-l '), 4.49 (1H, dd, J=12.2, 1.9 Hz, H- -6'a), 4.32 (1H, dd, J=12.2, 5.3 Hz, H-6'b), 4.17 (1H, ddd, J=9.6, 5.2, 1.9 H-5'), 1.29 (9H, s, C(CH₃)₃); ^l3C NMR (CDC1₃) δ (ppm): 165.9, 165.7, 165.1, 164.7 (CO), 156.7, 153.4 (triazole C-3, C-5), 149.7 (q), 135.5 (q), 133.5-123.7 (aromatics), 76.7, 73.9, 73.1, 69.9, 69.1 (C-Γ - C-5'), 62.9 (C-6'), 48.0 (PhCH₂), 34.2 (C(CH₃)₃), 31.1 (C(CH₃)₃).

Example 4

4-Benzyl-3-(4-trifluoromethylphenyl)-5-(2',3',4',6'-tetra-<?-benzoyl-p-D-gluco- pyranosyl)-l,2,4-triazole (14-Glc-g)

The title compound is prepared from 3-Glc (0.60 g, 0.93 mmol) and N-benzyl-4- -trifluoromethylbenzamide (13g, 0.78 g, 2.78 mmol) in toluene according to General procedure III. Reaction time: 16 hours. Purified by column chromatography (1 :4→ 1 : 1 EtOAc-hexane) to yield 0.72 g (88 %) white solid. Mp: 213-215 °C; [a]_D = -26 (c 0.54, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.94-6.95 (29H, m, aromatics), 6.06-5.98 (2 x 1H, m, H- -2' and/or H-3' and/or H-4'), 5.70 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2' or H-3' or H-4'), 5.60 (1H, d, J = 16.4 Hz, PhCH₂), 5.29 (IH, d, J = 16.4 Hz, PhCH₂), 5.21 (1H, d, J = 8.8 Hz, H- -Γ), 4.50 (IH, dd, J = 12.3, < 1 Hz, H-6'a), 4.34 (IH, dd, J = 12.3, 4.8 Hz, H-6'b), 4.23 (IH, ddd, J = 9.2, 4.8, < 1 Hz, H-5'); ¹ C NMR (CDC1₃) δ (ppm): 165.8, 165.7, 165.1, 164.8 (CO), 155.4, 150.3 (triazole C-3, C-5), 134.9-122.1 (aromatics, CF₃), 76.8, 73.7, 73.2, 69.9, 68.9 (C- -1 ' - C-5'), 62.7 (C-6'), 48.2 (PhCH₂).

Example 5

4-Benzyl-3-(4-methoxyphenyl)-5-(2',3',4',6'-tetra-0-benzoyl-P-D-glucopyranosyl)- -1,2,4-triazole (14-Glc-i)

The title compound is prepared from 3-Glc (1.0 g, 1.54 mmol) and N-benzyl-4- -methoxybenzamide (13i, 1.12 g, 4.64 mmol) in m-xylene according to General procedure III. Purified by column chromatography (1 :1→2: 1 EtOAc-hexane) to yield 0.81 g (68 %) white amorphous solid. R_f: 0.45 (2:1 EtOAc-hexane); [a]_D = -19 (c 0.55, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.98-6.98 (27H, m, aromatics); 6.87 (2H, d, J = 8.8 Hz, aromatics), 6.06- -5.91 (2 x 1H, m, H-2' and/or H-3' and/or H-4'), 5.65 (1H, pseudo t, J = 9.6, 9.6 Hz, H-2' or H-3' or H-4'), 5.50 (1H, d, J=16.6 Hz, PhCH₂), 5.29 (1H, d, J = 16.6 Hz, PhCH₂), 5.18 (1H, d, J = 9.6, Η-Γ), 4.48 (1H, dd, J= 12,3, 2.6 Hz, H-6'a), 4.32 (1H, dd, J= 12,3 and 5.4 Hz, H- -6'b), 4.19 (1H, ddd, J = 9.6, 5.4, 2.6 Hz, H-5'), 3.79 (3H, s, OMe); ¹³C NMR (CDG1₃) δ (ppm): 166.0, 165.8, 165.2, 164.8 (CO), 161.1 (MeOPh C-4), 156.7, 149.7 (triazole C-3, C-5), 135.5-126.1, 1 18.8, 1 14.2 (2) (aromatics), 76.7, 73.9, 73.2, 70.0, 69.1, (C-l ' - C-5'), 63.0 (C- -6'), 55.3 (OMe), 48.1 (PhCH₂). Example 6

4-Benzyl-3-(4-nitrophenyl)-5-(2',3',4',6'-tetra-<?-benzoyl-P-D-glucopyranosyl)- -1,2,4-triazole (14-Glc-j)

The title compound is prepared from 3-GIc (0.50 g, 0.77 mmol) and N-benzyl-4- -nitrobenzamide (13j, 0.59 g, 2.31 mmol) in toluene according to General procedure III. Reaction time: 16 hours. Purified by column chromatography (1 :1 EtOAc-hexane) to yield 0.25 g (38 %) yellow syrup. Rf. 0.28 (1 :1 EtOAc-hexane); [a]_D = -41 (c 0.50, CHC1₃); Ή NMR (CDCI3) δ (ppm): 8.18 (2H, d, J = 8.5 Hz, aromatics), 7.92-7.19 (25H, m, aromatics), 6.95 (2H, d, J = 6.9 Hz, aroamtics), 6.05, 6.00, 5.72 (3 x 1H, 3 pseudo t, J = 9.5, 9.5 Hz in each, H-2', H-3', H-4'), 5.66 (1H, d, J = 16.5 Hz, PhCH₂), 5.31 (1H, d, J= 16.5 Hz, PhCH₂), 5.26 (1H, d, J = 9.4 Hz, H-l '), 4.51 (1H, dd, J = 12.1, < 1 Hz, H-6'a), 4.35 (1H, dd, J = 12.1, 5.1 Hz, H-6'b), 4.27 (1H, ddd, J = 9.5, 5.1, 2.2 Hz, H-5'); ¹³C NMR (CDC1₃) δ (ppm): 165.8, 165.6, 165.1 , 164.9 (CO), 154.6, 150.7 (triazole C-3, C-5), 148.6 (q), 134.6-123.7 (aromatics), 76.8, 73.6, 73.2, 70.1, 68.9 (C-l ' - C-5'), 62.7 (C-6'), 48.4 (PhCH₂). Example 7

4-Benzyl-3-(3,5-dimethylphenyl)-5-(2 ',3 ',4 ',6 '-tetra-0-benzoyl-P-D-gluco- pyranosyl)- 1 ,2,4-triazole (14-GIc-m)

The title compound is prepared from 3-Glc (1.0 g, 1.54 mmol) and N-benzyl-3,5- -dimethylbenzamide (13m, 1.1 1 g, 4.64 mmol) in m-xylene according to General procedure III. Reaction time: 3 hours. Purified by column chromatography (1 : 1→2: 1 EtOAc-hexane) to yield 0.85 g (66 %) white solid. Mp: 225-227 °C; R_f: 0.28 (1 : 1 EtOAc-hexane); [a]_D = -19 (c 0.37, CHC1₃); 1H NMR (CDC1₃) δ (ppm): 7.98-7.00 (28H, m, aromatics), 6.12, 6.05, 5.75 (3 x 1H, 3 pseudo t, J = 9.5, 9.3 Hz in each, H-2', H-3', H-4'), 5.50 (1H, d, J = 16.4 Hz, PhCH₂), 5.32 (1H, d, J = 16.4 Hz, PhCH₂), 5.22 (1H, d, J = 9.6 Hz, Η- ), 4.52 (1H, dd, J = 12.5, 2.6 Hz, H-6'a), 4.39 (1H, dd, J = 12.6, 5.2 Hz, H-6'b), 4.26 (1H, ddd, J = 9.5, 5.2, 2.6 Hz, H-5'), 2.19 (6H, s, 2 x CH₃); ^l3C NMR (CDC1₃) δ (ppm): 165.6, 165.5, 164.9, 164.5 (CO), 156.7,

149.6 (triazole C-3, C-5), 138.0 (2q), 135.3-126.0 (aromatics), 76.4, 73.8, 72.6, 69.8, 68.8 (C- -1 ' - C-5'), 62.6 (C-6'), 47.9 (PhCH₂), 20.9 (2 x CH₃).

Example 8

4-Benzyl-3-(3,4,5-trimethoxyphenyl)-5-(2 ',3 ',4 ',6 '-tetra-0-benzoyl-p-D-gluco- pyranosyl)-l,2,4-triazole (14-Glc-p)

The title compound is prepared from 3-Glc (0.50 g, 0.77 mmol) and N-benzyl-3,4,5- -trimethoxybenzamide (13p, 0.7 g, 2.31 mmol) in /w-xylene according to General procedure III. Reaction time: 8 hours. Purified by column chromatography (3:2 EtOAc-hexane) to yield 0.45 g (65 %) pale yellow syrup. R_f: 0.15 (3:2 EtOAc-hexane); [a]_D = -33 (c 0.60, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.96-7.00 (25H, m, aromatics), 6.62 (2H, s, aromatics), 6.10-5.99 (2 x 1H, m, H-2' and/or H-3' and/or H-4'), 5.70 (1H, pseudo t, J = 9.3, 9.3 Hz, H-2' or H-3' or H-4'), 5.55 (1H, d, J= 16.8 Hz, PhCH₂), 5.31 (1H, d, J = 16.8 Hz, PhCH₂), 5.22 (1H, d, J = 9.3 Hz, Η-Γ), 4.45 (1H, dd, J = 10.8, < 1 Hz, H-6'a), 4.32-4.24 (2 x 1H, m, H-6'b, H-5'), 3.83 (3H, s, OMe), 3.59 (6H, s, 2 x OMe); ¹³C NMR (CDC1₃) δ (ppm): 165.8, 165.7, 165.0,

164.7 (CO), 156.5, 153.2, 150.0 (triazole C-3, C-5, 3,4,5-(MeO)₃Ph C-3, C-5), 135.7-121.5, 106.1 (2) (aromatics), 76.7, 73.8, 73.1, 70.0, 68.9 (C-l ' - C-5'), 62.8 (C-6'), 60.8 (OMe), 55.8 (2 x OMe), 48.1 (PhCH₂). Example 9

4-Benzyl-3-(2-naphthyl)-5-(2',3',4',6'-tetra-0-benzoyl-P-D-glucopyranosyl)-l,2,4- -triazole (14-Glc-q)

The title compound is prepared from 3-Glc (0.60 g, 0.93 mmol) and N-benzyl- -naphthalene-2-carboxamide (13q, 0.73 g, 2.78 mmol) in toluene according to General procedure III. Reaction time: 3 hours. Purified by column chromatography (1 : 1 → 3:2 EtOAc-hexane) to yield 0.41 g (52 %) pale yellow amorphous solid. Rf. 0.25 (1 :1 EtOAc- -hexane); [a]_D = -33 (c 0.50, CHC1₃);

Ή NMR (CDC1₃) δ (ppm): 7.96-7.01 (32H, m, aromatics), 6.08, 6.02, 5.70 (3 x 1H, 3 pseudo t, J = 9.3, 9.3 Hz in each, H-2', H-3', H-4'), 5.58 (1H, d, J = 15.9 Hz, PhCH₂), 5.38 (1H, d, J = 15.9 Hz, PhCH₂), 5.19 (1H, d, J = 9.3 Hz, Η-Γ), 4.49 (1H, dd, J = 11.9, 2.6 Hz, H-6'a), 4.35 (1H, dd, J = 11.9, 5.3 Hz, H-6'b), 4.23 (1H, ddd, J = 9.3, 5.3, 2.6 Hz, H-5'); ^{I 3}C NMR (CDC1₃) δ (ppm): 165.8, 165.7, 165.0, 164.7 (CO), 156.6, 149.9 (triazole C-3, C-5), 135.4- -123.9 (aromatics), 76.7, 73.8, 73.0, 69.9, 69.0 (C-Γ - C-5'), 62.8 (C-6'), 48.2 (PhCH₂).

Example 10

4-Benzyl-3-(4-benzyloxycarbonylphenyl)-5-(2',3',4',6'-tetra-i>-benzoyl-P-D-gluco- pyranosyl)-l,2,4-triazole (14-Glc-s)

The title compound is prepared from 3-Glc (0.30 g, 0.46 mmol) and N-benzyl-(4- -benzyloxycarbonyl)-benzamide (13s, 0.48 g, 1.39 mmol) in m-xylene according to General procedure III. Reaction time: 3 hours. Purified by column chromatography (1 :4→ 1 : 1 EtOAc-hexane) to yield 0.30 g (69 %) brownish foam. R_f: 0.23 (1 : 1 EtOAc-hexane); [<x]_D = -26 (c 0.54, CHCI3); Ή NMR (CDC1₃) δ (ppm): 8.07-6.94 (34H, m, aromatics), 6.01-5.99 (2 x 1H, m, H-2' and/or H-3' and/or H-4'), 5.68 (1H, pseudo t, J = 9.4, 8.6 Hz, H-2' or H-3' or H-4'), 5.57 (lH, d, J = 16.5 Hz, PhCH₂), 5.35 (2H, s, PhCH₂), 5.29 (1H, d, J = 16.5 Hz, PhCH₂), 5.18 (1H, d, J= 9.2 Hz, H-l '), 4.49 (1H, dd, J= 12.3, 2.0 Hz, H-6'a), 4.33 (1H, dd, J = 12.3, 5.3 Hz, H-6'b), 4.20 (1H, ddd, J= 9.5, 5.3, 2.0 Hz, H-5'); ¹³C NMR (CDCI₃) δ (ppm): 165.8, 165.7, 165.5, 165.0, 164.8 (CO), 155.8, 150.3 (triazole C-3, C-5), 135.6-126.0 (aromatics), 76.8, 73.7, 73.2, 70.0, 68.9 (C-l ' - C-5'), 67.0 (COOCH₂Ph), 62.8 (C-6'), 48.2 (PhCH₂). Example 11

4-BenzyI-3-phenyl-5-(2',3',4'-tri-0-benzoyl-P-D-xylopyranosyl)-l,2,4-triazole (14- -Xyl-d)

The title compound is prepared from tetrazole 3-Xyl (0.70 g, 1.36 mmol) and N- -benzylbenzamide (13d, 0.86 g, 4.08 mmol) in toluene according to General procedure III. Reaction time: 16 hours. Purified by column chromatography (1 : 1 EtOAc-hexane) to yield 0.65 g (68 %) white crystals. Mp: 230-231 °C; [a]_D = -33 (c 0.50, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.96-7.05 (25H, m, aromatics), 6.02, 5.92 (2 x 1H, 2 pseudo t, J = 9.4, 9.5 Hz in each, H-2', H-3 '), 5.49 (1H, d, J = 16.3 Hz, PhCH₂), 5.41 (1H, ddd, J = 9.8, 9.4, 5.3 Hz, H- -4'), 5.33 (1H, d, J = 16.3 Hz, PhCH₂), 4.94 (1H, d, J = 9.6 Hz, Η-Γ), 4.46 (1H, dd, J= 1 1.1,

5.3 Hz, H-5'a), 3.60 (1H, pseudo t, J = 10.8, 10.7 Hz, H-5'b); ^l3C NMR (CDC1₃) δ (ppm): 165.7, 165.4, 164.6 (CO), 156.4, 150.2 (triazole C-3, C-5), 135.3-126.3 (aromatics), 73.3, 73.3, 69.8, 69.7 (C-Γ - C-4'), 67.2 (C-5'), 48.0 (PhCH₂). Example 12

4-Benzyl-3-(4-tert-butylphenyl)-5-(2 ',3 ',4 '-tri-O-benzoyl-P-D-xylopyranosyl)- 1,2,4- -triazole (14-Xyl-f)

The title compound is prepared from tetrazole 3-Xyl (1.00 g, 1.94 mmol) and N-benzyl- -4-tert-butylbenzamide (13f, 1.56 g, 5.83 mmol) in w-xylene according to General procedure III. Reaction time: 4 hours. Purified by column chromatography (2:3 EtOAc- -hexane) to yield 0.60 g (42 %) white crystals. Mp: 234-236 °C; [a]_D = -18 (c 0.52, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.96-7.07 (24H, m, aromatics), 6.00, 5.90 (2 x 1H, 2 pseudo t, J =

9.4 Hz in each, H-2', H-3'), 5.47 (1H, d, J = 16.5 Hz, PhCH₂), 5.41-5.33 (2H, m, H-4', PhCH₂), 4.89 (1H, d, J = 9.7 Hz, H-l '), 4.44 (1H, dd, J = 1 1.2, 5.1 Hz, H-5'a), 3.57 (1H, pseudo t, J= 10.7, 10.7 Hz, H-5'b), 1.30 (9H, s, C(CH₃)₃); ¹³C NMR (CDC1₃) δ (ppm): 165.8, 165.4, 164.5 (CO), 156.5, 153.4 (triazole C-3, C-5), 150.0 (q), 135.5-123.7 (aromatics), 73.4, 73.2, 69.8, 69.7 (C-Γ - C-4'), 67.2 (C-5'), 48.0 (PhCH₂), 34.8 (C(CH₃)₃), 31.1 (C(CH

Example 13

4-Benzyl-3-(2-naphthyl)-5-(2',3',4'-tri-i?-benzoyl-P-D-xylopyranosyl)-l,2,4-triazole (14-Xyl-q)

The title compound is prepared from tetrazole 3-Xyl (1.00 g, 1.94 mmol) and N-benzyl- -naphthalene-2-carboxamide (13q, 1.52 g, 5.82 mmol) in m-xylene according to General procedure III. Reaction time: 3 hours. Purified by column chromatography (1 :1 EtOAc- -hexane) to yield 0.73 g (52 %) white crystals. Mp: 226-227 °C; [a]_D = -39 (c 0.47, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.97-7.08 (27H, m, aromatics), 6.04, 5.95 (2 x 1H, 2 pseudo t, J = 9.5, 9.4 Hz in each, H-2', H-3'), 5.55 (1H, d, J = 16.4 Hz, PhCH₂), 5.45-5.38 (2H, m, H-4', PhCH₂), 5.00 (1H, d, J = 9.6 Hz, Η-Γ), 4.47 (1H, dd, J = 11.2, 5.3 Hz, H-5'a), 3.62 (1H, pseudo t, J = 10.7, 10.7 Hz, H-5'b); ¹³C NMR (CDC1₃) δ (ppm): 165.7, 165.4, 164.7 (CO), 156.5, 150.3 (triazole C-3, C-5), 135.3-123.8 (aromatics), 73.3, 73.2, 69.9, 69.7 (C-l ' - C-4'), 67.2 (C-5'), 48.2 (PhCH₂).

Example 14

4-Benzyl-3-phenyl-5-(2',3',4',6'-tetra-i?-acetyl-p-D-galactopyranosyl)-l,2,4-triazole (14-Gal-d)

The title compound is prepared from 3-Gal (0.48 g, 1.20 mmol) and N- -benzylbenzamide (13d, 0.76 g, 3.59 mmol) in toluene according to General procedure III. Reaction time: 16 hours. Purified by column chromatography (2:3 acetone-hexane) to yield 0.44 g (65 %) brownish foam. R_f: 0.38 (1 : 1 acetone-hexane); [<x]_D = -13 (c 0.60, CHC1₃); Ή NMR (CDCI₃) δ (ppm): 7.47-6.97 (10H, m aromatics), 5.69 (1H, pseudo t, J= 10.1, 10.1 Hz, H-2'), 5.49 (2H, m, PhCH₂, H-4'), 5.32 (1H, d, J = 16.1 Hz, PhCH₂), 5.14 (1H, dd, J = 10.1, 3.1 Hz, H-3'), 4.78 (1H, d, J= 10.1 Hz, H-l '), 3.96 (1H, ddd, J= 6.9, 5.7, <1 Hz, H-5'), 3.88 (1H, dd, J = 1 1.4, 5.7 Hz, H-6'a), 3.80 (1H, dd, J = 11.3, 6.9 Hz, H-6'b), 2.1 1, 2.01, 1.99, 1.98 (4 x 3H, 4 s, CH₃); ¹³C NMR (CDC1₃) δ (ppm): 170.1, 170.0, 169.8, 169.5 (CO), 156.8, 149.9 (triazole C-3, C-5), 135.7-126.0 (aromatics), 74.7, 73.4, 71.4, 67.4, 66.3 (C-l ' - C-5'), 61.4 (C-6'), 48.0 (PhCH₂), 20.6 (1 x CH₃), 20.5 (3 x CH₃).

General procedure IV

for removal of 0-acyl protecting groups by the Zemplen protocol

An O-acylated compound was dissolved in dry MeOH (5 mL/100 mg, a few drops of CHCI₃ were added in case of incomplete dissolution) and a catalytic amount of a NaOMe solution (1 M in MeOH) was added. The mixture was kept at rt and monitored by TLC (7:3 CHCl₃-MeOH). When the starting material was consumed the mixture was neutralised with a cation exchange resin Amberlyst 15 (H⁺ form) or with acetic acid, then the resin was filtered off and the solvent removed. The residue was purified by column chromatography.

Example 15

4-Benzyl-5-(P-D-glucopyranosyl)-3-phenyl-l,2,4-triazole (15-Glc-d) The title compound is prepared from 14-Glc-d (0.82 g, 1.00 mmol) according to General procedure IV. Reaction time: 4 days. Purified by column chromatography (9: 1→ 4: lCHCl₃-MeOH) to yield 0.29 g (73 %) pale yellow syrup. R_f: 0.55 (7:3 CHCl₃-MeOH); [a]_D = -15 (c 0.60, MeOH); Ή NMR (D₂0) δ (ppm): 7.50-6.94 (10H, m, aromatics), 5.31 (2H, s, PhCH₂), 4.48 (IH, d, J = 10.6 Hz, H-l '), 3.98 (IH, pseudo t, J = 9.3, 9.3 Hz, H-2' or H-3' or H-4'), 3.67-3.47 (4 x IH, m, H-6'a, H-6'b, H-2' and/or H-3' and/or H-4'), 3.34 (IH, m, H-5'); ¹³C NMR (D₂0) δ (ppm): 156.9, 153.2 (triazole C-3, C-5), 135.2 (q), 131.2, 129.3 (2), 129.1 (2), 129.0 (2), 128.3, 126.4 (2), 125.4 (q) (aromatics), 80.3, 77.2, 72.1 , 71.8, 69.4 (C-r - C-5'), 60.8 (C-6'), 47.6 (PhCH₂).

Example 16

4-Benzyl-5-(P-D-glucopyranosyl)-3-(4-methylphenyl)-l,2,4-triazole (15-Glc-e)

The title compound is prepared from 14-Glc-e (0.52 g, 0.63 mmol) according to General procedure IV. Reaction time: 2 days. Purified by column chromatography (9: 1→ 4: lCHCl₃-MeOH) to yield 0.25 g (94 %) colourless syrup. R_f: 0.35 (4: 1 CHCl₃-MeOH); [a]_D = -4 (c 0.50, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.34-7.23 (7H, m, aromatics), 7.00 (2H, d, J = 6.6 Hz, aromatics), 5.41 (IH, d, J = 16.9 Hz, PhCH₂), 5.34 (IH, d, J = 16.9 Hz, PhCH₂), 4.34 (IH, d, J= 9.7 Hz, H-l '), 3.92 (IH, pseudo t, J= 9.1, 8.9 Hz, H-2' or H-3' or H-4'), 3.75 (IH, dd, J = 12.0, < 1 Hz, H-6'a), 3.63-3.54 (2H, m, H-6'b, H-2' or H-3' or H-4') 3.43-3.72 (2H, m, H-2' or H-3' or H-4', H-5'), 2.34 (3H, s, CH₃); ^{l 3}C NMR (CD₃OD) δ (ppm): 157.4, 155.0 (triazole C-3, C-5), 142.4 (q), 136.9 (q), 130.7 (2), 130.1 (2), 130.0 (2), 129.2, 127.5(2), 124.7 (q) (aromatics), 82.5, 79.3, 74.2, 73.6, 71.1 (C-l ' - C-5'), 62.7 (C-6'), 47.7 (PhCH₂), 21.5 (CH₃). Example 17

4-Benzyl-5-(P-D-glucopyranosyl)-3-(4-tert-butylphenyl)-l,2,4-triazole (15-Glc-f)

The title compound is prepared from 14-Glc-f (0.49 g, 0.56 mmol) according to General procedure IV. Reaction time: 1 day. Purified by column chromatography (4:1 CHCl₃-MeOH) to yield 0.25 g (98 %) yellow syrup. R_f: 0.31 (8:2 CHCl₃-MeOH); [a]_D = -3 (c 0.31 , MeOH); Ή NMR (CD₃OD) δ (ppm): 7.45 (2H, d, J= 8.3 Hz, aromatics), 7.35 (2H, d, J =8.3 Hz, aromatics), 7.23 (3H, m, aromatics), 6.99 (2H, d, J= 6.4 Hz, aromatics), 5.40 (IH, d, J = 16.8 Hz, PhCH₂), 5.33 ( H, d, J = 16.8 Hz, PhCH₂), 4.31 (IH, d, J = 9.7 Hz, H-l '), 3.89 (IH, pseudo t, J = 9.4, 9.0 Hz, H-2' or H-3' or H-4'), 3.74 (IH, dd, J = 12.1, 2.6 Hz, H- -6'a), 3.56 (IH, dd, J = 12.1, 5.3 Hz, H-6'b), 3.41-3.34 (2H, m, H-2' and/or H-3' and/or H- -4'), 3.25 (1H, ddd, J = 9.8, < 1 Hz, H-5'), 1 -27 (9H, s, C(CH₃)₃), ¹³C NMR (CD₃OD) δ (ppm): 157.3, 155.4, 155.1 , (triazole C-3, C-5, 4-tBuPh C-4), 136.9-124.7 (aromatics), 82.5, 79.3, 74.2, 73.6, 71.1 (C-l ' - C-5'), 62.7 (C-6'), 48.7 (PhCH₂), 35.8 (C(CH₃)₃), 31.6 (C(CH3)₃).

Example 18

4-Benzyl-5-(P-D-glucopyranosyl)-3-(4-trifluoromethylphenyl)-l ,2,4-triazole (15- -Glc-g)

The title compound is prepared from 14-Glc-g (0.50 g, 0.57 mmol) according to General procedure IV. Reaction time: 4 hours. Purified by column chromatography (4:1 CHCl₃-MeOH) to yield 0. 16 g (61 %) white crystals. Mp: 208-210 °C; [a]_D = -18 (c 0.48, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.77-7.05 (9H, m, aromatics), 5.51 (1H, d, J = 16.9 Hz, PhCH₂), 5.45 (1H, d, J = 16.9 Hz, PhCH₂), 4.48 (1H, d, J = 9.3 Hz, H-l '), 3.99 (1H, m, H-2' or H-3' or H-4'), 3.82 (1H, dd, J = 1 1.7, < 1 Hz, H-6'a), 3.65 (1H, dd, J = 1 1.7, < 1 Hz, H- -6'b), 3.47-3.37 (3 x 1H, m, H-2' and/or H-3' and/or H-4', H-5'); ¹³C NMR (CD₃OD) δ (ppm): 156.0, 155.6 (triazole C-3, C-5), 136.6-123.7 (aromatics, CF₃), 82.5, 79.3, 74.2, 73.6, 71.1 (C-l ' - C-5'), 62.7 (C-6'), 48.9 (PhCH₂).

Example 19

4-Benzyl-5-(P-D-glucopyranosyl)-3-(4-methoxyphenyl)-l,2,4-triazole (15-Glc-i)

The title compound is prepared from 14-Glc-i (0.80 g, 1.04 mmol) according to General procedure IV. Reaction time: 3 hours. Purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.23 g (62 %) yellow syrup. R_f: 0.33 (4: 1 CHCl₃-MeOH). [<x]_D = -14 (c 0.35, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.37 (2H, d, J = 8.8 Hz, aromatics), 7.32-7.20 (3H, m, aromatics), 7.05-6.99 (2H, m, aromatics), 6.96 (2H, d, J =8.8 Hz, aromatics), 5.42 (1H, d, J = 16,8 Hz, PhCH₂), 5.35 (1H, d, J = 16,8 Hz, PhCH₂), 4.35 (1H, d, J = 9.6 Hz, H- -1 '), 3.84 (1H, pseudo t, J = 10,8 Hz, H-2' or H-3' or H-4'), 3.78 (1H, s, OMe), 3,77 (1H, dd, J = 12,4, 2.3 Hz, H-6'a), 3.61 (1H, dd, J = 12,4, 5.3 Hz, H-6'b), 3.41-3.29 (3H, m, H- -2'and/or H-3' and/or H-4', H-5'); ¹³C NMR (CD₃OD) δ (ppm): 163.0 (4-MeOPh C-4), 157.2, 154.9 (triazole C-3, C-5), 136.9 (q), 131.6 (2), 130.1 (2), 129.1, 127.5 (2), 1 19.5 (q), 115.5 (2) (aromatics), 82.4, 79.3, 74.2, 73.6, 71.1 (C-l ' - C-5'), 62.6, (C-6') 55.9 (OMe), 48.6 (PhCH₂). Example 20

4-Benzyl-5-(P-D-glucopyranosyl)-3-(4-nitrophenyl)-l,2,4-triazole (15-GIc-j)

The title compound is prepared from 14-Glc-j (0.23 g, 0.27 mmol) according to General procedure IV. Reaction time: 6 hours. The product precipitated from the reaction mixture and was used after filtration without further purification. Yield 0.1 1 g (91 %) pale yellow needles. Mp: 153-155 °C; [a]_D = -20 (c 0.50, MeOH); Ή NMR (CD₃OD) δ (ppm): 8.29 (2H, d, J = 8.6 Hz, aromatics), 7.75 (2H, d, J = 8.6 Hz, aromatics), 7.28 (3H, m, aromatics), 7.05 (2H, d, J = 6.3 Hz, aromatics), 5.54 (1H, d, J = 16.8 Hz, PhCH₂), 5.48 (1H, d, J = 16.8 Hz, PhCH₂), 4.48 (1H, d, J = 9.7 Hz, Η-Γ), 3.98 (1H, pseudo t, J = 8.9 Hz, H-2' or H-3' or H-4'), 3.82 (1H, dd, J = 1 1.9, < 1 Hz, H-6'a), 3.65 (1H, dd, J = 12.0, 5.4 Hz, H- -6'b), 3.50-3.43 (2 x 1H, m, H-2' and/or H-3' and/or H-4'), 3.72 (1H, m, H-5'); ^l3C NMR (CD₃OD) δ (ppm): 155.9, 155.5 (triazole C-3, C-5), 150.4 (q), 136.5 (q), 133.9 (q), 131.4 (2), 130.2 (2), 129.3, 127.7 (2), 125.0 (2) (aromatics), 82.6, 79.4, 74.2, 73.7, 71.2 (C-l ' - C-5'),

62.7 (C-6'), 49.0 (PhCH₂).

Example 21

4-Benzyl-3-(3,5-dimethylphenyl)-5-(P-D-glucopyranosyl)-l,2,4-triazole (15-GIc-m)

The title compound is prepared from 14-Glc-m (0.64 g, 0.76 mmol) according to General procedure IV. Reaction time: 3 hours. Purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.20 g (62 %) yellow syrup. R_f: 0.66 (7:3 CHCl₃-MeOH); [a]_D = -8 (c 0.69, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.25-6.95 (8H, m, aromatics), 5.36 (1H, d, J =

16.8 Hz, PhCH₂), 5.29 (1H, d, J= 16.8 Hz, PhC¾), 4.38 (1H, d, J = 9.7 Hz, Η- ), 3.96 (1H, pseudo t, = 9.3, 8.9 Hz, H-2' or H-3' or H-4'), 3.76 (1H, dd, J = 12.2, 1.4 Hz, H-6'a), 3.60 (1H, dd, 7= 12.2, 5.4 Hz, H-6'b), 3.48-3.40 (2H, m, H-2' and/or H-3' and/or H-4'), 3.33-3.28 (1H, m, H-5'), 2.18 (6H, s, 2 x CH₃); ¹³C NMR (CD₃OD) δ (ppm): 157.7, 155.2 (triazole C-3, C-5), 140.2 (2q), 137.2 (q), 133.4, 130.3 (2), 129.4, 128.0 (2), 127.9 (2), 127.6 (q) (aromatics), 82.7, 79.5, 74.4, 73.8, 71.3 (C-l ' - C-5'), 62.9 (C-6'), 49.1 (PhCH₂), 21.6 (2 x CH₃). Example 22

4-Benzyl-5-( -D-glucopyranosyl)-3-(3,4,5-trimethoxyphenyl)- 1 ,2,4-triazole (15-Glc-

-P)

The title compound is prepared from 14-Glc-p (0.42 g, 0.46 mmol) according to General procedure IV. Reaction time: 6 hours. Purified by column chromatography (9: 1→ 4:lCHCl₃-MeOH) to yield 0.20 g (91 %) colourless syrup. R_f: 0.42 (4:1 CHCl₃-MeOH); [a]_D = -17 (c 0.53, MeOH);

1H NMR (CD₃OD) δ (ppm): 7.38-7.28 (3H, m, aromatics), 7.12 (2H, d, J = 7.3 Hz, aromatics), 6.69 (2H, s, aromatics), 5.50 (1H, d, J = 17.1 Hz, PhCH₂), 5.42 (1H, d, J = 17.1 Hz, PhCH₂), 4.45 (1H, d, J = 9.6 Hz, H-l '), 4.00 (1H, pseudo t, J = 8.6, 9.6 Hz, H-2' or H-3' or H-4'), 3.80 (1H, dd, J = 12.0, < 1 Hz, H-6'a), 3.77 (4H, m, H-6'b, 1 x OMe), 3.63 (7H, m, H-6'b, 2 x OMe), 3.50-3.43 (2 x 1H, m, H-2' and/or H-3' and/or H-4'), 3.63 (1H, m, H-5'); ¹³C NMR (CD₃OD) δ (ppm): 157.2, 155.2 (triazole C-3, C-5), 154.9 (2q), 141.0 (q), 137.4 (q), 130.2 (2), 129.1, 127.4 (2), 122.8 (q), 107.5 (2) (aromatics), 82.5, 79.3, 74.2, 73.6, 71.1 (C-r - C-5'), 62.8 (C-6'X 61.1 (OMe), 56.6 (2 x OMe), 48.8 (PhCH₂).

Example 23

4-Benzyl-5-(P-D-glucopyranosyl)-3-(2-naphthyl)-l,2,4-triazole (15-Glc-q)

The title compound is prepared from 14-Glc-q (0.50 g, 0.58 mmol) according to General procedure IV. Reaction time: 3 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.22 g (85 %) white crystals. Mp: 243-245 °C; [a]_D = -19 (c 0.51, MeOH); Ή NMR (DMSO-d₆) δ (ppm): 8.03-7.02 (12H, m, aromatics), 5.48 (1H, d, J = 16.9 Hz, PhCH₂), 5.42 (1H, d, J = 16.9 Hz, PhCH₂), 4.35 (1H, d, J = 9.3 Hz, H-l '), 3.86 (1H, pseudo t, J = 9.3, 9.3 Hz, H-2' or H-3' or H-4'), 3.62 (1H, dd, J = 1 1.9, < 1 Hz, H-6'a), 3.42 (1H, dd, J= 1 1.9, 5.3 Hz, H-6'b), 3.31-3.17 (3 x 1H, m, H-2' and/or H-3 ' and/or H-4', H-5'); ¹³C NMR (DMSO-d₆) δ (ppm): 154.3, 153.3 (triazole C-3, C-5), 136.1 -124.6 (aromatics), 81.2, 78.0, 72.3, 71.4, 69.8 (C-l ' - C-5'), 61.0 (C-6'), 46.8 (PhCH₂).

Example 24

4-Benzyl-3-phenyl-5-(P-D-xylopyranosyl)-l,2,4-triazole (15-Xyl-d)

The title compound is prepared from 14-Xyl-d (0.44 g, 0.63 mmol) according to General procedure IV. Reaction time: 4 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.21 g (91 %) white amorphous solid. R_f: 0.46 (4:1 CHCl₃-MeOH); [a]_D = -15 (c 0.50, DMSO);

Ή NMR (DMSO-d₆) δ (ppm): 7.49-7.41 (5H, m, aromatics), 7.23-7.22 (3H, m, aromatics), 6.94 (2H, d, J = 6.3 Hz, aromatics), 5.38 (1H, d, J = 19.2 Hz, PhCH₂), 5.32 (1H, d, J = 18.2 Hz, PhCH₂), 4.31 (1H, d, J= 9.6 Hz, H-l '), 3.86 (1H, pseudo t, J= 9.1, 8.9 Hz, H-2' or H-3'), 3.73 (1H, dd, J = 10.7, 5.8 Hz, H-5'a), 3.43 (1H, ddd, J = 5.8, < 1 Hz, H-4'), 3.26 (1H, pseudo t, J = 8.7 Hz, H-2' or H-3'), 3.16 (1H, pseudo t, J = 10.7, 10.6 Hz, H-5'b); ^l3C NMR (DMSO-d₆) δ (ppm): 154.8, 153.5 (triazole C-3, C-5), 136.2 (q), 130.2, 129.0 (2), 128.8 (2),

128.7 (2), 127.9, 127.3 (q), 126.5 (2) (aromatics), 78.1, 73.3, 71.8, 69.5 (C-l ' - C-4'), 70.2 (C-5'), 47.0 (PhCH₂). Example 25

4-Benzyl-3-(4-tert-butylphenyl)-5-(P-D-xylopyranosyl)-l,2,4-triazole (15-Xyl-f) Triazole 14-Xyl-f (0.53 g, 0.63 mmol) was dissolved in anhydrous MeOH (4 mL), 1M NaOH/MeOH (3mL) was added and the mixture was refluxed for 1 hour. The excess of NaOH was neutralized by AcOH. After evaporation the crude product was purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.19 g (63 %) white amorphous solid. R_f: 0.56 (4: 1 CHCl₃-MeOH); [ ]_D = -15.0 (c 0.50, DMSO); Ή NMR (DMSO-d₆) δ (ppm): 7.42 (4H, m, aromatics), 7.26-7.24 (3H, m, aromatics), 6.96 (2H, d, J = 6.5 Hz, aromatics), 5.37 (1H, d, J = 18.1 Hz, PhCH₂), 5.32 (1H, d, J = 17.8 Hz, PhCH₂), 4.23 (1H, d, J = 9.6 Hz, H-l '), 3.83 (1H, pseudo t, J = 9.1, 9.0 Hz, H-2' or H-3'), 3.72 (1H, dd, J = 10.6, 4.7 Hz, H-5'a), 3.40 (1H, ddd, J = 9.4, 4.9, < 1 Hz, H-4'), 3.21 (1H, pseudo t, J = 8.7, 8.7 Hz, H-2' or H-3'), 3.12 (1H, pseudo t, J = 10.7, 10.6 Hz, H-5'b), 1.25 (9H, s, C(CH₃)₃); ^l3C NMR (DMSO-d₆) δ (ppm): 154.6, 153.3 (triazole C-3, C-5), 152.8 (q), 136.2 (q), 128.8 (2), 128.4 (2), 127.8, 126.3 (2),

125.8 (2), 124.4 (q) (aromatics), 78.0, 73.3, 71.7, 69.4 (C-l ' - C-4'), 70.1 (C-5'), 46.8 (PhCH₂), 34.7 (C(CH₃)₃), 31.0 (C(CH₃)₃).

Example 26

4-Benzyl-3-(2-naphthyl)-5-(p-D-xylopyranosyl)-l,2,4-triazole (15-Xyl-q)

The title compound is prepared from 14-Xyl-q (0.34 g, 0.47 mmol) according to General procedure IV. Reaction time: 3 hours. Purified by column chromatography (9:1 CHCl₃-MeOH) to yield 0.15 g (76 %) white amorphous solid. R_f: 0.40 (4:1 CHCl₃-MeOH); [a]_D = -14 (c 0.50, DMSO);

Ή NMR (DMSO-d₆) δ (ppm): 8.04-6.97 (12H, m aromatics), 5.49 (1H, d, J = 18.3 Hz, PhCH₂), 5.44 (1H, d, J= 18.3 Hz, PhCH₂), 4.39 (1H, d, J= 9.6 Hz, Η- ), 3.91 (1H, pseudo t, J= 9.1, 9.0 Hz, H-2' or H-3'), 3.78 (1H, dd, J = 10.7, 4.8 Hz, H-5'a), 3.45 (1H, ddd, J = 9.6, 9.0, 5.1 Hz, H-4'), 3.29 (1H, pseudo t, J = 8.8, 8.7 Hz, H-2' or H-3'), 3.13 (1H, pseudo t, J = 10.8, 10.8 Hz, H-5'b); ¹³C NMR (DMSO-d₆) δ (ppm): 154.7, 153.8 (triazole C-3, C-5), 136.3- -124.7 (aromatics), 78.1, 73.4, 71.8, 69.5 (C-l ' - C-4'), 70.2 (C-5'), 47.2 (PhCH₂). General procedure V

for the synthesis of protected 3-substituted-5-(P-D-glycopyranosyl)-l,2,4-triazoIes (16) from protected N'-tosyI-C-(P-D-glycopyranosyI)formamidrazones (9)

A tosylamidrazone 9 (0.63 mmol) was dissolved in anhydrous CHC1₃ (10 mL) and anhydrous pyridine (92 μΐ,, 1.14 mmol, 1.8 equiv.) was added. The mixture was cooled in an ice bath, and the solution of an acid chloride (0.95 mmol, 1.5 equiv.) in 5 mL anhydrous CHCI3 was added dropwise over 15 minutes. Subsequently the mixture was stirred at rt and monitored by TLC (1 :1 EtOAc-hexane). After total consumption of the starting material the mixture was diluted with CHC1₃ (15 mL) and extracted with water (2 x 15 mL). The organic phase was dried over MgS0₄, concentrated under diminished pressure, and the crude product was purified by column chromatography.

General procedure VI

for the synthesis of protected 3-substituted-5-(P-D-glycopyranosyl)-l,2,4-triazoles (16) from protected β-D-glycopyranosylcarbonyl chlorides (10)

A C-(P-D-glycopyranosyl)formic acid 6 (1.92 mmol) in the presence of 3-4 drops of anhydrous DMF was heated in thionyl chloride (10 mL) at reflux temperature for one hour then the excess of the reagent was evaporated. Traces of thionyl chloride were removed by repeated co-evaporations with toluene. The residue was dissolved in anhydrous toluene (20 mL) and a carboxamidrazone 4 (2.88 mmol) was added, the mixture was reflux ed and monitored by TLC (EtOAc). After 36 hours the solvent was removed and the crude product was purified by column chromatography.

General procedure VII

for the synthesis of protected 3-substituted-5-(p-D-glycopyranosyl)-l,2,4-triazoles (16) from protected C-(P-D-glycopyranosyl)formamidines (11)

A formamidine 11 (1.12 mmol) and an arenecarboxamidrazone 4 (2.24 mmol, 2 equiv.) were dissolved in anhydrous pyridine (15 mL), the mixture was stirred at rt, and monitored by TLC (9: 1 CHCl₃-MeOH). After completion of the reaction (16 hours) the solvent was removed. Without further purification the obtained crude product was dissolved in anhydrous DMF (15 mL), and heated at reflux temperature for 0.5 hour. The mixture was cooled to rt, diluted with water (15 mL), and extracted with dietyl ether (5 x 20 mL). The combined organic phase was dried over MgS0₄, concentrated under diminished pressure, and the crude product was purified by column chromatography. General procedure VIII

for the synthesis of protected 3-substituted-5-(P-D-grycopyranosyl)-l,2,4-triazoles (16) from protected N-arenecarboximidoyl-C-(P-D-glycopyranosyl)carbohydrazonoyl bromides (12)

A) A hydrazonoyl bromide 12 (0, 1 mmol) was dissolved in anhydrous pyridine (6 mL). The mixture was stirred and heated at 110 °C. The reaction was monitored by TLC (1 :3 EtO Ac-toluene). When the reaction was complete the solvent was evaporated under reduced pressure. The residue was purified by coloumn chromatography.

B) A hydrazonoyl bromide 12 (0.14 mmol) was dissolved in glacial acetic acid (3 mL), then ammonium acetate (0.012 g, 0.15 mmol) was added. The mixture was stirred and heated at 70 °C. When the reaction was complete (TLC, 2:7 EtOAc-toluene) the mixture was diluted with water (6 mL) and washed with dichloromethane (3 x 7 mL). The organic layer was separated and washed with cold, saturated sodium hydrogencarbonate solution (8 mL), and water (8 mL), dried (MgS0₄), and evaporated under reduced pressure. The residue was purified by column chromatography (2:7 EtOAc-toluene).

Example 27

3-MethyI-5-(2',3',4',6'-tetra-i?-benzoyl-p-D-glucopyranosyl)-l,2,4-triazoIe (16-Glc- -a)

The title compound is prepared from amidrazone 9-Glc (0.60 g, 0.76 mmol) and acetyl chloride (81 iL, 1.14 mmol) according to General procedure V 5-methyl-3-(2',3',4',6'- -tetra-0-benzoyl-P-D-gluco-pyranosyl)-l-tosyl-l,2,4-triazole was obtained (Purified by column chromatography (3:7 EtOAc-hexane) to yield 0.38 g (62 %) white amorphous solid. R_f: 0.67 (1 :1 EtOAc-hexane); [a]_D = +89 (c 0.23, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.00- -7.04 (24H, m, aromatics), 6.02, 5.95, 5.80 (3 x 1H, 3 pseudo t, J= 10.6, 9.2 Hz in each, H-2', H-3\ H-4'), 4.97 (1H, d, J = 9.2 Hz, Η- ), 4.60 (1H, dd, J = 11.9, 2.6 Hz, H-6'a), 4.51 (1H, dd, J = 1 1.9, 5.3 Hz, H-6'b), 4.28 (1H, ddd, J = 9.2, 5.3, 2.6 Hz, H-5'), 2.71 (3H, s, CH₃), 2.28 (3H, s, CH₃); ^l3C NMR (CDCI3) δ (ppm): 166.1, 165.8, 165.1, 164.4 (CO), 159.1 , 157.0 (triazole C-3, C-5), 146.4 (TsCflCH₃), 133.4-128.0 (aromatics), 76.7, 74.4, 74.0, 70.7, 69.4

(C-r - C-5'), 63.4 (C-6'), 21.7 (CH₃), 14.5 (CH₃)).

This triazole (0.35 g, 0.43 mmol) was dissolved in THF (10 mL), a 1M solution of

Bu₄NF in THF (0.86 mL, 0.86 mmol) was added and the mixture was refluxed. After completion of the reaction (2 hours) monitored by TLC (1 :1 EtOAc-hexane), the solvent was removed under diminished pressure, and the residue was purified by column chromatography

(6:4 EtOAc-hexane) to yield 0.25 g (88 %) colourless syrup. R_f: 0.43 (3:1 EtOAc-hexane);

[<x]_D = +43 (c 0.22, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 12.03 (1H, s, triazole NH), 7.92-7.18

(20H, m, aromatics), 6.28, 6.08, 5.95 (3 x 1H, 3 pseudo t, J = 9.8, 9.8 Hz in each, H-2', H-3\ H-4'), 5.18 (1H, d, J = 9.2 Hz, H-l '), 4.62-4.53 (2H, m, H-6'a, H-6'b), 4.40 (1H, ddd, J = 9.2,

5.3, 2.6 Hz, H-5'), 2.35 (3H, s, CH₃); ^l3C NMR (CDC1₃) δ (ppm): 166.3, 166.0, 165.2, 165.0

(CO), 158.5, 154.7 (triazole C-3, C-5), 133.3-128.2 (aromatics), 76.6, 74.7, 74.3, 71.1, 69.5

(C-r - C-5'), 63.4 (C-6'), 12.1 (CH₃). Example 28

3-(tert-Butyl)-5-(2',3',4',6'-tetra-i?-benzoyI-P-D-gIucopyranosyl)-l,2,4-triazole (16- -Glc-b)

(CH₃)₃CCOCI

Q r,i_n ^abs' ^CHCI3' . C(CH₃)₃

^9"Glc abs. pyridine ' ^{3 3}

DMAP, reflux

Amidrazone 9-Glc (1.0 g, 1.26 mmol) and pivaloyl chloride (0.46 mL, 3.79 mmol, 3 equiv.) were dissolved in anhydrous CHC1₃ (20 mL), anhydrous pyridine (0.37 mL, 4.55 mmol, 3.6 equiv.) and 4-dimethylaminopyridine (7.7 mg, 0.06 mmol, 5 mol%) were added, and the mixture was stirred at rt for one hour, then refluxed for 6 hours. After completion of the reaction (monitored by TLC, 1 :1 EtOAc-hexane) the mixture was diluted with CHC1₃ (30 mL) and extracted with water (2 x 20 mL). The organic phase was dried over MgS0₄, concentrated under diminished pressure, and the crude product was purified by column chromatography (3:7 EtOAc-hexane) to yield 0.86 g (77 %) of iV*-(pivaloyl)-N^/-tosyl-C- -(2,3,4,6-tetra-0-benzoyl-P-D-glucopyranosyl)formamidrazone as a pale yellow oil. R_f.- 0.28 (3:7 EtOAc-hexane); [<x]_D = +6 (c 0.37, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 10.02 (1H, s, NH), 8.10-7.20 (22H, m, aromatics), 6.76 (2H, d, J = 7.9 Hz, aromatics), 5.92, 5.70, 5.36 (3 x 1H, 3 pseudo t, J = 9.6, 9.6 Hz in each, H-2, H-3, H-4), 5.71 (1H, dd, J = 12.3, < 1 Hz, H-6a), 4.56 (1H, d, J = 9.6 Hz, H-l), 4.47 (1H, dd, J = 12.3, 3.5 Hz, H-6b), 4.23 (1H, ddd, J = 9.6 Hz, 3.5, < 1 Hz, H-5), 2.11 (3H, s, CH₃), 1.27 (C(CH₃)₃); ^l3C NMR (CDC1₃) δ (ppm): 179.1 (COC(CH₃)₃), 165.9, 165.5, 165.0, 164.6 (CO), 143.7 (CNH), 143.0 (q), 135.2-127.1 (aromatics), 78.4, 76.4, 73.1, 69.4, 68.5 (C-l - C-5), 62.1 (C-6), 40.1 (C(CH₃)₃), 27.3 (C(CH₃)₃), 21.5 (CH₃).

The above amidrazone (0.32 g, 0.36 mmol) was heated in xylene at 120 °C for two hours. The solvent was removed and the crude product was purified by column chromatography (4:6 EtOAc-hexane) to yield 0.14 g (54 %) pale yellow oil. R_f: 0.31 (4:6 EtOAc-hexane); [a]_D = +25 (c 0.42, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 9.88 (1H, s, triazole NH), 7.93-7.05 (20H, m, aromatics), 6.30, 6.12, 6.04 (3 x 1H, 3 pseudo t, J = 9.9, 9.2 Hz in each, H-2', H-3', H-4'), 5.33 (1H, d, J= 9.9 Hz, H- '), 4.70-4.59 (2H, m, H-6'a, H-6'b), 4.45 (1H, ddd, J = 9.2, 4.9, 2.6 Hz, H-5'), 1.24 (9H, s, C(CH₃)₃); ^l3C NMR (CDC1₃) δ (ppm): 166.3, 166.0, 165.4, 164.8 (CO), 157.9 (triazole C-3, C-5), 133.3-128.0 (aromatics), 76.6, 74.5, 74.3, 71.5, 69.7 (C-Γ - C-5'), 63.5 (C-6'), 32.1 (C(CH₃)₃), 28.8 (C{CH₃)₃). Example 29

3-Phenyl-5-(2',3',4',6'-tetra-i?-benzoyl-p-D-glucopyranosyl)-l,2,4-triazole (16-Glc-

-d)

A) The title compound is prepared from amidrazone 9-Glc (0.55 g, 0.70 mmol) and benzoyl chloride (121 \ih, 1.04 mmol) in the presence of dry pyridine (100 μί, 1.25 mmol) according to General procedure V. Purified by column chromatography (3:7 EtOAc-hexane) to yield 0.35 g (69 %) white solid.

B) The title compound is prepared from amidine 11-Glc (0.70 g, 1.12 mmol) and benzamidrazone (4d, 0.30 g, 2.24 mmol) according to General procedure VII. Purified by column chromatography (1 :2 EtOAc-hexane) to yield 0.58 g (71 %) white solid.

C) The title compound is prepared from 12-Glc-d (0.04 g, 0.05 mmol) according to

General procedure VIII A. Purified by column chromatography (1 :3 EtO Ac-toluene) to yield 0.021 g (58 %) white solid.

D) The title compound is prepared from 12-Glc-d (0.18 g, 0.22 mmol) according to General procedure VIIIB. Purified by column chromatography (1 :4 EtO Ac-toluene) to yield 0.05 g (32%) white solid.

Mp: 219-221 °C; [a]_D = +14 (c 0.22, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 12.70 (1H, s, triazole NH), 7.93-7.1 1 (25H, m, aromatics), 6.32, 6.15, 6.00 (3 x 1H, 3 pseudo t, J = 10.6, 9.2 Hz in each, H-2', H-3', H-4'), 5.38 (1H, d, J = 10.6 Hz, H-l '), 4.63-4.55 (2H, m, H-6'a, H-6'b), 4.42 (1H, ddd, J= 10.6, 5.3, 2.6 Hz, H-5'); ¹³C NMR (CDC1₃) δ (ppm): 166.3, 166.1, 165.3, 165.1 (CO), 158.0, 157.7 (triazole C-3, C-5), 133.4-126.4 (aromatics), 76.7, 74.5, 74.2, 71.3, 69.6 (C-l ' - C-5'), 63.3 (C-6').

Example 30

3-(4-tert-Butylphenyl)-5-(2',3',4',6'-tetra-0-benzoyl-P-D-glucopyranosyl)-l,2,4- -triazole (16-Glc-f)

The title compound is prepared from amidrazone 9-Glc (0.1 g, 0.13 mmol) and 4-tert- -butylbenzoyl chloride (34 μΐ,, 0.19 mmol) in the presence of dry pyridine (18 μΐ,, 0.23 mmol) according to General procedure V. Purified by column chromatography (3:7 EtOAc- -hexane) to yield 0.06 g (58 %) white amorphous solid. R_f: 0.41 (4:6 EtOAc-hexane); [a]_D = - 3 (c 0.36, CHC1₃);

Ή NMR (CDC1₃) δ (ppm): 8.70 (1H, s, triazole NH), 7.94-7.15 (24H, m, aromatics), 6.31, 6.13, 5.99 (3 x 1H, 3 pseudo t, J= 10.6, 9.2 Hz in each, H-2', H-3', H-4'), 5.35 (1H, d, J= 9.2 Hz, H-l '), 4.67-4.56 (2H, m, H-6'a, H-6'b), 4.45 (1H, ddd, J = 9.2, 5.3, 2.6 Hz, H-5'), 1.27 (9H, s, C(CH₃)₃); ¹³C NMR (CDC1₃) δ (ppm): 166.3, 166.1, 165.3, 165.0 (CO), 157.9, 157.5 (triazole C-3, C-5), 153.4 (q), 133.3-124.7 (aromatics), 76.7, 74.6, 74.2, 71.3, 69.6 (C-l ' - C- -5'), 63.3 (C-6'), 34.7 (C(CH₃)₃), 31.0 (C(CH₃)₃).

Example 31

3-(4-Nitrophenyl)-5-(2',3',4',6'-tetra-i?-benzoyl-p-D-glucopyranosyl)-l,2,4-triazole (16-Glc-j)

The title compound is prepared from amidrazone 9-Glc (1.70 g, 2.15 mmol) and 4- -nitrobenzoyl chloride (0.60 g, 3.20 mmol) in the presence of dry pyridine (312 μΐ,, 3.87 mmol) according to General procedure V. Purified by column chromatography (3:7 EtOAc- -hexane) to yield 0.94 g (57 %) yellow solid. Mp: 183-185 °C; [a]_D = +35 (c 0.22, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 1 1.50 (1H, s, triazole NH), 8.08 (2H, d, J = 8.9 Hz, aromatics), 7.99-7.03 (20H, m, aromatics), 7.75 (2H, d, J= 7.4 Hz, aromatics), 6.16, 6.02, 5.93 (3 x 1H, 3 pseudo t, J = 9.7, 9.5 Hz in each, H-2', H-3', H-4'), 5.24 (1H, d, J = 9.7 Hz, Η- ), 4.73-4.63 (2H, m, H-6'a, H-6'b), 4.42 (1H, ddd, J= 9.7, 5.4, 2.7 Hz, H-5'); ¹³C NMR (CDC1₃) δ (ppm): 166.7, 165.8, 165.4, 165.2 (CO), 158.8, 155.0 (triazole C-3, C-5), 148.0 (q), 135.3 (q), 133.1- -123.7 (aromatics), 77.2, 73.7, 73.5, 71.4, 69.3 (C-l ' - C-5'), 63.3 (C-6'). Example 32

3-(4-Carboxyphenyl)-5-(2',3',4',6'-tetra-i?-benzoyl-P-D-glucopyranosyl)-l,2,4- -triazole (16-GIc-l)

Triazole 14-Glc-s (0.56 g, 0.59 mmol) was dissolved in anhydrous EtOAc (35 mL), 10% Pd(C) (55 mg) was added and ¾ was bubbled through the reaction mixture at 50°C. After disappearance of the starting material (6 hours, monitored by TLC, 1 :1 EtOAc-hexane) the reaction was filtered through a pad of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc) to yield 0.34 g (75 %) colourless syrup. R . 0.58 (1 :3 AcOH-toluene); [a]_D = -33 (c 0.48, MeOH); Ή NMR (CD₃OD) δ (ppm): 8.02-7.12 (24H, m, aromatics), 6.24 (1H, pseudo t, J = 9.5, 9.5 Hz, H-3'), 6.08 (1H, pseudo t, J = 9.6, 9.5 Hz, H-2'), 5.95 (1H, pseudo t, J = 9.5, 9.5 Hz, H-4'), 5.38 (1H, d, J = 9.9 Hz, H-l '), 4.66- -4.58 (3H, m, H-6'a, H-6'b, H-5'); ¹³C NMR (CD₃OD) δ (ppm): 169.2 (COOH), 167.6, 167.2, 166.7, 166.4 (CO), 134.7-127.4 (aromatics), 77.7 (C-5'), 75.7 (C-3'), 74.8 (C-Γ), 73.1 (C-2'), 71.1 (C-4'), 64.6 (C-6').

Example 33

3-(3,5-Dinitrophenyl)-5-(2',3',4',6'-tetra-0-benzoyl-p-D-glucopyranosyl)-l,2,4- -triazole (16-Glc-n)

The title compound is prepared from amidrazone 9-Glc (1.70 g, 2.15 mmol) and 3,5- -dinitrobenzoyl chloride (0.74 g, 3.22 mmol) in the presence of dry pyridine (0.34 mL, 3.87 mmol) according to General procedure V. Purified by column chromatography (3:7 EtOAc- -hexane) to yield 0.90 g (55%) yellow solid. Mp: 107-109 °C; [a]_D = +4.5 (c 0.47, MeOH); Ή NMR (CDC1₃) δ (ppm): 8.89 (2H, s, aromatics), 8.04-7.15 (21H, m, aromatics), 6.20, 5.96, 5.92 (3 x 1H, 3 pseudo t, J = 9.7, 9.6 Hz in each, H-2', H-3', H-4'), 5.29 (1H, d, J = 9.8 Hz, H-l '), 4.71 (2H, m, H-6'a, H-6'b), 4.48 (1H, ddd, J = 9.5, 5.4, 2.6 Hz, H-5'); ¹³C NMR (CDCI3) δ (ppm): 166.8, 166.0, 165.7, 165.4 (CO), 158.2, 154.8 (triazole C-3, C-5), 148.7 (2q), 133.8 (q), 130.0-126.0, 1 18.7 (aromatics), 77.2, 73.6, 73.5, 71.3, 69.4 (C-Γ - C-5'), 63.3 (C-6'). Example 34

5-(2',3',4',6'-Tetra-i?-benzoyl-p-D-glucopyranosyl)-3-(3,4,5-trimethoxyphenyI)- -1,2,4-triazole (16-Glc-p)

The title compound is prepared from amidrazone 9-Glc (0.20 g, 0.25 mmol) and 3,4,5- -trimethoxybenzoyl chloride (0.09 g, 0.38 mmol) in the presence of dry pyridine (37 μί, 0.45 mmol) according to General procedure V. Purified by column chromatography (3:7 EtOAc- -hexane) to yield 0.11 g (54 %) white solid. Mp: 125-127 °C; [a]_D = +10 (c 0.39, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 8.99 (1H, s, triazole NH), 7.93-7.05 (22H, m, aromatics), 6.23, 6.14, 5.99 (3 x 1H, 3 pseudo t, J= 10.6, 9.2 Hz in each, H-2\ H-3', H-4'), 5.31 (1H, d, J= 9.2 Hz, H-l '), 4.62 (2H, m, H-6'a, H-6'b), 4.42 (1H, ddd, J = 9.2, 5.3, 4.0 Hz, H-5') 3.80 (3H, s, OMe), 3.62 (6H, s, 2 x OMe); ¹³C NMR (CDC1₃) δ (ppm): 166.4, 165.9, 165.2, 165.0 (CO), 158.3, 157.0 (triazole C-3, C-5), 153.2 (2q), 139.2 (q), 133.4-128.0, 123.6 (q), 103.4 (2) (aromatics), 76.9, 74.2, 74.1, 71.4, 69.5 (C-l ' - C-5'), 63.3 (C-6'), 60.7 (OMe), 55.8 (2 x OMe).

Example 35

3-(2-Naphthyl)-5-(2',3',4',6'-tetra-0-benzoyl-p-D-glucopyranosyl)-l,2,4-triazole (16-Glc-q)

A) The title compound is prepared from amidrazone 9-Glc (0.50 g, 0.63 mmol) and 2- -naphthoyl chloride (0.18 g, 0.95 mmol) in the presence of dry pyridine (192 μΐ,, 1.40 mmol) according to General procedure V. Purified by column chromatography (3:7 EtOAc-hexane) to yield 0.27 g (56 %) white solid.

B) The title compound is prepared from amidine 11-Glc (0.50 g, 0.80 mmol) and naphthalene-2-carboxamidrazone (4q, 0.30 g, 1.61 mmol) according to General procedure VII. Purified by column chromatography (1 :2 EtOAc-hexane) to yield 0.44 g (71 %) white solid.

C) The title compound is prepared from 12-Glc-q (0.12 g, 0.14 mmol) according to General procedure VIIIB. Purified by column chromatography (2:7 EtOAc-toluene) to yield 0.06 g (55%) white solid. Mp: 222-224 °C; [ ]_D = -1 (c 0.22, CHCI3); Ή NMR (CDC1₃) δ (ppm): 12.50 (1H, s, triazole NH), 8.19-7.08 (27H, m, aromatics), 6.45, 6.24, 6.08 (3 x 1H, 3 pseudo t, J = 10.6, 9.2 Hz in each, H-2', H-3', H-4'), 5.47 (1H, d, J = 9.2 Hz, H-l '), 4.67-4.59 (2H, m, H-6'a, H-6'b), 4.49 (1H, ddd, J = 10.6, 5.3, 2.6 Hz, H-5'); ^,3C NMR (CDC1₃) δ (ppm): 166.3, 166.0, 165.2, 165.1 (CO), 157.9, 157.8 (triazole C-3, C-5), 133.8-123.3 (aromatics), 76.7, 74.5, 74.2, 71.4, 69.5 (C-l ' - C-5'), 63.2 (C-6').

Example 36

3-(2-Pyridyl)-5-(2',3',4',6'-tetra-0-benzoyl-p-D-glucopyranosyl)-l,2,4-triazole (16- -Glc-r) A) The title compound is prepared from 6-Glc (1.2 g, 1.92 mmol) and pyridine-2- -carboxamidrazone (4r, 0.39 g, 2.88 mmol) according to General procedure VI. Column chromatography in 1 :1 EtOAc-hexane. Yield 0.81 g (58 %) white solid.

B) The title compound is prepared from amidine 11-Glc (0.15 g, 0.24 mmol) and pyridine-2-carboxamidrazone (4r, 0.03 g, 0.24 mmol) according to General procedure VII.

Purified by column chromatography (1 : 1 EtOAc-hexane) to yield 0.14 g (80 %) white solid.

C) The title compound is prepared from 12-Glc-r (0.1 1 g, 0.1 mmol) according to General procedure VIIIA. Purified by column chromatography (1 :3 EtOAc-toluene) to yield 0.050 g (53 %) white solid.

D) The title compound is prepared from 12-Glc-r (0.25 g, 0.31 mmol) according to

General procedure VIIIB. Purified by column chromatography (2:7 EtOAc-toluene) to yield 0.07 g (31 %) white solid. Mp: 229-231 °C; [o]_D = -37 (c 0.22, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 13.14 (1H, s, triazole NH), 8.61 (1H, d, J = 5.3 Hz, Py), 8.14 (1H, d, J = 7.9 Hz, Py), 8.00-7.22 (22H, m, aromatics, Py), 6.24, 6.06, 5.90 (3 x 1H, 3 pseudo t, J = 10.6, 9.2 Hz in each, H-2', H-3', H-4'), 5.18 (1H, d, J= 9.2 Hz, H-l '), 4.67 (1H, dd, J = 1 1.9, 3.9 Hz, H-6'a), 4.57 (1H, dd, J = 1 1.9, 5.3 Hz, H-6'b), 4.42 (1H, ddd, J = 9.2, 5.3, 3.9 Hz, H-5'); ¹³C NMR (CDCI3) δ (ppm): 166.2, 165.9, 165.2, 164.7 (CO), 160.2, 154.8 (triazole C-3, C-5), 149.2, 145.5 (q), 137.7, 133.3-122.2 (aromatics), 76.6, 74.7, 74.6, 71.3, 69.7 (C-V - C-5'), 63.5 (C- -6').

Example 37

3-(Acetoxymethyl)-5-(2',3',4',6'-tetra-i?-benzoyl-p-D-glucopyranosyl)-l,2,4- -triazole (16-Glc-t)

The title compound is prepared from amidrazone 9-Glc (1.0 g, 1.26 mmol) and acetoxyacetyl chloride (204 μΐ,, 1.89 mmol) in the presence of dry pyridine (183 μί, 2.27 mmol) according the General procedure V. After extraction and evaporation the crude product was dissolved in THF (30 mL), 1 M solution of Bu₄NF in THF (2.53 raL) was added and the mixture was refluxed for 1.5 hours, then the solvent was removed under diminished pressure. The residue was purified by column chromatography (1 :1 EtOAc-hexane) to yield 0.55 g (61 %) white amorphous solid. R_f: 0.45 (6:4 EtOAc-hexane); [a]_D = +16 (c 0.50, CHCI3); Ή NMR (CDC1₃) δ (ppm): 10.19 (1H, s, triazole NH), 7.94-6.88 (20H, m, aromatics), 6.36, 6.22, 6.12 (3 x 1H, 3 pseudo t, J = 9.6, 8.8 Hz in each, H-2', H-3', H-4'), 5.36 (1H, d, J = 9.6 Hz, H-l '), 5.10 (2H, s, CH₂), 4.71-4.62 (2H, m, H-6'a, H-6'b), 4.49 ( 1H, ddd, J = 9.6, 4.9, 2.6 Hz, H-5'), 1.87 (3H, s, CH₃); ^{l 3}C NMR (CDC1₃) δ (ppm): 170.3, 166.0, 165.6, 164.9, 164.7 (CO), 157.1, 154.3 (triazole C-3, C-5), 133.1-127.7 (aromatics), 76.6, 74.1, 73.9, 71.3, 69.3 (C-Γ - C-5'), 63.2 (C-6'), 57.3 (CH₂), 20.0 (CH₃).

Example 38

3-(4-Acetoxyphenyl)-5-(2',3',4',6'-tetra-i?-benzoyl-p-D-glucopyranosyl)-l,2,4- -triazole (16-Glc-u)

The title compound is prepared from amidrazone 9-Glc (0.20 g, 0.25 mmol) and 4- -acetoxybenzoyl chloride (0.075 g, 0.38 mmol) in the presence of dry pyridine (37 μί, 0.46 mmol) according to General procedure V. After extraction and evaporation the crude product was dissolved in THF (6 mL), 1 M solution of BujNF in THF (0.50 mL) was added and the mixture was refluxed for 3 hours, then the solvent was removed under diminished pressure. The residue was purified by column chromatography (1 :4 EtOAc-toluene) to yield 0.12 g (60 %) white solid. Rf. 0.33 (1 :3 EtOAc-toluene); [a]_D = -8 (c 0.1 1, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 7.95-6.97 (24H, m, aromatics), 6.37, 6.21, 6.05 (3 x 1H, 3 pseudo t, J= 9.9, 9.2 Hz in each, H-2', H-3', H-4'), 5.40 (1H, d, J = 9.9 Hz, Η-Γ), 4.62 (2H, m, H-6'a, H-6'b), 4.48 (1H, ddd, J = 9.9, 5.5, 4.3 Hz, H-5'), 2.21 (3H, s, CH₃); ¹³C NMR (CDC1₃) δ (ppm): 168.7, 165.9, 165.6, 164.8, 164.6 (CO), 157.4, 156.6 (triazole C-3, C-5), 151.3 (q), 132.9- -121.4 (aromatics), 76.2, 74.1, 73.6, 71.0, 69.1 (C-Γ - C-5'), 62.8 (C-6'), 20.5 (CH₃). Final deprotections and other transformations of 1 ,2,4-triazoles

General procedure IX

for the removal of benzyl protecting groups

A benzylated compound (0.5 mmol) was dissolved in anhydrous MeOH (25 mL), 10% Pd(C) (20 mg) was added, and H₂ gas was bubbled through the reaction mixture at 50°C. After disappearance of the starting material (monitored by TLC, 7:3 CHCl₃-MeOH) the reaction mixture was filtered through a pad of celite, the solvent was evaporated, and the residue was purified by column chromatography. Example 39

5-(P-D-Glucopyranosyl)-3-methyl-l,2,4-triazole (17-Glc-a)

The title compound is prepared from 16-Glc-a (0.25 g, 0.38 mmol) according to General procedure IV. Reaction time: 3 days. Purified by column chromatography (7:3 CHCl₃-MeOH) to yield 0.07 g (73 %) colourless syrup. R_f: 0.55 (1 :1 CHCl₃-MeOH); [a]_D = +21 (c 0.36, MeOH); Ή NMR (D₂0) δ (ppm): 4.36 (1H, d, J= 9.2 Hz, H-l '), 3.82 (1H, dd, J = 11.9, < 1 Hz, H-6'a), 3.68-3.63 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.56-3.43 (3H, m, H- -2' and/or H-3' and/or H-4', H-5'), 2.36 (3H, s, CH₃); ^,3C NMR (D₂0) δ (ppm): 159.6, 156.2 (triazole C-3, C-5), 80.8, 77.7, 75.3, 73.1, 70.1 (C-Γ - C-5'), 61.5 (C-6'), 11.4 (CH₃).

Example 40

5-(p-D-Glucopyranosyl)-3-(tert-butyl)-l,2,4-triazole (17-Glc-b)

The title compound is prepared from 16-Glc-b (0.25 g, 0.36 mmol) according to General procedure IV. Reaction time: 2 days. (The mixture was neutralised with acetic acid.) Purified by column chromatography (8:2 CHCl₃-MeOH) to yield 0.10 g (98 %) colourless syrup. R_f: 0.51 (7:3 CHCl₃-MeOH); [a]_D = -6 (c 0.25, MeOH); Ή NMR (CD₃OD) δ (ppm): 4.33 (1H, d, J= 8.6 Hz, H-l '), 3.82 (1H, dd, J= 1 1.9, 2.5 Hz, H-6'a), 3.69-3.64 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.50-3.40 (3H, m, H-2' and/or H-3' and/or H-4', H-5'), 1.34 (9H, s, C(CH₃)₃); ^l3C NMR (CD₃OD) δ (ppm): 166.6, 162.1 (triazole C-3, C-5), 82.2, 79.3, 76.9, 74.2, 71.2 (C-Γ - C-5'), 62.8 (C-6'), 33.3 (C(CH₃)₃) 29.6 (C{CH₃)₃).

Example 41

5-(p-D-GIucopyranosyl)-3-hydroxymethyl-l,2,4-triazole (17-Glc-c)

The title compound is prepared from 16-Glc-t (0.18 g, 0.21 mmol) according to General procedure IV. Reaction time: 5 days. (The mixture was neutralised with acetic acid.) Purified by column chromatography (6:4 CHCl₃-MeOH) to yield 0.05 g (93 %) colourless syrup. R_f: 0.38 (1 : 1 CHCl₃-MeOH); [a]_D = -3 (c 0.42, MeOH); Ή NMR (CD₃OD) δ (ppm): 4.67 (2H, s, CH₂), 4.35 (1H, d, J = 9.2 Hz, H-l '), 3.83 (1H, dd, J = 12.3, < 1 Hz, H- -6'a), 3.68-3.59 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.49-3.40 (3H, m, H-2' and/or H-3' and/or H-4', H-5'); ^{l 3}C NMR (CD₃OD) δ (ppm): 160.5, 160.4 (triazole C-3, C-5), 82.2, 79.2, 76.3, 74.4, 71.2 (C-Γ - C-5'), 62.8 (C-6'), 57.4 (CH₂).

Example 42

5-(P-D-Glucopyranosyl)-3-phenyl-l,2,4-triazoIe (17-Glc-d)

A) The title compound is prepared from 15-Glc-d (0.20 g, 0.50 mmol) according to

General procedure IX. Reaction time: 4 hours. Purified by column chromatography (4: 1 CHCl -MeOH) to yield 0.13 g (85 %) colourless syrup.

B) The title compound is prepared from 16-GIc-d (0.25 g, 0.35 mmol) according to General procedure IV. Reaction time: 3 days. Purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.07 g (62 %) colourless syrup. R_f: 0.48 (7:3 CHCl₃-MeOH); [a]_D = +31 (c 0.20, H₂0); Ή NMR (D₂0) δ (ppm): 7.67-7.36 (5H, m, aromatics), 4.45 (1H, d, J = 9.2 Hz, Η-Γ), 3.87 (1H, dd, J = 11.9, < 1 Hz, H-6'a), 3.77-3.69 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.64-3.54 (3H, m, H-2' and/or H-3' and/or H-4', H-5'); ^l3C NMR (D₂0) δ (ppm): 159.1, 157.8 (triazole C-3, C-5), 130.9, 129.3 (2), 126.9 (q), 126.5 (2) (aromatics), 80.2, 77.2, 74.2, 72.8, 69.5 (C-Γ - C-5'), 61.0 (C-6').

Example 43

5-(P-D-Glucopyranosyl)-3-(4-methylphenyl)-l,2,4-triazole (17-Glc-e)

The title compound is prepared from 15-Glc-e (0.20 g, 0.49 mmol) according to

General procedure IX. Reaction time: 3 hours. Purified by column chromatography (4:1 CHCl₃-MeOH) to yield 0.14 g (90 %) white foam. R_f: 0.51 (7:3 CHCl₃-MeOH); [a]_D = +6 (c 0.45, MeOH); ^lH NMR (D₂0) δ (ppm): 7.31 (2H, d, J = 7.9 Hz, aromatics), 6.93 (2H, d, J = 7.9 Hz, aromatics), 4.36 (1H, d, J = 9.5 Hz, H-l '), 3.83 (1H, dd, J = 1 1.9, < 1 Hz, H-6'a), 3.72 (1H, dd, J= 1 1.9, 3.1 Hz, H-6'b), 3.66 (1H, pseudo t, J= 9.2, 8.9 Hz, H-2' or H-3' or H- -4'), 3.59-3.50 (3H, m, H-2' and/or H-3' and/or H-4', H-5'), 2.06 (3H, s, CH₃); ^l3C NMR (D₂0) δ (ppm): 159.5, 157.5 (triazole C-3, C-5), 141.9 (q), 130.0 (2), 126.6 (2), 123.8 (q) (aromatics), 80.5, 77.6, 75.2, 73.3, 69.9 (C-l ' - C-5'), 61.4 (C-6'), 21.1 (CH₃). Example 44

3-(4-tert-Butylphenyl)-5-(P-D-glucopyranosyl)-l,2,4-triazole (17-Glc-f)

The title compound is prepared from 15-Glc-f (0.20 g, 0.44 mmol) according to General procedure IX. Reaction time: 3 hours. Purified by column chromatography (8:2 CHCl₃-MeOH) to yield 0.13 g (79 %) colourless syrup. R_f: 0.22 (8:2 CHCl₃-MeOH); [a]_D = +8 (c 0.55, DMSO); Ή NMR (CD₃OD) δ (ppm): 7.90 (2H, d, J= 8.0, aromatics), 7.51 (2H, d, J = 8.0, aromatics), 4.48 (1H, d, J = 9.5 Hz, H-l '), 3.90 (1H, dd, J = 1 1.5, < 1 Hz, H-6'a), 3.77-3.73 (2H, m, H-6'b, H-2' or H-3' or H-4'), 3.59-3.51 (3H, m, H-2'and/or H-3', and/or H-4', H-5'), 1.33 (9H, s, C(CH₃)₃); ¹³C NMR (CD₃OD) δ (ppm): 161.6, 158.1 (triazole C-3, C-5), 154.7 (q), 127.4 (2), 126.9 (2) (aromatics), 82.0, 79.1, 76.3, 74.3, 71.1 (C-l ' - C-5'), 62.6 (C-6'), 35.7 (C(CH₃)₃), 31.6 (CfCH Q. ESI-MS (positive mode) m/z: 386.169 [M+Na]⁺

Example 45

5-(P-D-Glucopyranosyl)-3-(4-trifluoromethylphenyl)- 1 ,2,4-triazole (17-Glc-g) The title compound is prepared from 15-Glc-g (85 mg, 0.18 mmol) according to General procedure IX. Reaction time: 1.5 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 52 mg (77 %) white amorphous solid. R_f: 0.20 (4:1 CHCl₃-MeOH); [a]_D = +13 (c O.52, MeOH);

Ή NMR (CD₃OD) δ (ppm): 8.1 (2H, d, J = < 1 Hz, aromatics), 6.64 (2H, d, J = < 1 Hz, aromatics), 4.40 (1H, d, J = 7.2 Hz, Η-Γ), 3.80 (1H, dd, J = 10.7, < 1 Hz, H-6'a), 3.66-3.20 (5H, m, H-2', H-3', H-4\ H-5', H-6'b); ¹³C NMR (CD₃OD) δ (ppm): 160.2, 159.1 (triazole C-3, C-5), 134.9 (q), 132.5 (q), 132.1 (q), 127.9 (2), 126.8 (2) (aromatics, CF₃), 82.3, 79.2, 75.9, 74.6, 71.2 (C-l ' - C-5'), 62.7 (C-6').

Example 46

5-(p-D-Glucopyranosyl)-3-(4-hydroxyphenyl)-l,2,4-triazole (17-Glc-h)

The title compound is prepared from 16-Glc-u (0.57 g, 0.73 mmol) according to General procedure IV. Purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.16 g (67%) white solid. Mp: 172-174 °C; [a]_D = +14 (c 0.35, DMSO); Ή NMR (CD₃OD) δ (ppm): 7.69 (2H, d, J= 8.2 Hz, aromatics), 6.79 (2H, d, J = 8.5 Hz, aromatics), 4.38 (1H, d, J = 9.6 Hz, H-l ') 3.82 (1H, d, J= 1 1.0, < 1 Hz, H-6'a), 3.68-3.64 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.53-3.41 (3H, m, H-2' and/or H-3' and/or H-4', H-5'); ¹³C NMR (CD₃OD) δ (ppm): 162.1, 160.6, 157.6 (triazole C-3, C-5, 4-HOPh Cq-4), 129.2 (2), 126.9 (q), 1 16.8 (2) (aromatics), 82.0, 79.2, 76.5, 74.4, 71.2 (C-l ' - C-5'), 62.7 (C-6').

Example 47

5-(P-D-Glucopyranosyl)-3-(4-methoxyphenyl)-l,2,4-triazole (17-Glc-i)

The title compound is prepared from 15-Glc-i (0.24 g, 0.55 mmol) according to General procedure IX. to yield 0.18 g (95 %) colourless syrup. R_f: 0.52 (7:3 CHCl₃-MeOH); [ ]_D - +12 (c 0.41, MeOH);

Ή NMR (CD₃OD) δ (ppm): 7.82 (2H, d, J = 8.3 Hz, aromatics), 6.92 (2H, d, J = 8.3 Hz, aromatics), 4.46 (1H, d, J= 9.5 Hz, H-l '), 3.86 (1H, dd, J= 12.1, < 1 Hz, H-6'), 3.75 (5H, m, H-2' or H-3' or H-4', H-6'b, OMe), 3.60-3.50 (3H, m, H-2' and/or H-3' and/or H-4', H-5'); ¹³C NMR (CD₃OD) δ (ppm): 162.6 (4-MeOPh C-4), 60.1, 159.1 (triazole C-3, C-5), 129.0 (2), 121.5 (q), 115.3 (2) (aromatics), 82.0, 79.1 , 76.3, 74.3, 71.1 (C-l ' - C-5'), 62.7 (C-6'), 55.9 (OMe). Example 48

5-(P-D-Glucopyranosyl)-3-(4-nitrophenyl)-l,2,4-triazole (17-Glc-j)

The title compound is prepared from 16-Glc-j (0.65 g, 0.85 mmol) according to General procedure IV. Reaction time: 1 day. Purified by column chromatography (8:2 CHCl₃-MeOH) to yield 0.22 g (75 %) pale yellow solid. Mp: 166-169 °C; [c ]_D = +20 (c 1.3, DMSO); Ή NMR (DMSO-d₆) δ (ppm): 8.34 (2H, d, J= 8.2 Hz, aromatics), 8.26 (2H, d, J = 7.8 Hz, aromatics), 5.15, 5.10, 4.57 (4H, 3 broad s, OH), 4.34 (1H, d, J = 9.7 Hz, Η- ), 3.71 (1H, dd, J = 11.7, 5.4 Hz, H-6'a), 3.63 (1H, pseudo t, J = 9.2, 9.0 Hz, H-2' or H-3' or H-4'), 3.46-3.28 (3H, m, H-2' or H-3'or H-4', H-5', H-6'b), 3.18 (1H, pseudo t, J = 9.0, 8.9 Hz, H- -2' or H-3' or H-4'); ¹³C NMR (DMSO-d₆) δ (ppm): 158.2, 57.0 (triazole C-3, C-5), 147.5 (q), 136.7 (q), 126.8 (2), 124.2 (2) (aromatics), 81.6, 77.9, 74.0, 72.5, 70.0 (C-l ' - C-5'), 61.2 (C-6'). ESI-MS (positive mode) m/z: 375.093 [M+Na]⁺.

Example 49

3-(4-Aminophenyl)-5-(P-D-glucopyranosyl)-l,2,4-triazole (17-Glc-k)

17-Glc-j 17-Glc-k

Compound 17-Glc-j (0.10 g, 0.28 mmol) was dissolved in dry MeOH (3 mL), and 0.01 g Pd-C ( 10%) was added. The reaction mixture was stirred at rt under hydrogen atmosphere for one hour. After completion of the transformation monitored by TLC (1 :1 CHCl₃-MeOH) Pd- -C was filtrated over Celite pad, the solvent was evaporated in vacuo and the residue was purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.09 g (94 %) amorphous yellow product. R_f: 0.59 (1 :1 CHCl₃-MeOH); [a]_D = +9 (c 1.46, DMSO); Ή NMR (DMSO- -d₆) δ (ppm): 7.64 (2H, d, J = 8.0 Hz, aromatics), 6.60 (2H, d, J = 8.0 Hz, aromatics), 5.51 (2H, brs, NH₂), 4.98, 4.79, 4.53 (4H, 3 brs, OH), 4.13 (1H, d, J = 9.2 Hz, H-l '), 3.70-3.64 (2H, m, H-2 Or H-3' or H-4', H-6'a), 3.42 (1H, pseudo t, J = 9.2, 9.0 Hz, H-2' or H-3' or H- -4'), 3.30-3.18 (2H, m, H-5', H-6'b), 3.16 (1H, pseudo t, J = 9.0, 8.8 Hz, H-2' or H-3'or H- -4'); ^{l 3}C NMR (DMSO-d₆) δ (ppm): 161.3, 155.0 (triazole C-3, C-5), 150.3 (q), 127.1 (2), 114.7 (q), 113.6 (2) (aromatics), 81.4, 78.3, 75.7, 72.4, 70.2 (C-l ' - C-5'), 61.3 (C-6'). ESI- -MS (positive mode) m/z: 345.1 18 [M+Na]⁺. Example 50

3-(4-Carboxyphenyl)-5-(P-D-glucopyranosyl)-l,2,4-triazole (17-Glc-l)

The title compound is prepared from 16-Glc-l (0.24 g, 0.32 mmol) according to General procedure IV. Reaction time: 5 days. Purified by column chromatography (1 : 1 CHCl₃-MeOH) to yield 0.10 g (86 %) yellowish syrup. R_f: 0.55 (1 : 1 : 1 toluene-AcOH- -MeOH); [<x]_D = +6 (c 0.54, MeOH); Ή NMR (DMSO-d₆) δ (ppm): 8.10-8.04 (4H, m, aromatics), 4.33 (1H, d, J = 9.7 Hz, Η-Γ), 3.74-3.65 (2H, m, H-2' and/or H-3' and/or H-4', H-6'a), 3.47 (1H, ddd, J = 8.9, 5.3, < 1 Hz, H-5'), 3.37-3.25 (2H, m, H-2' and/or H-3' and/or H-4', H-6'b), 3.20 (1H, pseudo t, J = 9.0, 8.9 Hz, H-2' or H-3' or H-4'); ¹³C NMR (DMSO- -d₆) δ (ppm): 168.7 (COOH), 158.4, 157.8 (triazole C-3, C-5), 134.1 (q), 133.1 (q), 129.9 (2), 125.7 (2) (aromatics), 81.6, 78.1, 74.5, 72.6, 70.2 (C-l ' - C-5'), 61.3 (C-6').

Example 51

3-(3,5-Dimethylphenyl)-5-(P-D-glucopyranosyl)-l,2,4-triazole (17-Glc-m)

The title compound is prepared from 15-Glc-m (0.14 g, 0.34 mmol) according to

General procedure IX. Reaction time: 3 hours. Purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.11 g (98 %) colourless syrup. R_f: 0.54 (3: 1 CHCl₃-MeOH); [a]_D = +12 (c 0.57, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.48 (2H, s, aromatics), 6.99 (1H, s, aromatics), 4.43 (1H, d, J = 9.6 Hz, Η-Γ), 3.85 (lH, dd, J = 12.0, 1.3 Hz, H-6'a), 3.73-3.68 (2H, m, H-2' or H-3' or H-4', H-6'b,), 3.56-3.40 (3H, m, H-2'and/or H-3'and/or H-4', H-5'), 2.25 (6H, s, 2 x CH₃); ^l3C NMR (CD₃OD) δ (ppm): 162.2, 157.6 (triazole C-3, C-5), 139.7 (2q), 132.7, 128.0 (q), 125.2 (2) (aromatics), 82.0, 79.1, 76.2, 74.3, 71.1 (C-l ' - C-5'), 62.7 (C-6'). 21.3 (2 x CH₃). Example 52

3-(3,5-Dinitrophenyl)-5-(P-D-glucopyranosyl)-l,2,4-triazoIe (17-Glc-n)

The title compound is prepared from 16-Glc-n (0.52 g, 0.63 mmol) according to General procedure IV. Reaction time: 3 day. Purified by column chromatography (7:3 CHCl -MeOH) to yield 0.18 g (72%) white solid. Mp: 203-205 °C; [a]_D = -21 (c 0.11, DMSO); Ή NMR (DMSO-d₆) δ (ppm): 9.02 (2H, s, aromatics), 8.83 (1H, s, aromatic), 4.37 (1H, d, J = 9.8 Hz, Η-Γ), 3.69 (1H, dd, J = 11.9, < 1 Hz, H-6'a), 3.58 (1H, pseudo t, 7 = 9.1, 9.1 Hz, H-2' or H-3' or H-4'), 3.47 (1H, dd, J = 11.9, 5.6 Hz, H-6'b), 3.35-3.30 (2H, m, H-2' or H-3' or H-4', H-5'), 3.22 (1H, pseudo t, J = 9.1, 9.1 Hz, H-2' or H-3' or H-4'); ^l3C NMR (DMSO-d₆) δ (ppm): 162.2, 157.3 (triazole C-3, C-5), 148.5 (2q), 137.7 (q), 124.1 (2), 115.5 (aromatics), 80.8, 77.9, 75.8, 73.2, 70.5 (C-Γ - C-5'), 61.3 (C-6').

Example 53

3-(3,5-DiaminophenyI)-5-(P-D-glucopyranosyl)-l,2,4-triazoIe (17-Glc-o)

Compound 17-Glc-n (0.07 g, 0.18 mmol) was dissolved in dry MeOH (10 mL), and 0.015g Pd-C ( 10%) was added. The reaction mixture was stirred at rt under hydrogen atmosphere for one hour. After completion of the transformation monitored by TLC (1 : 1 CHCl₃-MeOH) Pd-C was filtrated over Celite pad, the solvent was evaporated in vacuo and the residue was purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.04 g (72 %) amorphous yellow product. R_f: 0.33 (1 :2 CHCl₃-MeOH); ¹³C NMR (DMSO-d₆) δ (ppm): 159.7, 158.8 (triazole C-3, C-5), 149.6 (2q), 130.6 (q), 102.3 (2), 102.1 (aromatics), 81.2, 78.2, 75.4, 73.1, 70.3 (C-Γ - C-5'), 61.5 (C-6').

Example 54

5-(P-D-Glucopyranosyl)-3-(3,4,5-trimethoxyphenyl)-l,2,4-triazole (17-Glc-p)

The title compound is prepared from 15-Glc-p (0.18 g, 0.37 mmol) according to

General procedure IX. Reaction time: 3 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.14 g (92 %) colourless syrup. R_f: 0.37 (4: 1 CHCl₃-MeOH); [a]_D = +5 (c 0.44, MeOH); Ή NMR (D₂0) δ (ppm): 6.64 (2H, s, aromatics), 4.57 (1H, d, J = 9.3 Hz, Η-Γ), 4.05 (1H, dd, J = 1 1.9, < 1 Hz, H-6'a), 3.92 (1H, dd, J = 11.9, < 1 Hz, H-6'b), 3.88- -3.72 (4H, m, H-2', H-3', H-4', H-5'), 3.65-3.64 (9H, m, 3 x OMe); ^{l 3}C NMR (D₂0) δ (ppm): 159.8, 157.4 (triazole C-3, C-5), 152.6 (2q), 138.3 (q), 122.7 (q), 103.2 (2) (aromatics), 80.5, 77.5, 75.0, 73.4, 70.0 (C-Γ - C-5'), 61.5 (C-6'), 61.2 (OMe), 56.1 (2 x OMe).

Example 55

5-(P-D-GlucopyranosyI)-3-(2-naphthyl)-l,2,4-triazole (17-GIc-q) A) The title compound is prepared from 15-Glc-q (0.10 g, 0.23 mmol) according to General procedure IX. Reaction time: 3 hours. Purified by column chromatography (4: 1 CHCl₃-MeOH) to yield 0.07 g (70 %) colourless syrup.

B) The title compound is prepared from 16-Glc-q (0.27 g, 0.35 mmol) according to General procedure IV. Reaction time: 3 days. Purified by column chromatography (9:1

CHCl₃-MeOH) to yield 0.10 g (81 %) colourless syrup. R_f: 0.68 (7:3 CHCl₃-MeOH); [a]_D = +24 (c 0.21 , DMSO); Ή NMR (CD₃OD) δ (ppm): 8.50-7.51 (7H, m, aromatics), 4.47 (1H, d, J = 9.2 Hz, Η-Γ), 3.88 (1H, dd, J = 11.9, < 1 Hz, H-6'a), 3.74-3.63 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.54-3.47 (3H, m, H-2' and/or H-3' and/or H-4', H-5'); ¹³C NMR (DMSO-d₆) δ (ppm): 158.2, 158.1 (triazole C-3, C-5), 133.2, 132.9, 128.4 (2), 127.7, 126.6 (2), 125.0, 124.5, 123.5 (aromatics), 81.5, 78.0, 74.4, 72.4, 70.0 (C-Γ - C-5'), 61.1 (C-6').

Example 56

5-(P-D-GlucopyranosyI)-3-(2-pyridyl)-l,2,4-triazole (17-Glc-r)

The title compound is prepared from 16-Glc-r (0.31 g, 0.43 mmol) according to

General procedure IV. Reaction time: 3.5 hours. Purified by column chromatography (7:3 CHCl₃-MeOH) to yield 0.05 g (40 %) colourless syrup. R_f: 0.36 (7:3 CHCl -MeOH); [<x]_D = +30 (c 0.22, H₂0); Ή NMR (D₂0) δ (ppm): 8.63-7.52 (4H, m, Py), 4.64 (1H, d, J = 9.2 Hz, H-l '), 3.96 (1H, dd, J= 11.9, < 1 Hz, H-6'a), 3.86-3.81 (2H, m, H-2' or H-3' or H-4', H-6'b), 3.73-3.60 (3H, m, H-2' and/or H-3' and/or H-4', H-5'); ¹³C NMR (D₂0) δ (ppm): 158.5, 156.8 (triazole C-3, C-5), 149.4, 145.3 (q), 138.3, 125.5, 122.0 (Py), 80.0, 76.8, 74.3, 72.5, 69.3 (C-r - C-5'), 60.7 (C-6'). ESI-MS (positive mode) m/z: 331.100 [M+Na]⁺, 639.217 [2M+Na]⁺, 309.118 [M+H]⁺. Example 57

3-Phenyl-5-(P-D-xylopyranosyl)-l,2,4-triazole (17-Xyl-d)

The title compound is prepared from 15-Xyl-d (0.20 g, 0.54 mmol) according to General procedure IX. Reaction time: 2 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.14 g (91 %) white amorphous solid. Rf. 0.30 (4:1 CHCl₃-MeOH); [a]_D = -24 (c 0.48, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.90 (2H, brs, aromatics), 7.40 (3H, m, aromatics), 4.37 (1H, d, J = 9.6 Hz, H-l '), 4.00 (1H, dd, J = 1 1.1, 5.3 Hz, H-5'a), 3.80 (1H, brs, H-5'b), 3.68 (1H, ddd, J = 10.1 , 9.0, 5.3 Hz, H-4'), 3.49 (1H, pseudo t, J = 9.0, 9.0 Hz, H-2' or H-4'), 3.36 (1H, pseudo t, J - 10.9, 10.8 Hz, H-2' or H-4'); ¹³C NMR (CD₃OD) δ (ppm): 163.0, 156.9 (triazole C-3, C-5), 131.1 (q), 129.9, 127.5 (aromatics), 79.5, 77.2, 74.2, 71.1 (C-l ' - C-4'), 71.5 (C-5').

Example 58

3-(4-tert-Butylphenyl)-5-(p-D-xylopyranosyl)-l,2,4-triazoIe (17-Xyl-f)

The title compound is prepared from 15-XyI-f (0.18 g, 0.43 mmol) according to General procedure IX. Reaction time: 2 hours. Purified by column chromatography (9:1 CHCl₃-MeOH) to yield 0.11 g (77 %) white amorphous solid. Rf. 0.43 (4:1 CHCl₃-MeOH); [a]_D = -24 (c 0.49, MeOH); Ή NMR (CD₃OD) δ (ppm): 7.88 (2H, d, J = 8.2 Hz, aromatics), 7.47 (2H, d, J= 8.2 Hz, aromatics), 4.38 (1H, d, J= 9.7 Hz, H-l '), 4.01 (1H, dd, J = 11.1, 5.3 Hz, H-5'a), 3.83 (1H, pseudo t, J = 8.6, 8.3 Hz, H-5'b), 3.68 (1H, ddd, J = 10.0, 9.2, 5.3 Hz, H-4'), 3.50 (1H, pseudo t, J = 9.0, 9.0 Hz, H-2' or H-4'), 3.37 (1H, pseudo t, J = 11.0, 11.0 Hz, H-2' or H-4'), 1.29 (9H, s, C(CH₃)₃); ¹³C NMR (CD₃OD) δ (ppm): 162.1 , 158.4 (triazole C-3, C-5), 154.6 (q), 127.4 (2), 126.9 (2) (aromatics), 79.5, 77.3, 74.2, 71.1 (C-l ' - C-4'), 71.5 (C-5'), 35.6 (C(CH₃)₃), 31.6 (C(CH₃)₃).

Example 59

3-(2-Naphthyl)-5-(p-D-xylopyranosyl)-l,2,4-triazoIe (17-Xyl-q)

The title compound is prepared from 15-Xyl-q (0.14 g, 0.33 mmol) according to General procedure IX. Reaction time: 16 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.10 g (90 %) white amorphous solid. R_f: 0.44 (4:1 CHCl₃-MeOH); [a]_D = -22 (c 0.47, MeOH);

Ή NMR (CD₃OD) δ (ppm): 8.36 (1H, s aromatics), 7.93 (1H, d, J= 8.2 Hz, aromatics), 7.78- -7.69 (3H, m, aromatics), 7.38-7.35 (2H, m, aromatics), 4.40 (1H, d, J = 9.7 Hz, H-l '), 4.00 (1H, dd, J= 1 1.0, 5.3 Hz, H-5'a), 3.84 (1H, pseudo t, J= 8.9, 8.7 Hz, H-5'b), 3.71 (1H, ddd, J = 9.9, 9.5, 5.3 Hz, H-4'), 3.51 (1H, pseudo t, J= 8.9, 8.9 Hz, H-2' or H-4'), 3.37 (1H, pseudo t, J = 10.8, 10.8 Hz, H-2' or H-4'); ¹³C NMR (CD₃OD) δ (ppm): 160.7, 159.0 (triazole C-3, C-5), 138.8 (q), 135.3 (q), 134.4 (q), 129.7, 129.5, 128.7, 128.1, 127.7, 127.2, 124.5 (aromatics), 79.5, 77.2, 74.3, 71.1 (C-l ' - C-4'), 71.5 (C-5').

Preparation of 4(5)-substituted-2-( -D-glycopyranosyl)-imidazoles General procedure X

for the synthesis of protected 4(5)-substituted-2-(P-D-glycopyranosyl)-iniidazoles (18) from protected C-(P-D-glycopyranosyl)formimidates (5)

A formimidate 5 (0.15 mmol) and an a-aminoketone 20 (0.31 mmol) were dissolved in anhydrous pyridine (4 mL), stirred at rt and monitored by TLC (4:6 EtOAc-hexane). After completion of the reaction (1 day) the solvent was removed and the residue was purified by column chromatography.

General procedure XI

for the synthesis of protected 4(5)-substituted-2-(P-D-glycopyranosyl)-imidazoles (18) from protected C-(P-D-glycopyranosyl)formamidines (11)

A formamidine 11 (0.80 mmol), a-bromoketone 21 (0.80 mmol), and K₂C0₃ (0.11 g, 0.80 mmol) were stirred in THF-water solvent mixture (20 mL and 2.5 mL, respectively) at rt, and the reaction was monitored by TLC (9: 1 CHCl₃-MeOH and 1 :1 EtOAc-hexane). After two days the mixture was concentrated under diminished pressure, the residue was dissolved in CH₂C1₂ (40 mL), and extracted with water (40 mL). The organic phase was dried over MgS0₄, the solvent was evaporated, and the residue was purified by column chromatography.

Example 60

4(5)-Phenyl-2-(2',3',4',6'-tetra-0-benzoyl-p-D-glucopyranosyl)-imidazoIe

(18-Glc-d)

A) The title compound is prepared from 5-Glc (0.1 g,- 0.15 mmol) and phenacylamine hydrochloride (20d, 0.05 g, 0.31 mmol) according to General procedure X. Column chromatography in 4:6 EtOAc-hexane yielded 0.05 g (45 %) pale yellow syrup.

B) The title compound is prepared from amidine 11-Glc (0.5 g, 0.80 mmol) and 2-

-bromo-1 -phenyl ethanone (21d, 0.16 g, 0.80 mmol) according to General procedure XI. Purified by column chromatography (3:7 EtOAc-hexane) to yield 0.17 g (29 %) pale yellow syrup. R_f: 0.31 (4:6 EtOAc-hexane); [ ]_D = -2 (c 0.20, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 10.19 (1H, s, imidazole NH), 8.02-7.19 (26H, m, aromatics, imidazole CH), 6.10, 5.85-5.80 (3 x 1H, 3 pseudo t, J= 9.2, 9.2 Hz in each, H-2', H-3', H-4'), 5.14 (1H, d, J= 9.2 Hz, H-l '), 4.68 (1H, dd, J = 11.9, 2.6 Hz, H-6'a), 4.52 (1H, dd, J = 11.9, 4.0 Hz, H-6'b), 4.35 (1H, ddd, J = 9.2, 4.0, 2.6 Hz, H-5'); ¹³C NMR (CDC1₃) 5 (ppm): 166.3, 165.7, 165.6, 165.2 (CO), 142.8 (imidazole C-2), 138.8 (imidazole Cq-4), 133.4-124.7 (aromatics, imidazole CH), 76.6, 74.4, 73.8, 71.4, 69.5 (C-l ' - C-5'), 63.1(C-6'). ESI-MS (positive mode) m/z: 745.214 [M+Na]⁺, 723.232 [M+H]⁺.

Example 61

4(5)-(2-Naphthyl)-2-(2',3',4',6'-tetra-0-benzoyl-p-D-glucopyranosyl)-imidazole (18-Glc-q)

The title compound is prepared from amidine 11-Glc (1.2 g, 1.93 mmol) and 2-bromo- -l -(2-naphthyl)ethanone (21q, 0.48 g, 1.93 mmol) according to General procedure XI. Purified by column chromatography (3:7 EtOAc-hexane) to yield 0.15 g (10 %) pale yellow syrup. R_f: 0.28 (3:7 EtOAc-hexane); [a]_D = -3 (c 0.21, CHC1₃); Ή NMR (CDC1₃) δ (ppm): 10.02 (1H, s, imidazole NH), 8.05-7.21 (28H, m, aromatics, imidazole CH), 6.13, 5.88-5.80 (3 x 1H, 3 pseudo t, J = 10.6, 9.2 Hz in each, H-2\ H-3', H-4'), 5.20 (1H, d, J = 9.2 Hz, H- -1 '), 4.72 (1H, dd, J = 1 1.9, 2.6 Hz, H-6'a), 4.55 (1H, dd, J = 11.9, 5.3 Hz, H-6'b), 4.38 (1H, ddd, J= 9.2, 5.3, 2.6 Hz, H-5'); ^l3C NMR (CDC1₃) δ (ppm): 166.4, 165.7, 165.6, 165.2 (CO), 143.1 (imidazole C-2), 138.5 (imidazole Cq-4), 133.5-122.9 (aromatics, imidazole CH), 76.7, 74.3, 73.7, 71.4, 69.4 (C-l ' - C-5'), 63.1(C-6').

Example 62

2-(P-D-Glucopyranosyl)-4(5)-phenyl-imidazole (19-Glc-d)

The title compound is prepared from 18-Glc-d (0.19 g, 0.26 mmol) according to

General procedure IV. (The mixture was neutralised with acetic acid.) Reaction time: 3 hours. Purified by column chromatography (85:15 CHCl₃-MeOH) to yield 0.06 g (74 %) colourless syrup. R_f: 0.34 (8:2 CHCl₃-MeOH); [ ]_D = -3 (c 0.40, H₂0); Ή NMR (D₂0) δ (ppm): 7.64-7.24 (6H, m, aromatics, imidazole CH), 4.42 (1H, d, J = 9.2 Hz, H-l '), 3.84 (1H, dd, J = 1 1.9, <1 Hz, H-6'a), 3.74-3.52 (5H, m, H-2', H-3', H-4', H-5', H-6'b); ^l3C NMR (D₂0) δ (ppm): 146.2 (imidazole C-2), 138.8 (imidazole Cq-4), 132.8 (q), 129.6 (2), 128.0, 125.4 (2) (aromatics), 117.0 (imidazole CH), 80.5, 77.7, 75.6, 73.4, 70.0 (C-l ' - C-5'), 61.4 (C-6'). Example 63

2-(p-D-Glucopyranosyl)-4(5)-(2-naphthyl)-imidazole (19-Glc-q)

The title compound is prepared from 18-Glc-q (0.17 g, 0.22 mmol) according to General procedure IV. Reaction time: 3 hours. Purified by column chromatography (9: 1 CHCl₃-MeOH) to yield 0.06 g (77 %) colourless syrup. R_f: 0.49 (7:3 CHCl₃-MeOH); [<x]_D = +30 (c 0.21, MeOH); Ή NMR (CD₃OD) δ (ppm): 8.17-7.40 (8H, m, aromatics, imidazole CH), 4.43 (1H, d, J = 9.2 Hz, H-l '), 3.92 (1H, dd, J = 11.9, < lHz, H-6'a), 3.76 (1H, dd, J = 1 1.9, 4.0 Hz, H-6'b) 3.70 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2'or H-3'or H-4'), 3.57-3.49 (3H, m, H-2'and/or H-3'and/or H-4', H-5'); ¹³C NMR (CD₃OD) δ (ppm): 148.4 (imidazole C-2), 139.1 (imidazole Cq-4), 135.2 (q), 134.1 (q), 131.3 (q), 129.4, 129.0, 128.7, 127.4, 126.7, 124.6, 123.8 (aromatics), 1 18.0 (imidazole CH), 82.1, 79.4, 76.9, 74.7, 71.3 (C-Γ - C-5'), 62.7 (C-6').

Pharmacological Examination:

The examplary compounds described above were tested for their activity using the test described below.

Enzyme Assays

Glycogen phosphorylase b was prepared from rabbit skeletal muscle according to the method of Fischer and Krebs [Fischer, E. H.; Krebs, E. G. Methods EnzymoL, 5, 369-372 (1962)] using 2-mercaptoethanol instead of L-cysteine, and recrystallized at least three times before use. The kinetic studies with glycogen phosphorylase were performed as described previously [Osz, E.; Somsak, L.; Szilagyi, L.; Kovacs, L.; Docsa, T.; Toth, B.; Gergely, P. Bioorg. Med. Chem. Lett., 9, 1385-1390 (1999)]. Kinetic data for the inhibition of rabbit skeletal muscle glycogen phosphorylase by monosaccharide compounds were collected using different concentrations of a-D-glucose-1- phosphate (4, 6, 8, 10, 12 and 14 mM) and constant concentrations of glycogen (1% w/v) and AMP (1 mM). The enzymatic activities were presented in the form of double- reciprocal plots (Lineweaver-Burk) applying a nonlinear data-analysis programme. The inhibitor constants (Ki) were determined by Dixon plots, by replotting the slopes from the Lineweaver-Burk plots against the inhibitor concentrations. The means of standard errors for all calculated kinetic parameters averaged to less than 10% [Somsak, L.; Kovacs, L.; Toth, M.; Osz, E.; Szilagyi, L.; Gyorgydeak, Z.; Dinya, Z.; Docsa, T.; Toth, B.; Gergely, P. J. Med. Chem., 44, 2843-2848 (2001); Oikonomakos, N. G.; Skamnaki, V. T.; Osz, E.; Szilagyi, L.; Somsak, L.; Docsa, T.; Toth, B.; Gergely, P. Bioorg.Med. Chem., 10, 261-268 (2002)]. IC₅₀ values were determined in the presence of 4 mM glucose 1 -phosphate, 1 mM AMP, 1 % glycogen, and varying concentrations of an inhibitor.

In Table 2 the inhibitory properties of the compounds according to the invention are characterised by inhibitor constants K; or IC50 values against rabbit muscle glycogen phosphorylase b.

Table 2

Claims

CLAIMS la I

wherein

X is -CH= or -N= or -N(R") -;

Y is -N= or -N(R") -;

R is a Ci-6 alkyl group, which is unsubstituted or substituted with a substituent selected from the group of hydroxyl, azide, nitro, amino, sulfanyl, alkoxy, alkylthio, carboxyl and halogen; an C_6-io aryl group or heteroaryl group of 5-10 ring atoms which include 1 -3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, which aryl or heteroaryl groups are unsubstituted or substituted with 1-3 substituents selected from the group of Ci_-4 alkyl, halogen, trifluoromethyl, hydroxyl, Ci_₄ alkoxy, carboxyl, unsubstituted or N-(mono or di)substituted carbamoyl, amino and nitro;

R' is hydrogen or PG¹, where

PG¹ is C[.₆ alkyl, C_3-7 cycloalkyl, (Ci_-6 alkyl)carbonyl, (C_3-7 cycloalkyl)carbonyl, tetrahydropyranyl, allyl, (C₆-io aryl)carbonyl, (C_6-io aryl)(Ci_-6 alkyl) optionally carrying one or more substituents selected from the group of halogen, C_1- alkyl, Ci_-6 alkoxy and nitro;

K is hydrogen or PG , where

PG² is Ci_-6 alkyl, C_6-i₀ aryl, (C_6-i₀ aryl)(Ci_-6 alkyl), Ci_-6 alkylsulfonyl, C_6-io arylsulfonyl, Ci- alkoxycarbonyl or benzyloxycarbonyl optionally carrying one or more substituents selected from the group of halogen, Ci_-4 alkyl, Q_-6 alkoxy and nitro; is hydrogen or R'OCH₂-;

is an integer of 1 to 3;

in the Gly moiety of fo each R'O- is attached to a -CH₂-unit of the ring; moiety A of formula

includes a heteroaromatic ring which may have only one NR" ring member,

or its stereoisomer or its tautomer or a pharmaceutically acceptable salt thereof.

2. A compound of formula I according to claim 1,

wherein

moiety A stands for any of formulae formula i, ii and iii

i ii iii

wherein

R is methyl, tert-butyl, hydroxymethyl, acetoxymethyl, phenyl, naphthyl, tert-

-butylphenyl, tnfluoromethylphenyl, hydroxyphenyl, acetoxyphenyl, carboxyphenyl, benzyloxycarbonylphenyl, mono- or diaminophenyl, mono- or dinitrophenyl, mono-, di- or trimethylphenyl, mono-, di- or trialkoxyphenyl, pyridyl;

R" is hydrogen, benzyl or tosyl;

moiety Gly stands for any of formulae Glc, Xyl, and Gal

wherein

R' is hydrogen, acetyl, benzoyl, or benzyl; and

R"' is as defined in claim 1.

3. A compound of formula I according to claim 1, wherein

moiety A stands for formula iv or v

iv v

wherein

R is phenyl or naphthyl;

R" is hydrogen or benzyl or tosyl;

moiety Gly stands for any of formulae Glc, Xyl, and Gal

Glc Xyl Gal wherein

R' is hydrogen, acetyl, benzoyl or benzyl; and

R'" is as defined in claim 1.

4. The compound of formula I according to any of claims 1 to 3 for use as a glycogen phosphorylase inhibitor.

5. Compounds of formula I according to claim 1, which are

5-(P-D-glucopyranosyl)-3-phenyl- 1 ,2,4-triazole,

5-(β-D-glucopyra osyl)-3-(4-methyl henyl)-l,2,4-triazole,

3-(4-aminophenyl)-5-(P-D-glucopyranosyl)- 1 ,2,4-triazole,

5-( -D-glucopyranosyl)-3-(2-naphthyl)- 1 ,2,4-triazole,

3-(2-naphthyl)-5-(P-D-xylopyranosyl)-l,2,4-triazole,

2-( -D-glucopyranosyl)-4(5)-phenyl-imidazole,

2-( -D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole,

4(5)-phenyl-2-( -D-xylopyranosyl)-imidazole, and

4(5)-(2-naphthyl)-2-(P-D-xylopyranosyl)-imidazole.

6. Process for the preparation of compounds of formulae I according to claim 1 , characterized in that

(a) to obtain a compound of formula I wherein X is -N= or -NR"- and Y, R, R', R", R'" and n are as defined in claim 1,

13' is reacted with a compound of formula 3

{PG¹

wherein R, PG , PG\ R'" and n are as defined in claim 1 , or

(ii) a compound of formula 9

is reacted with RCOCl, wherein R, PG¹, R'" and n are as defined in claim 1 , or

(iii) a com ound of formula 10

is reacted with a compound of formula 4

wherein R, PG¹, R'" and n are as defined in claim 1,

(iv) a compound of formula 11

is reacted with a compound of formula 4

wherein R, PG^l, R"' and n are as defined in claim 1 , (v) compound of formula 12

wherein R, PG¹, R'" and n are as defined in claim 1,

is treated with NH₄OAc,

(vi) compound of formula 12

wherein R, PG¹, R'" and n are as defined in claim 1 ,

is heated in pyridine; or

(i) a compound of formula 5

is reacted with a compound of formula 20

wherein R, R", R'", PG¹ and n are as defined in claim 1 ,

(ii) a compound of formula 11

is reacted with a compound of formula 21

21

wherein R, R'", PG¹ and n are as defined in claim 1,

1 2

and if desired, substituents PG and/or PG are removed,

7. Compounds of formulae 5, 9 and 11 wherein PG¹, R'" and n are as defined in claim 1, and compounds of formula 12 wherein PG¹, R, R'" and n are as defined in claim 1.

8. Pharmaceutical compositions containing an effective amount of a compound of formula I according to any of claims 1 to 5 and at least one suitable pharmaceutical carrier or additive.

9. Pharmaceutical compositions according to claim 8 for use in the treatment or prevention of type 2 diabetes or early stage cardiovascular diseases, or in the stabilization of cardiac arrhythmia or in the protection against ischaemic lesions or in the prevention of tumorous growth.

10. Method of treatment of type 2 diabetes or early stage cardiovascular diseases or cardiac arrhythmia or ischaemic lesions or tumorous growth, said method comprising administering an effective amount of a compound of formula I optionally together with at least one suitable pharmaceutical carrier or additive to a patient suffering from said diseases.