CH623060A5 - Process for the preparation of monosaccharides substituted by an ether functional group - Google Patents

Description

The present invention relates to a process for the preparation of monosaccharides substituted with an ether function from particular monosaccharide derivatives. It also relates to a process for partial or total hydrolysis of the monosaccharide derivatives with ether function obtained.

United States Patent Applications Nos. 337,134 and 424,786 filed March 1, 1973 and December 14, 1973 by Paul Gordon describe certain monoethers of monosaccharides and monosaccharide derivatives, respectively. These compounds give important biological signals that allow living cells to resist viral infections. The compounds are also useful in other types of cellular chemical reactions, for example implemented for the formation of memory.

The synthesis of the abovementioned compounds cannot be carried out conveniently, with an acceptable yield and a sufficiently high purity for pharmaceutical applications, by the very commonly used method of synthesis of ethers, that is to say the Williamson synthesis. For example, this synthesis has significant drawbacks when preparing 3-0-ethers of protected monosaccharides such as 1,2: 5,6-di-O-isopropylidene-D-glucose, in part because of the problems stereochemicals that arise. The only secondary hydroxyl group available in 1,2,2,6,6-di-0-isopropylidene-D-20 glucose is so sterically hindered that it cannot react at a rate that can be practically used with metallic sodium for formation of a sodium salt. In addition, the sodium salt formed is almost insoluble in the solvents commonly used in Williamson synthesis, such as ethyl ether or benzene. The handling and preparation of the metallic sodium necessary for the synthesis of large amounts of 3-0 -ethers of protected monosaccharides and the rejection of excess sodium after the end of the reaction also present significant dangers.

The second step of a Williamson synthesis, comprising the condensation of an alkyl halide with the sodium salt, is effective and gives high yields. However, the preparation of alkylamino ethers of monosaccharides poses other problems. The aminoalkyl halide used for the condensation step must be in the form of the free amine and not of the corresponding salt of a mineral acid. Many aminoalkyl halides are volatile and very toxic when in the form of a free amine, but they are not when they are in the form of a salt of a mineral acid. A completely satisfactory process for synthesizing the 3-O-ethers of the monosaccharides must therefore allow the use of the aminoalkyl halide in the form of a salt of a mineral acid, avoiding the disadvantages of volatility and toxicity.

45 U.S. Patent No. 2,715,121 describes another process for condensing organic halides with protected monosaccharides. This process comprises the autoclave treatment of the reaction mixture, at elevated temperature and under a pressure imposed by water vapor and, when this process is used for the preparation of alkylamino ethers of monosaccharides, yields are obtained low in impure secondary products given the preponderance of auxiliary reactions and the synthesis of different products. Separation of a substantially pure ether of monosaccharides from the reaction mixture with a sufficiently small amount of impurities for use in the therapeutic treatment of warm-blooded animals is also very difficult.

Thus, a completely satisfactory process for the preparation of ethers of monosaccharides, with a high yield and purity, not requiring the use of dangerous chemicals or too harsh reaction conditions is therefore not currently known. and is very desirable.

The invention relates to such a process for preparing ethers of monosaccharides with a high yield and purity. 65 It also relates to such a preparation process in which the side reactions and their products are almost absent, the rational conditions being mild and the reagents being practically neither toxic nor dangerous.

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The process for the preparation according to the invention of a monosaccharide substituted with an ether function comprises the reaction

(1) of a monosaccharide derivative having the general formula AOH, O representing oxygen, H hydrogen and A is the residue of a monosaccharide chosen from the group which comprises pentoses, hexoses and heptoses , and having been combined with at least one substance from the group comprising (1-a) at least one aliphatic alcohol containing 1 to 18 carbon atoms and preferably 1 to 4 carbon atoms, so that it forms an acetal group with the location of at least one available hydroxyl residue, (1-b) at least one aldehyde containing 1 to 18 and preferably 1 to 4 carbon atoms, so that at least one acetal group is formed at the location of at least one available hydroxyl residue, (1-c) at least one ketone containing 1 to 18 and preferably 1 to 4 carbon atoms so that at least one ketal group is formed at the location of at least one available hydroxyl residue, and (1-d) at least one organic acid residue containing 1 to 18 and preferably 1 to 4 carbon atoms, so that an ester group forms at the location of at least one available hydroxyl residue, with 20

(2) an organic halide having the formula YX, X being chosen from the group which comprises chlorine, bromine and iodine, and Y being chosen from the group which comprises (2-a) the monovalent nitrogenous organic residues and radicals and cyclic, and (2-b) the monovalent organic residues and radicals having the general formula -Rj-B, B being selected from the group which comprises

—N -R2, —O-R4 and —S-R4, Ri being an organic radical or 1 to 4 carbon atoms, and R2, R3 and R4 are chosen individually from the group comprising hydrogen and / or hydrocarbon radicals having the lengths of linear carbon chains of 1—3 or 1-4 carbon atoms.

Examples of the compounds from which the abovementioned residues and cyclic radicals are derived are (a) saturated, unsaturated or aromatic monovalent nitrogen carbocyclic compounds containing approximately 4 to 8 carbon atoms in the nucleus and preferably approximately 5 or 6 carbon atoms in the nucleus and at least one nitrogen atom attached to the nucleus or an organic substituent thereof, (b) heterocyclic organic compounds containing about 3 to 8 carbon atoms in the nucleus and at least one nitrogen atom in the nucleus, and (c) derivatives of the preceding compounds, comprising at least one substituent such as -OH, -SH, a halogen (F, Cl, Br and / or I), branched and unbranched and saturated hydrocarbon radicals or not containing 1 to 7 and preferably 1 to 3 carbon atoms, radicals -OR6 and / or -SR6, R6 being chosen from branched or unsaturated and saturated or unsaturated hydrocarbon radicals containing 1 to 7 and preferably 1 to 3 atoms carbon, carbocyclic acid residues containing 1 to 7 and preferably 1 to 3 carbon atoms, and amino groups and aminohydrocarbon radicals containing 1 to 7 and preferably 1 to 3 carbon atoms.

The residue A of the monosaccharide derivative can be in cyclic form or in an open chain, corresponding for example to one of the following formulas:

R3 (a)

30

divalent having a linear carbon chain length of 1 to 7 carbon atoms, R2 and R3 being chosen from the group which comprises -H, -OH, -SH, halogens and monovalent organic residues and radicals having a carbon chain length HO linear from 1 to 7 carbon atoms, R4 being chosen from the group which includes -H and monovalent organic residues and radicals having a linear carbon chain length from 1 to 7 carbon atoms, N representing nitrogen, O l 'oxygen, S sulfur and H hydrogen,

the reaction thus forming a monosaccharide derivative substituted by the ether function, having the general formula A-O-Y,

A and Y having the meaning given above. The monosaccharide derivative (1) and the organic halide (2) react at an elevated temperature, preferably in a practically anhydrous organic solvent, and in the presence of a strong solid mineral base practically anhydrous of a metal chosen from the group. which includes alkali and alkaline earth metals.

When R2 or R3 is a halogen, this can be F, Cl,

Br or I, Cl and Br being usually preferable. The organic radical R 1 and R 2, R 3 and R 4, when they are in the form of 50 organic radicals, can comprise linear carbon chains unbranched or branched and they can be saturated or not; when saturated, the linear and / or branched carbon chains may contain one or more carbon or carbon double or triple bonds. The linear and / or branched carbon chains of R15 R2, R3 and R4 may be substituted or unsubstituted and, when they are substituted, they may comprise one or more substituents such as -OH, -SH,

halogen (F, Cl, Br and / or I), branched or unsaturated and saturated or unsaturated hydrocarbon radicals containing 1 to 7 and preferably 1 wl to 3 carbon atoms, -ORs and / or -SR5, R5 radicals , being a branched or unbranched and saturated or unsaturated hydrocarbon radical,

containing 1 to 7 and preferably 1 to 3 carbon atoms, carboxylic acid residues containing 1 to 7 and advantageously 1 to 3 carbon atoms, and amino groups and r, 5 aminohydrocarbon radicals containing 1 to 7 and preferably 1 to 3 carbon atoms. R, is advantageously a hydrocarbon radical having a length of linear carbon chain from 1 to 3

0 = C — Zj I

Ç = (H, OW) C = (H, OW)

—I—

Ç = (H, OW) Z2

H "

(H, OW)

OH

(vs)

(H,

(H, OW)

(II, OW)

OH

5

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in which Zx and Z2 represent -H, -OH or monovalent hydroxyalkyl, alkoxyl and / or alkoxyalkyl radicals containing at most 3 carbon atoms, W represents hydrogen or monovalent alkyl, alkenyl, cycloal-cane, cycloaromatic or acyl radicals containing 1 to 18 and preferably 1 to 6 carbon atoms, or acyl containing 1 to 18 and preferably 1 to 4 carbon atoms, at least one of the radicals or residues Zh Z2 and W other than -H or -OH. Preferably, all of the reactive -OH positions, except those which must be substituted with the ether function, are combined and therefore represent groups other than -H or -OH. The general formulas indicated represent the various isomers of pentoses, hexoses and heptoses, the relative spatial configuration of the groups -H and -OH around the nucleus and their substitution according to an advantageous embodiment of the invention. The hydroxyl or alkoxyl residue of the hemi-ketal or hemicetal bond can take an alpha or beta configuration, and the monosaccharide derivatives can be in the form of anomers or mixtures of anomers.

The configurations of the various isomer derivatives of pentoses, hexoses and heptoses are well known to specialists and there are many reference works on the subject. One can for example consult the works "Textbook of Biochemi-stry", 4th Edition, by West et al. (1966) and "The Monosaccharides" by Stanek, Cerny, Kocourek and Pacak (1963). For example, a total of eight open chain isomers are known for reducing hexoes, and an even greater number of open chain isomers for reducing heptoses. The D series or the L series of pentoses, hexoses and heptoses can be used for the implementation of the invention, the D 30 series being usually advantageous. Hexoses often give the best results, including D-talose, D-galactose, L-galactose, D-idose, D-gulose, D-manose, D-gluco-se, L-glucose , D-altrose and D-allose. Pentoses,

The above hexoses and heptoses can be substituted on one or more hydroxyl groups, then can be substituted by the ether function at any of the remaining reactive positions available. It should be noted that the substitution by the ether function of certain available reactive positions of particular monosaccharide derivatives causes the formation of more active therapeutically or less toxic compounds. For example, the substitution by the ether function of the 3-0_- position of 1,2-O-isopropylidene-D-glucofuranose or 1,2: 5,6-di-0-isopropylidene-D-glucofuranose and of position 6-O- of 1,2-O-isopropylidene-D-galactopyranose or of 45 l, 2: 3,4-di-0-isopropylidene-D-galactopyranose gives particularly valuable compounds.

The following substituents, that is to say Y in the general formula AOY indicated above, can be attached to one of the acid ether positions of the reagent organic halide 5 ′ of the above-mentioned formula YX, '' any of the available reactive positions of the various isomers of derivatives of pentoses, hexoses and heptoses, so that non-toxic compounds having exceptional therapeutic activity are formed: 55

- (n-propylamino),

- (N ', N'-dimethylamino-n-propyl),

- (N ', N'-dimethylaminaminopropyl),

- (N'-methylpiperidyl), 6I)

- (N ', N'-dimethylaminoethyl),

- (N ', N' -diethylaminoethyl),

- (2 ', N', N'-trimethylamino-n-propyl),

-dimethylamino,

-N'N'-dimethylaminomethyl), 65

- (N ', N'-dimethylaminopropyl), - (N', N'-dimethylamino-iso-butyl),

- (N ', N' ■ -dimethy lamino-n-butyl),

- (N ', N'-dimethylamino-iso-pentyl),

- (N ', N'-dimethylaminopentyle),

- (N'-methylamino-n-propyl),

- (N'-methyl-N'-ethylamino-n-propyl),

- (N ', N'-diethylamino-n-propyl),

- (amino-n-propyl),

- (N'-ethylamino-n-propyl),

- (N'-propylamino-n-propyl),

- (N ', N'-isopropylamino-n-propyl),

- (1 ', 2' -ethylamino-n-propyl),

- (1 '-n-propylpyrrolidyle),

- (1 '-n-propylpiperidyl),

-piperidyl, and

- (N ', N' -dimethylamino-sec. -Butyle).

The substituent - (N ', N'-dimethylamino-n-propyl) currently constitutes the most advantageous substituent Y of the substituents listed in the formulas YX and AOY, in particular when it is substituted in the available position 3-0- from 1 , 2-0-isopropylidene-D-glucofuranose or 1,2,2,6,6-di-0-isopropyli-dene-D-glucofuranose or in the 6-O- position of 1,2-O-iso-propylidene- D-galactopyranose or 1,2,2,4-di-0-isopropyli-dene-D-galactopyranose.

The following compounds of the above general formula AOY have antiviral activity over an exceptionally wide spectrum as well as other valuable therapeutic properties, and they can be prepared by carrying out the process of the invention, by use, as reagents , corresponding monosaccharide derivatives AOH (or their hydrolysable precursors) and organic halides YX:

3-0-3 '- (n-propylamino) -1,2-0-isopropylidene-D-glucofu-ranose,

3-0-3 '- (N'N'-dimethylamino-n-propyI) -1,2-0-isopropylidene-D-glucofuranose,

3 -0-4 '- (N' -methylpiperidyl) -1,2-O-isopropylidene-D-glucof u-ranose,

3-0-2 '- (N', N'-dimethylaminoethyl) -1,2-0-isopropylidene-D-glucofuranose,

3-0-3 '- (2', N ', N'-trimethylamino-n-propyl) -1,2-0-isopropylidene-D-glucofuranose,

3-0-2 '- (N', N'-diethylaminoethyl) -1,2-0-isopropylidene-D-glucofuranose,

3-0-2 '- (N', N'-dimethylaminopropyl) -1,2-0-isopropylidene-D-glucofuranose,

6-0-3 '- (N', N'-dimethylamino-n-propyI) -1,2-0-isopropyli-dene-D-galactopyranose,

6-0-2 '- (N', N'-dimethylaminonpropyl) -1,2-0-isopropylidene-D-galactopyranose,

3-0-3 '- (n-propylamino) -1,2: 5,6-di-0-isopropy lidene-D-glu-cofuranose,

3-0-3 '- (N', N'-dimethylamino-n-propyl) -1,2: 5,6-di-0-isopro-pylidene-D-glucofuranose,

3-0-4 '- (N'-methylpiperidyl) -1,2: 5,6-di-0-isopropylidene-D-glucofuranose,

3-0-2 '- (N', N'-dimethylaminoethyl) -1,2: 5,6-di-0-isopropyli-dene-D-glucofuranose,

3-0-2 '- (N', N'-diethylaminoethyl) -1,2: 5,6-di-O-isopropylidè-ne-D-glucofuranose,

3-0- 3 '- (2', N ', N'-trimethylamino-n-propyl) -1,2: 5,6-di-0-iso-propylidene-D-glucofuranose,

3-0-2 '- (N', N'-dimethylaminopropyl) -1,2: 5,6-di-0-isopropylidene-D-glucofuranose,

6-0-3 '- (N', N'-dimethylamino-n-propyI) -1,2: 3,4-di-O-isopro-pylidene-D-galactopyranose,

6-0 -2 '- (N', N'-dimethylaminopropyl) -1,2: 3,4-di-0-isopropyli-dene-D-galactopyranose,

a-N ', N'-dimethylamino-isopropyl-2,3: 5,6-di-0-isopropylidè-

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ne-D-glucofuranoside, and their salts of organic and mineral acids.

Other compounds of general formula A-O-Y in which Y represents

-r, -n <t \ r2

which can be prepared by implementing the process of the invention when the reagents are the corresponding monosaccharide derivatives A-O-H (or their hydrolysable precursors) and organic halides Y-X, are listed below:

Monosaccnanaic Kesiau

(AT)*

auostituant (Y)

Ri

R2

R3

3-0-1,2-O-isopropylidene-

3'-n-propyle

H

methyl

D-glucofuranosis

do do

ethyl do do do

H

ethyl do

2'-isopropyl methyl methyl do

3'-l, 2-propes-

nyle do do do sec.-butyle do do do

3'-butyIe do do do

2'-ethyl

H

H

do methyl

H

H

6-0 -1,2-O-isopropylidene-

D-galactopyranose

3'-n-propyle

H

methyl do do

ethyl do do do

H

ethyl do

3'-1.2-prop-

nyle methyl methyl do

2'-isopropyl do do do sec. Butyle do do do

3'-butyle do do do

2'-ethyl

H

H

do methyl

H

H

3-0-1.2: 5.6-di-O-iso-

propylidene-D-glucofuranosis

3'-n-propyle

H

methyl do do

ethyl do do do

H

ethyl do

2'-isopropyl methyl methyl do

3'-1.2-prop-

do

nyle do do do sec.-butyle do do do

3'-butyl

H

do do

2'-ethyl

H

H

do methyl

H

6-0-1.2: 3,4-di-O-iso-

propylidene-D-galactopyranose

3'-n-propyle

H

methyl do do

ethyl do do do

H

ethyl do

3'-1.2-prop-

nyle methyl methyl do

2'-isopropyl do do do sec.-butyle do do do

3'-butyle do do do

2'-ethyl

H

H

methyl

H

H

* A or a hydrolyzable precursor of A.

Other compounds of general formula A-O-Y, in the-

61)

when the reagents are the monosaccharide derivatives such as Y is a residue or organic nitrogenous monovalent nitrogen radical A-O-H (or their hydrolysable precursors) and cyclics, which can be prepared by the process of the invention organic halides Y-X, are the following:

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Monosaccharide residue

Substitute

(AT)*

(Y)

Radical

Substitute for

cyclic radical cyclic

3-0-1,2-O-isopropylidene-

D-glucofuranosis

4'-piperidyle

H

do

3'-piperidyl methyl,

H

do

2'-piperidyle do do do

3'-pyrrolidyle do do do

2'-pyrrolidyle do do

6-0-1,2-O-isopropylidene-

D-galactopyranose

4'-piperidyle

H

do

3'-piperidyl methyl

H

do

2'-piperidyle do do do

3'-pyrrolidyle do do do

2'-pyrrolidyle do do

3-0-l, 2: 5,6-di-0-iso-

propylidene-D-glucofuranosis

4'-piperidyle

H

H

do

3'-piperidyl methyl do

2'-piperidyle do do do

3'-pyrrolidyle do do do

2'-pyrrolidyle do do

6-0-l, 2: 3,4-di-0-iso-

propylidene-D-galacto-

pyranose do do do do

4'-piperidyle

3'-piperidyle

2'-piperidyle

3'-pyrrolidyl

2'pyrrolidyle

H

methyl do do do

H

do do do

* A or a hydrolyzable precursor of A.

The process of the invention also allows the preparation of certain new compounds of general formula A-O-Y-which can be prepared when the corresponding monosaccharide derivatives A-O-H (or their hydrolysable precursors) and the corresponding organic halides Y-X are used as reactants, for example:

3-0-2 '- (N'N'-dimethylaminoethyl) -1,2-0-isopropylidene-glucofuranose,

3-0-3 '- (2', N ', N'-trimethylamino-n-propyl) -1,2-0-isopropylidene-glucofuranose,

3-0-2 '- (N', N'-dimethylaminopropyl) -1,2-0-isopropylidene-glucofuranose,

6-0-3 '- (N', N'-dimethyIamino-n-propyI) -1,2-0-isopropylidè-ne-galactopyranose

6-0-2 '- (N', N'-dimethylaminopropyl) -1,2-0-isopropylidene-galactopyranose,

3-0-3 '- (N', N'-dimethylamino-n-propyl) -1,2: 5,6-di-0-isopro-pylidene-glucofuranose,

3-0-4 '- (N'-methylpiperidyl) -1,2: 5,6-di-0-isopropylidene-gIu-cofuranose,

3-0-2 '- (N', N'-dimethylaminoethyl) -1,2: 5,6-di-0-isopropyl-dene-glucofuranose,

3-0-3 '- (2', N ', N'-trimethylamino-n-propyl) -1,2: 5,6-di-0-iso-propylidene-glucofuranose,

3-0-2 '- (N', N'-dimethylaminopropyl) -1,2: 5,6-di-0-isopropyl-dene-glucofuranose,

6-0-3 '- (N', N'-dimethylamino-n-propyl) -1,2: 3,4-di-0-isopro-pylidene-galactopyranose,

6-0-2 '- (N', N'-dimethyIaminopropyI) -1,2: 3,4-di-0-isopropyli-dene-galactopyranose,

a-N ', N'-dimethylamino-iso-propyl-2,3: 5,6-di-0-isopropylidene-ne-glucofuranoside,

40

50

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60

and their salts of organic and mineral acids.

The dextrorotatory o or levorotatory species of the new indicated compounds can be prepared by the process of the invention, by selection, as reactants, of the corresponding monosaccharide derivatives dextrorotatory and levorotatory A-O-H (or their hydrolysable precursors), and the corresponding organic halides Y-X.

When the organic halide is an amine, it is advantageous to use its salt of an organic or mineral acid rather than the free amine, in particular when the latter is volatile and / or toxic. Thus, the process of the invention can use a non-volatile and / or non-toxic form of the organic halide which forms the reagent. In this way, the dangers normally presented by Williamson's synthesis and analogous reactions of this type are eliminated.

The monosaccharide derivative is condensed with the organic halide in the presence of a strong solid mineral base which is practically anhydrous of an alkali and / or alkaline earth metal. The most advantageous alkali metals are sodium and potassium, and the most advantageous alkaline earth metal is calcium. The mineral base may for example be in the form of an oxide or hydroxide of the alkali and / or alkaline-earth metal. Hydroxides are advantageous and practically anhydrous sodium hydroxide usually gives the best results. These can be further improved by heating the mineral base to a high temperature so that moisture, carbon dioxide and other absorbed substances are removed so that a new surface is regenerated. The heating temperature must advantageously exceed 100 ° C. and can reach any value necessary for the removal of moisture and carbon dioxide and for the regeneration of the new surface, provided that the temperature does not exceed the temperature of

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fusion of the mineral base. Likewise, the heating period must be long enough for the harmful moisture and / or carbon dioxide to be removed and the new surface of the mineral base to be regenerated. Extended heating does not normally have an adverse effect when moisture and carbon dioxide have been removed. In most cases, the mineral base can be heated to a temperature of about 100-200 ° C for about 6 to 48 hours and preferably at about 160 ° C for about 12 to 24 hours, before use. It is also advantageous for the mineral base to be in particulate form, for example granules, flakes, pastilles or other small pieces. The large surface formed seems to facilitate the reaction. The particle size can vary over a wide range and it is sufficient that the surface is sufficient for the reaction to be facilitated. The mineral base may for example be in the form of thin flakes of sodium hydroxide or sodium hydroxide pellets of 0.42 mm or less. However, flakes, pellets or particles of much smaller or much larger dimensions are also suitable, for example with a ratio of up to 1 to 5 in one direction or the other. Powdered or powdered mineral bases, and in particular sodium hydroxide in fine or powdered powder, are suitable because they give a very large surface area per unit of weight.

The mineral base will preferably be present in an amount corresponding to at least 1 chemical equivalent for each mole of reactive organic halide when the latter is not an amine salt. In the latter case, the organic base will preferably be present in an amount at least equal to 2 chemical equivalents per mole of organic halide so that it can react with the organic or mineral acid forming the amine salt and that the mineral base is in excess sufficient for it to react with the halide which is released by reaction of the organic halide with the monosaccharide derivative. Much larger amounts of organic base can be used than these minimum amounts, for example two to ten times and more than the theoretical amounts required for the reactions indicated.

The monosaccharide derivative and the organic halide react at an elevated temperature when dissolved in a substantially anhydrous organic solvent. Any practically anhydrous organic solvent which is inert under the reaction conditions with respect to the reactants and the mineral base is suitable. Examples of such organic solvents are cyclic and open chain ethers containing about 4 to 8 carbon atoms, for example 1,4-dioxane and tetrahydrofuran as well as ethyl ether, and hydrocarbons, halogenated hydrocarbons and ketones containing about 2 to 10 carbon atoms, such as benzene, hexane, carbon tetrachloride and acetone. The most advantageous solvents are 1,4-dioxane and tetrahydrofuran, the former giving exceptional results. The reagents and the desired reaction product must be soluble in the solvent chosen and this solvent must be present in an amount sufficient for the dissolution of the reactants and of the reaction product. Much higher amounts of solvents can be used, for example one to ten times or more the minimum amount necessary for dissolving the reactants and the desired reaction product.

The temperature and duration of the reaction can vary over wide ranges. It suffices to use sufficiently high temperature conditions for the reaction to take place between the monosaccharide derivative and the organic halide without significant thermal decomposition, and for the reaction to continue for a time which allows the desired degree of transformation. The reaction temperature can be, for example, about 30 to 150 ° C and preferably about 60 to 120 ° C. The best results are usually obtained with a reaction temperature of about 95 to 105 ° C. The reflux temperatures 1,4-dioxane, tetrahydrofuran, acetone, ethyl ether and carbon tetrachloride are entirely satisfactory. If necessary, the reaction can be carried out at a pressure higher than atmospheric pressure, since the reaction temperature can then be increased, in particular in the case of solvents with a low boiling temperature such as ethyl ether. Atmospheric humidity and / or water from other sources must not be allowed to contaminate the reaction mixture for the best results.

The reaction is advantageously carried out in the presence of a water-fixing agent which is inert under the reaction conditions. Any water-fixing agent which is inert is suitable, including anhydrous calcium chloride, anhydrous sodium sulfate and the like. The first of these compounds is usual; slightly preferable. The water-fixing agent is preferably present in an amount sufficient to fix the reaction water and / or additional water which can inadvertently enter the reaction mixture. Much larger quantities may be present, corresponding to one to ten times and more the minimum quantity indicated, for example.

The reaction of the monosaccharide derivative with the organic halide may be prolonged for a time sufficient for the transformation to reach the desired degree. As a general rule, it is advantageous for the transformation to exceed 75% and preferably 90% of the maximum value. The progress of the reaction can advantageously be checked by chromatographic analysis in the gas phase and, in certain cases, the reaction can be stopped after transformation of the desired percentage.

When the reaction is complete, it is advantageous to filter the reaction mixture so that the solid residue which is essentially formed by the mineral base and the water fixing agent is removed. The filtration step must be carried out in a non-oxidizing atmosphere and without contact with an oxidizing gas such as air, unless the reaction mixture has first been cooled to a temperature low enough for it to oxidize. not. It is usually advantageous for the hot reaction mixture to be filtered under an inert gas such as nitrogen, argon or helium, directly in a distillation flask using a filter candle or other suitable device. filtration preventing contact with atmospheric air. The solid residue from the filter can be discarded and the various constituents of the filtrate can be separated by distillation under reduced pressure. The solvent advantageously has a boiling point lower than that of the reactants and of the desired reaction product and, in certain cases, the fraction representing the solvent is recovered first. After drying with a drying material such as anhydrous calcium chloride, the recovered solvent can be reused. After removal of the fraction representing the solvent, the fraction containing the organic halide which has not reacted usually distills, before an azeotropic mixture of the monosaccharide derivative which has not reacted and of the desired product. After distillation of the azeotropic mixture, the final fraction which passes is the desired product, that is to say the monosaccharide substituted by the ether function.

Although the sequence indicated is advantageous for treating the reaction mixture and recovering the desired ether-substituted monosaccharide product, it should be noted that other conventional treatment techniques are also suitable. However, it can be seen that the above-mentioned sequence of steps is very satisfactory since it allows the recovery of the desired product with a high yield and very high purity. As the products thus obtained are useful in the form of therapeutic agents, high purity is particularly important since the quantities of other possibly harmful products and other impurities must be kept to a minimum.

5

10

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20

25

30

35

40

45

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(> n h?

9

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In a variant of the invention, a hydrolysable monosaccharide derivative is chosen for the reaction with the organic halide, this derivative having the general formula A] -0-H, O representing oxygen, H hydrogen and A1 the residue of a monosaccharide chosen from the group which comprises pentoses, hexoses and heptoses and which has been substituted by at least one substance chosen from the group which comprises (1-a) at least one aliphatic alcohol containing 1 to 18 carbon atoms, so that a hydrolyzable acetal group is formed at the location of at least one available hydroxyl residue, 10 (1-b) at least one aldehyde containing 1 to 18 carbon atoms so that it forms at least one hydrolyzable acetal group at the location of at least one available hydroxyl residue, (1-c) at least one ketone containing 1 to 18 carbon atoms so that it forms at least one ketal group hydrolyzable to contain at least one available hydroxyl residue, and (1-d) at least one residue u organic acid containing 1 to 18 carbon atoms so that a hydrolyzable ester group is formed at the location of at least one available hydroxyl residue. The reaction produces a monosaccharide derivative substituted with the ether function and having the general formula Aj-O-Y, A! and O having the meaning indicated above and Y having the same meaning as previously for the organic halide Y-X. In this case, we can consider that A! is a hydrolyzable precursor of A, A having the meaning indicated above for the compound A-O-Y. The hydrolysable monosaccharide derivatives Aj-O-H can react with the organic halide under the same conditions and with the same methods as described above for the preparation of the compound having the general formula A-O-Y. 30

The ether-substituted monosaccharide derivative having the general formula A, -0-Y can be recovered from the reaction mixture by carrying out the steps indicated above for the recovery of the compound A-O-Y. Then, at least one acetal, ketal and / or hydrolyzable ester group is removed from A! by hydrolysis in an aqueous acid medium at a pH below 7 so that an ether-substituted monosaccharide having the general formula A2-0-Y, O and Y having the meaning already given and A2 being the residue of a corresponding monosaccharide is formed to Ai, as described above, from which at least one of the 40 acetal, ketal and / or ester groups has been removed. When the aqueous acid medium has a pH of between approximately 3 and 6 and preferably between approximately 4.0 and 4.5, only part of the acetal, ketal and / or ester groups may be removed. When the pH is less than 3, for example between approximately 1 and 2.5, it is possible, if necessary, to remove all of the acetal groups,

ketal and ester of substituted -OH positions. The aqueous medium used for the hydrolysis step may have a pH adjusted by the addition of any suitable organic and / or mineral acid which gives the desired pH. Mineral acids such as sulfuric and hydrochloric are usually preferable. When the organic halide is an amine, the resulting product, hydrolysed in whole or in part, is recovered in the form of the salt of the mineral acid by lyophilization. The recovered product can be recrystallized from a suitable organic solvent, for example methanol, so that it constitutes a pure final product. The aqueous acid medium used for the hydrolysis should practically not oxidize the desired product, because it could then form oxidized impurities.

The hydrolysis is carried out at an elevated temperature and for a time long enough for it to reach the desired degree. For example, it can be carried out at the reflux temperature of the aqueous acid medium for approximately 6 to 48 hours and preferably approximately 12 to 24 hours or until the desired degree of hydrolysis is obtained as indicated by <, 5 check of the progress of the reaction by gas chromatographic analysis. In the latter case, the hydrolysis is interrupted when the analytical data indicate the disappearance of a peak representing the starting compound and the appearance of a new peak representing the desired product of the hydrolysis. Then, the aqueous solution can be cooled and the pH can be adjusted to about 6.0 and preferably to about 6.5, before lyophilization. The resulting desired product obtained by hydrolysis is precipitated and recovered as crystals which can be purified by recrystallization from organic solvents as described above.

It should be noted that the preparation of salts of the compounds described falls within the scope of the process of the invention. For example, free amine compounds are basic and form salts of organic and mineral acids. The salts can be prepared by known techniques, for example by adding the free amine compound to water and then adding the desired organic or mineral acid in an amount sufficient for the free amine to be neutralized. Examples of such acids are HCl, HBr, H2SO4, HNO3, benzoic acid, p-hydroxybenzoic acid, p-acetamidobenzoic acid, p-hydroxybenzoic acid, alkanesulfonic acids, p-toluenesulfonic acid , acetic acid, alkylcarboxylic acids, oxalic acid, tartaric acid, lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid and acid glucuronic. The aqueous solution of the resulting salt can be evaporated to the volume necessary for the precipitation of the salt during cooling. The precipitated salt is recovered by filtration, washed then dried and forms the final product in the form of an amine salt. Amine salts are often prepared for use in therapeutic compositions because they are crystalline and relatively low in humidity. Amine salts are also more suitable than free amines for intramuscular injection.

It is also possible to use known protection techniques for the substitution of the monosaccharide which must react with the organic halide, such techniques being, for example, acetonization and acetylation. Known suitable protection methods are described in the aforementioned US Patent No. 2,715,121 and in the specific examples which follow. When an aldehyde or ketone reacts with hydroxyl groups of adjacent carbon atoms, the original compound can be dissolved in the desired aldehyde or acetone under anhydrous conditions and a Lewis acid catalyst can be added in an amount causing catalysis, for example in the form of 1% zinc chloride or anhydrous phosphoric acid. Acetone is often the most beneficial protective agent, but higher molecular weight aldehydes and ketones are suitable where appropriate, especially those which may contain up to 25 carbon atoms. The reaction mixture can be stirred at room temperature for a long time such as 24 to 48 hours. The compound can be protected at several positions, for example 1,2- and / or 5,6-.

One or more free hydroxyl positions of the compound can also be protected by an ester group, the carboxylic acid residue of which contains 1 to 18 and preferably 1 to 3 carbon atoms. The ester-substituted derivatives can be prepared in an analogous manner according to known techniques, for example by reaction of a carboxylic acid anhydride with the compound, according to known methods. In addition, derivatives substituted in alpha or beta by an alkyl group of monosaccharide derivatives, such as 2,3: 5,6-di-O-isopropylidene-D-glucofuranoside, can be prepared according to known methods. In the latter case, the compound is dissolved in a dry alcohol having the desired length of carbon chain, with the abovementioned residues, and it reacts in the presence of a catalyst such as the hydrochloric acid of an "Dowex" acid resin 50 H +. Although the derivatives described above are currently preferable, it should be noted that other simple derivatives can be prepared according to known methods and used for the implementation of the invention. In addition, the compounds can be

623,060

10

monosubstituted products of monosaccharide derivatives in which the substrate Y can be replaced by a substituent Rs which is itself a halogenated, ketonic, amino, lower alkyl derivative, mercapto, ulkenyl, alkynylic, aromatic, heterocyclic or alkylcarboxylic acid and its derivatives a deoxymonosaccharide. R8 can also represent the same groups as the preceding substrate for the monosaccharide ethers. Other compounds have the general formula AOY in which Y represents -R9-S-R10, R9 being a saturated or unsaturated hydrocarbon radical containing 1 to 7 carbon atoms and RI0 10 being a saturated or unsaturated monovalent hydrocarbon radical containing 1 to 7 carbon atoms and hydrogen.

The compounds prepared by carrying out the process of the invention are particularly useful in the form of broad spectrum antiviral agents for the therapeutic treatment of warm-blooded animals. They exhibit potential antiviral activity against viruses of both RNA and DNA types, unlike known antiviral agents. The compounds produce a remarkable suppression of the multiplication of viral particles and of cell alteration under the effect of viruses in animal and human histological cultures,

against highly variable viruses such as herpes simplex, influenza A, mumps, poliovirus and rhinovirus.

25

Example 1

189.7 g (1.2 mole) of 3-chloro-N, N-dimethyl-aminopropane in the form of the hydrochloride, and 144 g (3.6 moles) of sodium hydroxide are added to a solution of 104 g (0.4 mole) of 1.2: 5,6-di-0-isopropylidene-D-glucofuranose in 30,550 ml of 1,4-dioxane. The suspension is mechanically stirred and heated at reflux for 18 hours. The reaction mixture thus prepared is filtered, the solids are washed with 1,4-dioxane and the washing liquors are combined with the filtered liquor. The solvent is removed under reduced pressure and a viscous oil of amber color is obtained.

The oil is distilled under high vacuum (less than 1 mm of mercury) by carrying out a very slight purge with anhydrous nitrogen, to obtain fractions of high and low boiling point. The low boiling fraction consists of unreacted 3-chloro-N, N-dimethylaminopropane. The fraction of high boiling point boils at 148-154 ° C under a vacuum of 2.5 mm of mercury and consists of a clear viscous oil whose rotation

O ^

optical tion [a] ^ is equal to —19.3 ° without dilution (100 mm) 45

and the specific weight is 0.95 g / cm3. The refractive index, 26

A portion of the oil is partially hydrolyzed to 1,2-0 -isopropyIidene-3-0-3 '- (N', N'-dimethylamino-n-propyl) -D-glucofuranose by dissolution in distilled water and adjusting the pH of the approximately molar solution to 3.0 ± 0.2 with 6N hydrochloric acid. The solution is extracted twice with chloroform and the clear aqueous solution is heated at reflux for about two hours. The end of the partial hydrolysis reaction is monitored by gas chromatography, based on the disappearance of the peak of the starting compound and the appearance of a new peak with greater retention time. The solution is then refridried, basified with 30% sodium hydroxide at a pH of 10.5, then extracted with chloroform. The chloroform phase is separated, dried over anhydrous magnesium sulfate and distilled in vacuo to remove the solvent. The resulting colorless viscous oil has an alpha optical rotation without dilution of -12 ° and a refractive index of 1.4687 at 25 ° C. Alternatively, the compound can be obtained in the form of the hydrochloride by lyophilization of the aqueous solution after partial hydrolysis at a pH of 4.0 to 4.5. A white crystalline substance is obtained which is recrystallized from methanol. The crystalline hydrochloride of 1,2-0-isopropylidene -3-0-3 '- (N', N'-dimethylamino-n-propyl) -D-glucofuranose melts at 181-183 ° C and its purity, according to gas chromatography is 98+%. Infrared spectrophoto-metry reveals the presence of an intense -OH band which is not present in the starting oil.

Elementary analysis:

Calculated for the hydrochloride: Found (sample obtained in a typical batch):

vs%

H%

NOT %

Cl%

0%

49.19

8.19

4.09

10.39

28.11

49.09

8.40

4.14

10.22

28.12

tion n j-j is equal to 1.4576. Gas chromatography gives a purity greater than 99%. There are at 50 the elementary analysis 59.13% of carbon, 8.99% of hydrogen, 4.12% of nitrogen and 27.7% of oxygen. The yield of 1,2: 5,6-di-0-isopropylidene-3-0-3 '- (N', N'-dimethylamino-n-propyl) -D-glucofuranose (new compound) is 80%.

A portion of the oil indicated above (10 55 g) is hydrolyzed in aqueous sulfuric acid at a pH of 1.9 to 2.1 for 10 hours at reflux. The resulting solution is adjusted to a pH of 4.5 with a saturated barium hydroxide solution Ba (OH) 2, centrifuged and filtered on an ultrafine filter. The filtrate is lyophilized to give a white solid tending to 60 slightly yellow, melting at 78-80 ° C. Gas chromatography indicates a purity of more than 99% of the new compound called 3-0-3 '- (N', N'-dimethylamino-n-pro-pyl) -D-glucopyranose. In thin layer chromatography, a flow rate Rf of 0.356 is found on silica gel 65, using as solvent a mixture of n-propanol, ethyl acetate, water and ammonia, in the volume proportion of 60: 10: 30: 10.

The gas and liquid chromatography for the intermediate compound and the new final compound indicated above was carried out on a Beckman GC model 72-5 apparatus with a hydrogen flame detector. The column used for the new intermediate compound is a commercial “SE-52” column, in which methylphenyl resins constitute the stationary phases supported on “Chromosorb W” (H.P.) from the firm Johns-Manville Corporation. The new final compound is chromatographed on a glass column of "Chromosorb 103", packed with porous resins. The materials listed above are commercially available.

Example 2

Starting with 51 g (0.3 mole) of 4-chloro-N-methylpiperidine hydrochloride and 26 g (0.1 mole) of 1,2: 5,6-di-0-isopropylidene-D-glucofuranose and 36 g of NaOH in 150 ml of 1,4-dioxane, condensation is carried out using the general procedure described in Example 1. The residue which remains after the vacuum distillation is dissolved and recrystallized from hot methanol. The melting point is 106-107.5 ° C (net values).

Hydrolysis of the product indicated above in sulfuric acid to a pH of 2.1 gives 3-0'-4 '- (N'-methylpiperidyl) -D-

25

glucopyranose whose optical rotation (alpha) ^ is equal to

+ 38.42 ° in HzO. Analysis by gas chromatography according to Example 1 reveals that the purity of the product is greater than 96%. The melting point is 62-65 ° C.

Example 3

A solution of 0.1 mol of l: 2: 5,6-di-0-isopro-pylidene-D-glucofuranose in 50 ml of tetrahydrofuran is added to

11

623,060

a suspension of 0.3 mole of 2-chloro-N, N-diethylaminoethane hydrochloride and 36 g of sodium hydroxide in 100 ml of tetrahydrofuran. The suspension is mechanically stirred and heated under reflux for about 16 hours, then the reaction mixture is treated as indicated in Example 1. The desired product, namely l, 2: 5,6-di-0-isopropy ! idene-3-0-2 '- (N', N'-diethyIaminoethyl) -D-glucofuranose is obtained in the form of a light yellow liquid (boiling at 144-150 ° C /

0.15 mm of mercury) including optical rotation (without dilution)

90 OC

[a] j-j is equal to - 20.6 ° and whose refractive index n ^

is equal to 1.4532. The liquid solidifies on exposure to air, presumably as a result of the formation of carbonate. The yield is 85%.

10 g of the product indicated above are hydrolyzed with an aqueous solution of sulfuric acid at a pH of 1.9-2.1 for 10 hours at reflux. The pH of the resulting solution is adjusted to 4-5 with a saturated barium hydroxide solution, then the solution is centrifuged and filtered. By lyophilization of the filtrate, 6.55 g of a light brown crystalline substance consisting of 3-0-2 '- (N', N'-diethylaminoethyl) -D-glucopyra- are obtained.

25

nose. The optical rotation (a) ^ in water is equal to

+ 36.33 °. Analysis by gas chromatography according to Example 1 revealed a purity greater than 99%.

Example 4

0.3 mole of 3-bromo-propionitrile in 50 ml of tetrahydrofuran is added dropwise over one hour to 26 g (0.1 mole) of l: 2: 5,6-di-0-isopropylidene-D -glucofuranose and 30 of 36 g (0.9 mole) of sodium hydroxide in 150 ml of tetrahydrofuran at reflux. The reaction mixture is refluxed for another 6 hours, then filtered. The solid is washed with tetrahydrofuran and the washing liquors and the filtrate are combined. The solvent is removed under reduced pressure and the 1,2: 5,6-di-O-isopropylidene-3-0-3'-propionitrile-D-glucofuranose is obtained. The decomposition point is 165 ° C and the compound is sensitive to light, which shows its interest in photographic applications.

5 g (0.016 mol) of the product indicated above are dissolved in anhydrous ether and the solution is added dropwise to a suspension of 0.76 g (0.02 mol) of lithium hydride and aluminum in ether. The resulting complex is dissolved in cold hydrochloric acid and the solution is quickly neutralized with sodium bicarbonate. The suspension thus produced is extracted with chloroform and the solvent is removed, giving a yellow oil in a yield of 250 mg. Gas chromatography according to the example

1, indicates a purity of 98% and a clear infrared 5C band is observed at 3400 cm- *. The oil is hydrolyzed to a pH of 2.1 in sulfuric acid and lyophilized to dryness. The yield of 3-0-3 '- (n-propylamino) -D-glucopyranose is 85 mg.

Example 5 55

The derivative 3-0-2 '- (N', N'-dimethylaminopropyli-que) of 1,2: 5,6-di-0-isopropylidene-D-glucofuranose is prepared in condensate 0.1 mole of 1.2 : 5,6-di-0-isopropylidene-D-glucofura-nose with 0.3 mole of 2-chloro-N, N-dimethyl-aminopropane hydrochloride in the presence of 0.9 mole of sodium hydroxide 60 in 150 ml of 1,4-dioxane. The reaction mixture is subjected to fractional distillation under reduced pressure and gives a yellow viscous oil (boiling point 142-145 ° C / 0.07 mm of mercury) in a yield of 81%. Optical rotation

25 65

(a) q is equal to —21.5 ° (without dilution) and the index of

25

refraction n ^ is equal to 1.4549. Chromatography in phase

40

gas carried out in accordance with Example 1 reveals the presence of a single component.

The yellow viscous oil prepared as indicated above (10 g) is hydrolyzed with aqueous sulfuric acid at a pH of 2.0, by heating at reflux for 10 hours. The pH of the hydrolyzed sat is adjusted to 4-5 with a saturated solution of barium hydroxide, and the hydrolyzate is filtered and lyophilized giving 10.5 g of light yellow crystals of 3-0-2 '- (N', N'-dimethyl-

25

, aminopropyl) -D-g! ucopyranose. Optical rotation (a) ^

in water is equal to + 37.86 °. Gas chromatography carried out in accordance with Example 1 indicates a purity greater than 82%.

A portion of the oil consisting of 1,2: 5,6-di-0-isopropylidene-3-0-2 '- (N', N'-dimethylamino-propyl) -D-glucofuranose is partially hydrolyzed at a pH of 3.0 ± 0.2, as indicated in Example 1. White crystals of hydrochloride are obtained by lyophilization. The salt obtained is very hygroscopic, its purity determined by gas chromatography being 1 of the order of 80%.

Example 6

0.3 mole of 2, N, N-trimethylaminopropyl chloride hydrochloride and 36 g of sodium hydroxide are added to

0.1 mole l, 2: 5,6-di-0-isopropylidene-D-glucofuranose. The general reaction process is that of Example 1. The oil which results from the reaction has a boiling point of 144-146 ° C under a vacuum of 0.6 mm of mercury and a rotary power (a)

^ equal to —20.05 ° (without dilution).

The product indicated above is hydrolyzed according to the general procedure described in Example 1, giving 3-0-3 '- (2', N ', N'-trimethylamino-n-propyl) -D-glucopyranose

20

longed for. The optical rotation (a) t-j of the product in water is equal to + 38.0 °.

A portion of the oil consisting of 1,2: 5,6-di-0-isopropylidene-3-0-3 '- (2', N ', N'-trimethyl-amino-n-propyl) is partially hydrolyzed -D-glucofuranose at a pH of 3.0 ± 0.2 following the procedure described in Example 1. White crystals of 1,2-0-isopropylidene-3-0-3'-hydrochloride are obtained- (2 ', N', N-trimethylamino-n-propyl) -D-glucofuranosis of a very hygroscopic nature. The optical rotation of the hydrochloride at a pH of 7.0 and at 25 ° C is equal to - 21.33 °. Analysis by gas chromatography shows that the dominant component has a purity of more than 99%.

Example 7

Following the general procedure described in the example

1, 0.02 mol of l, 2: 5,6-di-0-isopropylidene-D-glucofuranose in 1,4-dioxane is reacted with 0.0225 mol of 2- (2-chlorethyl) hydrochloride - N-methylpyrrolidine and 0.0675 mole of sodium hydroxide. After 18 hours, the solvent is removed and the resulting orange-colored oil is distilled under vacuum, under a nitrogen atmosphere. The residue consists of the desired product, namely 1,2: 5,6-di-0-isopropylidene-3-0-2 '- {2 "- (N" -methyl) -pyrrolidyl} -ethyl-D-glucofuranose of rotation

25

optic (a) D in chloroform equal to —22.95 °.

Example 8

0.1 mol of l, 2: 5,6-di-0-isopro-pylidene-D-glucofuranose and 0.15 mol of N- (2-chlorethyl) -pyrrolidine hydrochloride are mechanically stirred and the mixture is heated. at reflux with 0.45 mole of sodium hydroxide in 150 ml of tetrahydrofuran for 18 hours. Tetrahydrofuran is removed from the reaction products and the resulting oil is distilled

623,060

12

under vacuum, under nitrogen atmosphere. The 3-0-2 '- {N'-pyrrolidyl) -ethyl} derivative of 1,2: 5,6-di-0-isopropylidene-D-glu-cofuranose has a boiling point of 165-171 ° C under a vacuum of 0.15 mm of mercury. Gas chromatography reveals a purity of 99%. By following process 5

hydrolysis described in Example 1, 10 g of the protected oil is hydrolyzed and lyophilized to obtain a hygroscopic crystalline solid, white in color.

Example 9 10

The N ', N'-dimethylamino-n-pentyl derivative of 1,2: 5,6-di-O-isopropylidene-D-glucofuranose is obtained by condensation of N, N-dimethylamino-n- hydrochloride pentyl with 1,2: 5,6-di-0-isopropylidene-D-glucofuranose in the presence of sodium hydroxide powder in freshly purified anhydrous 1,4-dioxane, as described in the procedure for Example 1. The identity of the product is confirmed by gas chromatography and by the infrared spectrum.

N, N-dimethyl-2Q amino-n-pentyl chloride hydrochloride is obtained from a commercial sample of N, N-dimethylamino-n-pentyl alcohol, by treatment with thionyl chloride (SOCI2). To do this, 10.7 g of thionyl chloride are cooled in a round bottom flask with three tubes of 250 ml capacity, immersed in a salt and ice bath and stirred vigorously. 10 g of N, N-dimethylamino-n-pentyl alcohol are added dropwise to the cooled solution. The reaction is exothermic and the temperature is carefully controlled. The mixture is stirred for one hour after the evolution of SO2 and HCl has ceased. It is allowed to cool to room temperature and stirred for about 16 hours. Absolute alcohol is added to destroy the excess thionyl chloride. 10 g of crude N, N-dimethylamino-n-pentyl chloride hydrochloride are obtained in the form of a white solid which is used directly in the condensation reaction with 1,2: 5,6-di -0-isopropylidene-D-glucofura-nose without further purification. The alcohol and chloride can be separated on a gas chromatography column packed with "Chromosorb 103".

40

Example 10

9.8 g of bromine are slowly added dropwise to a mechanically stirred mixture of 50 g of crushed ice and a cooled aqueous sodium hydroxide solution (7 g / 20 ml of water). When the addition of bromine is complete, four g are added, every 15 minutes, 15 g of 1,2: 5,6-di-0-isopropylidene-3-O-acetamido-D-glucofuranose (prepared by general procedure described in example 1, by condensation of 1,2: 5,6-di-0-isopropylidene-D-glucofuranose with 2-chloroacetamide in the presence of sodium hydroxide). The reaction mixture is heated for one hour in a water bath. Then add an additional volume of aqueous sodium hydroxide solution (20 g / 20 ml) and continue heating for another hour. The mixture is cooled and extracted three times with ether. The ether extraction phase is dried over anhydrous magnesium sulfate. The yellow hygroscopic solid which remains after removal of the ether by evaporation is the desired 1,2: 5,6-di-0-isopropylidene-3-O-aminomethyl-D-glucofuranose. The product is identified by the disappearance of the carbonyl elongation at 1670 cm-1 which is found in the starting acetamido compound.

Example 11

The well-established methods of the prior art are used to determine the antiviral power of 1,2-O-isopropylidene-D-glucofuranose hydrochloride derivatives against poliovirus type 1 and rhinovirus type 1A in a tissue culture with 37 ° C using “HeLa” cells covered with agar, and, respectively, WI-38 cells (see C. Wallis, F. Morales, J. Powell and JL Melnick, “Plaque enhancement of enteroviruses by magnesium chloride, cysteine, and pancreatin "," J. Bacte-rio. "91: 1932—1935,1966). The alteration of cells by the poliovirus is determined by the study of plaque formation and the rhinovirus is examined for the cytopathic effect. Table I reproduces the virus inhibition effects of three concentrations of the derivative 3-0-3 '- (N', N'-dimethyl-amino-n-propyl). The results are indicated by the degree of inhibition of the infectious power, identified by the formation of plaques in the poliovirus system and by the cytopathic effect in the rhinovirus study system. The results obtained in accordance with the invention indicate that, at the appropriate dose, the medicament can completely inhibit 1000 units of plaque formation of the poliovirus and reveal a DICT50 dose of rhinovirus 1A equal to 1000, that is to say a viral dose of 1000 times the amount required to destroy 50% of cells in histological culture.

1,2-O-isopropylidene-D-glucofuranose hydrochloride derivatives Table I

Summary of antiviral action in a tissue culture

Derivative

Dose

System

Virus

Determined

Effect of

Type

Drug title

3-0-3 '- (N'.N'-

1 (ig / ml

HeLa cells

Poliovirus

50 UFP (1)

Number of

Dimethylamino inhibition

in vitro with type 1

total n-propyl plates)

recovery of

agar

do

20 (xg / ml do do

250 UFP

do do do

40 [ig / ml do do

1000 UFP

do do

3-0-3 '- (N', N'-

2 (ig / ml

WI-38 cells

Rhinovirus

100 DICT50

Cyto effect

Dimethylamino inhibition

type 1A

n-propyl total pathology)

do

20 ug / ml do do

1000 dict50

do do do

do do iooodict50

do do

40 [Ag / ml

(1) Plate forming units

(2) Infectious dose in tissue culture involving 50% of cells

13

623,060

Example 12

The ability of 2-0-isopropylidene-D-glucofuranose hydrochloride derivatives to combat influenza A2 in mice has been studied and their ability to protect mice from death and from non-fatal nervous system disease caused by the encephalomyocarditis virus. In these studies, the effect of the drug on the pulmonary pathology produced by | an ID50 dose of influenza virus equal to 15. This dose i represents 15 times the dose which produces the disease in 50% of the animals. The disease and the effect of the drug on the latter were determined by the gain and weight loss of the lung. In the encephalomyocarditis study, the dose capable of killing 50% of the animals was administered ten times and the degree of non-fatal disease and death was determined, as well as the inhibition of these parameters by the drug. The results of these experiments are summarized in Table II and indicate a significant reduction in the weight gain of the lungs by the drug, as well as a remarkable inhibition of death and non-lethal disease under the effect of the l virus. encephalomyocarditis. These effects are more powerful for the 3-0-3 '- (N', N'-dimethylamino-n-propyl) derivative than for the two other io derivatives which have been studied.

1,2-O-isopropylidene-DO-glucofuranose hydrochloride derivatives • Table II

Antiviral effects produced in vivo in mice

Derivative

3-0-3 '- (N', N'-dimethylamino-n-propyl

3-0-3 '- (N', N'-dimethyiamino-n-propyl)

do

3-0-2 '- (N', N'-dimethylamino isopropyl)

do

3-0-3 '- (2', N'-N'-trimethyl-amino-n-propyli-que)

do

Dose

20 mg / kg

80 mg / kg

160 mg / kg 80 mg / kg

System

Mouse, in vivo

Mouse, in vivo do do

Virus type

Headline

Determination

Influenza, type A

Encephalo-myocarditis do do

DI50 (1), 15 Weight gain of the lungs

DLS0 (2), 10 CNS involvement (3) and death

160 mg / kg

80 mg / kg 160 mg / kg do do do do do do

(1) Infectious dose involving 50% of the animals

(2) Lethal dose destroying 50% of animals

(3) Central nervous system

Example 13

This example concerns the preparation of 1,2: 5,6-di-0-iso-propylidene-3-0-2 '- (N', N'-trimethylamino-n-propyl) -D-glu-cofuranose.

To 104 g (0.4 mole) of l: 2: 5,6-di-0-isopropylidè-ne-D-glucofuranose, 0.6 mole of 3-chloro-N, N-2 hydrochloride chloride is added. -trimethylpropylamine, 1.8 moles of sodium hydroxide pellets previously placed in the oven, 10 g of anhydrous magnesium sulfate and 500 cm3 of 1,4-dry dioxane in a three-necked 3-liter reaction flask fitted with 'a mechanical stirrer and a reflux condenser. The reaction mixture is stirred vigorously and it is treated at reflux for approximately 20 hours. The progress of the reaction is monitored by gas chromatographic analysis. The reaction mixture then cools, then it is filtered, and the dioxane and the unreacted amine are removed from the filtrate under reduced pressure using a rotary evaporator. A colorless to slightly yellow viscous oil (135 g) is obtained by fractional distillation at 144-146 ° C, at a pressure of 0.6 torr. The oil has an optical rotation, without dilution and at a pressure of

50

55

do do do do do do do do do do do

Effect of the drug

Significant reduction in lung weight gain Significant inhibition of death and non-lethal disease do Noticeable inhibition, but less than in the case of the n-pro-pyl derivative do do do

100 torrs, of [a] q1 = —20.05 °. The yield exceeds 85%.

Example 14

This example relates to the preparation of 1,2: 5,6-di-0-iso-propylidene-3-0-3'-propanol-D-gIucofuranose.

52 g of 1.2: 5.6-di-O-isopropylidene-D-glucofuranose, 25 g of 3 are placed in a three-necked reaction flask fitted with a mechanical stirrer and a reflux condenser. -chloro-propanol, 24 g of sodium hydroxide, 5 g of anhydrous calcium chloride and 250 to 300 cm3 of dry dioxane. The reaction mixture is gently treated at reflux for 16 to 20 hours and checked by gas chromatography. The solvent and unreacted 3-chloropropanol are removed by fractional distillation. The yield exceeds 70%.

A similar reaction is carried out, but in an autoclave, under a pressure fixed by steam. The yield is lower and dark brown-red impurities are formed, the isolation of which is difficult chemically or by column chromatography.

623,060

14

Example 15

This example relates to the preparation of 1,2: 5,6-di-0-iso-propylidene-3-O-methylthiomethyl-D-glucofuranose.

A reaction mixture which contains 52 g of 1,2: 5,6-di-O-isopropylidene-D-glucofuranose, 58 g of methyl chloromethyl sulfide, 48 g is treated at reflux overnight, with effective mechanical stirring. sodium hydroxide treated in the oven and 200 cm3 of dry tetrahydrofuran. The mixture is filtered and then dried and the solvent is removed under reduced pressure. After fractional distillation, the fraction which boils between 140 and 148 ° C is collected under a pressure of 0.1 torr, in the form of a yellowish oil. The oil also contains part of the 1,2: 5,6-di-0-isopropylidene-D-glucofuranose which has not reacted. This compound is removed by selective crystallization from a hot solution of hexane. The final product is a yellow oil having an optical rotation without dilution and at 100 torr of [a] ° = -42.5 °.

Example 16

A solution of 26.0 g of 1,2: 3,4-di-0-isopropylidene-D-galactopyranose in 50 cm 3 of anhydrous tetrahydrofuran is mixed with a suspension of 0.3 mole of 3-chloro-N hydrochloride, N-dimethylaminopropane and 36 g of sodium hydroxide in 100 cm3 of tetrahydrofuran. The mixture is vigorously stirred and treated at reflux for 3 hours. The brownish solution obtained is cooled and filtered, and most of the solvent is evaporated so that a brown oil remains. The remaining solvent and unreacted 3-chloro-N, N-dimethylaminopropane hydrochloride are removed by fractional distillation under reduced pressure. The residual oil is extracted with chloroform, bleached with activated carbon and dried over anhydrous magnesium sulfate. Removal of the solvent chloroform gives 13.4 g of a yellow oil, the identification of which indicates that it is 1,2: 3,4-di-0-isopropylidene-6-0-3 '- (N ', N'-dimethylamino-n-propyl) -D-galactopyranose. Infrared and gas chromatographic analysis, as described in Example 1, indicates the presence of a

28

main ingredient with refractive index T] = 1.461 25

and an optical rotation [a] q = -49.4 ° in chloroform.

The oil is treated at reflux with 50 cm3 of 0.5N sulfuric acid for 18 hours. The resulting solution is washed with chloroform and the pH is adjusted to 4.2. After lyophilization, the aqueous solution gives 4.67 g of 6-0-3 '- (N', N'-dimethylami-no-n-propyl) -D-galactopyranose solid crystalline having a ro-25

optical tation [a] d-d = + 77.2 ° in water. An analysis by

Gas chromatography, as indicated in Example 1, shows that the purity of the product exceeds 95%.

3-0-3 '- (N', N'-dimethylamino-n-propyl) -glucose to fight influenza A2 from Hong Kong in mice. In this study, mice are infected with a non-lethal but sufficient dose of the human influenza virus suitable for mice, and they are treated either with distilled water (control) or with a compound at a rate of 40 mg / kg. 50% of the drug administered has a hydrophilic character reduced by the addition of the labile organic group acetone at the 1,2- position, facilitating absorption in the cells and slowing down the release by io fats from the body. The medication is administered orally, starting 24 hours after infection. The progression of the disease and the effect of the drugs are evaluated after 8 days by examining the pneumonic consolidation of the bronchi, according to the method of T.W. Chang and L. Weinstein (Am. J. is Med. Sci., 1973, in press) and by the objective technique of weighing the lungs. It should be noted that the increase in weight of the lungs during influenza infection reflects edemas, hemorrhages and virus contents (as described in the article P. Gordon and ER Brown, Canad. J. Micro. 20 18: 1463.1972). The objective data obtained by weighing the lungs, indicated in table III, part A, indicates a suppression of 82% of the disease by implementation of the derivative according to the invention.

The ability of the indicated drug to prevent the death of mice with lethal A / PR / 8 infection is also examined. The drug is introduced subcutaneously at three dose levels 90 times before infection at one time. The results indicate significant protection against death, dependent on the dose as indicated in Table III, part B.

Table III

A. Action on mice suffering from influenza A2 from Hong-Kong

35

Average Weight Group Suppression Frequency of Lung Disease Lung (mg)% Normal

(170 mg)

40

Normal 160 21/21

Infected witness 258 1/21

Infected and treated 177 82 13/21

B. Action on mice having been infected with influenza A / PR / 8 with a fatal dose

Drug

50

Example 17

This example concerns the preparation of 6-0-2 '- (N', N'-dimethylamonopropyl) -D-galactose.

The process described in general in Example 16 is followed, but 2-chloro-N, N-dimethyla-minopropane hydrochloride is used as the raw material in place of the corresponding 3-chloro derivative. The intermediate product has an optical rotation in water of [a] = —54.5 °, and a refractive index of r) ^ = 1.4552. The final product has a flow rate value Rf = 0.376 during a thin layer chromatographic analysis according to Example 1.

Example 18

We examine the suitability of the most powerful of the derivatives cited,

0 (control) 10 mg / kg 40 mg / kg ss 160 mg / kg

Frequency of mortality after 8 days

42/44 18/22 16/22 10/22

Mortality

%

95 81 72 45

Protected population,

%

14 23 50

60

65

Example 19

The known and well-established methodology is used for the determination of the antiviral ability of the compounds against the Hong Kong strain of the influenza A2 virus, in histological cultures, using divided cells of kidneys of baby hamsters (as described in the article by RM Muldoon, L. Mezny and GG Jackson "Antimicrobial Agents and Chemothe-rapy" 2: 224-228,1972). The power of infection of the virus is evaluated both by hemagglutination techniques and by cytopathogenic effects, and identical results are obtained with the two methods. Table IV shows the virus inhibiting effects of two drug concentrations, 3 and 10

15

623,060

micrograms / cm3. The results are represented in the form of the logarithmic reduction of the power of infection of the viral inocu-lum. A log reduction of 4.0 is the maximum value that can be obtained, which represents the total suppression of virus growth in the system under consideration. The viral inoculum of day 0 is always equal to a hundred times the amount necessary to kill 50% of the cells of the histological culture (100 times the TCD50 dose). These results indicate that different derivatives suppress viral growth with a factor between 3 and 10,000, the most important effect being that of 3-0-3 '- (N', N'-dimethylamino-n-propyI) -glucose.

Table IV

Compound Log reduction in the power of infection of the viral inoculum at the concentration:

5

3 ng / cm3

10 [ig / cm3

3-0-3 '- (N', N'-dimethyIami-

no-n-propyl) -D-glucose

3.2

4.0 (max)

3-0-4 '- (N -methylpiperidyl) -

D-glucose

2.5

3.5

io 3-0-2 '- (N', N'-dimethylami-

no-ethyl) -D-glucose

2.5

3.5

3-0-3 '- (2', N ', N'-trimethyl-

amino-n-propyl) -D-glucose

2.4

3.0

a-N, N-dimethylaminoisopro-

i5 pyl-glucoside

1.5

2.5

6-0-3 '- (N', N'-dimethyl-

amino-n-propyl) -D-galactose

1.0

2.0

3-0-2 '- (N', N'-dimethylami-

nopropyl) -D-glucose

1.0

2.0

20 3-Ò-2 '- (N', N'-diethylamino-

ethyl) -D-glucose

0.5

1.0

6-0-2 '- (N', N'-dimethylami-

nopropyl) -D-galactose

0.1

0.5

VS

Claims (20)

623,060 2 CLAIM Process for the preparation of monosaccharides substituted with an ether function and corresponding to the general formula: A-O-Y and their salts with mineral and organic acids, formula in which A represents the residue of a monosaccha-ride chosen from the group which includes pentoses, hexoses and heptoses and which has been combined with at least one substance chosen from the group which comprises (1-a) at least one aliphatic alcohol having 1 to 18 carbon atoms, so that an acetal group is formed at the location of at least one available hydroxyl residue, (1 — b) at at least one aldehyde containing 1 to 18 carbon atoms so that at least one acetal group forms at the location of at least one available hydroxyl residue, (1-c) at least one ketone containing 1 to 18 carbon atoms so that at least one ketal group is formed at the location of at least one available hydroxyl residue, and (1-d) at least one organic acid residue containing 1 to 18 carbon atoms so that it forms a ester group at the location of at least one available hydroxyl residue, and Y represents (2-a) the cyclic monovalent nitrogen-containing organic residues and radicals, and (2-b) the monovalent organic residues and radicals having the general formula -Rt-B in which B is chosen from the group which comprises -N - R2, -O-R4 and -S-R4 I r3 Ri is a divalent organic radical having a linear carbon chain length of 1 to 7 carbon atoms, R2 and R3 are chosen from the group which comprises -H, -OH, —SH, halogens and monovalent organic residues and radicals having a length of linear carbon chain of 1 to 7 carbon atoms, R4 is chosen from the group which comprises -H and monovalent organic residues and radicals having a length of linear carbon chain of between 1 and 7 carbon atoms, N is l nitrogen, O is oxygen, S is sulfur and H is hydrogen, characterized in that a monosac-charide of the general formula is reacted: A-OH in which A has the above meaning, with a halogenated organic compound of general formula: Y-X in which Y has the above meaning and X represents a chlorine, bromine or iodine atom, at elevated temperature in the presence of a strong and solid mineral base substantially anhydrous of a metal chosen from alkali and alkali metals - earthy. SUB-CLAIMS 1. Method according to claim, characterized in that the monosaccharide derivative (1) and the organic halide (2) react in the presence of a dehydrating agent which constitutes a water-fixing agent. 2. Method according to claim 1, characterized in that the dehydrating agent is anhydrous calcium chloride. 3. Method according to claim, characterized in that one operates in an organic solvent chosen from 1,4-dioxane and tetrahydrofuran. 4. Method according to sub-claim 3, characterized in that the organic solvent is 1,4-dioxane. 5. Method according to claim, characterized in that the mineral base is chosen from the group which comprises the substantially anhydrous oxides and hydroxides of sodium, potassium and calcium. 6. Method according to claim, characterized in that the mineral base is in particulate form and consists of anhydrous sodium hydroxide. 7. Method according to claim, characterized in that the monosaccharide derivative (1) has a general formula chosen from the group which comprises: (at) read H-O 0 = C — Z] I C = (H, OW) I C = (H, OW) -H- Ç = (H, OW) Z, (b) (H, OW) (H, OW) OH and 40 (VS) (H, OW) (H, OW) 45 (H, OW) OH 50 60 65 where Z1 and Z2 are chosen from the group which includes -H, -OH and monovalent hydroxyalkyl, alkoxylic and alkoxyalkyl radicals containing at most 3 carbon atoms, W is chosen from the group which includes H and monovalent alkyl, alkenyl, cycloalkane, cycloaromatics, and acyls containing 1 to 18 carbon atoms, Zb Z2 or W at least representing a group other than -H or -OH. 8. Method according to claim 1, characterized in that at least one of the acetal, ketal or ester groups of A is split, by hydrolysis in an aqueous acid medium at a pH below 7 so that a ether-substituted monosaccharide having the general formula A2-0-Y in which O and Y have the meanings already indicated and A2 is the residue of a monosaccharide corresponding to Aj having the meaning indicated above, of which at least one of the acetal groups , ketal or ester has been removed. 9. Method according to sub-claim 8, characterized in that A! has several acetal, ketal or ester groups, and the hydrolysis is carried out in an essentially non-oxidizing aqueous acid medium having a pH between 3 and 6 so that only part of the acetal, ketal and ester groups is removed. 3 623,060 10. Method according to sub-claim 8, characterized in that A! has several acetal, ketal or ester groups, and the hydrolysis is carried out in an aqueous acid medium that is practically non-oxidizing at a pH of less than 3 so that all of the acetal, ketal or ester groups are removed. 11. Method according to claim or sub-claim 7, characterized in that the monosaccharide derivative (1) is chosen from the group which comprises glucose derivatives and galactose derivatives. 12. Method according to sub-claim 11, characterized in that the glucose derivative is substituted in all the -OH positions with the exception of the lO- or 3-0- position, and the galactose derivative is substituted in all the -OH positions with the exception of the 6-0 position, the glucose carrying a single ether substituent in the 10- or 3-0 position and the galactose having a single ether substituent in the 6-0 position. 13. Method according to claim, characterized in that the monosaccharide derivative (1) is 1,2: 5,6-di-O-isopropyli-dene-D-glucofuranose. 14. Method according to claim or one of sub-claims 7,12 and 13, characterized in that Y is the radical -R, -N-R2 I R3 R [is a hydrocarbon radical having a linear chain length between 1 and 3 carbon atoms, and R2, R3 are chosen from the group which comprises hydrogen and hydrocarbon radicals having a linear carbon chain length from 1 to 3 carbon atoms. 15. Method according to claim or one of sub-claims 7,12 and 13, characterized in that Y is chosen from the group which comprises the radicals: - (n-propylamino), - (N ', N'-dimethylamino-n-propyIe), - (N ', N' -dimethylaminoisopropyl), - (N-methylpiperidyl), - (N ', N'-dimethylaminoethyl), - (N ', N'-diethylaminoethyl) and - (2 ', N', N '-trimethylamino-n-propyl). 16. Method according to claim or one of sub-claims 7,12 and 13, characterized in that Y is the radical - (N ', N'-dimethylamino-n-propyl). 17. Method according to claim and sub-claim 12, characterized in that the hydrolysis is carried out in an aqueous acidic medium practically non-oxidizing having a pH between 3 and 6 so that only part of the acetal, ketal and ester groups either removed from the substituted -OH positions. 18. The method of claim and sub-claim 12, characterized in that the hydrolysis is carried out in an aqueous acidic medium substantially non-oxidizing having a pH less than 3 so that all of the acetal, ketal or ester groups are removed from the positions -OH substituted. 19. Method according to sub-claims 12 and 16, characterized in that the hydrolysis is carried out in an aqueous acid medium which is practically non-oxidizing and having a pH of between 3 and 6 so that only one of the isopropylidene groups is removed. 20. Method according to sub-claims 12 and 16, characterized in that the hydrolysis is carried out in an aqueous acidic medium which is practically non-oxidizing and has a pH below so that the two isopropylidene groups are removed.