DE2612717A1 - METHOD OF MANUFACTURING MONOSACCHARIDAETHERS - Google Patents

Description

Strategic Medical Research Corp., Chicago, 111. / USA

Process for the production of monosaccharide ethers

The invention relates to a process for the preparation of monosaccharide ether derivatives from certain selective monosaccharide derivatives. During execution. ^{r of} the method according to the invention are:

1. Monosaccharide derivatives of the general formula A ^ -OH, where 0 is oxygen, H is hydrogen and A _{1 is} the residue of a monosaccharide derivative selected from the group consisting of pentoses, hexoses and heptoses, reacted with at least one substance from group (1-a) at least an aliphatic alcohol with 1 to 18 carbon atoms with formation of a hydrolyzable acetal group at a point of at least one available hydroxyl radical, (1-b) at least one aldehyde with 1 to 18 carbon atoms

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609842/1024

2B12717

lenstoffatomen with the formation of at least one hydrolyzable Acetal group in a position of at least one available hydroxyl group, (1-c) at least one Ketone containing 1 to 18 carbon atoms with formation of at least one hydrolyzable ketal group in place of at least one available hydroxyl group and (1-d) at least one organic acid residue having 1 to 18 carbon atoms to form a hydrolyzable one Ester group in place of at least one available hydroxyl group, the corresponding Derivative was obtained.

2) an organic halide of the general formula YX, wherein X is chlorine, bromine or iodine and Y (2-a) cyclic monovalent nitrogen-containing organic groups and radicals or (2-b) monovalent organic groups and radicals of the general formula -R * -B denotes, wherein B denotes -N-Rp, -0-R ^ or -SR ^, R ^ is a divalent

denotes organic group with a linear carbon chain length of about 1 to 7 carbon atoms, R ₂ and R, H, -OH, -SH, halogen or monovalent organic groups and radicals with a linear carbon chain length of about 1 to 7 carbon atoms denote, R ^ - H or monovalent organic groups or radicals with a linear carbon chain length of approximately 1 to 7 carbon atoms, N denotes nitrogen, 0 denotes oxygen, S denotes sulfur and H denotes hydrogen,

60984? / 102 /,

to form an ether-substituted monosaccharide derivative of the general formula AOY, where A, Y and 0 are as defined above. The monosaccharide derivative 1) and the organic halide 2) are dissolved at elevated temperature in an essentially anhydrous organic solvent in the presence of a solid, essentially anhydrous strong inorganic base of a metal from the group consisting of alkali metals and alkaline earth metals. The resulting ether-substituted monosaccharides or monosaccharides containing ether groups can be partially or completely in one
aqueous acidic medium can be hydrolyzed. At a
In a preferred embodiment, 1,2: 5,6-di-0-isopropylidene-3-0-3 '- (N ¹ , N ¹ -dimethylamino-n-propyl) -D-glucofuranose is prepared and, if desired, then partially or completely with formation of 1,2-0-isopropylidene-3-0-3 '- (N', N'-dimethylamino-n-propyl) -D-glucofuranose
or 3-0-3 '- (N ¹ , N'-dimethylamino-n-propyl-D-glucose to
hydrolyzed the free amine and / or salt forms. With
the process can be used to produce the ether-substituted monosaccharides in high yield and purity, with
the formation of by-products is kept to a minimum.
The resulting compounds show surprising antiviral activity and / or have other therapeutically valuable properties and are suitable for treatment
suitable for warm-blooded animals and humans.

The invention relates to a new process for the production of ether-like substituted monosaccharides or of ether-substituted monosaccharides or of monosaccharide ether derivatives or of monosaccharide ethers

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60984 2/10 2 A

26-27 1?

(these terms are used synonymously in the following) from selective monosaccharide derivatives or monosaccharides, which have been converted into selective derivatives (these terms are also used synonymously in the following)

The invention also relates to an improved process for partial or complete hydrolysis the resulting ether-substituted monosaccharide derivatives.

In the German Offenlegungsschrift 2 409 654 and in the German patent application P 24 55 026.3 (corresponding to the US applications with SN Nos. 337,134 and 424,786) are certain monosubstituted monosaccharide ether and Monosaccharide derivatives described. These compounds give important biological signals and that is what makes it possible for living cells to resist viral infection. The connections are also for the control of others Processes in cell chemistry useful, such as processes that influence memory or enable memory.

The compounds described above can be used in acceptable yields and in sufficiently high purity for pharmaceutical Applications according to the most widely used method for the synthesis of ethers, i.e. according to the Williamson's synthesis, not made. at the production of the 3-0 ethers of blocked or protected or masked (these expressions are used in the following used synonymously) Monosaccharides ^ as of 1,2: 5,6 di-O-isopropylidene-D-glucose, possesses the Williamson's marriage Synthesis major disadvantages, due in part to the occurrence of

-5-

6 0 9> U? / 1 π ? /,

tending stereochemical difficulties. The only secondary hydroxyl group found in the 1,2: 5,6-di-0-isopropylidene-D-glucose is present is so sterically hindered that it interacts with sodium metal to form the sodium salt not responding at a practical rate. In addition, the resulting sodium salt is usually in the Solvents used in the Williamson synthesis, such as ethyl ether or benzene, are insoluble. the Handling and production of the sodium metal which is used for the synthesis of substantial quantities of 3-0 ethers of blocked Monosaccharides is required and elimination excess sodium after the reaction is complete also present significant physical difficulties represent.

The second stage of the Williamson synthesis, in which an alkyl halide is condensed with the sodium salt, proceeds well and high yields are obtained. However, other difficulties arise in the preparation of alkylamino ethers of monosaccharides. The alkyl amino halide used in the condensation step must be in the free amine form and the corresponding mineral acid salt cannot be used. Many <* - l- Aminoalkylhalogenide are volatile and very toxisc · when present as free amines, however, nieht wc · \ present as mineral acid salt. In a satisfactory process for the synthesis of 3-0 ethers of monosaccharides, it must therefore be possible to use aminoalkyl halides in the form of the mineral acid salts so that the inherent disadvantages of volatility and toxicity are avoided.

-6-

h Π ■ '- ·. ■ -: · _; "> ι ι η" ■ ./,

8AD OBiGINAi-

Another method of condensing organic halides with blocked monosaccharides is described in U.S. Patent 2 715 121. In this process, the reaction mixture is at high temperature and Vapor pressure is implemented in the autoclave and in the production of alkylamino ethers from monosaccharides are low Yields of impure reaction products obtained due to the predominance of side reactions and the synthesis of by-products. It is also difficult to obtain the desired essentially pure monosaccharide ethers separated from the reaction mixture so that they are essentially free of impurities and for the therapeutic treatment of warm-blooded animals or warm-blooded animals can be used.

From the above, it follows that there is a need for a satisfactory process for the manufacture of Ithern the monosaccharides in high yield and purity is made with no dangerous chemicals or severe reaction conditions are required. Such a procedure is not yet available.

The present invention is therefore based on the object of a new process for the production of monosaccharide ethers to create in high yield and purity.

It is said to be a new process for the production of monosaccharide ethers be created in which almost no side reactions and by-products occur and in which mild reaction conditions and relatively non-toxic and harmless reactants are required.

6 P 9 R λ? / ι Π; ■ / _t

The inventive method for the preparation of ether-substituted Monosaccharides is characterized in that one

1) a monosaccharide derivative of the general formula AOH, in which 0 is oxygen, H is hydrogen and A is the remainder of a monosaccharide from the group of pentoses, hexoses and heptoses which has been converted into a derivative with at least one compound selected from the group (1-a ) at least one aliphatic alcohol containing 1 to 18 carbon atoms, and preferably 1 \ to carbon atoms, an acetal group being formed in place of at least one available hydroxyl group, (1-b) of at least one aldehyde containing 1 to 18 carbon atoms and preferably 1 to 4 carbon atoms, with formation of at least one acetal group in place of at least one available hydroxyl group, (1-c) of at least one ketone, containing up to 18 carbon atoms and preferably 1 to 4 "carbon atoms, with formation of at least? - ^j incr ketal group in the place of at least one * available hydroxyl group, and (1-d) at least one organic acid residue, containing 1 to 18 carbon atoms and preferably 1 to 4 carbon atoms, with formation of an ester group in place of at least one available hydroxyl group,

2) an organic halide of the general formula Y-X, in which X is chlorine, bromine or iodine and Y is is selected from the group (2-a) cyclic monova-

-8th-

organic groups and residues containing lent nitrogen, and (2-b) monovalent organic groups and radicals of the general formula -R.-B, in which B -N-Rp, -0-R. or -S-R ^

R ₁ denotes a divalent organic group with a linear carbon chain length of about 1 to 7 carbon atoms, Rg and R, H, -OH, -SH, halogen or monovalent organic groups and radicals with a linear carbon chain length of about 1 to 7 carbon atoms , R ^ -H or monovalent organic groups or radicals with a linear carbon chain length of approximately 1 to 7 carbon atoms, N denotes nitrogen, 0 denotes oxygen, S denotes sulfur and H denotes hydrogen,

to form an ether-substituted monosaccharide derivative of the general formula A-O-Y, wherein A and Y have the definitions given above. The monosaccharide derivatives (1) and the organic halides, (2) are dissolved in iron at an elevated reaction temperature essentially anhydrous organic solvent in the presence of a solid, essentially anhydrous strong inorganic base of a metal from the group of alkali metals and alkaline earth metals.

When Rg or R, is halogen, the halogen can be F, Cl, Br or J, of which Cl or Br are usually preferred. The organic group R ₁ and Rp, R, and R., when they are organic groups, can contain branched or unbranched, linear carbon chains and they can be saturated or unsaturated and, when

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if they are saturated, the linear and / or branched carbon chains can contain one or more double bonds or triple carbon-to-carbon bonds. The linear and / or branched carbon chains of R ₁ , R2, R- * and R ^ can be substituted or unsubstituted and, if substituted, one or more substituents can be present, such as -OH, -SH, halogen (F, Cl, Br and / or J), branched or unbranched and saturated or unsaturated hydrocarbon groups with 1 to 7 and preferably with 1 to 3 carbon atoms, -ORtf and / or -SRc groups, in which R 1 is a branched or unbranched and saturated or unsaturated hydrocarbon groups having 1 to 7 and preferably 1 to 3 carbon atoms, carboxylic acid radicals having 1 to 7 and preferably 1 to 3 carbon atoms, and amino groups and amino hydrocarbon groups having 1 to 7 and preferably 1 to 3 carbon atoms. Preferably, R ^ is a hydrocarbon group with a linear carbon chain length with 1 to 3 or 1 to 4 carbon atoms and R2, R- * and R ^ are individually hydrogen and / or hydrocarbon groups with linear carbon chain lengths with 1 to 3 or 1 to 4 carbon atoms.

Examples from which the aforementioned cyclic groups and radicals are derived may include (a) monovalent, or monovalent (these terms become

used synonymously) Nitrogen-containing saturated, unsaturated or aromatic carbocyclic compounds, containing about 4 to 8 carbon atoms in the ring and

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60984? / 10n

preferably about 5 to 6 carbon atoms in the ring and at least one nitrogen atom bonded to it or to an organic substituent, (b) heterocyclic organic compounds having about 3 to 8 carbon atoms in the ring and at least one ring nitrogen atom and (c) derivatives of the compounds described above, in which at least one substituent is present, such as -OH, -SH, halogen (F, Cl, Br and / or J), branched or unbranched and saturated or unsaturated hydrocarbon groups with 1 to 7 and preferably 1 to 3 carbon atoms, -ORg- and / or SRG groups wherein Rg branched or unbranched and saturated or unsaturated hydrocarbon groups having from 1 to 7 and preferably 1 to 3 carbon atoms, carbocyclic acid residues _r containing from 1 to 7 and preferably 1 to 3 carbon atoms, and amino groups and AminokohlenwassersLcffgruppen containing 1 to 7 and preferably 1 to 3 carbon atoms.

The monosaccharide residue A in derivative form can be used as an open Chain or cyclic form with, for example, the general formulas:

H-O

0 = C -
I. ²⁵ I. OW) I.
C = (H, I. OW) C =
I. (H, OW) I.
C =
I. (H, I.
^Z 2

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Cb)

- H

(H, OW)

(H, OW)

0-Η ·

(c)

(H, OW) (H, OW)

0 Z,

(H, OW) -

Ο-Η

wherein Z * and Zp are selected from -H, -OH, and monovalent hydroxyalkyl, alkoxy and / or alkoxyalkyl groups containing up to about 3 carbon atoms including, WH or a monovalent alkyl, alkenyl group, a cyclic alkane group, a cyclic aromatic Group or an acyl group each having 1 "to 18 carbon atoms and preferably 1 to

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Is carbon atoms or an acyl group with 1 to 18 carbon atoms and preferably 1 to 4 carbon atoms and where at least one of the groups Z ₁ , Z ₂ or ¥ has a meaning other than -H or -OH. All reactive -OH positions, with the exception of the -OH position or the positions which are ether-substituted, are preferably present in derivative form and are other than -H or -OH. The above general formulas explain the various isomers of pentoses, hexoses and heptoses, the relative spatial configurations of the —H or —OH groups around the ring and their derivative formation therefrom in accordance with a preferred embodiment of the invention. The hydroxyl or alkoxyl radical of the hemiacetal or hemiketal group can adopt an α or β configuration and the monosaccharide derivatives can be present in the form of the anomers or as mixtures of the anomers.

The configurations of the various derivatives of the isomers of pentoses, hexoses and heptoses are well known and numerous textbooks are available in this field, and examples are "Textbook of Biochemistry "4th Edition, by West et al (1966), and" The Monosaccharides "by Stanek, Cerny, Kocourek and Pacak (1963) · In the literature it is described, for example, that there are a total of eight open-chain isomers for reducing hexoses and an even larger number of open-chain isomers for reducing heptoses gives. In the practice of the present invention, either the D-series or the L-series of pentoses, Hexoses and heptoses can be used, but it is generally preferred to use the D-series.

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The hexoses often give better results and in particular D-Talose, D-Galactose, L-Galactose, D-Idose, D-GuIose, D-mannose, D-glucose, L-glucose, D-altrose and D-allose. The above-described pentoses, hexoses and heptoses can be attached to one or more of the hydroxyl groups into the derivatives and then in any remaining available positions or positions in the ether derivatives are transferred. The ether substitution at certain available reactive positions of specific monosaccharide derivatives gives therapeutic results more active or less toxic compounds. For example, an ether substitution results in the 3-0 position of 1,2-0-isopropylidene-D-glucofuranose or 1,2: 5,6-di-O-isopropylidene-D-glucofuranose and the 6-0-position of 1,2-0-isopropylidene-D-galactopyranose or 1,2: 3,4-di-O-isopropylidene-D-galactopyranose particularly valuable connections.

The following substituents can be present as the ether substituent Y in the general formula A-O-Y if one uses an organic halide reactant of the formula Y-X mentioned above, or they can be any available reactive positions of the various isomers of the pentoses present in derivative form, Hexoses and heptoses with the formation of non-toxic compounds with surprising therapeutic properties Activity be present:

- (n-propylamino),

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

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- (N'-Methylpiperidyl), - (NSN ¹ -Dimethylaminoäthyl), - (NSN ¹ -Diethylaminoäthyl), - (2SNSN ¹ -Trime thylamino-n-propyl), -Dimethylamino,

- (NSN ¹ -Dimethylaminomethyl), - (NSN ¹ -Dimethylaminopropyl), - (N ¹ , N ¹ -Dimethylamino-isobutyl), - (NSN ⁸ -Dimethylamino-n-butyl), - (N ', N' - Dimethylaminoisopentyl),

- (NSN * -dimethylaminopentyl), - (N'-methylamino-n-propyl), - (N ^f -methyl-N'-ethylamino-n-propyl), - (N ¹ , N'-diethylamino-n-propyl ), - (Amino-n-propyl) _f - (N'-Ethylamino-n-propyl), - (N'-Propylamino-n-propyl), - (NSN ¹ -Isopropylamino-n-propyl), - (1S 2'-ethylimino-n-propyl), - (1 * -n-propylpyrrolidyl), - (1'-n-propylpiperidyl), -piperidyl and

- (N ·, N ¹ -dimethylamino-sec-butyl).

Of the aforementioned substituents - (NSN'-dimethylamino-n-propyl) is currently preferred as Y in the formula YX and AOY, and particularly when it is in
the available 3-0-position of 1,2-0-isopropylidene-D-glucofuranose or 1,2: 5y6-di-0-isopropylidene-D-glucofuranose or in the 6-0-position of 1,2-0- Isopropylidene-D-galactopyranose or 1,2: 3,4-di-0-isopropylidene-D-galactopyranose is present.

609842/102 4

The following compounds of the general formula A-O-Y described above have antiviral activity with surprisingly broad spectrum and other valuable therapeutic properties and they can according to the invention Process can be produced when the corresponding monosaccharide derivatives are used as reactants A-O-H or hydrolyzable precursors thereof and organic ones Halides Y-X used:

3-0-3 '- (n-Propylamino) -i, 2-0-isopropylidene-D-glucofuranose, 3-0-3' - (N ¹ , N ^l -dimethylamino-n-propyl) -1,2- 0-isopropylidene-D-gluco-urano se,

3-0-4 '- (N'-methylpiperidyl) -1,2-0-isopropylidene-D-glucofuranose,

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

3-0-2 · - (N », N ^f -diethylaminoethyl) -1,2-0-isopro ^ ylidene-D-glucofuranose,

3-0-3 '- (2 *, N ¹ , N ^l -trimethylamino-n-propyl) -1,2-0-isopropylidene-D-gluco urano se,

3-0-2 '- (N ¹ , N • -Dimethylaminopropyl) -'! , 2: 5,6-di. O-isopropy-1iden-D-glukofurano se,

3-0-2 ^f - (N ', N' -Dimethylaminopropyl) -1,2-0-isopx'opyliden-D-glukofurano se,

6-0-3 '- (N', N '-Dimethylamino-n-propyl) -1,2-0-isopropylidene-D-galactopyranose,

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

3-0-3 '- (n-Propylamine) -1,2: 5,6-di-O-isopropylidene-D-glukofurano se,

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3-0-3 '- (N ", N'-dimethylamino-n-propyl) -1,2: 5,6-di-O-isopropylidene-D-glucofuranose _f

3-0-4 »- (N» -Methylpiperidyl) -1,2! 5,6-di-O-isopropylidene-D-glucofuranose,

3_0-2 '- (N', N ^t -dimethylaminoethyl) -1,2: 5,6-di-0-isopropylidene-D-glucofuranose,

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

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

6-0-3 '- (N ^f , N »-Dimethylamino-n-propyl) -1,2: 3,4-di-0-isopropylidene-D-galactopyranose,

6-0-2 ^! - (N ', N'-Dimethylaminopropyl) -1,2: 3,4-di-0-isopropyliden-D-galactopyranose,

aN ^! , N'-Dimethylamino-isopropyl-2,3: 5,6-di-O-isopropylidene-D-glucofuranoside and their organic and inorganic salts.

Additional compounds of the general formula A-O-Y, wherein Y

R ₂

means that according to the process according to the invention using the corresponding monosaccharide derivatives A-O-H (or their hydrolyzable precursors) and organic halides Y-X are prepared as reactants are listed below:

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Monosaccharide residues
(A) * Substituents
^R 1 (Y)
R ₂ ^R 3 3-0-1,2-0-isopropyli-
den-D-glukofurano se 3 »-n-propyl H methyl Il ti ethyl It Il Il H ethyl Il 2'-isopropyl methyl methyl Il 3'-1,2-propenyl It ti Il sec-butyl It π ti 3'-butyl η π ti 2'-ethyl H H Il methyl H H 6-0-1,2-0-isopropyli-
den-D-galactopyranose 3'-n-propyl H methyl Il It ethyl π ti Il H - • Ethyl Il 3 '-1,2-propenyl methyl methyl ti 2'-isopropyl π It It sec-butyl It ti It 3'-butyl ti It It 2'-ethyl H H ti methyl H H 3-0-1.2: 5,6-Di-O-iso-
propyliden-D-glukofu-
ranose 3'-n-propyl H methyl Il Il ethyl π It It H ethyl Il 2'-isopropyl methyl methyl Il 3 * -1,2-propenyl η η Il sec-butyl It It ti 3'-butyl It It Il 2 «-ethyl H H Il methyl H H

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2/1024

6-0-1.2: 3,4-Di-O-iso-
propylidene-D-galacto-
pyrinosis 3'-n-propyl H methyl Il It ethyl Il Il Il H ethyl It 3 '-1,2-propenyI L methyl methyl It 2'-isopropyl It η It sec-butyl π η Il 3'-butyl η ti ti 2 «-ethyl H H π methyl H H

* A or a hydrolyzable precursor thereof.

Further compounds of the general formula A-O-Y, wherein Y is a cyclic monovalent nitrogen-containing organic Group or a radical means, according to the process according to the invention using the corresponding Monosaccharide derivatives A-O-H or their hydrolyzable precursors and organic halides Y-X as Reactants can be produced are those the following: -

Monosaccharide residue substituent (Y)

(A) * cyclic group substituent

on the cyclic residue

3-0-1,2-0-isopropylidene-D- 4'-piperidyl H H gluco furanose 3'-piperidyl Methyl, Il Il 2 "-piperidyl η Il Il 3'-pyrrolidyl η π It 2 »-pyrrolidyl Il Il

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6-0-1,2-0-1sopropylidene-D-galactopyrano se

Il

3-0-1,2: 5,6-di-O-isopropylidene-D-glucofuranose

η ti

6-0-1,2: 3,4-di-O-isopropylidene-D-galactopyrano se

It It Il

4 "-piperidyl H H 3 ^! -Piperidyl Methyl, η 2 »-piperidyl π It 3 * pyrrolidyl η π 2 "-pyrrolidyl η 4'-piperidyl H H 3'-piperidyl Methyl, η 2 "-piperidyl ti η 3'-pyrrolidyl π η 2'-pyrrolidyl η 4 "-piperidyl H H 3'-piperidyl Methyl, Il 2 ^! -Piperidyl It It 3'-pyrrolidyl Il n 2 "-pyrrolidyl η

* A or a hydrolyzable precursor thereof.

According to the method according to the invention one can 'certain produce new compounds of the general formula A-O-Y, which can be prepared when one is a reactant the corresponding monosaccharide derivatives A-O-H (or their hydrolyzable precursors) and the corresponding organic halides Y-X are used, and which are listed below:

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

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3-0-3 "- (2 ', N ¹ , N ^! -Trimethylamino-n-propyl) -1,2-0-isopropy-

lidenglukofurano se,

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

gluko furano s e,

6-0-3 '- (N ¹ , N ^f -dimethylamino-n-propyl) -1,2-0-isopropyli-

dengalaktopyrano se,

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

galactopyranose,

3-0-3 «- (N ·, N'-Dimethylamine-n-propyl) -1,2: 5,6-di-0-isopro-

pylidene glucofuranose,

3_0-Zf ι _ (N'-methylpiperidyl) -1,2: 5,6-di-0-isopropylidene-

glucofuranose,

3-0-2 '- (N ¹ , N'-dimethylaminoethyl) -1,2: 5,6-di-0-isopropy-

eyelid glucofuranose,

3-0-3 "- (2 ', N., N. ¹ -trimethylamino-n-propyl) -1,2: 5,6-di-0-

isopropylidene glucofuranose,

3-0-2 '- (N ¹ , N ^f -dimethylaminopropyl) -1,2: 5,6-di-0-isopropy-

lidenglukofurano se,

6_0-3 «- (N ^I , N ^t -Dimethylamino-n-propyl) -1,2: 3,4-di-0-iso-

propylidengalactopyranose,

6-0-2 '- (N ¹ , N ¹ -dimethylaminopropyl) -1,2: 3,4-di-0-isopropy-

lidengalaktopyrano se,

a-N ', N'-dimethylaminoisopropyl-2,3: 5,6-di-O-isopropylidene-

glucofuranoside, and their organic and inorganic acid salts.

The right-handed or left-handed species of the above new compounds can be prepared by the process of the invention by the corresponding dextrorotatory or levorotatory monosaccharide derivatives A-O-H (or

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their hydrolyzable precursors) and the corresponding organic halides Y-X are used.

When an amine is used as the organic halide, it is preferable to use its organic acid salt or Use inorganic acid salt in place of the free amine and especially when the free amine is volatile and / or is toxic. In the method according to the invention, it is thus possible to use non-volatile and / or to use non-toxic forms of the organic halide as reactants. This removes the dangers avoided, which usually occur in the Williamson synthesis or in similar reactions of this type.

The monosaccharide derivative is made with an organic halide in the presence of a solid, substantially anhydrous, strong inorganic base of alkali metals and / or alkaline earth metals condensed. The preferred alkali metals are sodium and potassium and the preferred one Alkaline earth metal is calcium. The inorganic base * can, for example, be in the form of an oxide or hydroxide the alkali metal and / or the alkaline earth metal are present. The hydroxides are preferred and that is essentially the case anhydrous sodium hydroxide generally gives the best results. Even better results will be obtained when the inorganic base to remove moisture, carbon dioxide or other absorbed Connections was heated to elevated temperatures and a fresh surface was regenerated in the process. the The heating temperature should preferably be above 100 C and can be as high as required

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To remove moisture and carbon dioxide and regenerate a fresh surface, provided that the temperature does not exceed the melting point of the inorganic base. Similarly, the length of time should be sufficient be long so that the harmful moisture and / or carbon dioxide are removed and that on the inorganic Base regenerates a fresh surface. Extensive heating usually has no adverse effect once the moisture and carbon dioxide are removed. In most The inorganic base can precipitate at a temperature of about 100 to 200 ° C for about 6 to 48 hours and preferably at about 160 ° C for about 12 to Warmed for 24 hours before use. It is also advantageous to use the inorganic base in particulate Form, such as in the form of pellets, flakes, beads or other small shaped bodies to be used. The existing one increased surface area seems to be the implementation too

Jive. The size of the particles can be large within ^! ; oiche vary and it is only necessary that an au? sufficient surface is available so that the implementation is activated. The inorganic base can, for example, be in the form of small, thin sodium hydroxide flakes or in the form of sodium hydroxide beads corresponding to a sieve with a mesh size of 0.42 mm (40 mesh). However, flakes, beads, or particles several times smaller or larger than these, such as 1 to 5 times smaller or larger, can be used. Powdered or pulverized inorganic bases, and particularly finely powdered or powdered sodium hydroxide, can be used so that a high surface area per unit weight can be obtained.

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The inorganic base should be in an amount of at least one chemical equivalent for every mole of the organic Halide reactant may be present in cases where the organic halide is not an amine salt is. In the latter case, the inorganic base should be in an amount of at least two chemical equivalents may be present per every mole of organic halide so as to co-ordinate with the organic or inorganic Acid which forms the amine salt can react and so that a sufficient excess of inorganic base for the reaction with the halide is present in the reaction of the organic halide with the Monosaccharide derivative is released. Much larger amounts of inorganic base than this minimum can be used Amounts used are such as 2 to 10 times or more the theoretical amounts required for the reactions described above are required.

The monosaccharide derivative and the organic halide are reacted at an elevated reaction temperature while they are dissolved in a substantially anhydrous organic solvent. You can choose any suitable essentially anhydrous organic solvent based on the reaction conditions on the reactants used and the inorganic base which is inert. Examples of such organic solvents include cyclic and open chain ethers with approximately 4 to 8 carbon atoms, such as 1,4-dioxane and tetrahydrofuran and ethyl ether, and hydrocarbons, halogenated hydrocarbons and Ketones with about 2 to 10 carbon atoms, such as ben-

609842/102 4

zol, hexane, carbon tetrachloride, and acetone. The preferred Solvents are 1,4-dioxane and tetrahydrofuran, of which 1,4-dioxane is particularly good Results. The reactants and the desired reaction products should be in the selected solvent be soluble and the solvent should be present in an amount sufficient to dissolve the reactants and the reaction product. It can much larger amounts of solvent can be used, such as 1 to 10 times or even more than the minimum Amount required to dissolve the reactants and the desired reaction product.

The reaction time and temperature can vary within wide ranges. It is only necessary to use a temperature which is sufficiently high that a reaction between the monosaccharide derivative and the organic halide takes place without substantial thermal decomposition and that the reaction can proceed for a sufficiently long time that the desired degree of conversion is achieved . The reaction temperature may be from 30 to 150 ° C for example, approximately and is preferably about 60 to 120 ⁰ C. Usually the best results are achieved at a Reakrtionstemperatur of about 95 to 105 ° C. The reflux temperatures of 1,4-dioxane, tetrahydrofuran, acetone, ethyl ether and carbon tetrachloride are very suitable. If desired, the reaction can be carried out at above atmospheric pressure, whereby higher reaction temperatures can be used, and especially when low-boiling solvents such as ethyl

-25-

8-42 / 102 ^

ether, can be used. Atmospheric moisture and / or external water sources should not be present, so that the reaction mixture is not contaminated and thereby better results are obtained.

The reaction is preferred in the presence of a cleaning agent or absorbent or collecting agent (these terms are used synonymously in the following) for water, which is inert under the reaction conditions, carried out. Any suitable inert absorbent can be used for water such as calcium chloride anhydrous, sodium sulfate anhydrous and the like. Calcium chloride anhydrous is usually preferred. The absorbent is preferably present in an amount which is sufficient, the water of the reaction and / or any additional water required for the reaction mixture is disadvantageous to absorb. Much larger amounts can be used, such as 1 to 10 times or more the aforementioned minimum amount must be present.

The reaction of the monosaccharide derivative with the organic halide can take a sufficiently long time Time to elapse to obtain the desired percentage conversion. As a general rule, it is preferred that the conversion is greater than 75% complete, and preferably greater than 90% complete. The progression the reaction can conveniently be followed by gas chromatographic analysis and in these cases the reaction can be terminated at the desired percentage conversion.

-26-

6098 4 2

When the reaction is complete, the reaction mixture is filtered to remove the remaining residue, which consists mainly of the inorganic base and the absorbent. The filtration step should be carried out in a non-oxidizing atmosphere and without contact with an oxidizing gas such as air j unless the reaction temperature has first been cooled to a temperature low enough to prevent oxidation. It is generally preferred that the hot reaction mixture be filtered under an inert gas atmosphere such as nitrogen, argon or helium directly into a distillation flask using a candle-type filter or other suitable filtration device so that contact or contact with atmospheric air is avoided. The solid filter residue can be discarded and the various components in the filtrate can be separated by distillation under reduced pressure. Preferably the solvent has a boiling point lower than that of the reactants and of the desired reaction product, and in such cases the solvent fraction is recovered first. After drying with a drying agent such as anhydrous calcium chloride, the recovered solvent can be reused. After the solvent fraction has been removed, an unreacted organic halide fraction generally distills over and then an azeotropic mixture of unreacted monosaccharide derivative and the desired product. The azeotropic mixture is then distilled and an end fraction is obtained which contains the desired product, ie the ether-substituted monosficcharide.

-27-

■ 609842/1024

The sequence of stages described above is used in the work-up of the reaction mixture to obtain the desired ether-substituted monosaccharide product is preferred, but it is understood that also other suitable machining methods can be used. However, it has been found that the above Steps are very satisfactory in producing the desired product in high yield and very high Purity. Since the products of the present invention are useful therapeutic agents, high purity is very high important and potentially harmful by-products and other contaminants must be kept to a minimum.

It is a further variant of the present invention that a hydrolyzable monosaccharide derivative is selected for the reaction with the organic halide which has the general formula A ^ -OH, where 0 is oxygen, H is hydrogen and A _{1 is} the remainder of a monosaccharide the group pentoses, hexoses and heptoses, which has been converted into a derivative with at least one substance from group (1-a) at least one aliphatic alcohol having 1 to 18 carbon atoms, a hydrolyzable acetal group being formed in place of at least one available hydroxyl group , (1-b) at least one aldehyde having 1 to 18 carbon atoms, with at least one hydrolyzable acetal group being formed in the place of at least one available hydroxyl group, (1-c) at least one ketone having 1 to 18 carbon atoms, with at least one hydrolyzable ketal group is formed at the site of at least one available hydroxyl radical, un d (1-d) at least one organic acid residue

-28-

60984 2/1024

having 1 to 18 carbon atoms, with a hydrolyzable ester group being formed in the place of at least one available hydroxyl group. The corresponding reaction gives an ether-substituted monosaccharide derivative of the general formula A ₁ -OY, in which A ₁ and 0 have the definitions given above and Y has the definition given in connection with the organic halide YX. In these cases, A- can be viewed as a hydrolyzable precursor A, as defined above in connection with the compound AOY. _{The hydrolyzable monosaccharide A 1} -OH, which is present in derivative form, can be reacted with the organic halide under the same conditions and by the same processes as were explained above for the preparation of a compound of the general formula AOY.

The ether-substituted monosaccharide derivative of the general formula A ₁ -OY can be isolated from the reaction mixture according to the steps as indicated above for the preparation of the compound AOY. Then • at least one of the hydrolyzable acetal, ketal and / or ester groups is removed from A ₁ by hydrolysis in an acidic aqueous medium with a pH below 7, an ether-substituted monosaccharide of the general formula A2-OY being formed, where 0 and Y have the definitions given above and Ap denotes the radical of a monosaccharide which _{corresponds to A 1} , as defined above, at least one acetal, ketal and / or ester group having been removed therefrom. When the acidic aqueous medium has a pH of about 3 to 6

-29-

• 809842/1024

and preferably from about 4.0 to 4.5, it is possible to use only a portion of the acetal, ketal and / or Remove ester groups. If the pH is below 3, such as about 1 to 2.5, it is optional possible to all acetal, ketal and ester groups from the -OH positions, which are present as derivatives remove. The pH of the aqueous medium used for the hydrolysis step can be adjusted by adding a suitable organic and / or inorganic acid which has the desired pH. Mineral acids such as sulfuric acid and hydrogen chloride acid, are generally preferred. If the organic halide is an amine, the resulting will be hydrolyzed or partially hydrolyzed product obtained as a mineral salt by lyophilization. The won Product can be made from a suitable organic solvent, such as methanol, to produce the pure product Final product to be recrystallized. The acidic aqueous Medium for the hydrolysis stage should suitably based on the desired product, have a non-oxidizing effect, otherwise oxidized impurities will be formed can be.

The hydrolysis stage is at elevated temperature and during carried out a time sufficient to achieve the desired To give degree of hydrolysis. For example, the hydrolysis stage at the reflux temperature of the acidic aqueous medium for a time of about 6 to 48 hours and preferably for about 12 to 24 hours or until the desired degree of hydrolysis is achieved, which is determined by measuring the

609842/1024

the progress of the conversion is followed by gas chromatographic analysis. In the latter case, the hydrolysis is terminated, when the analytical values indicate that the peak characteristic of the starting compound has disappeared and that a new peak appears which is characteristic of the desired hydrolysis product. Afterward the aqueous solution can be cooled and the pH can be above 6.0 and preferably to about 6.5 and then lyophilize. The resulting desired hydrolysis product is precipitated and obtained in the form of crystals, which are obtained by recrystallization from organic solvents, can be cleaned as described above.

The preparation of simple derivatives of the compounds described in the present application is also possible Subject of the invention. Such derivatives can be prepared by methods and techniques known per se will. For example, the free amine compounds are basic and form organic acid salts and inorganic acid salts. The salts can be prepared by processes known per se; Add free amine compound to water and then add the desired organic acid or mineral acid in an amount add sufficient to neutralize the free amine. Examples of suitable acids include HCl, HBr, HpSO ^, HNO ,, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoic acid, p-hydroxybenzoic acid, alkanesulfonic acid, p-toluenesulfonic acid, acetic acid, alkylcarboxylic acids, oxalic acid, Tartaric acid, lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid and glucuronic acid. the

-31-

609842/1024

Aqueous solutions of the resulting salt can be evaporated to the volume that is necessary with it the salt precipitates as it cools. The precipitated salt is filtered off, washed and dried, whereby one the finished amine salt product is obtained. The amine salts are often preferred for formulating therapeutic agents, since they are crystalline and relatively unshygroscopic. The amine salts are also for intramuscular injection better suited than the free amines.

Known blocking methods can be used to convert the monosaccharides into derivatives which be reacted with the organic halide, such as the reaction with acetone and acetylation. Suitable known Blocking methods (or protection methods) are described in U.S. Patent 2,715,121 and the following Examples described. For example, it is an aldehyde or ketone with hydroxyl groups on adjacent carbon atoms implemented, the initial compound in the desired aldehyde or ketone are dissolved under anhydrous conditions and a Lewis acid catalyst can be added in a catalytic amount, such as 1% zinc chloride or anhydrous phosphoric acid, often is Acetone is the preferred blocking agent, but higher molecular weight aldehydes or ketones can be used if desired can be used, such as those containing up to 25 carbon atoms. The reaction mixture can be Room temperature for an extended reaction time of 24 to 48 hours. The connection can be protected in a variety of positions such as the 1,2 and / or 5,6 positions.

-32-

609842 / 10-2

It is also possible to protect one or more free hydroxyl units of the compound with an ester group, the carboxylic acid radical containing 1 to 18 and preferably 1 to 3 carbon atoms. The ester derivatives can be prepared in a similar manner by methods known per se, such as by reacting a carboxylic acid anhydride with the compound. In addition, the α- or β-alkyl derivatives of the monosaccharide derivatives, such as 2,3: 5,6-di-0-isopropylidene-D-glucofuranoside, can be prepared by processes known per se. In the latter case, the compound is dissolved in a dry alcohol of the desired carbon length with the aforementioned residue and reacted with the compound in the presence of a catalyst such as the hydrochloride of Dowex 50 H + resin. Although the derivatives described above are preferred, other simple derivatives can be prepared by methods known per se and used in the present invention. The compounds can also contain monosaccharide derivatives, where the substrate Y can be replaced by a substituent Rg, where Rq is a deoxymonosaccharide derivative of a halogen, keto, amino, lower alkyl, mercapto, alkenyl, alkynyl, an aromatic, heterocyclic or alkyl carboxylic acid or its derivatives. Rg can also mean the same groups as the above substrate of the monosaccharide derivative ethers. Other compounds have the general formula AOY, where Y is -Rg-SR ₁₀ , where Rq is a saturated or unsaturated hydrocarbon group with 1 to 7 carbon atoms and R ^ _{0 is} a single

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609842/102

valued saturated or unsaturated hydrocarbon group with 1 to 7 carbon atoms and hydrogen
mean.

Those produced by the process of the invention
Compounds are useful, wide spectrum antiviral agents for the therapeutic treatment of warm blooded animals. They show a potent antiviral activity against RNA and DNA viruses, which is in contrast to the known antiviral agents. The connections show remarkable suppression
virus particle multiplication and virus-induced cell damage in animal and human
Cell tissue culture systems against a wide variety of viruses such as herpes simplex, influenza A, mumps, poliovirus and rhinovirus.

609842 / 102Λ

The following examples illustrate the invention without restricting it.

example 1

To a solution of 104 g (0.4 mol) 1.2: 5.6 = di ~ 0j-isopropylidene ~ J) -glucofuranose in 550 ml of 1,4-dioxane is added 189.7 g (1.2 mol) 3-chloro-N, N-dimethylaminopropane in the form of the hydrochloride salt and 144 grams (3.6 moles) of sodium hydroxide. The suspension is stirred mechanically and refluxed for 18 hours. the The reaction mixture thus prepared is filtered, the solids are washed with 1,4-dioxane and the washing solutions are combined with the filtered liquid. The solvent is removed under reduced pressure and one obtains an amber-colored, viscous oil.

The oil is distilled in a high vacuum (less than 1 mm Hg) while purging very little with dry nitrogen, resulting in high and low boiling fractions. The low-boiling fraction is identified as unreacted 3-chloro-N, N-dimethylaminopropane. The high-boiling fraction has a boiling point of 148 to 154 ° C at 2.5 mmHg and is a clear, viscous oil with an optical rotation of Ia] J ³ = -19.3 ° pure (100 mm) and a density of 0 * 95 g / cc. The refractive index is n _D = 1.4576. Gas chromatography shows a purity higher than 99%. An elemental analysis gives: C 59.13%, H 8.99%, N 4.12%, O 27.7%. The yield is 80% of the new compound 1,2: 5,6-di-O-isopropylidene-3-O-3 '- (N', N '-dimethylamine-n-propyl) -D-glucofuranose.

-35-60984 2/102/4

A portion of the above oil (10 g) is hydrolyzed in aqueous sulfuric acid at a pH of 1.9 to 2.1 for 10 hours with refluxing. The resulting solution is adjusted to pH 4.5 with saturated Ba (OH) ₂ solution, centrifuged and filtered through an ultrafine filter. The filtrate is lyophilized, a colorless to slightly yellow solid with a melting point of 78 to 80 ° C. being obtained. The gas chromatography data indicate that the compound is over 99% pure 3-0-3 '- (N ¹ , N'-dimethylamino-n-propyl) -D-glucopyranose. In thin-layer chromatography, the flow rate on silica gel with a solvent mixture of n-propanol, ethyl acetate, H ₂ O and NH, in a volume ratio of 60: 10: 30: 10 as an R _f value = 0.356.

A portion of the oil is partially hydrolyzed to 1,2-0_-isopropylidene-3-0-3 '- (N ¹ , N'-dimethylamino-n-propylJ-Dj-glucofuranose by dissolving it in distilled water and adjusting the pH The value of the approximately 1M solution is adjusted to 3.0 + 0.2 with 6N HCl, the solution is extracted twice with chloroform and the clear, aqueous solution is refluxed for approximately 2 hours Disappearance of the peak of the basic compound followed and the appearance of a new peak with a longer retention time. The solution is then cooled, made alkaline with 30% sodium hydroxide to pH 10.5 and 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 optical rotation of a °. = -12 ° and a refractive index of 1.4687 at 2 5 ° C. Alternatively, the compound can be obtained as the hydrochloride salt by lyophilization of the aqueous solution after partial hydrolysis at pH 4.0 to 4.5. A colorless, crystalline material is obtained which is recrystallized from methanol. The crystalline hydrochloride of 1,2 ^ 0-isopropylidene-3-Q-3 ^t - (N ^f , N'-dimethylamino-n-

609842/1024

-36-

propyl) -J> gXucofuranose has a melting point of 181 up to 183 ° C and the purity, determined by gas chromatography, is 98 +%. Infrared spectrophotometry shows the presence a strong -OH band not present in the base oil. The elemental analysis is for the hydrochloride salt shown in a * typical approach:

calculated: C 49.19% H 8.19% N 4.09% Cl 10.39% 0 28.11% found: 49.09 8.40 4.14 10.32 28.12.

The gas-liquid chromatograms for the above intermediate and for the new end connections are made on a Beckman GC, Model 72-5, with a hydrogen flame detector recorded. The column used for the intermediate is a commercially available SE-52 column in which Methylphenyl resins act as stationary phases and Chromosorb ¥ (H.P.) acts as a carrier, which is made by the Johns-ManvilIe Corporation will be produced. The new end compound is chromatographed on a Chromosorb 103 glass column lined with porous resins is packed. The materials described above are commercially available.

Example 2

51 g (0.3 mol) of '4-chloro-N-methylpiperidine hydrochloride are used and 26 g (0.1 mole) 1,2: 5,6-di-.0_-isopropylidene-J} -glucofuranose and 36 g of NaOH in 150 ml of 1,4-dioxane as starting materials and carries out the condensation as described in Example 1. The one after the subsequent vacuum distillation remaining residue is dissolved in hot methanol and recrystallized. The m.p. is 106 to 107.5 ° C (sharp).

The hydrolysis of the above product in H ₂ SO ^ at a pH of 2.1 gives 3-O.-4 ^f - (N'-methylpiperidyl) -J> -glucopyranose with a dopic rotation of [oc] jp = + 38.42 ° in H ₂ O. One. Gas chromatography analysis according to the procedure of Example 1 shows that the purity of the product is over 96%.

6098 4 2/1024 " ³⁷ "

The m.p. is 62 to 65 ⁰ C.

Example 3

A solution of 0.1 mol of 1,2: 5,6-di ~ JD-isopropylidene-J) - glucofuranose in 50 ml of tetrahydrofuran becomes a suspension of 0.3 mol of 2-chloro-N, N-diethylaminoethane hydrochloride and 36 g of sodium hydroxide are added to 100 ml of tetrahydrofuran. The suspension is stirred mechanically and refluxed overnight and the reaction mixture is treated as described in Example 1. The desired product, 1,2: 5,6-Di-J) -isopropylidene-3-_0-2 «- (N ', N ^f -diethylaminoethyl) -D-glucofuranose, is obtained as a clear, yellow liquid (bp 144 until

QQ

150 C / 0.15 mm Hg) with an optical rotation of ΓαI ^ = -20.6 (pure) and a refractive index of V ^ = 1.4532. The liquid solidifies under the action of air, presumably due to the formation of the carbonate salt. The yield is 85%

10 g of the above product are hydrolyzed with aqueous sulfuric acid at a pH of 1.9 to 2.1 for 10 hours under reflux. The pH of the resulting solution is adjusted to 4 to 5 with saturated barium hydroxide solution, and it is then centrifuged and filtered. Lyophilization of the filtrate gives 6.55 g of light brown, crystalline 3-0-2 '- (N ¹ , N ¹ -diethylaminoethyl) -JD-glucopyranose. The optical rotation in water is [a] _D = + 36.33 °. A gas chromatography analysis according to Example 1 shows that the purity is above 99-6.

Example 4

To 26 g (0.1 mole) 1,2: 5,6-di - ^ - isopropylidene - ^ - glucofuranose and 36 g (0.9 mol) of sodium hydroxide in 150 ml of refluxed tetrahydrofuran are added dropwise in the course of 0.3 mol of 3-bromopropionitrile in 50 ml of tetrahydrofuran for 1 hour. The reaction mixture is refluxed for a further 6 hours and then filtered. The solids are treated with tetrahydro-

609842/1024, 0

30th

furan and the wash waters are combined with the filtrate. The solvent is removed under reduced pressure and becomes solid. 1,2: 5,6-di- _: 0-isopropylidene-3 - ^ - 3 ^l -propionitrile ~ j3-glucofuranose is obtained. The decomposition point is 15 ° C and it is photosensitive, which indicates its usefulness in photographic applications.

5 g (0.016 mol) of the above product are dissolved in anhydrous ether and added dropwise to a suspension of 0.76 g (0.02 mol) lithium aluminum hydride in ether was added. Of the . the resulting complex is dissolved in cold hydrochloric acid and quickly neutralized with sodium bicarbonate. The suspension thus formed is extracted with chloroform and the solvent is removed to give a yellow oil in a yield of 250 mg. The gas chromatography according to example 1 shows a purity of 98% and a sharp one is obtained Infrar.otbande at 3400 cm ". The oil is at pH hydrolyzed from 2.1 in sulfuric acid and lyophilized to dryness. The yield is 85 mg of 3- ^ 0-3 '- (n-Propylamino) -D-glucopyranose

Example 5

The 3 - ^ - 2 '- (N ^1, N'-dimethylaminopropyl) derivative of 1,2: 5,6-Di_P_-isopropylidene-I) -glucofuranose is prepared by ^r ~ to 0.1 mol 1.2 : 5,6-Di- _: 0-isopropylidene-D-glucofuranose condensed with 0.3 mol of 2-chloro-N, N-dimethylaminopropane hydrochloride in the presence of 0.9 mol of sodium hydroxide in 150 ml of 1,4-dioxane. The reaction mixture is fractionally distilled under reduced pressure, giving a yellow, viscous oil (boiling point 142 to 145 ° C./0.7 mm Hg), yield 81%. The optical rotation is [α] ™ = -21.5 ° (pure) and the refractive index is rj ■> = 1.4549. Gas chromatography according to Example 1 shows that only one component is present.

609842/1024

The yellow, viscous oil prepared above (10 g) is hydrolyzed with aqueous sulfuric acid at a pH of 2.0 while heating under reflux for 10 hours. The pH of the hydrolyzate is adjusted to 4 to 5 with saturated barium hydroxide solution, then it is filtered and lyophilized, whereby 10.5 g · light yellow crystals of 3-0.-2 ^f - (N ^f , N »-dimethylaminopropyl) - D-glucopyranose receives. The optical rotation in water is [a] ^ = + 37.86 °. Gas chromatography according to Example 1 shows a purity of over 82%.

Part of the oil, 1,2: 5,6-di-ü-isopropylidene-3 - ^ - 2 »- (NJ, N'-dimethylaminopropyl) - ^ D-glucofuranose, is partially hydrolyzed at a pH of 3.0 + 0.2 as described in Example 1. A white, crystalline hydrochloride salt is obtained on lyophilization. The salt obtained is very hygroscopic and its purity as determined by gas chromatography is on the order of 80%.

B ^ i s pi e 1 6

0.3 mol of 2-N, N-trimethylaminopropyl chloride hydrochloride together with 36 g of sodium hydroxide are added to 0.1 mol of 1.2: 5, e-di-JJ-isopropylidene-JD-glucofuranose. In general, the procedure described in Example 1 is followed. The oil obtained from the reaction has a boiling point of 144 to 146 ° C at 0.6 mmHg and an optical rotation of [a] _D = -20.05 ° (neat).

The above product is hydrolyzed according to the general procedure of Example 1 to give the desired 3 - ^ - 3 ^f - (2 ^f -N ¹ , N ¹ -trimethylamino-n-propyl) -JD-glucopyranose. The optical rotation of the product in water is [oc] q = + 38.0 °.

A portion of the oil, 1,2: 5,6-Di-isopropylidene-3 .0 ₁ 0. 3 ^l - (2 ^{t l} -N, N ¹ -trimethylamino-n-propyl) ~ D.-glucofuranose , is partially at a pH value of 3.0 + 0.2 according to the described in Example 1

. -40-609842 / 1024

beneath process hydrolyzed. Colorless, crystalline 1,2-O-isopropylidene-3- £ -3 '- (2 ^! -N ¹ , N ¹ -trimethylamine-npropyl) -D-glucofuranoεe hydrochloride, which is very strongly hygroscopic, is obtained. The optical rotation of the hydrochloride salt at pH 7.0 and 25 ° C is -21.33 °. Gas chromatography analysis indicates that it is more than 99% pure major component.

B is ρ ie 1 7

Using the general procedure described in Example 1, 0.02 mol of 1,2: 5,6-di- _I 0-isopropylidene-I) -glucofuranose in 1,4-dioxane with 0.0225 mole of 2- (2-chloromethyl ) -N-methylpyrrolidine hydrochloride and 0.0675 mol of sodium hydroxide reacted. After 18 hours the solvent is removed and the resulting orange oil is distilled in vacuo under nitrogen. The residue contains the desired product, 1,2: 5,6-Di-J3-isopropylidene-3-0-2 «- (2" - (N "-methylpyrrolidyl) ethyl-vD-glucofuranose, with an optical rotation of ί «] Ψ = -22.95 ° in chloroform.

Example 8

1,2: 5,6-Di- ^ isopropylidene-D ^ -glucofuranose (0.1 mol) and N- (2-chloroethyl) pyrrolidine hydrochloride (0.15 mol) are stirred mechanically and with 0 , 45 moles of sodium hydroxide in 150 ml of tetrahydrofuran for 18 hours, heated to reflux. The tetrahydrofuran is removed from the reaction products and the resulting oil is distilled in vacuo under nitrogen. The .3 - ^ - 2 ^f - (N «-pyrrolidyl) ethyl -1,2: 5,6 ~ di-0_-isopropylidene-D ^ glucofuranose derivative has a boiling point of 165 to 171 ° C / 0, 15 mmHg. Gas chromatography shows a purity of 99%. Using the hydrolysis procedure described in Example 1, 10 grams of the blocked oil is hydrolyzed and lyophilized to give a colorless, crystalline, hygroscopic pesticide.

609842/102 4

Example

The N ^ N'-dimethylamino-n-pentyl derivative of 1,2: 5,6-di-0-isopropylidene-J> -glucofuranose is prepared by adding N ₁ N-dimethylamino-n-pentyl-5-chloride hydrochloride with 1,2: 5,6-Di-0-isopropylidene -]> - glucofuranose in the presence of powdered sodium hydroxide in frischgereinigtem, dry 1,4-dioxane according to _t .nren condenses the author described in example. 1 The product is confirmed by gas chromatography and infrared spectrum.

Ν, Ν-Dimethylamino-n-pentylchloride hydrochloride is made from a commercially available. available sample of Ν, Ν-dimethylamino-n-pentyl alcohol prepared by treatment with thionyl chloride (SOCl ₂ ). Specifically 10.7 g of thionyl chloride in a 250 ml three-necked round bottom flask are cooled in a salt-ice water bath and stirred vigorously. 10 g of Ν, Ν-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 1 hour after the formation of SO ₂ and HCl by-products. The mixture is warmed to room temperature and stirred overnight. Absolute alcohol is added to destroy excess thionyl chloride. 10 g of crude NjN-dimethylamino-n-pentyl chloride hydrochloride are obtained as a colorless solid. This is used directly for the condensation reaction with 1,2: 5,6-di-_0 ^ -isopropylidene-Dj-glucofuranose without further purification. The alcohol and chloride can be separated on Chromosorb 103 in a gas chromatography column.

Example 10

Bromine (9.8 g) is slowly added dropwise to a mechanically stirred solution of 50 g of crushed ice and a cooled, added aqueous sodium hydroxide solution (7 g / 20 ml water). After the addition of bromine is complete, 15 g of 1,2: 5,6-Di ^ Pj-isopropylidene-3-O-acetamido-D-glucofuranose are added (manufactured according to the

6098Ο / 1Π? /, · -42-

general method described in Example 1 by condensation of 1 ^^, ö-Di-JDj-isopropylidene-Dj-glucofuranose with 2-chloroacetamide in the presence of. Sodium hydroxide) in four parts added with an interval of 15 minutes. The reaction mixture is heated in a water bath for 1 hour. After this At this point, an additional aqueous solution of sodium hydroxide (20 g / 20 ml) is added and another heated Hour. The mixture is cooled and extracted three times with ether. The ether extract is dried over anhydrous magnesium sulfate. The yellow, hygroscopic solid that remains after evaporation of the ether is the desired 1,2: 5, ö-di-O-isopropylidene - ^ - Oj-aminomethyl-Dj-glucof uranose derivative. The product is characterized by the disappearance of the carbonyl

-1

oscillation identified at 1670 cm, which in the fundamental

Acetaraido compound occurs.

Example 11

Known, well-developed methods are used to determine the antiviral potency of derivatives of 1,2-0-isopropylidene-JD-glucofuranose'HCl against poliovirus, type 1, and rhinovirus, type 1A, in tissue cultures at ^ 7 ° C, using HeLa cells with an agar overlay and WI-38 cells (cf. C. Wallis, F. Morales, J. Powell and JL Melnick, Plaque enhancement of enteroviruses by magnesium chloride, cysteine, and pancreatin, J. Bacteriol.91_ »1932-1935, 1966). Poliovirus cell damage was determined by examining platelet formation and the rhinovirus was examined for cytopathic effects. Table I shows the virus-inhibiting effects of three concentrations of the 3 - ^ - 3 '- (N ^f , N ^f -dimethylamino-n-propyl) derivative. The results are reported as the rate of inhibition of infection, identified as platelet formation in the poliovirus system, and as the cytopathic effect in the system in which the rhinovirus is tested. The results indicate that at the appropriate dose, the drug completely formed 1000 platelets

609842/102 4 " ⁴ ^ -

Units (PFU) of poliovirus inhibited and a 1000 TCTD ^ Q dose of Rhinovirus 1A, a virus dose that is 100O times the amount required to kill 50% of the cultured tissue cells.

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609842/1024

Derivatives of 1.Z-ü-IsoOropyliden-B-glucofuranose'HCl

Table I - Summary of Antiviral system virus Type 1 Titer PFU ¹ Effects in tissue culture drug derivative dose Poliovirus
Type 1 50 PFU determination effect / µg / ml HeLa cells in
vitro with agar
Overlay Il 1 250 PFU total inhi
bation 2 - & - 3 ¹ - (NSN ¹ -Dime-
thylamino-n-propyl) 1 Il. ' It 1 000 TCID ^ Number of platelets Il Il 20th It Rhinovirus
Type 1A 100 It Il Il ti 40 WI-38 cells ti 000 Il ti total inhi
bation 3-0.-3 ^f - (Ν », Ν« -Dime-
ethylmethylamino-n-
propyl) 2 Il ti 000 cytopathi-
2) see we- It Il 20th dd dd dd 40 Il

1) Tile-forming units

2) infectious tissue culture dose on 50% of the cells

Example 12

Derivatives of 1 ^ -JD-isopropylidene-D-glucofuranose hydrochloride are being tested for their ability to suppress influenza A 2 diseases in mice and for their ability to suppress fatal and non-lethal nervous system diseases caused by encephalomyocarditis virus in mice will. In these investigations, the drug effect on pulmonary pathology is investigated, which is obtained by 15 ID ₁ -Q dose of influenza virus. This dose is 15 times the dose that gives disease in 50% of the animals. The disease and the drug effect on the disease are determined by the weight gain and loss of the lungs. In the encephalomayocarditis examination, 10 times the amount required to kill 50% of the animals is given and the extent of non-lethal disease and fatalities is determined, as is the drug inhibition of both of these parameters. The results of these experiments are summarized in Table II and indicate the formation of a remarkable reduction in lung weight gain by the drug as well as a remarkable inhibition of the fatal and non-lethal disease caused by encephalomyocarditis virus. These effects are more pronounced for the 3-0.-3 '- (N ¹ , N ¹ -dimethylaminen-propyl) derivative than for the other two derivatives investigated.

-46-

60984?

Derivatives of 1.2-ü-IsopropYliden-fi-glucofuranose'HCI

derivative

Table II - Summary Type the antiviral effect in ¹ V determination vivo in mice dose system virus vivo influenza
Type a LD ₅₀ Drug action mg / kg Encephalo-
myocarditis Titer Il Lung weight
increasing 20th Mice in Il 15th Il Occurrence of
CNs3; and death • considerable reducers,
id lung weight
increase 80 Il Il 10 ■ II Il considerable inhibition
tion at deadly and
non-fatal disease 160 Il Il 10 Il It ti 80 Il Il 10 Il considerable inhibition.,
but less than at
the n-propyl derivative 160 Il 10 Il Il - 80 Il 10 Il

2 (S dimethylaminonopropyl)

O CD CO

3-0.-2 '- (N ¹ , N ¹ -. Dimethylaminoisopropyl)

Trimethylaminonopropyl) 160

10

1) infectious dose at which 50% of the animals are affected

2) lethal dose at which 50% of the animals are killed

3) central nervous system

Example 15

This example describes the preparation of 1,2: 5,6-di-O-isopropylidene-3-0-2 '- (N', N ^f -triraethylamino-n-propyl) -D-glucofuranose.

0.6 mol of 3-chloro-N, N-2-trimethylpropylamine chloride hydrochloride, 1.8 mol of preheated sodium hydroxide beads, 10 g of anhydrous magnesium sulfate and 500 ml of dry 1,4-dioxane in a three-necked 3-liter reaction flask equipped with a mechanical stirrer and a reflux condenser. The reaction mixture is stirred well and refluxed for approximately 20 hours. The course of the reaction is followed by gas chromatography analysis. The reaction mixture is allowed to cool and is then filtered and the dioxane solvent and unreacted amine are removed from the filtrate under reduced pressure on a rotary evaporator. 135 g of a colorless, somewhat yellow, viscous oil are obtained in the fractional distillation at 144 to 146 ° C. at a pressure of 0.6 mm Hg. The oil has an optical rotation of [a] o undiluted, 100 mm Hg = -20, 05 ⁰ C. The yield is over 85%.

Example 14

This example uses the preparation of 1,2: 5,6-di-O-isopropylidene-3-0-3'-propanol-D-glucofuranose explained.

Into a three-necked reaction flask equipped with a mechanical stirrer and a reflux condenser,

-48-

.609842 / 10? /,

52 g of 1,2: 5,6-di-0-isopropylidene-D-glucofuranose are added, 25 g of 3-chloropropanol, 24 g of sodium hydroxide, 5 g of anhydrous calcium chloride and 250 to 300 ml of dry 1,4-dioxane. The reaction mixture is refluxed moderately for 16 to 20 hours and the reaction is gas chromatographed tracked. The solvent and unreacted 3-chloropropanol are removed by fractional distillation removed. The yield is over 70%.

A similar reaction is then carried out in an autoclave at steam pressure. The yield is lower and dark brown-red impurities are formed, which are difficult to achieve by chemical methods or column chromatography are to be isolated.

Example 15

This example describes the preparation of 1,2: 5,6-di-O-isopropylidene-3-O-methylthiomethyl-D-glucofuranose explained.

A reaction mixture containing 52 g of 1,2: 5,6-di-0-isopropylidene-D-glucofuranose, 58 g chloromethyl methyl sulfide, 48 g preheated sodium hydroxide and 200 ml dry tetrahydrofuran is heated to reflux overnight with good mechanical stirring. The mixture is filtered, then dried and the solvent is removed under reduced pressure. With fractional distillation a fraction which boils between 140 to 148 ° C. at 0.1 mm Hg pressure is collected as a yellowish oil. The oil also contains some unreacted 1.2: 5.6-

-49-

609842/10? k

Di-0-isopropylidene-D-glucofuranose. The latter is through selective crystallization removed from hot hexane solution. The end product is a yellow oil with an optical appearance Rotation of [αΙ ^^^ η ^, 100 mm Hg = -42.5 °.

Example 16

A solution of 26.0 g of 1 ^^^ - Di-O-isopropylidene-D-galactopyranose in 50 ml of anhydrous THF is mixed with a suspension of 0.3 mol of 3-chloro-N, N-dimethylaminopropane hydrochloride and 36 g of sodium hydroxide mixed in 100 ml of THF. The mixture is stirred well and refluxed for 3 hours. The resulting brownish solution is cooled, filtered and most of the solvent is evaporated, a brown oil remains. The remaining solvent and unreacted 3-chloro-N, N-dimethylaminopropane are removed by fractional distillation under reduced pressure. The remaining oil is with Chloroform extracted, decolorized with activated charcoal and dried over anhydrous magnesium sulfate. The distance of the chloroform gives 13.4 g of a yellow oil which is found as 1,2: 3,4-di-O-isopropylidene-6-0-3 '- (N', N'-dimethylamino-n-propyl) -D-galactopyranose is identified. The infrared spectrum and gas chromatography according to the example 1 show the presence of a main component with

28
a refractive index of 1 \ n = 1.461 and an optimal

see rotation of C ⁰ Ot) = -49.4 in chloroform.

The oil is refluxed with 50 ml of 0.5N sulfuric acid for 18 h warmed up. The resulting solution is washed with chloroform and the pH is adjusted to 4.2.

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On lyophilization, the aqueous solution gives 4.67 g of colorless crystalline solid 6-0-3 '- (N ¹ , N'-dimethylamino-n-propyl) -D-galactopyranose with an optical rotation of [a] ^ ⁵ = + 77.2 ° in H ₂ O. A gas chromatographic analysis according to Example 1 shows that the purity of the product is above 95%.

Example 17

This example illustrates the preparation of 6-0-2 '- (N ¹ , N ¹ -dimethylaminopropyl) -D-galactose.

One proceeds according to general manner as described in Example 2, except that 2-chloro-N, N-dimethylaminopropanhydrochlorid is used as starting material in place de * corresponding 3-chloro derivative. The intermediate product has an optical rotation in water of [α] τ-) = -54.5 and a refractive index of n ^ = 1.4552. The end product has a flow rate in the thin layer chromatography analysis corresponding to Example 1 with an Rp of 0.376.

Example 18

The most effective of the above derivatives, 3-0-3 ⁸ ~ (N ', N ^f -dimethylamino-n-propyl) -glucose * is being studied for its ability to suppress Influenza Ap / Hong Kong disease in mice. In this experiment, mice are infected with a sublethal, disease-causing dose of human influenza virus adapted for mice and either with distilled water (control) or with

609842/102

40 mg / kg of compound treated. 50% of the drug administered is in a form with reduced hydrophilicity due to the addition of the labile organic acetone group at the 1,2-positions to improve absorption in cells and slow release of body fat. The drug is administered orally and begins 24 hours after infection. The disease progression and the drug effect are evaluated after 8 days by examining the lungs for hepatization according to the method of TW Chang and L. Weinstein (Am. J. Med. Sci. 1973) and according to an objective method by weighing the lungs. An increase in the weight of the lungs during influenza indicates edema, bleeding and virus content (see P. Gordon and ER Brown, Canad. J. Micrp. 18: 1463, 1972). In the following Table III, Part A, di · :. objective fourth given for the lung weights and it can be seen that an 82% suppression of the disease is possible by the derivative according to the invention.

The above drug was also tested for its ability to kill mouse disease with Iethaler Prevent influenza A / PR / 8 infection. The drug is administered subcutaneously in three doses, the first time 90 min before infection. The results explain a considerable dose-dependent Protection against death and are listed in Table III, Part B.

609842 / 10Ή

Table III
A. Influence on mouse disease in influenza A ₂ / Hong Kong disease

Group Average % Disease Frequency of Normal Lungs

Lung Weight (mg) Suppression (<170 mg)

normal 160 21/21

infected comparison group 258 1/21

ο infected treated group 177 82 13/21

* "B. Influence on mouse disease in a lethal influenza A / PR / 8 infection

ο Drug mortality frequency % mortality % protected population

O (comparison)

10 mg / kg 18/22 81 14

40 mg / kg 16/22 72 23

160 mg / kg 10/22 45 50

Mortality frequency % Mortality after 8 days 42/44 95 18/22 81 16/22 72 10/22 45

Example 19

Known well-developed methods are used to determine the antiviral potency of the compounds against Hong Kong Influenza Ap virus strain in tissue cultures using hamster kidney cell line methods in small hamsters (see the so-called baby hamster kidney cell line method (see RL MuI-doon, L. Mezny and GG Jackson in "Antimicrobial Agents and Chemotherapy" 2: 224-228, 1972). Virus infectivity is assessed both according to the hemaglutination method and according to cytopathogenic effects, with identical results being obtained with both methods. The following Table IV shows the virus-inhibiting effects at two low drug concentrations, 3 and 10 µg / ml. The results are presented as the log decrease in the infectivity of the virus inoculum. A log decrease of 4.0 is the maximum decrease obtainable and it represents a complete suppression of virus growth in the system. The virus inoculum of day 0 is almost 100 times the amount required by 50% of the tissue culture cells to kill (100 TCD, -q). These results show that the different derivatives suppress virus growth by 3 to 10,000 times, with 3-0-3 '- (N ¹ , N ¹ -dimethylamino-n-propyl) -glucose showing the greatest effect.

Table IV

link

Log decrease in the infectivity of the virus inoculum at concentrations of 3 mg / ml 10 η g / ml

3-0-3 '- (N', N'-dirnethylamino-n-propyl) ■ D-glucose

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

3-0-2 ^f - (N ·, N »-dimethylaminoethyl) -D-glucose

3-0-3 '- (2', N ', N ¹ -Tr imethylamino-n-propyl) -D-glucose

α-Ν, Ν-dimethylaminoisopropyl glucoside

6-0-3 '- (N ^f , N • -Dimethylamino-n-propyl) -D-galactose

3-0-2 '- (N', N »-Dimethylaminopropyl) -D-glucose

3-0-2 '- (N', N ^l -diethylaminoethyl) -D-glucose

6-0-2 '- (N ^f , N' -Dimethylaminopropyl) -D-galactose

3.2 4.0 (max.) 2.5 3.5 2.5 3.5 2.4 3.0 1.5 2.5 1.0 2.0 1.0 2.0 0.5 1.0 0.1 0.5

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609842/10? H

Claims (38)

Claims 1. j Process for the preparation of an ether-substituted monosaccharide, characterized in that one 1) a monosaccharide derivative of the general formula A-O-H, where 0 is oxygen, H is hydrogen and A the remainder of a monosaccharide from the group of pentoses, hexoses and heptoses mean that with at least a substance from the following group was converted into a derivative (1-a) with at least one aliphatic alcohol containing 1 to 18 carbon atoms with an acetal group in place is formed by at least one available hydroxyl group, (1-b) with at least one aldehyde, containing 1 to 18 carbon atoms, with at least an acetal group is formed in the place of at least one available hydroxyl group • is containing (1-c) with at least one ketone 1 to 18 carbon atoms, with at least one Ketal group is formed in the place of at least one available hydroxyl group, and (1-d) with at least one organic acid residue containing 1 to 18 carbon atoms, with an ester group is formed in the place of at least one available hydroxyl group, 2) an organic halide of the general formula Y-X, in which X is chlorine, bromine or iodine and -56- 2/102/4 Y is selected from the group (2-a) cyclic monovalent nitrogen-containing organic groups and radicals and (2-b) monovalent organic groups and radicals of the general formula -R ₁ -B, wherein B -NR ₂ , -0-R ₄ or -SR ₄ is, R _{1 is} a two- is a valent organic group with a linear carbon chain length of about 1 to 7 carbon atoms, R ₂ and R, -H, -OH, -SH, halogen and monovalent organic groups and radicals with a linear carbon chain length of about 1 to 7 carbon atoms, R ₄ -H or monovalent organic groups or radicals with a linear carbon chain length of approximately 1 to 7 carbon atoms, N denotes nitrogen, 0 denotes oxygen, S denotes sulfur and H denotes hydrogen, to form an ether-substituted monosaccharide derivative of the general formula A-O-Y, wherein A and Y has the definition given above, and wherein the monosaccharide derivative (1) and the organic halide (2) at an elevated reaction temperature while being in one substantially anhydrous organic solvents are dissolved, in the presence of a solid substantially anhydrous strong inorganic base of an alkali metal or an alkaline earth metal are implemented. 2. The method according to claim 1, characterized in that the monosaccharide derivative (1) and the organic halide (2) in the presence of a dehydrating agent which is an absorbent for Water is to be implemented. -57- 609842 / 102A 3. The method according to claim 2, characterized in that the dehydrating agent is anhydrous Calcium chloride is used. 4. The method according to claim 1, characterized in that the organic solvent is 1,4-dioxane and / or tetrahydrofuran is used. 5 · The method according to claim 1, characterized in that the organic solvent 1,4-dioxane is used. 6. The method according to claim 1, characterized in that the inorganic base is anhydrous Oxides and / or hydroxides of sodium, potassium and / or calcium can be used. 7. The method according to claim 1, characterized in that the organic base is in particulate Is in the form and is essentially anhydrous sodium hydroxide. 8. The method according to claim 1, characterized in that Y -R ₁ -N _x ^ is where R ^ is a hydrocarbon group with a linear carbon chain length of 1 to 3 carbon atoms and R ₂ and R denote, hydrogen or hydrocarbon groups with a linear carbon chain length of 1 to 3 carbon atoms. -58- 6O98A? / In? Z, 9. The method according to claim 1, characterized in that Y is selected from the group! - (n-propylamino), - (N ^f , N · -Dimethylamino-n-propyl), - (N ¹ , N ¹ -dirnethylaminoisopropyl), - (N-methylpiperidyl), - (N ¹ , N ^f -dimethylaminoethyl), - (N «, N «-Diethylaminoethyl) and - (2 ', N', N '-trimethylamino-n-propyl). 10. The method according to claim 1, characterized in that Y - (N ¹ , N ¹ -dimethylamino-n-propyl) is. 11. The method according to claim 1, characterized in that the monosaccharide derivative (1) the has general formula selected from the group: (a) H-O O = C. - ^z i OW) I. - C. = (H. OW) I. C. = (H, I. OF) I. C. = (H, I. Z -59- 609842/1024 (b) (H, ow) (H, OW) 0-H (C) (H, OW) (H, OW) (H, OW) ■ * 0-H wherein Z ₁ and Zp denote -H, -OH or monovalent hydroxyalkyl, alkoxyl or alkoxyalkyl groups with up to and including 3 carbon atoms, WH or monovalent alkyl, alkenyl, cyclic alkane, cyclic aromatic or acyl groups with 1 to 18 carbon atoms and at least one of the substituted Z ^, Zp or ¥ has a meaning other than -H or -OH. -60- 609842/10? / 12. The method according to claim 11, characterized in that YR _{1 is} -NR ^, R _{1 is} a Koh- R ₂ Hydrogen group with a linear carbon chain length from 1 to 3 carbon atoms and Rp and R, Hydrogen or hydrocarbon groups with a linear carbon chain length of 1 to 3 carbon atoms mean. 13. The method according to claim 11, characterized in that Y is selected from the group: - (n-Propylamino), - (N ', N'-Dimethylaminopropyl), - (N', N ¹ -Dimethylaminoisopropyl), - (N-MethyIpiperidyl), - (N ¹ , N'-Dimethylaminoethyl), - (N 'jN'-diethylaminoethyl) ^ and - (2', N ', N' -trimethylamino-ιί-propyl). 14. The method according to claim 11, characterized in that Y - (N ¹ , N '-diinethylamino-n-propyl) is. 15. The method according to claim 11, characterized in that the monosaccharide derivative (1) is a Is a glucose derivative or a galactose derivative. 16. The method according to claim 15 *, characterized in that the glucose in all -OH positions with the exception of the 1-0 or 3-0 position was converted into derivative form and that the galactose in all -OH- -61- 609842/102 /, Positions with the exception of the 6-0 position in derivative form was transferred, the glucose being monoether-substituted in the 1-0 or 3-0 position and the galactose in the 6-0 position is monoether-substituted. 17. The method according to claim 16, characterized in that Y -R ₁ -NR ₉ , R _{1 is} a hydrocarbon ^R 3 substance group with a linear carbon chain length of 1 to 3 carbon atoms and R2 and R, hydrogen or Mean hydrocarbon groups with a linear carbon chain length of 1 to 3 carbon atoms. 18. The method according to claim 16, characterized in that Y is selected from the group: - (n-propylamino), - (N ', N'-Dimethylamino-n-propyl), - (N', N'-Dimethylamineisopropyl), - (N-Methylpiperidyl), - (N ·, N ^! -Dimethylaminoethyl), - (Ν ', Ν ¹ -diethylaminoethyl) and - (2'SN ¹ , N'-trimethylamino-n-propyl). 19. The method according to claim 16, characterized in that Y - (NSN ¹ -dimethylamino-n-propyl) is. 20. The method according to claim 1, characterized in that the monosaccharide derivative (1) Is 1,2: 5,6-di-O-isopropylidene-D-glucofuranose. -62- 21. The method according to claim 20, characterized in that Y is -R ₁ -NR ₂ , R _{1 is} a carbon denotes hydrogen group with a linear carbon chain length of 1 to 3 carbon atoms and R _? and R, represent hydrogen or hydrocarbon groups with a linear carbon chain length of 1 to 3 carbon atoms. 22. The method according to claim 20, characterized in that Y is selected from the group: - (n-propylamino), - (N ', N'-Dimethylamino-n-propyl), - (N ¹ , N'-dimethylaminoisopropyl), - (N-methylpiperidyl), - (N ·, N «-dirnethylaminoethyl), - (N«, N «-Diethylaminoethyl) and - (2 ', N', N'-trimethylamino-n-prop-rl). 23. The method according to claim 20, characterized in that Y - (N ¹ , N ^f -dimethylamino-n-propyl) is. 24. A method for the production of an ether-substituted monosaccharide, characterized in that that he 1) a monosaccharide derivative of the general formula A ₁ -OH, where 0 is oxygen, H is hydrogen and A _{1 is} the remainder of a monosaccharide from the group consisting of pentoses, hexoses and heptoses, which is denoted by -63- 60984? / 10? Λ at least one compound from the following group has been converted into the derivative form (1-a) with at least an aliphatic alcohol having 1 to 18 carbon atoms to form a hydrolyzable one Acetal group in place of at least one available hydroxyl group, (1-b) with at least one Aldehyde containing 1 to 18 carbon atoms with formation of at least one hydrolyzable acetal group in the place of at least one available hydroxyl group, (1-c) with at least one ketone, containing 1 to 18 carbon atoms, with formation of at least one hydrolyzable ketal group in place of at least one available hydroxyl group and (1-d) with at least one organic Acid radical containing 1 to 18 carbon atoms to form a hydrolyzable ester group the location of at least one available hydroxyl group 2) an organic halide of the general formula YX, wherein X is chlorine, bromine or iodine and Y is selected from the group (2-a) cyclic monovalent nitrogen-containing organic groups and radicals and (2-b) monovalent organic groups and radicals general formula -R ^ -B, where B is selected from the group -NR ₂ , -OR ^ or -SR ^, R ^ means a divalent organic group with a linear carbon chain length of 1 to 7 carbon atoms, R ₂ and R, -H, -OH, -SH, -64- 609842 / running meter Halogen or monovalent organic radicals or groups with a linear carbon chain length of 1 "to 7 carbon atoms, R- - H or monovalent organic groups or radicals with a linear Carbon chain length of about 1 to 7 carbon atoms means N nitrogen, 0 oxygen, S is sulfur and H is hydrogen, with the formation of an ether-substituted monosaccharide derivative of the general formula A ₁ -OY, wherein A ₁ , Y and 0 have the definitions given above, and wherein the monosaccharide derivative (1) and the organic halide (2) at elevated reaction temperature while they are in one Substantially anhydrous organic solvents are dissolved, are reacted in the presence of a solid, substantially anhydrous strong inorganic base of an alkali metal or an alkaline earth metal, the ether-substituted monosaccharide derivative of the general formula A ₁ -OY separates from the reaction mixture and at least one of the acetal, ketal or Ester groups are removed from A ₁ by hydrolysis in an acidic aqueous medium with a pH value below 7 with the formation of an ether-substituted monosaccharide of the general formula Ap-OY, where 0 and Y have the definition given above and Ap is the remainder of a monosaccharide which A ₁ corresponds to as defined above, where at least one acetal, ketal or ester group has been removed from the remainder. 25. The method according to claim 24, characterized in that A _{1 contains} a plurality of acetal, ketal, or ester groups and that the hydrolysis in the -65- 609842/102 U essentially non-oxidizing acidic aqueous medium with a pH of about 3 "to 6 is carried out remove only part of the acetal, ketal or ester groups. 26. The method according to claim 24, characterized in that A ^ a plurality of acetal, ketal or contains ester groups and that the hydrolysis is carried out in a substantially non-oxidizing acidic aqueous Medium with a pH ¥ ert below 3 to remove all acetal, ketal or ester groups is carried out. 27. The method according to claim 24, characterized in that the monosaccharide derivative (1) is a Is a glucose derivative or a galactose derivative. 28. The method according to claim 27, characterized in that the glucose derivative in all -OH positions with the exception of the 1-0 or 3-0 position is converted into derivative form and that the Gaüakto ^ ederivat in all -OH positions with the exception of the 6-0 position in Derivative form is converted and that the glucose is ether monosubstituted in the 1-0 or 3-0 position and that the Galactose is ether monosubstituted in the 6-0 position. 29. The method according to claim 28, characterized in that the hydrolysis in one substantially non-oxidizing acidic aqueous medium with a pH of about 3 to 6 is carried out to only to remove some of the acetal, ketal or ester groups from the -OH positions, which are in derivative form. -66- 30. The method according to claim 28, characterized in that the hydrolysis in one substantially non-oxidizing acidic aqueous medium with a pH below 3 to remove all acetal, ketal or Ester groups from the -OH positions, which are present in derivative form, is carried out. 31. The method according to claim 24, characterized in that the monosaccharide derivative (1) 1,2: 5,6-di-O-isopropylidene-D-glucofuranose is. 32. The method according to claim 31, characterized in that the hydrolysis in one substantially non-oxidizing acidic aqueous media having a pH of about 3 to 6 for the removal of only one the isopropylidene groups is carried out. 33 · The method according to claim 31 , characterized in that the hydrolysis is carried out in an essentially non-oxidizing acidic aqueous medium with a pH value below 3 to remove both isopropylidene groups. 34. The method according to claim 31, characterized in that Y is -R _-1 -NR ₅ , R ^ is a Denotes hydrocarbon group with a linear carbon chain length of 1 to 3 carbon atoms and Rp and R, Hydrogen or hydrocarbon groups with a linear carbon chain length of 1 to 3 carbon atoms mean. 609 8 42/102 /, 35. The method according to claim 31, characterized in that Y is selected from the group: - (n-propylamino), - (N ¹ , N'-dimethylamino-n-propyl), - (N ·, N'-dimethylaminoisopropyl), - (N-methylpiperidyl), - (N ", N'-dimethylaminoethyl), - (N", N «-Diethylaminoethyl) and - (2 ¹ , N ¹ , N'-trimethylamino-n-propyl). 36. The method according to claim 31, characterized in that Y - (N ¹ , N'-dimethylamino-n-propyl) is. 37. The method according to claim 36, characterized in that the hydrolysis in one substantially non-oxidizing acidic aqueous medium with a pH of about 3 to 6 for the removal of only one the isopropylidene groups is carried out. 38. The method according to claim 36, characterized in that the hydrolysis in a substantially ixcht-oxidizing acidic aqueous medium with a pH below 3 is carried out to remove both isopropylidene groups. 609842/1024