IE902157L - Cyclomalto-oligosaccharide derivatives and processes for¹preparing same - Google Patents

Description

IE 902157 Cvclomalto-oliqosaccharide derivatives and processes for preparing them The present invention relates to new cyclomalto-oligosaccharide derivatives and processes for preparing 5 them.

More precisely, it relates to branched cyclo-malto-oligosaccharide derivatives obtained by fixing an oside residue or an oligosaccharide residue on the carbons in the 6-position of the cyclic oligosaccharide 10 via a sulphur atom.

The cyclomalto-oligosaccharides, more commonly called cyclodextrins, are cyclic oligosaccharides of D-glucose most commonly containing from six to eight D-glucopyranosyl units linked by a-(1+4) chains, which 15 confers on them a morphology of a toric type. By virtue of this molecular geometry and related electronic structures, a hydrophobic character is associated with the internal cavity of the cycle, while the external surface of the molecule is hydrophilic. This arrangement 20 favours the formation of inclusion complexes with hydro phobic molecules by apolar association, thus improving the dissolution of these molecules in water. These properties are very widely utilized in many sectors, such as the pharmaceutical, veterinary, agrochemical, food-25 stuffs and cosmetics sectors, including flavourings and perfumes. The cyclodextrins are thus used to stabilize labile molecules, to improve the molecular transport towards target sites or to promote interfacial reactions, as described in Drug Development and Industrial Pharmacy, B. 10062.3 MDT IE 902157 12, 11-13, p. 2193-2216, 1986.

It is known that the solubility of cyclomalto-oligosaccharides in water, but also in non-aqueous solvents, and consequently that of the inclusion pro-5 ducts, is considerably improved when the molecule is substituted by hydrophilic groups. This is the case, in particular, for branched cyclomalto-oligosaccharides, which contain one or more a-D-glucopyranosyl or a-malto-syl substituents or one or more higher oligosaccharide 10 homologue substituents in the C-6 hydroxymethyl position of the cyclic oligosaccharide.

These branched cyclomalto-oligosaccharides can be prepared by techniques employing enzymology, chemical synthesis or a combination of the two. 15 Thus, in I. Int. Symp. on Cyclodextrins, Buda pest, 1981, p. 51 to 60, Kobayashi et al. describe a process for the preparation of glucosyl-cyclodextrins by the action of Bacillus macerans cyclomaltodextrin glu-canotransferase on starch. Processes for the preparation 2 0 of branched cyclodextrins starting from cyclodextrins and glucose or a malto-oligosaccharide using pullulanase as the catalyst for the transfer reaction of the glucose or the malto-oligosaccharide are also known from the documents GB-A-2,165,549 and Chemical Abstracts, vol. 107, 25 1987,'p. 603, No. 107:57465n (JP-A-6,206,696 (8,706,696).

In the processes described above, a mixture of diversely branched cyclodextrins is obtained and the purification of these compounds, carried out on the B. 10062.3 MDT IE 902157 laboratory scale, is long and difficult, so that these products are generally marketed in the form of mixtures.

The synthesis processes, by a chemical route only, using, for example, glycosylation of a partially 5 protected derivative of a cyclomalto-oligosaccharide by a benzyl derivative of a suitably activated glucopyra-nose, as described by Fvigedi et al. in Carbohydr. Res., 175 (1988), 173-181, enable this disadvantage to be overcome since they lead to pure and homogeneous pro-10 ducts. However, they necessitate a significant number of steps and the product yields are low.

The present invention relates to new branched cyclomalto-oligosaccharide derivatives which can be prepared in a more simple manner, in the form of pure 15 products, and which have the same advantages as the branched cyclomalto-oligosaccharides disclosed in the abovementioned documents.

According to the invention, the new cyclomalto-oligosaccharide derivatives correspond to the formula: B. 10062.3 MDT IE 902157 in which n is an integer from 3 to 10 and the Rs, which may be identical or different, represent OH or ZY, where Z represents a single bond or a divalent radical of formula -S-R1- in which R1 represents a saturated or unsaturated divalent hydrocarbon radical and S is linked to CH2, and Y represents a radical of formula: HO f?2 HO (II) or of formula HO.

* (HI) in which formulae R2 represents H or CH2OH, p is 0 or is an integer from 1 to 9, the X or Xs, which may be different, represent 0, S or a radical corresponding to the formulae: R2 HO , (IV) or OH (V) B. 10062.3 MDT 902157 in which formulae the X's, which may be identical or different, represent O or S, and R2 has the meaning given above, with the proviso that at least one of the Rs represents ZY.

These new derivatives are thus differentiated from the known branched cyclodextrins by the fact that the hydrophilic substituent, which is a glycosyl or oligoglycosyl residue, is fixed on the ring via a sulphur atom. This is a significant advantage because the 10 thioglycoses are much better nucleophilic reactants than the corresponding glycoses when they take part in coupling reactions involving electrophilic sites of other glucide residues.

Moreover, the fixation of these substituents via 15 a sulphur atom confers on the branched cyclomalto-oligo- saccharide derivatives of the invention a better stability towards enzymatic degradation agents, which is very valuable when these derivatives are intended to be used for the transport of pharmacophore molecules in the 20 biological media.

According to a first embodiment of the invention, the cyclomalto-oligosaccharide contains a single substituent R of formula ZY. In this case, Y can represent, as has been seen above, either a monosaccharide residue 25 formed from a hexose or a pentose in the cyclic pyranose or furanose form, bonded in the anomeric position by a sulphur bond which can be of alpha or beta configuration, or an oligosaccharide residue likewise bonded in the B. 10062.3 MDT 902157 anomeric position by a sulphur bond; this oligosaccharide residue originates from an oligosaccharide in which the interoside bonds are oxygen atoms and/or sulphur atoms.

When Y is an oligosaccharide residue it can 5 originate from oligosaccharides such as maltose, cellobiose or lactose. It can also originate from oligosaccharides containing one or more interoside sulphur bonds.

By way of example of a monosaccharide residue Y, 10 those corresponding to the following formulae may be mentioned: HOC H? S HO C H 2 HO 0 H The residue Y can be bonded directly to the 15 cyclomalto-oligosaccharide or can be fixed thereto via a thio-hydrocarbon chain Z.

By way of example, this hydrocarbon chain Z can correspond to the formula -S-(CH2)m, in which m is an integer from 1 to 20. It can also contain an ethylenic 20 unsaturation and correspond, for example, to the formula (VI) (VII) B. 10062.3 MDT IE 902157 -S-(CH2)q-CH=CH-(CH2)r , in which q and r are integers from 1 to 17 with q+r being at least equal to 18.

By way of examples of cyclomalto-oligosaccharide derivatives corresponding to this first embodiment, the 5 derivative of formula: or the derivative of formula: H0CH2 B. 10062.3 MDT IE 902157 may be mentioned.

According to a second embodiment of the invention, the cyclomalto-oligosaccharide contains several substituents, these being several radicals R which may be 5 identical or different. In this case, the radicals R can contain, as above, a monosaccharide residue originating from a hexose or a pentose, or an oligosaccharide residue in which the interoside bonds can be of the 0 and/or S type and of alpha or beta configuration. 10 Similarly, this residue can be bonded directly to the cyclomalto-oligosaccharide via the sulphur atom or via a thiohydrocarbon chain corresponding to the formula SR1, where R1 represents a saturated or unsaturated divalent hydrocarbon radical which can correspond to the 15 formulae given above.

The cyclomalto-oligosaccharide derivatives of the present invention can be prepared easily starting from the corresponding cyclomalto-oligosaccharides.

Also, the invention likewise relates to a process 20 for the preparation of a cyclomalto-oligosaccharide derivative corresponding to the formula I given above, which consists in reacting a cyclomalto-oligosaccharide derivative of formula: B. 10062.3 MDT IE 902157 * 3 C H 2 in which the R3s, which may be identical or different, represent OH or a group of formula R6S03, in which R6 is an alkyl or aryl radical, and n is an integer from 3 to 5 10, at least one of the R3s representing a group of formula R6S03, with a 1-thiomonosaccharide or a 1-thiomalto-oligosac-charide of formula: or of formula B. 10062.3 MDT IE 902157 in which formulae R2 represents CH2OH, H or CH2OR4, X represents 0, S or a radical corresponding to the formulae: R 2 —-*°\ (IV) °r (V) in which formulae the X's, which may be identical or different, represent 0 or S, and R2 has the meaning given above, RA represents a hydrogen atom or a group protecting a hydroxyl function, R5 represents the same protective group as R4* or an alkali metal, p is 0 or is an integer 10 from 1 to 9 and Z represents a single bond or -R1S-, where R1 represents an alkyl or aryl radical and S is bonded to R5.

In this process a sulphonic ester of the desired cyclomalto-oligosaccharide is thus used as the starting 15 material and is reacted with a thio-mono- or thio-oligo- saccharide in the form of an alkali metal salt, for example the sodium salt, or of a protected derivative, for example the acetyl derivative.

The sulphonic ester R6S03 can be an arylsulphonate 20 or an alkylsulphonate.

The alkyl radicals which may be used for R6 can be straight-chain or branched and they generally have from 1 to 5 carbon atoms.

B. 10062.3 MDT IE 902157 The aryl radicals which can be used for R6 can be phenyl, benzyl, tolyl, naphthyl radicals etc.

The radicals R4 which can be used as protective group for OH can also be very varied. Examples of such 5 radicals which may be mentioned are the ester or acetyl radicals.

Thus, for carrying out this process the starting materials may be the tolylsulphonic ester of the cyclomalto-oligosaccharide and 1-thioglycose or a 1-thio-malto-oligosaccharide in which the hydroxyl groups are 10 protected. These latter compounds can be prepared by the action of sodium thioacetate on the corresponding glycosyl chloride in which the hydroxyl groups are protected, for example, by acetyl groups, in an appropriate solvent such as hexamethylphosphoramide. 15 In order to carry out the reaction, the sulphur nucleophile is first activated by the action of sodium methanolate in methanol and the sodium salt of the thioglycoside derivative thus obtained is then reacted with the sulphonic ester in a solvent having a polarity 20 which permits a sufficient activation of the sulphur anion.

Examples which may be mentioned of solvents which can be used are 1,3-dimethyl-2-oxo-hexahydropyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, hexamethyl-25 phosphoramide, dimethylformamide and dimethyl sulphoxide.

The reaction can be carried out at ambient temperature or preferably at a higher temperature, for example at 70°C.

B. 10062.3 MDT IE 902157 Under these conditions the derivative of the invention is obtained directly with a degree of purity which can be 70%. In order to obtain the analytically pure derivative, a supplementary purification step is 5 carried out by liquid chromatography using, for example, a column of graft silica of the C18 type and a water/methanol mixture as eluant.

The sulphonic esters of cyclomalto-oligosaccharides used as starting materials in this process can 10 be prepared by conventional processes, starting from the corresponding cyclomalto-oligosaccharides, for example by the process described by Matsui et al. in Bull. Chem. Soc. Jpn., 51 (1978), 3030-3034.

The sulphur derivatives of the monosaccharides or 15 of the disosaccharides (sic) used as starting materials in this process can also be prepared by conventional processes. Thus, the thioacetyl derivative can be prepared by the process described by M. Blanc-Muesser et al. in Carbohydr. Res., 1978, 67, 305. The sodium salt 20 can be prepared by the process described by Cerny et al. in Collect. Czech. Chem. Comm., 26 (1961) 2084-2086.

The cyclomalto-oligosaccharide derivatives of formula (I) of the invention can also be obtained by a second process, which consists in reacting a cyclomalto-25 oligosaccharide derivative of formula: B. 10062.3 MDT IE 902157 R7 CHj (XIII) in which n is an integer from 3 to 10 and R7 represents OH or SH, at least one of the R7s representing SH, with a mono- or oligo-saccharide derivative of formula: R4 — 0 0R^ 1 (XIV) ZR8 or of formula: r2 OR^ 1 r2 OR' ZRS (XV) in which formulae the R2 or R2s, which may be identical or different, represent H, CH2OH or CH2OR\ R4 represents H or a group protecting an OH function, X represents S, 0 or a radical corresponding to the formulae: B. 10062.3 MDT IE 902157 r2 X '■ 'IV) or v, (v) H ( OH X ' in which formulae the X's, which may be identical or different, represent 0 or S, and R2 has the meaning given above, p is 0 or is an integer from 1 to 9, Z represents 5 a single bond or -R1-S-, where R1 represents a saturated or unsaturated hydrocarbon radical, and R8 is a group capable of generating a positive charge.

The mono- or oligo-saccharide derivative used can be, in particular, a halide, such as a bromide or a 10 chloride.

The cyclomalto-oligosaccharide derivative used as starting material for this preparation can be prepared in the form of the corresponding sodium thiolate by the method described by Griffiths et al. in Adv. Cat. 23 15 (1973), p. 209. The mono- or oligo-saccharide halides also used as starting materials for this reaction can be prepared by the processes described by Lemieux et al. in Methods Carbohydr. Chem., 2 (1963), 221-222 and 224-225. The same polar aprotic solvents as in the first process 20 described above can be used to carry out the reaction.

In the two processes, when the hydroxyl functions in the monosaccharide or oligosaccharide derivative used are protected by an R4 group, a deprotection step, for example deacetylation, is carried out at the end of the B. 10062.3 MDT IE 902157 operation.

As before, the product obtained is then purified by chromatography using, for example, the same column of graft silica and the same eluant.

Other characteristics and advantages of the invention will become more apparent on reading the following examples which, of course, are given by way of illustration and are non-limiting.

Example 1; Preparation of 6-S-alpha-D-qlucoPYranosvl-6-10 thio-cvclomaltoheptaose (compound No. 1) KOCH? suspension of 1.3 g (3.2 mmols) of 2,3,4,6-tetra-0-acetyl-l-S-acetyl-l-thio-alpha-D-glucopyranose in 27 ml 15 of methanol. The solution obtained is kept at ambient temperature for 12 hours and is then concentrated under reduced pressure. The solid residue obtained is then B. 10062.3 MDT IE 902157 dissolved in DMPU and 2.08 g (1.6 mmols) of pulverulent 6-0-p-tolylsulphonylcyclomaltoheptaose are added to the solution.

The reaction mixture is stirred for 3 hours at 5 7 0°C under a nitrogen atmosphere, after which the solvent is concentrated under reduced pressure (54°C/6 Pa) and a brown solid residue is obtained which is dissolved in 2 0 ml of water and which is demineralized by passing through a column of Amberlite MB-13 resin. The colourless 10 aqueous solution is subjected to an extraction with dichloromethane and is then lyophilized, which enables 1.9 g of a solid residue to be obtained.

This solid residue is subjected to high performance liquid chromatography using a column of silica gel 15 of C18 type and a methanol/water (9:91, V/V) mixture as eluant and a refractometric detector, which confirms the presence of a principal compound (k'12). A purification is then carried out by preparative liquid chromatography using a Prep Pak 500/C18 column, the same solvent and a 20 pressure of 1.52 x 103 kPa with a flow rate of 100 ml/min. 1.4 g of 6-S-glucosyl-cyclomaltoheptaose, which is compound No. 1, are thus obtained, which corresponds to a yield of 66%.

The characteristics of this product are as follows: - melting point: 282-284°C (dec) [a]20 = +172°C (sic) (c 0.6, water); - XH NMR, (D20) : 55.45 (d, 1H, J12 5.4, H-1A) , 5.09 (d, B. 10062.3 MDT IE 902157 1H, 4Hz, H-IB or H-1C), 5.03 (m, 5H, H-1C), 4.99 (d, 1H, 4Hz, H1B or H-1C) , 4.07 - 3.78 (mm, H-5A, H-5B, H-5C, H6A, H-6C), 3.76 (dd, 1H, H-2A, J2 3 9.8), 3.66 3.47 (mm, H-2C, H-3A, H-4C) , 3.88 (dd, 1H, J3ll 9.8, J(( 5<1,H-4A) 3.14 5 (dd, 1H, J5 6a 2.6Hz, J6a 6b 12.5Hz, H-6aB) , 3.13 (dd, 1H, J5 6b 5Hz , H-6b) ; - mass spectrometry: (f.a.b.+, thioglyceral matrix), m/z 1313 (100%, (M+H)+); with the addition of Nal : m/z 1335 ( 100%, (M+Na) + ) , 1173 (8%, (M+Na-162)+ ) , 1140 (8%, (M+Na-195)+ ) - elementary analysis: C H S calculated for C48H80O39S 43.88 6.14 2.44 found 44.62 6.27 2.54 As is seen above, mass spectrometry in ionization mode by bombardment of accelerated atoms enables the protonated molecular ions to be detected at m/z 1313, which signals are shifted to m/z 1335 (M+Na)+ by the addition of sodium iodide to the thioglycerol matrix. The 20 13C nuclear magnetic resonance (NMR) spectrum of this compound is given in the appended Table 1. This spectrum, like that of the *H NMR, the attributes of which have been confirmed by the two-dimensional heteronuclear correlation technique, confirms the structure corres-25 ponding to formula (VIII) given above.

In the appended Table 2, the solubility in water of the compound No. 1 has been given, as well as the solubility in water of the inclusions complex formed B. 10062.3 MDT IE 902157 between this compound and 2-naphthol, hydrocortisone or tolnaftate (O-2-naphthyl methyl-(3-methylphenyl)carbo-mothioate).

By way of comparison, the solubilities in water 5 of these same compounds and that of unmodified cyclo- maltoheptaose (CG) and those of the inclusions complexes of CG7 with 2-naphthol, hydrocortisone and tolnaftate have been given in this table.

On looking at these tables, it is noted thciw the 10 solubility in water of the compound No. 1 of the inven tion is improved relative to that of CG7 and that the solubility of the inclusion complexes is multiplied by a factor of 14 and 4390 relative to the solubility in water.

The stability constants of the complexes formed have also been indicated in Table 2. It is also found that the stability constant of the complexes formed is of the same order as that of the complexes formed with CG7. This makes it possible to predict a similar behaviour 20 in respect of the possible bioavailability of the in cluded product for applications of the invention in the therapeutic field.

B. 10062.3 MDT IE 902157 Example 2; Preparation of 6-S-beta-D-qlucopyranosvl-6-thio-cvclomaltoheptaose (compound No. 2).

H0CH2 ^ 67 mg (0.31 mmol) of the sodium salt of 1-thio-5 beta-D-glucopyranose are added to a solution of 0.33 g (0.26 mmol) of 6-O-p-tolylsulphonyl-cyclomaltoheptaose in 1.5 ml of DMPU. The reaction mixture is stirred for 5 hours at 70°C under a nitrogen atmosphere and the solvent is then evaporated under reduced pressure (54°C/6 Pa); a 10 solid residue is thus obtained which is dissolved in 5 ml of water and which is then demineralized by passing through a column of Amberlite MB-13.

The colourless aqueous solution obtained is then extracted with 5 ml of dichloromethane and is then 15 lyophilized. 0.305 g of colourless solid are thus obtained, which on high performance liquid chromatography shows a principal compound under the same conditions as B. 10062.3 MDT IE 902157 those used in Example 1. This product is purified by-preparative liquid chromatography under the same conditions as those of Example 1 and 0.2 g of analytically pure 6-S-glucosyl-cyclomaltoheptaose (compound No. 2) are 5 thus obtained, which are recrystallized from methanol. The yield is 60 %.

The characteristics of this compound are as follows: - melting point: 268-272°C (dec); -[a]o°+116°, c 1, water); - XH NMR, 5 5.09 (d, 1H, 4Hz, H-1B or H-1C), 5.03 (m, 6H, H-1C or H-1B—5H-1C) , 4.60 (d, 1H, j1-2 10.2Hz, H-1A) , 4.12-3.75 (mm, H-5A, H-5B, H-5C, H-6A, H-6C), 3.7-3 (mm, H-2A, H-2C, H-3C, H-4A, H-4B, H-4C, H-5A, H-6aB), 2.95 (m, 1H, H6bB); - mass spectrometry: (f.a.b., thioglycerol matrix), m/z 1313 (100%, M+M) + ); with addition of Nal: m/z 1335 (100%, (M+Na) + , 1173 (12%, (M+Na-162)+, 1140 (10%, (M+Na-195)+). - elementary analysis: CHS calculated for CA8H80O39S 43.88 6.14 2.44 found: 43.62 5.89 2.39 The 13C nuclear magnetic resonance spectrum of this compound is given in the appended Table 1 and these 25 results, as well as the *H NMR spectrum, confirm the structure corresponding to formula (IX) given above.

The solubility in water of the compound No. 2, as well as those of its inclusion complexes with 2-naphthol, B. 10062.3 MDT IE 902157 hydrocortisone and tolnaftate, are also given in the appended Table 2.

The stability constants of the inclusion complexes formed have also been indicated in Table 2.

As in the case of compound No. 1, the solubility in water is very much improved relative to that of cyclomaltoheptaose and a significant improvement in the dissolution of the apolar compounds in water is also obtained since the solubility of tolnaftate is increased 10 3090 times. Similarly, 2-naphthol, which already posses ses a certain solubility in water, nevertheless sees this solubility improved 14 times in the presence of compounds No. 1 and No. 2, although this rate of dissolution is improved only 5 times in the presence of cyclomalto-15 heptaose.

Similarly, the apparent stability constants of the complexes formed between 2-naphthol and hydrocortisone are not appreciably modified relative to those of the corresponding complexes formed with cyclomalto-20 heptaose under the same conditions.

Thus, the new derivatives of the invention enable the solubility in water of apolar inclusion compounds or, more generally, of inclusion compounds which are insoluble or sparingly soluble in this solvent, to be 25 improved in significant proportions in comparison with the corresponding cyclomalto-oligosaccharides, while preserving the complexing capacities of these latter compounds. These properties are therefore close to those B. 10062.3 MDT IE 902157 of the branched cyclomalto-oligosaccharides obtained by the processes of the prior art which are much more difficult to carry out.

B. 10062.3 MDT TABLE 1 13C NMR Msasureraents carried out in deuterium oxide with methanol-d, as external standard Compound Structural unit to which the attribution relates Chemical shifts [A, p.p.m] of the carbon atoms C-l C-2 C-3 C-4 C-5 C-6 1 A 85.9 71.3 73.7 69.8 72.5 60.6 [99.4] [72.2] [73.7] [70.3] [71.6] [61.2] B 102 72.2 73.2 84.2 70.7 31 [102.1] [72.3]

[74] [82.4] [72.7] [67.8] C 102 72.2 73.2 81.4 71.9 60.5 [102.1] [72.41] [74.01] [81.9] [72.7] [61.2] 2 A 87.1 72 1 79.8 69.7 77.4 61.2 B 102 72.1 73 84.9 71.9 32.8 C 102 72.1 73 81.2 71.9 60.4 - Tolnaftate: 0-2-Naphthyl methyl-[3-methylphenyl]-carbarothioate.

- The solubility improvement factor is given relative to water.

TABLE 2 Comparative solubility of 6-S-qlucosvl-6-thio-cycicma Itoheptaoses 1 and 2 . cyclomaltoheptaose and their inclusion complexes with a few apolar molecules. The solubility improvement factors are given between brackets and the apparent stability constants between square brackets.

Solute Solubility in water Og/ml] Solubility [/ig/ml] stability constant of the complexes [in mol"1] Cyclomaltoheptaose (CG;) Compound 1 19 x 103 43 x 10* 1.7 x 10"z mol/1 aqueous solution Of CG; 3.10"2 mol/1 aqueous solution of ccropound No. 1 3.10"2 mol/1 aqueous solution of canpourid No. 2 Canpound 2 x 103 2-Naphthol 810 4,150 [x 5] [ 30 ] 11,010 [x 14] [ 44 ] 11,010 [x 14] [ 44 ] Hydrocortisone 410 2,255 [x 6j [3,720] 82,610 [x 200] [1,660] 70,610 [x 170] [2,790] Tolnaftate1 12 840 [x 70] [1,330] 52,690 [x 4390] [34,320] 37,090 [x 3,090] [17,230] 1. Tolnaftate: 0-2-Naphthyl-methyl-[3-methylphenyl]-carbomothioate. 2. The solubility improvement factor is given relative to water.

IE 902157

Claims (4)

1. Cyclomalto-oligosaccharide derivative correspond ing to the formula: in which n is an integer from 3 to 10 and the Rs, which may be identical or different, represent OH or ZY, where Z represents a single bond or a divalent radical of formula -S-R1- in which R1 represents a saturated or unsaturated divalent hydrocarbon radical and S is linked to CH2, and Y represents a radical of formula: or of formula: B. 10062.3 MDT IE 902157 - 26 - HO. R ? R2 \ HO OH OH (III) in which formulae R2 represents H or CH2OH, p is 0 or is an integer from 1 to 9, the X or Xs, which may be different, represent 0, S or a radical corresponding to the formulae: x • (IV) or OH (V) X ' in which formulae the X's, which may be identical or different, represent 0 or S, and R2 has the meaning given above, with the proviso that at least one of the Rs represents ZY.

2. Cyclomalto-oligosaccharide derivative according to Claim 1, characterized in that Y represents: HOCH (VI) B. 10062.3 MDT IE 902157 - 27 -

3. Cyclomalto-oligosaccharide derivative according to Claim 1, characterized in that Y represents:

4. Cyclomalto-oligosaccharide derivative according to any one of Claims 1 to 3, characterized in that Z represents a single bond.

5. Cyclomalto-oligosaccharide derivative according to any one of Claims 1 to 3, characterized in that Z represents a radical of formula -S-(CH2)m- in which m is an integer from 1 to 20.

6. Cyclomalto-oligosaccharide derivative according to any one of Claims 1 to 3, characterized in that Z represents a radical of formula S-(CH2)q-CH=CH-(CH2)r- in which q and r are integers from 1 to 17 with q+r being at least equal to 18.

7. Cyclomalto-oligosaccharide derivative according to Claim 1, characterized in that it corresponds to the formula: B. 10062.3 MDT IE 902157 - 28 - to Claim 1, characterized in that it corresponds to the formula: H0CH2

9. Process for the preparation of a cyclomalto- oligosaccharide derivative according to Claim 1, characB. 10062.3 MDT IE 902157 29 terized in that it consists in reacting a cyclomalto-oligosaccharide derivative of formula: in which the R3s, which may be identical or different, represent OH or a group of formula R6S03, in which R6 is an alkyl or aryl radical, and n is an integer from 3 to 10, at least one of the R3s representing a group of formula R6S03, with a 1-thiomonosaccharide or a 1-thiomalto-oligosaccharide of formula: R 3 C H 2 (X) S P or of formula: B. 10062.3 MDT IE 902157 - 30 - R4 0-" P (XII) in which formulae R2 represents CH20H, H or CH2ORA, X represents 0, S or a radical corresponding to the formulae: in which formulae the X's, which may be identical or different, represent 0 or S, and R2 has the meaning given above, R* represents a hydrogen atom or a group protecting a hydroxyl function, R5 represents the same protective group as R* or an alkali metal, p is 0 or is an integer from 1 to 9 and Z represents a single bond or -R1-S-, where R1 represents a saturated or unsaturated hydrocarbon radical and S is bonded to R5.

10. Process according to Claim 9, characterized in that RA and R5 represent the acetyl group.

11. Process according to any one of Claims 9 and 10, (V) X B. 10062.3 MDT IE 902157 - 31 - characterized in that R6 is the tolyl radical.

12. Process according to Claim 9, characterized in that RA is a hydrogen atom and R5 is sodium.

13. Process for the preparation of a cyclomalto-oligosaccharide derivative according to Claim 1, characterized in that it consists in reacting a cyclomalto-oligosaccharide derivative of formula: in which n is an integer from 3 to 10 and R7 represents OH or SH, at least one of the R7s representing SH, with a mono- or oligosaccharide derivative of formula: (XIV) B. 10062.3 MDT IE 902157 or of formula: *2 - 32 - R2 .J Oft' Zft8 (XV) in which formulae the Rz or Rzs, which may be identical or different, represent H, CH2OH or CH2OR4, R4 represents H or a group protecting an OH function, X represents S, 0 or a radical corresponding to the formulae: R2 (IV) or (V) OH in which formulae the X's, which may be identical or different, represent 0 or S, and R2 has the meaning given above, p is 0 or is an integer from 1 to 9, Z represents a single bond or -R1-S-, where R1 represents a saturated or unsaturated hydrocarbon radical, and Ra is a group capable of generating a positive charge.

14. Process according to Claim 13, characterized in that R8 is a halogen atom. B. 10062.3 MDT IE 902157 - 33 -

15. A compound as claimed in Claim 1, substantially as hereinbefore described and exemplified.

16. A process for the preparation of a compound as claimed in Claim 1, substantially as hereinbefore described and exemplified.

17. A compound as claimed in Claim 1, whenever prepared by a process claimed in a preceding claim. Dated this the 14th day of June, 1990. F. R. KELLY & CO. BY: - EXECUTIVE 27 Clyde Road, Ballsbridge, Dublin 4. AGENTS FOR THE APPLICANTS.