IE893771A1 - Process for the specific synthesis of new dithiocarbamic¹acid esters by substitution of hydroxylated sites on mono-or¹polyhydroxylated molecules, products obtained therefrom and¹their applications - Google Patents

Abstract

A process for preparation of dithiocarbamic acid esters having the formula in which R]_ and R2 are saturated or unsaturated alkyl radicals , which may substituted with carbon lO groups or heteroatoms or else form with the nitrogen atom a saturated,or unsaturated ring which may contain heteroatoms from alcohols or polyols, characterized in that in a preliminary step at least one hydroxylated group of the mono- or polyhydroxylated 15 molecule is transformed into a leaving group (Y) such as iodide, tosylate, brosylate, triflate or imidazole sulfonate and in that the leaving group (Y) is displaced by the anion wherein Rp and R2 nave the above meaning, as introduced 20 in the form of a salt, preferably a lithium salt, in the appropriate medium. The new obtained derivatives may be used as drugs, notably as immunomodulators

Description

A PROCESS FOR THE SPECIFIC SYNTHESIS OF NEW DITHIOCARBAMIC ACID ESTERS BY SUBSTITUTION OF HYDROXY LATED SITES ON MONO- OR POLYHYDROXYLATED MOLECULES, PRODUCTS OBTAINED THEREFROM AND THEIR APPLICATIONS This invention relates to a process for specific preparation of new dithiocarbamic acid esters from mono- and polyhydroxylated molecules.

It also relates to products obtained by this process as well as their applications, notably as drugs.

It is known that N,N-dialkyl-dithiocarbamic acids and their salts are used as chelating and complexing agents, notably for transition metals. It is known that these compounds also have interesting biological properties and that they are used as radioprotectors, as antiviral and antitumoral agents.

It is known that the synthesis of dithiocarbamic acid esters can only be made by direct action of dithiocarbamic acids on the OH group(s) of alcohols or 2U polyols.

One of the aims of this invention is to suggest a process for specific preparation of dithiocarbamic acid esters from mono- or polyhydroxylated molecules with high yields even on the secondary hydroxylated, other than anomeric, sites, and which may easily be put into practice.

Another aim of this invention is to provide new dithiocarbamic esters which, through their biological properties, find a particularly interesting application iU as immunomodulating and antiviral drugs.

The inventive process is characterized in that in a preliminary step at least one hydroxy 1 group of mono- or polyhydroxylated molecules is transformed into a leaving group, (Y), and in that this leaving j_5 group (Y) is displaced by the anion wherein R_[ and R2 represent saturated or unsaturated alkyl radicals, substituted or non substituted with carbon groups or heteroatoms, or else forming with the nitrogen atom a saturated 2U or unsaturated ring which may or not bear heteroatoms, and which is introduced as a salt in the appropriate medium.

The leaving group (Y) is preferably made up by an halogenide such as an iodide or else by a sulfonate such as brosylate, tosylate, triflate, imidazole sulfonate .

In order to prepare intermediate products denoted MY resulting from the transformation of hydroxyl groups into leaving groups (Y), one can make use of known processes.

One can use for instance : - for iodized derivatives, the process as described in French Patent Application N° 88 05230 registered April 20, 1988 in the name of the University of Picardy , jlU - for chlorinated and brominated derivatives the process as described by HANESSIAN in Carbohydrate Research 24, p. 45 (1972), - for sulfonic esters, the process as described in French Patent Application N° 88 05231 registered April 20, 1988 in the name of the University of Picardy .

In the case of polyhydrox ylated molecules denoted |Su(OH)n], one may obtain a dithiocarbamatation on one or several hydroxylated sites. If dithio20 carbamatation is desired on one OH site only, one must protect the other OH groups.

As applied to the preparation of dithiocarbamic acid monoesters from polyols [Su(OH)n], the process comprises sequentially : - the selective protection of (n-1) OH groups with the help of a keton or an aldehyde to yield Is u(O-A)n-pOH] , - the tranformation of the OH group into a leaving group (Y) to yield [Su(O- A) n -1~Y1, denoted 3U iSu P-Y], - the esterification by reacting with 1Su P-YJ a sa.lt of dithiocarbamic acid having formula S C - SH, to yield the ester Ξ II Su (0-A) - S - C n - 1 R. - and liberation of previously protected hydroxylated sites in the form of dioxolane.

The regeneration of hydroxylated sites may 5 be a partial or total one so as to obtain dithiocarbamic monesters having different physicalchemical properties, notably as to their solubility in water and oil.

Among polyhydroxylated molecules which are lU particularly suitable for carrying out the invention, are glycerol, galactose, glucose, mannose, fructose, itols and, more generally, mono-, di- or polysaccharides The preparation of dithiocarbamic esters from the halogenide or sulfonate |Su(O-A)n_i - Y) denoted i5 ISu P-Y], comprises the following steps : - contacting the halogenide or sulfonate I Su P-Y], and a salt of dithiocarbamic acid in the presence of a polar aprotic solvent, the acid salt being used in excess to the stcechiometric amount, - eliminating the solvent and absorbing the residue with an organic solvent, - eliminating the residual dithiocarbamic salt, - evaporating the organic phase containing the dithiocarbamic ester, - purifying said ester, - and, perhaps partially or totally deprotecting OH sites which are protected in the form dioxolane.

The dithiocarbamic acid salt which is reacted with intermediary ISu P-Y] is advantageously made up of an alcaline metal salt such as a lithium, sodium, ±0 or potassium salt.

This dithiocarbamic acid salt is added to the polar aprotic solvent in a molar ratio generally between 1.1 and 2, and preferably about 1.5 in relation to the intermediary [Su(O-A)n_i~YJ .

As a polar aprotic solvent, one can use acetone, hexamethyl-phosphorotriamide (HMPA), dimethylformamide (DMF), dimethoxyethane (DME), dimethylsulfoxide (DMSO) or a mixture of these solvents. One can also associate one of these solvents or the mixture of these solvents with another organic solvent which may be an aromatic solvent such as toluene, xylene, benzene or a saturated hydrocarbon, or a mixture of saturated hydrocarbons .

After reacting the dithiocarbamic acid salt with intermediary [Su P-Y1, and eliminating the aprotic solvent, the residue is absorbed by an organic solvent such as ethyl ether which solubiliz es the ester, the unreacted dithiocarbamic acid being eliminated by filtration.

After evaporating the organic phase containing the ester, the later is purified by recrystallization or by silica gel liquid phase chromatography.

In the case where dithiocarbamic esters are obtained by reacting the dithiocarbamic acid salt with a sulfonic ester (the leaving group (Y) is a sulfonate), one carries out a filtration step when the reaction is ended so as to eliminate the saline sulfonate which is formed.

In the case when one starts from polyhydroxylated molecules whose OH sites,which must not be esterified,have been protected, the partial or Ϊ0 total deprotection of these protected OH sites is carried out either in heterogeneous acid-catalysis by passing a solution of the dithiocarbamic ester in a mixture of alcanol/water solvants, in pure alcanol or a mixture of alcanols through a column packed with an acid resin which is maintained at a controlled temperature, or in an homogeneous acidcatalysis in the same solvents in the presence of a strong mineral acid at a concentration between 0.05 and IN, while stirring at the same controlled temperature and during the appropriate length of time. One obtains according to operating conditions, a partial or total deprotection of hydroxyl functions.

The dithiocarbamic esters obtained by the inventive process and which are new esters, present similar properties to that of sodium diethyldithiocarbamate (DEDTC-Na), which is commercially available, but with a delayed therapeutic action, a lesser toxiciry and an administration which is eased by the modulation of chemical and physical properties due to the choice of the starting mono- or polyhydroxylated molecule.

The inventive dithiocarbamic esters find an interesting application in the preparation of immunomodulator products. Such drugs may advantageously be used for the treatment and prevention of diseases linked with immune disorders of the child or infant, and notably mucoviscidosis, recurring respiratory infections, juvenile polyarthritis. These drugs may also be useful in the case of auto-immune adult deseases and notably i0 rhumatoid polyarthritis, systemic lupus erythemato sus, long term or recurring bacterial infections, septic complications of chronic bronchitis, bird short retinopathy and lymphocyte deficiencies.

These dithiocarbamic esters may also be _l5 interestingly applied in the preparation of a drug which is active in the prevention and the treatment of viral diseases, notably those due to HIVi or 2 viruses .

The inventive dithiocarbamic acid esters are administered at doses which are generally between 1 and 500 mg/kg body weight.

The administration of these drugs may be made for example orally, either in the form of a solution or in solid form, for example in the form of gelatin capsules with gastric protection.

A few examples for carrying out the invention are given below as illustrations but not as limitations.

For these examples, the type ISu(OA)η_ι~ΟΗ1 intermediary is either a commercial product or a product prepared by protecting hydroxylated sites in the form of dioxolane from polyhydroxylated [Su(OH)n] molecules according to conventional lit erature methods.

The type [Su P-Yj intermediate is either a tosylate, or a mesylate, a triflate, or an iodide.

The tosylate is prepared according to French Patent 88 05231 : One adds into a flask containing 200 ml of anhydrous acetone maintained at 0°C, 0.1 mol hydroxylated I Su(OA)n_]_-OH ] molecule, 1.11 mol triethylamine and 0.11 mol paratoluene sulfonyl chloride, while stirring. One leaves the mixture to return to room temperature while stirring during hours. The triethylamine hydrochloride cristals are eliminated by filtration. The filtrate is evaporated under reduced pressure, the residue is thrice recristallised in an hexane/ethyl ether mixture, 50/50 (V/V). The pure tosylate yields are between 60 and 90%.

The mesylate is prepared from methane sulfonyle chloride by replacing in the preceeding protocol acetonewith ethyl ether/hexane, 50/50 (V/V) and bringing back the reaction time to one hour instead of 10 hours. When the melting point of the mesylate is low, purification is carried out on silica gel. The pure mesylate yields are between 75 and 95%.

The triflate is prepared according to the method given byFLECHNER (Carbohydrate Research 77 , (19 79), 262-266) by adding ISu(OA)n_g-OH] to a triflic anhydride cooled solution in dichloromethane in the presence of pyridin. After 90 minutes reaction at -10°C, one neutralizes with ΝΑΗΌΟβ, the organic phase is washed with an aqueous 3% HCl solution, and it is purified by silica gel chromatography or by recristallisation.

The iodide is prepared according to French Patent 88 05230 : 0.1 mol [Su(OA)n_i~OH] hydroxylated molecule, 0.105 mol triphenylphosphine and 0.2 mol imidazol are added in a refrigerated flask containing 500 ml xylene. To this mixture, which is brought to 80°C with stirring, are added 0.1 mol iodine, and the whole is brought to reflux during 3 hours. The reaction mixture is then transferred to a 2 liter ιϋ erlen neyer, wherein 500 ml of the saturated HNaCC>3 aqueous solution are added. After stirring during 10 minutes, iodine is added till the organic phase is coloured, then the necessary sodium thiosulfate in aqueous solution is added to observe a decolori15 zation. The organic phase is decanted, dried on Na2SC>4, filtrated and evaporated under reduced pressure. The residue is purified either by two successive recrystallizations in a hexane/ethyl ether mixture, 90/10 (V/V), or by silica gel chromatography.

The yields are between 60 and 90%.

Example 1 : Synthesis of deoxy-1 Ν,Ν-diethyl dithiocarbamate O-isopropylidene-2,3 glycerol from O-isopropylidene2,3 glycerol sulfonate and deoxy-1 iodo-l-O-iso25 propylidene-2,3-glycerol. g (8.2xl0-2mol) of o-isopropylidene-2,3 glycerol tosylate (solketal tosylate) and 27.75 g (12.3χ10-2 mol) of trihydrated sodium Ν,Ν-diethyl dithiocarbamate (DEDTC-Na) are placed in a 1 liter three neck flask containing 500 ml aceton. While stirring, the mixture is brought to reflux ; the progress of the reaction is controlled by HPLC. hours after the beginning of reflux, one observes a solketal-tosylate conversion ratio of 96%.

After return to room temperature, the filtrate 5 containing the diethyldithiocarbamic derivative is filtrated on sinteredN°4, the precipitate being sodium tosylate.

The acetone is eliminated under reduce pressure.

The residue is absorbed with ethyl ether which j.0 selectively solubilizes the ester, the DEDTC-Na being eliminated by filtration.

The ethyl ether is eliminated under reduced pressure, the raw product (24·09 g) which is observed in the form of an oil, is purified by HPLC. j.5 The raw product is introduced into the eluent which is a technical hexane/acetone 93/7 (V/V) mixture on a silica gelcolumn. One obtains 17.85 g (94.2%) of O-isopropylidene-2,3 glycerol Ν,Ν-diethyl dithiocarbamate (solketal DEDTC) in pure form after HPLC, ^H and MNR analysis.

The synthesis was also made according to the above described protocol, from O-isopropylidene-2,3 glycerol mesylate (solketal mesylate). After 24 hours reaction, the yield in solketal diethyldithio25 carbamate is only 40%. By replacing the pure aceton solvent with an aceton/HMPA 80/20 (V/V) mixture one obtains, after 24 hours, a solketal mesylate conversion ratio of 90%.

The synthesis was also made according to the above described protocol from deoxy-1 iodo-1 O-isopropylidene-2 , 3 glycerol (iodo-solketal). After 12 hours refluxing in acetone the conversion of iodo solketal is total. On obtains after purifying 96% solketal Ν,Νdiethyldithiocarbamate . 13 The H and C MNR spectral characteristics of the obtained solketal DEDTC are respectively given in tables I and II.

From tosylate, mesylate and iodo solketal, are prepared, according to the same protocol, deoxy1 N,N dimethyl dithiocarbamate O-isopropylidene 2,3 glycerol (solketal DMDTC) with yields above 90% lO (purity controlled by HPLC and MNR) Example 2 : Synthesis of deoxy-6 N,N-diethyldithiocarbamate di-O-isopropylidene-1,2 : 3,4-a-D galactopyrannose from deoxy-6 iodo-6 di-O-isopropylidene 1,2:3,4-a-D galactopyrannose. g (6.7x10 mol) deoxy-6 iodo-6 di-Oisopropylidene 1,2:3,4-a-D-galactopyrannose (iodo diacetone galactose) and 22.78 g (10.2.10“^mol) DEDTC-Na are placed in a 1 liter three neck flask containing 500 ml aceton. While stirring the mixture is brought to reflux ; control of the reaction in progress is made by HPLC. 24 hours after the beginning of reflux, a total disappearance of iodo diaceton galactose is observed. Acetoneis evaporated under reduced pressure. The residue is absorbed with ethyl ether ; unreacted DEDTC-Na is eliminated by filtration. The filtrate is evaporated under reduced pressure. 26 g raw product are obtained. The purification is carried out through a double ' recrystallization in technical hexane.

One obtains 24.1 g (92%) pure diaceton galactose Ν,Ν-diethyldithiocarbamate after HPLC, ^H and ^^C MNR analyses. on F = 84°C ; lal = 13.6° (CHC13).

D 13 The H and C MNR spectral characteristics of the obtained DEDTC diacetone galactose are given in tables III and IV, respectively.

Example 3 : Synthesis of deoxy-6 N,N-dimethyldithiocarbamate di-O-isopropylidene-1,2:3,4-a-D galactopyrannose from deoxy-6 iodo-6 di-O-isopropylidene 1,2: 3,4-a-D galactopyrannose. 2.9 g (7.84x10 ^mol) deoxy-6 iodo-6 di-O10 isopropylidene 1,2:3,4-a-D galactopyrannose and 2.1 g (11.7 xlO mol) dihydrated sodium dimethyldithiocarbamate in a 100 ml flask containing 58 ml aceton. While stirring, the mixture is brought to reflux.

After 24 hours, the complete disappearance of the substrate is observed, the reaction is stopped, the mixture is extracted according to the above described protocol (example 2). The purification is obtained by a double recrystallization in technical hexane. 2.5 g (87.8 %) pure diacetone galactose N,Ndimethyldithiocarbamate are obtained after and 13C MNR and HPLC analyses.

F = 128-129°C ; [ ot ] = 10.3° (CHCI3) Example 4: Synthesis of deoxy-6 N,N dimethyl dithiocarbamate and deoxy N,N diethyl dithiocarbamate di-O30 isopropylidene 1,2 : 3,4-a-D galactopyrannose from tosylate-6 di-O-isopropylidene 1,2:3,4-a-Dgalactopyrannose (diacetonegalactose tosylate) and corresponding lithium dithiocarbamates.

The lithium N,N dimethyl dithiocarbamate and N, N diethyl dithiocarbamate (DMDTC-Li and DEDTC-Li) are first prepared as follows : to a solution containing 11 g L12SO4 and 45 g DEDTC-Na, 3 H2O in 110 ml water, stirred for 30 minutes, are added 500 ml ethanol/water 95/5 (V/V). The Na2SC>4 precipitate is discarded by filtration. The filtrate which is evaporated under reduced pressure and dried up during 12 hours in a dessicator in the presence of P2°5 yields 34 g DEDTC-Li of a purity above I5 90% after control by flame photometry. A purity above 99% was obtained by passing the above filtrate on an ion exchange column (saturated in lithium ions ).

A solution containing 11 g Li2SC>4 and .8 g DMDTC-Na, 2 H2O treated in the above conditions yields 29.8 g DMDTC-Li of a purity above 90%. The purity above 99% was obtained after passing the filtrate on an ion exchange column.

Preparation of deoxy-6 N,N diethyl dithio25 carbamate-6 di-O-isopropylidene 1,2:3,4-a-D galactopyrannose. 0.10 md diacetone galactose tosylate and O. 13 mol DEDTC-Li are placed in a flask containing 450 ml toluene/HMPA 66/34 (v/v) solvent, after 2 hours reaction with stirring at 110 °C, extraction and purification, the product is obtained with a 94% yield Preparation of deoxy-6 N,N dimethyl dithiocarbamate-6 di-O-isopropylidene l,2;3,4-a-D galactopyrannose. 0,10 mol diacetonegalactose tosylate and 0.13 5 mol DMDTC-Li are treated as above. After purification, the product is obtained with a 93.5% yield.

Example 5 : Synthesis of deoxy-3 N,N diethyldithiocarbamate di-O-isopropylidene-1,2:5,6-a-D glucofurannose from deoxy-3 iodo-3 di-O-isopropylidene-1,2:5,6-a-D allofurannose. g (2.7χ10~2 mol) deoxy-3 iodo-3 di-Oisopropylidene-1, 2 : 5 , 6-a-D allofurannose and 12.18 g (5.4x10 mol) trihydrated sodium N,N-diethyldithio5 carbamate (DEDTC-Na) are placed in a 250 ml three neck flask containing 150 ml hexamethyl phosphorotriamide (HMPA). While stirring, the mixture is brought to 60°C. The reaction is stopped after 24 hours reaction, the conversion being 95% after HPLC control.

An hexane/ethyl ether 90/10 (V/V) mixture is added to the reaction medium, then the resulting mixture is washed with iced water. The aqueous phase is dried up on anhydrous sodium sulfate and evaporated under reduced pressure. 18 g raw product are obtained. >5 Purification is obtained by passing on a silica column; after elution with an hexane/ethyl ether 85/15 (V/V) mixture, 8.6 g (87%) pure diacetone glucose N,N-diethyldithiocarbamate are isolated after HPLC, 1 H and q mNR analyses.

F = 83-84°C ; [a]* = 44.3° (CHCl3) 13 Tables V and VI respectively give H and C MNR spectral characteristics of the obtained diaceton glucose DEDTC.

By replacing pure HMPA solvent with an aceton/ HMPA 50/50 (V/V), mixture one obtains after 48 hours, a conversion ratio of iodo diaceton allose of 85%.

By replacing the HMPA solvent with toluene/HMPA (50/50) (v/v) mixture, one obtains after 18 hours at 110°C an iodo-diacetoneallose conversion ratio of 96%. lO The dimethyls are obtained with the DMDTC salts.

By operating in the toluene/HMPA (50/50)(v/v) mixture and by replacing DEDTC-Na with the corresponding lithium salt one obtains after 2 hours at 110 °C an iodo-diacetoneallose conversion ratio of 85%. ±5 By taking trifluoromethyl sulfonate-3 di-Oisopropylidene 1,2:5,6 α-D glucofurannose in the place of iodo-3 diacetone allose and by operating in the HMPA/toluene (50/50) (v/v) mixture with DEDTC-Li in % excess, one obtains deoxy-3 diethyl dithio20 carbamate-3 di-O-isopropylidene 1,2:5,6 α-D alloturannose.

Example 6 : Preparation of deoxy-1 N,N diethyl dithiocarbamate di-O-isopropylidene 2,3 α-D fructopyrannose (diaceton fructose DEDTC) : 0.1 mol deoxy-1 iodo-1 di-O-isopropylidene 2,3 : 4,5 α-D fructopyrannose (iodo diaceton fructose) and 0.13 mol DEDTC-Na are placed in a flask containing 250 ml HMPA. After 8 hours reaction at 70°C the conversion ratio of iodo diacetone fructose is 88%, after extraction and purification, the product is obtained with a 74% yield. [a]^° = -5,02° (CHC13) F = 100°C Pi Tne ^H and MNR spectra are given in tables VII and VIII.

By operating with the HMPA/toluene (50/50) (v/v) mixture at 110 °C, the conversion ratio of iodo diaceton fructose is 82% after 18 hours reaction.

Example 7 : Products obtained by deprotection of hydroxylated sites .

The deprotection of products of the formula Su-(OA)n .-S n-1 S J II / •C-N j.5 was carried out in ethanol/water 95/5 (V/V) by acidcatalysis either in heterogeneous phase on an AMBERLIST 11+ Wet (ROHM & HAAS)column or in homogeneous phase in the presence of H2SO4 at a concentration of 0.2N - Preparation in heterogeneous phase of deoxy1 Ν,Ν-diethyl dithiocarbamate-1 glycerol (DEDTCglycerol) from deoxy-1 N,N(diethyl dithiocarbamate-1 O-isopropylidene-2,3 glycerol (DEDTC-solketal) and deoxy1 N,N dimethyl dithiocarbamate-1 glycerol (DMDTCglycerol) from deoxy-1 N,N dimethyl dithiocarbamate1 O-isopropylidene 2,3 glycerol (DMDTC solketal).

A solution of 10 g DEDTC-solketal in 100 ml 95° alcohol, is passed with a flow rate of 2 ml/minute on the thermostated 65°C column containing 100 g AMBERLIST H+ resin. The colon is rinsed with 100 ml 95° alcohol. After evaporating the solvent and purifying on silica gel, 50/50 (V/V) 8.4 g DEDTC glycerol are obtained (92% yield), a liquid at room temperature, pure after HPLC,, and 12C MNR analyses. [n]°0 = 1-5803. 13 The H and C MNR spectral characteristics of obtained glycerol DEDTC are given in tables IX and X, respectively.

Under the same conditions, DMDTC glycerol is obtained from DMDTC solketal with an 88% yield.

Preparation of di-O-butanoyl-2,3-deoxy-l N,N diethyl dithiocarbamate-1 glycerol (DEDTC glycerol dibutyrate). 1.5 x 10“2 mol DEDTC glycerol are placed in 15 ml pyridine/toluene (-50/50) (v/v) mixture and 3.0 x 10~2 mol butyryl chloride dissolved in 10 ml toluene are added dropwise while stirring ; after hours reaction at room temperature, the reaction mix ture is washed once with a IN HCl aqueous solution and twice with water, the organic phase is dried on Na2SC>4 then evaporated, the residue is purified on silica gel with the technical acetone/hexane mixture as an eluent. After purification, an 80% yield is obtained.

In)20 = 1.5142 -1 13 H and C MNR spectr a are given in tables XI and XII.

Preparation of di-0-palmitoyl-2,3 deoxy-1 N,N diethyl dithiocarbamate-1 glycerol (DEDTC glycerol dipalmitate).

One proceeds under the same conditions as for 5 DEDTC glycerol dibutyrate. The residue, after extraction and evaporation of the solvent, is purified by recrystallization in technical hexane.

An 88% yield is obtained. 13 The H and C MNR spectra are given in tables 10 XV and XVI.

-Preparation in heterogeneous phase of deoxy-3 N,N diethyl dithiocarbamate-3 O-isopropylidene1,2 α-D-glucofurannose (DEDTC-MaGlu) and deoxy-3 N;N diethyl dithiocarbamate -3 D-glucopyrannose (DEDTC glucose) from deoxy-3 N,N diethyl dithiocarbamate-3 di O-isopropylidene 1,2:5,6 α-glucofurannose (DEDTCDAGlu).

The deprotection of hydroxylated sites by scid catalysis on a H resin column was carried out under the same solvent concentration, flow rate, and temperature conditions as above. After ringing the column with 95° alcohol and evaporating the solvent one obtains from 10 g starting product 8.5 g raw product. Silica gel chromatography (60 g) yields 3 fractions : -0.58 g (5.8%) starting product, eluated with the hexane/aceton, 85/15 (V/V) mixture. -6.8 g (75%) DEDTC-MAGlu, eluated with the hexane/aceton, 70/30 (V/V) mixture, pure after HPLC, ''Η and ''^C MNR analyses.

F = 78-80°C, [alp = + 90.8 (CHCI3) - 0.6 g (7.5%) DEDTC glucose, eluated with acetone alone, pure after HPLC analysis.

For a given starting substrate concentration and a given amount of resin, the proportion of totally unprotected derivative, (DEDTC glucose) may be increased at the expense of the monodeprotected derivative (DEDTC-MAGlu) by lowering the flow rate and/or increasing the temperature ; for instance at 70°C with a flow rate of 0.5 ml/minute, one obtains the complete disappearing of the starting products and the DEDTCMAGlu and DEDTC-glucose products in the proportion of 30/70.

The same operating conditions allowed one to prepare deoxy-3 N;N dimethyl dithiocarbamate-3 015 isopropylidene 1,2 α-D glucofurannose (DMDTC-MAGlu) and deoxy-3 N,N dimethyl dithiocarbamate-3 D glucopyrannose (DMDTC-glucose) from DMDTC diacetone glucose with similar yields.

- Preparation in homogeneous phase, in the presence of H2SO4 of DEDTC-MAGlu and DEDTC-glucose from DEDTC-DAGlu.

Deprotection of hydroxylated sites by acid catalysis in the presence of 0.2N H2SO4 was carried out in 95° ethanol at the controlled temperature of 50°C, from 10 g DEDTC-DAGlu (25.5 mmol) in 100 ml solvent, while stirring. After one hour, 96% of the substrate having reacted, one proceeds to a neutralization at pH 7, with 8N caustic soda lye.

The formed sodium sulfate is filtrated on sintered felt number 4 and the evaporated filtrate gives 8.3 g of a raw product which is subjected to a chromatography as above, to yield : - 0.35 g (3.5%) starting product ; - 6.3 g (70%) pure DEDTC-MAGlu ; - 0.5 g (6%) pure DEDTC-Glu.

By carrying out for 20 hours the acid catalysis 5 under the same temperature, solvent and acidity conditions, the deprotection of hydroxylated sites of DEDTC-DAGlu is obtained in a proportion above 90%, but the percentage of DEDTC-Glu does not exceeds 60%, while such a reaction time triggers a degradation of the product by the solvent. 13 The H and C MNR spectral characteristics of the obtained monoacetoneglucose (DEDTC-MAGlu) are respectively given in tables XV and XVI.

The C MNR spectral characteristic of the _L5 obtained glucose DEDTC are given in table XVII.

Example 8 : Preparation in pseudohomogeneous phase of deoxy-6 Ν,Ν-diethyl dithiocarbamate D-galactopyrannose (DEDTC- galactose) and deoxy-5 N,N dimethyl dithiocarbamate D-galactopyrannose (DMDTC-galactose). _2 M DEDTC-diaceton galactose are added into a flask containing 40 ml dioxane and 10 ml 12N aqueous HC1.

After stirring during 1 hour at 50°C, the 25 solution becomes limpid and the DEDTC diaceton galactose totally disappeared after thin layer chromatography controls. One then proceeds to neutralization by slowly adding triethylamine (TEA) and the TEA hydrochloride precipitate is separated by filtration.

The filtrate is then evaporated and absorbed with water to precipitatethe expected product. The DEDTC13 galactose is obtained with a 60% yield. The C MNR spectrum is given in table XVIII.

DMDTC-galactose is obtained under the same operating conditions with a 58% yield.

The same process may be applied to the preparation of deoxy-1 N,N diethyl (dimethyl) dithiocarbamate of glucose, fructose, mannose or other monosaccharides from di-O-isopropylidene precursors.

Example 9 : The biological properties, (mice LD50) of dithiocarbamic esters described in examples 2,3,4, and 8, are compared with those of saline diethyldithiocarbamate DEDTC-Na, commercially available.

The obtained results are given in table XIX.

One may conclude from these results that the inventive dithiocarbamic acid esters have a notably lower toxicity than the commercially available DEDTC-Na.

Furthermore, it turns out that the intermediate lithium dithiocarbamates products, notably lithium dimethyldithiocarbamate and lithium diethyldithiocarbamate are very active, have a very low toxicity and may be used pure or associated, as drugs for the same applications, for example with similar doses to those which are used in the case of sodium DEDTC.

The use of lithium dithiocarbamates in the process for the preparation of inventive esters is preferred to that of other saline dithiocarbamates because the reactions are quicker at lower temperature, and one can use a wider range of solvents.

TABLE I MNR SPECTRUM OF SOLKETAL DEDTC FORMULA H I H-Cr- S R II H—C2 °'C'CHj H—€-Oz 'cHj r H S CH.-CH, t *ω-ι w C-N s CH.-CH, Ld Li PROTONS Nature of the signal δ inpD^/TMS in COCl^ Coupling constants : H-l d1 3.58 3 1-.-2 =5,9 ' ’. H - 1 1 : H'2 m 4 .41 0 2-3 =6,1 : h-3 dd 4 ,10 3 3-3'=8. - H - 3 ’ dd r 3 - 74 • • ch3 i 5 1 ,-44 : CH3i' s 1. 34 : CH2< ΩΊ) m 3.98 3 = 7.3 m 3.68 3 = 7 • CH3 Ω t 1. 30 3 = 7.2 • CH3 Ω t 1, 27 3 = 7.1 FORMULA TABLE II C MNR SPECTRUM OF SOLKETAL DEDTC CARBONS ό inppm/TMS in. CDC13 H I H-C-S R IIH”^3”°Z 'CH> H ( ( ( ( ( ( ( ( ( ( ( ( (· S CH-CH, / *ίχΙ·1 W R= C-N 'CHrCH, wli ( Ω-1) CH2 < Ω ' - 1 ) CH3( Ω) CH^(Ω’) cs. 9_. 9 9 4. 41 6.42 109.29 26,61-25.40 49, 67 46. 44 12c 42 11,. 4 1 194,51 TABLE III 1H mnr SPECTRUM OF DEDTC PIACETONEGALACTOSE (DETTC-DAGal) ( ( FORMULA ( ( ( ................

( ( ( CH-rCHj B= c-N'CH:-ch, . ( ( ( ( ( ( ( ( ( (· ( ( t PROTONS Nature of the signal δ in ppm/lMS in COClj Coupling constants 1 H- 1 d 5. 51 J 1-2 = 5 H-2 q 4.29 02-3=2-4 H-3 q 4.62 0 3-a = 7.95 H - A q 4.24 0 A-5 = 1.8 H-5 hex 3.92 0 5-0 = 6 »6 Η * o q 3 ·31 0 ό -6 ' LJ Z / 0 5-6 = 6 .9 H · o 3 >63 s 1.31 4CH, s 1, 36 s 1 .47 ( isoprop .) s 1. 48 CH2( Ω-1) q 3 -72 CH2(Ω'-1) q 4.08 CH3( Ω ) t 1- 24 οη3(ω ·) t 1-29 3 β - Ω-1 =7 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) i ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) TABLE IV C MNR SPECTRUM OF DIACETONEGALACTOSE DEDTC FORMULA CARBONS δ in ppm/TMS in CDC1, ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (· ( ( ( 96.48 70.90 70,56 6 6 ? 7 6 72.37 36.88 ) ) ) ) -) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) S CH-CH, it / “ω ω R= C-N CHfCH, , w'-i w C-7 C-8 4CH3( isoprop .) 109 .27 108,78 24,37-25 05-25.90 25.90 CS.

CH2( Ω-1) CH2(2'-1) CH.

CH. 195, 27 49*38 46.70 12.45 11» 43 TABLE V ~*~H MNR SPECTRUM OF DEDTC DIACETONEGLUCOSE (DEDTC-DAGlu) TABLE VI MNR SPECTRUM OF DIACETONSGLUCOSE DEDTC (DEDTC-DAGlu) ( ( ( (· ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( { ( ( ( ( ( ( ( ( ( ( ( ( ( (· ( ( ( FORMULA CARBONS S · CH.-CH, N / Λ it) R= C-N 'CH.-CH, ω-ι ω' 6in ppm/TMS in CDCl 3 e-i C-2 C-3 C-4 C-5 C-6 104.47 86.69 57.12 78. 96 73· 87 67· 44 C-7 112.12 C-8 109.45 4CH. fisoprop . ) 26.29-26 .52—25.20- ....._2.6,7_4_............ CH2( Ω-1) 49. 29 CH2(fl'-l) 46.63 CH3( Ω) 12. 44 CH3(«’) 11.43 CS2 191.92 TABLE VII 1H MNR SPECTRUM OF DEDTC-1 of DIACETONE FRUCTOSE FORMULA Nature PROTONS Qf the signal in ppm/TMS Coupling Constants in CDC13 ; (I) Hl HI’ H3 H4 H5 H6 H6’ 2CH, R — C N'CH l CH 3 UN'CH2-CK3 j-u-i Λ CH, CH, ch3-ch2 ch3-ch2 d 3-81 . J1.2-1,2Hz d 4,29 J3-4-2.5 dd 4.52 J4-3-2.4 J4-5-7.9 dd 4*16 J5-6-1.9 J5-4=7,9 dd 3,81 J5-6=1.9 J5-6’=0,7 dd 3.69 J6-6’=13.5 s 1.46 s 1,39 s 1,28 m 1.23 jn-to-D - 1.21 computable m 3,92 jn-Cn-D - computable TABLE VIII 13C MNR SPECTRUM OF DEDTC-1 OF DIACETONE FRUCTOSE FORMULA inppm/IMS CARBON in CDClj R- £hrCH2-CH3 K_ U'CH2-CH3 C1 46.49C2 102.68C3 ' 73,16C4 70,43C5 70,43C6 ' 61,39 109.01 108.38 % 26,29 ch3 25,88 ch3 25.08 ch3 24.04 CVC^ 12.50 11,47 CHj-CHz 49,67 46.69 cs2 195.29 TABLE IX 1H MNR SPECTRUM OF THE DEDTC GLYCEROL ( ( ( ( ( (-( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( < ( ( ( ( ( ( ( ( _ FORMULA PROTONS Nature of the signal δ in pp«/ TMS in CDClj Coupling Constants (j) H H-l H-l ’ (Π 3.53-3.66 □ 3 1-1 ’ 1-2 H-C.-S R H-2 m 3.9 3 • 14-2 | 1 h-c2-0 H H-3 dd 3.44 3 2-.3 H—C—OH I3 H H-3 ' dd 3.49 3 2-3’ / S CH,-CHj It / <*> R= C-N sCHfCH3 ω'-ι cfi2(n -1) d 3. 98 3 = 7.1 CH2 (Ω -1) q 3.73CH3 t 1.26 CH3 Ω t 1.22 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) TABLE X 13C MNR SPECTRUM OF DEDTC GLYCEROL ( ( ( ( (( ( ( ( ( ( ( ( ( ( ( f ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (·· ( ( ( FORMULA CARBONS δ in ppm/TMS in CDClj . Η I C-l ' · 39- 06 * H-C-SR I1 C-2 71.36 H-C-0 H H—C—OH C-3 64 .51 |3 H R= I-N CH,-CH, * ω-1 ω . ’ω' ω-1 CH2(n-i) 50 .16 CH2(n·-l) 47,07 ch3 Ω 12.38 CH3 Ω' 11,47 CS2 195,75 TABLE XI MNR SPECTRUM OF DIBUTYRATE DEDTC GLYCEROL FORMUIA 11 CH,-CH, h2c scKch’.ch’ < 12 J M' 11 15 HC—OCCh^CHiCHj O ( 1O1o' 12 13 H2C—OCCHiCHjCHj O PROTONS Nature of the signal H-1 dd H-1 ’ ' dd H2 m H-3 ./ H-3’ dd H-7,7’ qb H-8,8’ qb H-9,9’ t H-10,10’ t ‘H-11 11’, 12 12? h CH3C13) , CHj C14) m ’ CH3(15) , CHjCW m : inppm/TMS in CDClj Coupling Constants ¢1) 3.63' J1-V-14. 2 J1-2 -4.9 3.35 * · J1-1’-14.1 J1 ’-2-7,4 5,17 4.23 J3-3’«11.9 J3-2-3.5 4.02 J3-2=3.5 3.86 J=6.8 3-59 J-6.8 2.15 J-7.39 2.14 J-7,31 1.50 J-7.38 1.13 ; 1.11 J-6.81 0,795 J-7.31 ; 7.35 TABLE XII 13C MNR SPECTRUM OF DEDTC GLYCEROL DIBUTYRATE FORMULA δ 'inppm/IMS CARBON inCDClj S, 7 11 HC—SC N'CHj'CHj H2C 5CN.Ch2.CH3 < 12 S M 11 15 HC—OC CHjCHjCH, O β 1010* 12 13 H2C—OC CH2CH2CH, O cr 37.23C2 . 69.83C3 63.68c6«0 172.85C5=0 172.34C4 193.67 CH2C7) 49-76 CH2C8) 46.64 CH2(9) 35.95 0^(10) 35.78 ch2cio 18,22 CH2(12) CHjCW 12.36 CH3C14) .11.34 CH3(15) 13.46 CH3C16) TABLE XIII FORMULA MNR SPECTRUM OF DEDTC GLYCEROL DIPALMITATE PROTONS Nature of the signal δ in ppm/TMS in CDC13 Coupling Constants CO HC— I 11 J ] » 13 11*11 HC—OCCH,CH,(CH,)CHjCH,CH, ' II u it » O . 1 11« 1« 17*11 HC—OCCHjCHjfcHJCHjCHjCH, II 17 11 41 H-1 dd 3,74 J1-1’«14.0 J1-2-5.0 H-1 ’ dd 3.46 J1’-1«14.2 J1’-2-7.4 H-2 m 5,28 H-3 dd 4,33 J3-3’=12.1 J3-2=3 .6 H-3’ dd 4.13 J3’-3-12.0 J3’2=5.7 H-7 and H-7’ qb 3.97 J-7.0 H-8andH-8’ qb 3,69 J-6.8 H-9 and H-9’ m 2,27 J-7,5 H-10 and H-10’ m 2.26 J-7-4 TABLE XIV 13C MNR SPECTRUM OF DEDTC GLYCEROL DIPALMITATE FORMULA CARBON δ in ppm/IMS in CDClj hc-scfA^1 H2C-5CNCHj.CHj S IS *24 HC—OCCH^CH^CHjJCHjCHjCH, 2« 31 o « t« U 27-»« H C—OC CH, CH JCH ,)CHXCH ,CH, 3 II 27 3« «· o c-i 37.39C2 69.95C3 63.84 c6=o 173.29cs=0 172.74 C4»5 193.90 CH2 (9) 34.25 CH2 (10) 34 .87 CH2 (13and 14) 31 .85 CH7 (15 to 24 and Z 27and36) 29.61 to28.95 CH2 (25and 37) 24.87 CH2 (26 and 38) 22.62 CH3 (39 and 40) 14.04 CH2 (7) 49.87 CH2 (8) 46. 69 ch3 (11) 12.45 CH, (12) 11.45 TABLE XV H MNR SPECTRUM OF DEDTC-3 MONOACETONE GLUCOSE (DEDTC-MAGlu) ( J FORMULA ( ( (.................

( ( ( CH,-CH, _ I» R= C-N ω-ι ω-ι PROTONS Nature of the signal δ in ppmr/TMS in COCl^ Coupling (I) Constants H- 1 d 5,73 1 ^2 = 3.6 H-2 d 4.73J 2-3 = 0.6 H-3 dd 4.83J 3-4 = 3.4 H-A dd 4.35J 4’5 8. 8 H-5 J 5-0 H - δ m .3.55-3,87 0 δ -s' / H- 0 5-0' 2CH3 s 1 .26 (Isoprop . ) s 1,49 CH?( Ω-1) qd 3.93 CH2(H'-1) qd 4,00 .CH3( Ω) t 1.23 CH, (£2 ’) t 1,26 3Ω- Ω-1 = 7.1 3 • OH. . s 3.46 . 5 °H6 s 2.51 TABLE XVI C MNR SPECTRUM OF DEDTC-3 MONOACETONE’ GLUCOSE (DEDTC-MAGlu) ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (· ( ( ( FORMULAE 'CARBONS δ in ppm/TMS -in CDC13 CH.-CH, R= C-N 'CH.-CH, , ω'-ι ω C -1 ' 104.47 C -2 85-86 C-3 58.69 C -4 78 - 98 C *5/' 70.30 C -6 64.13 C -7 112.26 2CH3( isoprop . ) 26.24-26 .42 CH2( Ω-1) 47. 41 CH2(fl’-l) 50.34 CH3( Ω) 11.46 CH3(Ω * ) 12 ,49 CS2 192.73 ) ) ) ) -) J ) ) ) ) .) ) ) ) ) ) ) ) -) ) ) ) ) ) ) ) -) ) ) ) ) ) ) ) ) ) ) ) TABLE XVII 13< MNR SPECTRUM OF GLUCOSE DEDTC FORMULA CARBONS δ in ppm/TMS in CDCl^ 91.77 '98,11 p S CH.-CH, R= C-N 70,72 70.14 57. 38 59.90 69.93 73.15 72,44 (<*, fl ) W-l ω cu * c, 0 62.18 > ) 61,96 !CS2 ) 196.36 } 195-99 ) CH2(n-i) 50.37 j ) CH2(SI’ -1) J 47 .84 ) ) CH3 Ω ) 11.62 > CH3 β’ 12.57 TABLE XVIII 13C MNR SPECTRUM OF GALACTOSE DEDTC-6 δ in ppm/IMS FORMULA CARBON in CDClj r = cN'CHfCH, v'CH2-CH, _Λ.-ί Λ β Form C1 • 99:36C2 74,52C3 75.57C4 72.53CS 76,48C6 ' 39.39 c - s » 197.33 FormC1 95.24C2 73.04C3 71 ·01C4 72.53C5 71.96C6 39.51 O S 197.33 nd a Forms ch2 53,16 50.55 CH3 14.25 CH ’ 13,64 TABLE XIX MICE LD50 • SOLVENT P.O. Cg/kg) I.P. CgAg) DEDTC-Na commercial water DMSO 1 4.00 ± 0.32 1.90 ± 0.34 1 „5 1.15 ± 0.01 DEDTC diacetone glucose DMSO > 8 4 20 */0.48 DEDTC diacetone galactose DMSO > 8 2 65 ± 0.53 DMDTC diacetone galactose DMSO > 8 2.15 ± 0.35 DMDTC glycerol DMSO 4.00 ± 0.30 1.4 ± 0.28 Dipalmitate DEDTC glycerol DMSO > 8 4.2 ± 0,46 Dibutyrate DEDTC glycerol DMSO > 8 3.5 ± 0.42

Claims (41)

1. A process for preparation of dithiocarbamic acid esters having the formula s II c - SH in which and R2 are saturated or unsaturated alkyl radicals, which may be substituted with carbon groups or heteroatoms or else forming with the nitrogen atom a saturated or unsaturated ring which may bear heteroatoms from alcohols or polyols, characterized in that at least one hydroxylated group of mono- or polyhydroxylated molecule is transformed in a preliminary step into a leaving group (Y) and in that the leaving group (Y) is displaced with the anion R. Rz S II C wherein R]_ and R2 have the above quoted meaning, as introduced in the form of a salt in the 15 appropriate medium, and in that the leaving group (Y, may be an iodide or a tosylate or a brosylate or a triflate or an imidazole sulfonate which, notably in the case of mono- or di-saccharides, may be grafted unto a secondary site other than anomeric as well as unto a primary or anomeric site.

2. A process according to claim 1, characterized in that, when it is applied to the preparation of a dithiocarbamic acid monoester from polyols, denoted 5 [Su(OH) n ], the process comprises the sequence of following steps: - selective protection of (n-1) OH groups to give 1 Su(O-A) n _j_-OH J , preferably in the form of dioxolane, - transformation of the OH group into a leaving 10 group (Y) to yield [ Su(O-A) n _j_-Yi , denoted I Su P-Y] - esterification through the action of a salt preferably a lithium salt, of dithiocarbamic acid R.» N - C - SH R. on ISu(O-A) n _i~Y] denoted [Su P-Y] which yields Su (0-A) n _ 1 ~ S S II c R. 15 - and partial or total regeneration of protected selected sites.

3. A process according to any of claims 1 and 2, characterized in that the leaving group (Y) is made up by an halogenide. 20

4. A process according to claim 3, characterized in that the halogenide is iodide.

5. A process according to any of claims 1 and 2, characterized in that the leaving group (Y) is made up by a sulfonate.

6. A process according to claim 5, characterized in that the sulfonate is chosen among the group made up by brosylates, tosylates, triflates, imidazole sulfonates . 5

7. A process according to any of claims 1 to 6, characterized in that the preparation of the dithiocarbamic ester includes the following steps : - contacting the intermediate (Su P-Y] and a dithiocarbamic acid salt R- S \ |i N - C - ΞΗ / R 2 in the presence of a polar aprotic solvent, the dithiocarbamic acid salt being used in excess to the stoschiometric amount, - reacting the mixture while stirring during the necessary time to yield a conversion ratio of 15 [Su(O-A) n _i-Y] denoted [Su P-YI above 95%, - eliminating the polar aprotic solvent, - absorbing the residue by an organic solvent, - eliminating the residual dithiocarbamic acid salt, - evaporating the organic phase containing the dithiocarbamic ester, - purifying this ester.

8. A process according to claim 7, characterized in that the dithiocarbamic acid salt is an alcaline metal salt.

9. A process according to claim 8, characterized in that the alcaline metal salt of the dithiocarbamic acid is the lithium, sodium or potassium salt.

10. A process according to any of claims 7-9, characterized in that the dithiocarbamic acid salt is added to the polar aprotic solvent in a molar ratio generally between 1.1 and 2, and preferably about 1.5 5 to the intermediate iSu(O-A) n _q-Y] denoted [Su P-Y].

11. A process according to any of claims 7-10, characterized in that the polar aprotic solvent is chosen among the group made up of aceton, hexamethyl phosphorotriamide, dimethylformamide, dimerhoxyethane, 10 dimethylsulfoxide or else a mixture of these solvents.

12. A process according to any of claims 7-11, characterized in that the polar aprotic solvent or mixture of polar aprotic solvents is associated with another organic solvent. 15

13. A process according to claim 12, characterized in that the organic solvent associated with the polar aprotic solvent is an aromatic solvent such as toluene, xylene, benzene.

14. A process according to claim 12, characteri20 zed in that the organic solvent associated with the polar aprotic solvent is a saturated hydrocarbon or else a mixture of saturated hydrocarbons.

15. A process according to claim 7, characterized in that the organic solvent into which the 25 residue is absorbed, after eliminating the polar aprotic solvent is ethyl ether.

16. A process according to claim 7, characterized in that the residual dithiocarbamic acid salt is eliminated by filtration after absorbing 30 the residue in the organic solvent;

17. A process according to claim 7, characterized in that the dithiocarbamic ester is purified by recrystallization or by silica gel liquid phase chromatography.

18. A process according to claim 7, characterized, in the case of sulfonic esters, in that one carries out a filtration as to eliminate the sulfonate which is formed.

19. A process according to any of claims 1 and 2, characterized in that the polyol Su(OH) is chosen among glycerol, glucose, galactose, mannose, fructose, itols or mono-, di- or polysaccharides.

20. A process according to any of preceeding claims, characterized in that it comprises the selective or total deprotection of protected OH sites of the dithiocarbamic ester by homogeneous acid catalysis in a water/alcanol mixture, in pure alcanol or in J-5 a mixture of alcanol or by acid catalysis in pseudohomogeneous phase or in heterogeneous phase on a resin.

21. A process according to claim 20, characterized in that the selective or total deprotection of protected OH sites of the dithiocarbamic 20 ester is carried out by passing a solution of the dithiocarbamic ester in a water/alcanol solvent mixture, in pure alcanol or in a mixture of alcanols on a column packed with an acid resin maintained at a controlled temperature. 25

22. Dithiocarbamic acid esters having the formula SH in which Rp and R2 are saturated or unsaturated alkyl radicals, which may be substituted with carbon groups or heteroatoms, or forming with the nitrogen atom a saturated or unsaturated ring which may bear 5 heteroatoms and glycerol, in the acetal or deprotected form, excluding glycerol DEDTC.

23. Dithiocarbamic acid esters having the formula S ii C - SH in which R^ and R2 have the above meaning and galactose, in the forme of acetal or deprotected, excluding diaceton galactose DMDTC.

24. Dithiocarbamic acid esters having the formula R 1 S \ II in which R]_ and R2 have the above meaning,and glucose 15 in the form of acetal,or deprotected.

25. Dithiocarbamic acid esters having the formula h C - SH in which R^ and R2 have the above meaning and itols, in the acetal or deprotected form.

26. Deoxy-1 Ν,Ν-diethyl dithiocarbamate-1 0isopropylidene-2,3 glycerol. 5

27. Deoxy-1 Ν,Ν-dimethyl dithiocarbamate-1 glycerol.

28. Di-O-butanoyl (or palmitoyl)-2,3 deoxy-1 N,N diethyl (or dimethyl)dithiocarbamate-l-glycerols.

29. Deoxy-3 diethyl (or dimethyl) dithio1θ carbamate-3 di-O-isopropylidene 1,2:5,6°<-D allofurannoses

30. Deoxy-1 N,N diethyl dithiocarbamate-1 di-Oisopropylidene 2,3 : 4,5*-D fructopyrannose.

31. Deoxy-6 Ν,Ν-diethyl dithiocarbamate-6 diO-isopropylidene-1 , 2 : 3,4 - 15

32. Deoxy-3 Ν,Ν-diethyl (or dimethyl) dithiocarbamate-3 di-O-isopropylidene-1,2 : 5,5-«*D glucofurannoses.

33. Deoxy-3 Ν,Ν-diethyl (or dimethyl) dithiocarbamate-3 O-isopropylidene l,2-o(-D glucofuran20 noses.

34. Deoxy-3 Ν,Ν-diethyl (or dimethyl) dithiocarbamate-3 D-glucopyrannoses.

35. Immunomodulating drug characterized in that it contains as an active substance one of the -5 dithiocarbamic esters as defined in claims 22 to 34.

36. A drug for the treatment of viral diseases, notably those that are due to HIV A or 2 viruses, characterized in that it contains as an active substance one of the dithiocarbamic esters '0 as defined in claims 22 to 34.

37. Lithium dithiocarbamates, including the DMDTC-Li and DEDTC-Li;

38. Immunomodulating drug characterized in that it contains as an active substance a compound according to claim 37.

39. A drug for the treatment of viral diseases 5 notably those due to HIV 1 ou 2 viruses, characterized in that it contains as an active substance a compound according to claim 37.

40. A process for the preparation of compounds of the formula stated in claim 1, substantially as hereinbefore described by way of Example.

41. Compounds of the formula stated in claim 1, whenever prepared by a process as claimed in any of claims 1 to 21 or 40.