# Patent

## Title
2,4-disubstituted 1,3-dioxolanes and pharmaceutical use

## Abstract

N-substituted derivatives of 1-desoxynojirimycin and 1-desoxymannojirimycin of the formula ##STR1## in which one of R and R' are hydroxyl and the other is hydrogen substituted aryl or by pyridyl, thienyl, furyl, pyrimidyl, pyrazinyl or quinolyl or R.sub.1 is cycloalkyl or R.sup.2 is optionally substituted by aryl or R.sup.2 is a saturated bridged heterocycle or R.sup.1 and R.sup.2 together can form a heterocyclic ring which is optionally substituted. These compounds are useful in the treatment of and prophylaxis of viral infections.

## Background
The invention relates to N-substituted derivatives of 1-desoxynojirimycin and 1-desoxymannonojirimycin, processes for their preparation and their use in medicaments, in particular in antiviral medicaments.

It has been disclosed that derivatives of 1-desoxynojirimycin and 1-desoxymannonojirimycin are glucosidase inhibitors and can be employed for the treatment of disorders of carbohydrate metabolism [EP 947; EP 8,058; EP 34,784; EP 2,848,117; EP 193,770]. Moreover, it is known that certain 1-desoxynojirimycin derivatives exhibit herbicidal properties [DE 3,024,901] and 1-desoxynojirimycin and 1-desoxymannonojirimycin and derivatives thereof influence the biosynthesis of glycoproteins [U. Fuhrmann, E. Bause and H. Ploegh; Review: Biochimica et Biophysica Acta 825, 95-110 (1985)].

The present invention relates to N-substituted derivatives of 1-desoxynojirimycin and 1-desoxymannonojirimycin of the general formula (I) ##STR2## in which R or R' stands for a hydroxyl group and in which the other R' or R in each case stands for hydrogen, having up to 3 carbon atoms or for benzyl, and which can be substituted by aryl having 6 to 10 carbon atoms, where the aryl radical can carry up to 4 identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, cyano, nitro, alkyl, alkoxy, alkylthio or arylthio each having up to 6 carbon atoms, dioxymethylene, dioxyethylene, trifluoromethyl, trifluoromethoxy, difluoromethoxy, carboxyl or alkoxycarbonyl having up to 4 carbon atoms, or which can be substituted by pyridyl, thienyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl or quinolyl, or monosubstituted to tetrasubstituted by fluorine, chlorine, bromine, iodine, cyano, alkyl having up to 6 carbon atoms, alkoxy having up to 12 carbon atoms, alkylsulphonyl having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, difluoromethylene, difluoromethoxy, trifluoromethylthio, dioxymethylene, dioxyethylene, by cycloalkyl having 3 to 7 carbon atoms, by carboxyl or alkoxycarbonyl having up to 4 carbon atoms, by aryloxy having 6 to 10 carbon atoms, where the aryl radical can carry up to 4 identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, alkyl, alkoxy, alkylthio having up to 6 carbon atoms, dioxymethylene, dioxyethylene, trifluoromethyl, trifluoromethoxy or difluoromethoxy, or by halogenoalkoxy having up to 6 carbon atoms and up to 5 fluorine and/or 3 chlorine atoms, or by hydroxyalkoxy, hydroxyalkyl or cyanoalkyl each having up to 8 carbon atoms, or by alkenyloxy having up to 6 carbon atoms, or by a group --XR.sup.3, the substituents being identical or different, up to 8 carbon atoms, and up to 4 identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, cyano, alkyl, alkoxy, alkylthio each having up to 6 carbon atoms, nitro, dioxymethylene, dioxyethylene, trifluoromethyl, trifluoromethoxy, difluoromethoxy or trofluoromethylthio, or can be fused to benzene and which can contain oxygen, sulphur or up to 2 nitrogen atoms as hetero atoms, or alkylcarbonyloxy having up to 18 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or alkylamino or dialkylamino each having up to 6 carbon atoms per alkyl group, or 6-membered ring which can be anellated, which can be interrupted by oxygen, sulphur or the group --NR.sup.4, and which can be substituted by alkyl having up to 4 carbon atoms, hydroxyl, phenyl, carboxyl or alkoxycarbonyl having up to 4 carbon atoms, up to 4 identical or different substituents from the group comprising fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, alkyl, alkoxy, alkylthio having up to 6 carbon atoms, dioxymethylene, dioxyethylene, trifluoromethyl, trifluoromethoxy or difluoromethoxy, or quinolyl, or monosubstituted or disubstituted by phenyl which is optionally substituted by chlorine, dioxymethylene or trifluoromethyl, hydroxyl, amino, alkylamino, dialkylamino each having up to 3 carbon atoms per alkyl group, fluorine, chlorine, bromine, cycloalkyl having 3 to 6 carbon atoms, by carboxyl or alkoxycarbonyl having up to 6 carbon atoms, by pyridyl, pyrimidyl, pyrazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl or pyrrolidinocarbonyl, by morpholinocarbonyl, by alkylaminocarbonyl, dialkylaminocarbonyl or phenylalkylaminocarbonyl each having up to 6 carbon atoms per alkyl group, the substituents being identical or different.

Preferred compounds of the general formula (I) which may be mentioned are those in which which can be substituted by pyridyl, thienyl or by phenyl, where the phenyl radical can carry up to 3 identical or different substituents from the series comprising fluorine, chlorine, bromine, hydroxyl, alkyl, alkoxy having up to 4 carbon atoms, dioxymethylene, dioxyethylene or carboxyl, or trisubstituted by fluorine, chlorine, bromine, cyano, alkyl having up to 4 carbon atoms, hydroxyalkyl or hydroxyalkoxy having up to 4 carbon atoms, trifluoromethyl, trifluoromethoxy, dioxymethylene, dioxyethylene, by phenyl which is optionally substituted in the aromatic part by fluorine, chlorine, bromine, hydroxyl, alkyl, alkoxy having up to 9 carbon atoms, dioxymethylene, trifluoromethyl or carboxyl, or by straight-chain or branched alkenyloxy having up to 4 carbon atoms, or by a group --XR.sup.3, the substituents being identical or different, atoms and fluorine, chlorine, bromine, hydroxyl, alkyl, alkoxy having up to 4 carbon atoms, dioxymethylene, trifluoromethyl or carboxyl, the substituents being identical or different, or cyclopropyl, cyclopentyl or cyclohexyl or per alkyl group, or ##STR3## where R.sup.4 trisubstituted by fluorine, chlorine, bromine, hydroxyl, alkyl, alkoxy having up to 4 carbon atoms, dioxymethylene, trifluoromethyl or carboxyl, the substituents being identical or different, or atoms, which can be monosubstituted or disubstituted by phenyl which is optionally substituted by chlorine, trifluoromethyl or dioxymethylene, by hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, cyclopropyl, cyclopentyl, cyclohexyl or alkoxycarbonyl having up to 4 carbon atoms, by morpholinyl, pyrrolidinyl or pyrrolidinocarbonyl, or by morpholinocarbonyl, dialkylamino or phenylalkylamino each having up to 4 carbon atoms, the substituents being identical or different.

Particularly preferred compounds of the general formula (I) which may be mentioned are those in which which can be substituted by thienyl or phenyl, trisubstituted by fluorine, chlorine, bromine, cyano, alkyl having up to 4 carbon atoms, hydroxyalkyl having up to 6 carbon atoms, alkoxy having up to 9 carbon atoms, hydroxyalkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl or trifluoromethoxy, the substituents being identical or different, or ##STR4## where R.sup.4 fluorine, chlorine, bromine, hydroxyl, alkyl or alkoxy having up to 4 carbon atoms, the substituents being identical or different, or atoms, which can be monosubstituted or disubstituted by phenyl which is optionally substituted by chlorine, trifluoromethyl or dioxymethylene, by hydroxyl, amino, dimethylamino, cyclopropyl or alkoxycarbonyl having up to 4 carbon atoms, by morpholinyl, pyrrolidinyl or pyrrolidinocarbonyl, the substituents being identical or different.

The following compounds may be mentioned as very particularly preferred: amide, ionamide, namide, namide, e, pionamide, -yl)propionamide, amide, ucit-N-yl)propionamide, amide, mide, e, e, de, amide, namide, yl)piperazine, de, namide, onamide, amide, ionamide, namide, opionamide, de, pionamide, -yl)propionamide, amide, nnit-N-yl)propionamide, amide, mide, e, e, de, amide, namide, yl)piperazine, de, namide, onamide azine, ine, de, razine, ne, ne, ine, -chlorophenyl])piperazine, ethyl])piperazine, ine, mide, ucit-N-yl)butanamide, noline.

In the context of investigations which led to the present invention, it was surprisingly found that the compounds of the general formula (I) according to the invention possess an exceedingly good action against retroviruses.

The compounds according to the invention can be prepared by reacting carboxylic acids of the general formula (II) ##STR5## in which n has the abovementioned meaning, by known methods, if appropriate, via a reactive acid derivative, with amines of the general formula (III) ##STR6## in which R.sup.1 and R.sup.2 have the abovementioned meaning, if appropriate in the presence of an inert organic solvent.

Reactive acid derivatives which may be mentioned, for example, are: activated esters, hydroxysuccinimide esters, acid imidazolides, acid halides, mixed anhydrides, or the reaction in the presence of carbodiimides, such as, for example cyclohexylcarbodiimide.

The process according to the invention can be illustrated, for example, by the following equation: ##STR7##

Carrying out the process according to the invention relies on the method known in the literature for the conversion of carboxylic acids into carboxamides. Thus, the carboxylic acid is first converted into an activated form, such as, for example, the acid chloride or the imidazolide, which are either isolated as such and reacted in a second reaction step, or which are amidated directly to the compounds according to the invention in situ. As activating reagents, carbodiimides such as dicyclohexylcarbodiimide or 1-cyclohexyl-3-[2-(N-methylmorpholino)ethyl]carbodiimide-p-toluenesulphona tes or N-hydroxyphthalimide or N-hydroxy-benzotriazole in the presence of dicyclohexylcarbodiimide may be mentioned, for example, in addition to the inorganic halides such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or carbonyldiimidazole. Naturally, piperidin-N-yl carboxylic acids can also be employed in the form of their salts. [The method of amidation is described, for example, in: Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & Sons Inc. (1967), pages 231-236;  J. C. Shihan and G. P. Hess, J. Am. Chem. Soc. 77, 1067 (1955); U. Goodman, G. W. Kenner, Adv. in Protein Chem. 12, 488 (1957); W. A. Bonner, P. I. McNamee, J. Org. Chem. 26, 254 (1961); H. A. Staab, Angew. Chemie Int. Ed. 1, 351 (1962); Fieser & Fieser, Reagents for Organic Synthesis, John Wiley & Sons Inc. 1967, 116, 114; H. C. Beyerman, U. O. van der Brink, Re. Trav. 80, 1372 (1961); C. A. Buehler and D. E. Pearson, John Wiley & Sons, Volume I (1970), page 895 ff, Volume II (1977)].

Suitable solvents for the process according to the invention are, in addition to water, all inert organic solvents which are not changed under the reaction conditions. These preferably include ethers such as diethylether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether or halogenated hydrocarbons such as dichloromethane, trichloromethane or tetrachloromethane, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or hydrocarbons such as benzene, toluene or xylene, or acetonitrile, nitromethane, pyridine, dimethyl sulphoxide or ethyl acetate. Mixtures of the solvents mentioned can also be used.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out in a range from -70.degree. C. to +140.degree. C., preferably from -20.degree. C. to +100.degree. C.

The reaction can be carried out at normal pressure, but also at elevated or reduced pressure. In general, the reaction is carried out at normal pressure.

When carrying out the process according to the invention, the ratio of the substances participating in the reaction is arbitrary. In general, the reaction is carried out with molar amounts of reactants. However, it has proved favorable to employ the amine in a 5 to 10-fold molar excess. The use of the amine in a large excess directly as the solvent is particularly expedient.

The D-gluco configuration carboxylic acids of 1-desoxynojirimycin employed as starting materials are known [DE 3,024,901; DE 2,758,025; DE 2,922,760; JP 81/103,153].

The D-manno configuration carboxylic acids of 1-desoxynojirimycin employed as starting materials and their preparation are new.

Carboxylic acids which are used, for example, according to the invention are:

The amines employed as starting materials are known or can be prepared by known methods, such as are described, for example, in Beilstein's Handbuch der Organischen Chemie (Beilstein's Handbook of Organic Chemistry).

Amines which are used, for example, according to the invention are:

It was surprisingly found in the context of investigations which led to the present invention that the compounds of the general formula (I) according to the invention possess an exceedingly strong action against viruses and, in particular, against both DNA viruses and also RNA viruses. The DNA viruses include, for example, the piconda-, papova-, adeno-, herpes-, hepatitis- and smallpox viruses. The RNA virus group includes, for example, the picorna-, reo-, toga-, corona-, othomyxo- and rhabdo viruses. The compounds according to the invention are particularly effective against the retroviruses included by the RNA viruses. This is illustrated by the experimental data indicated further below, for example, for the compounds on Visna virus in cell cultures. Visna virus and HIV virus (Human Immunodeficiency Virus) both belong to the retrovirus subfamily of the Lentiviruses [Haase A. T., Nature (1986) 322, 130-136]. Both viruses have a similar genome organization and a complex transcription pattern compared to the other retroviruses [Sonijo P. et al., Cell (1985), 42, 369-382; Davis J. L. et al., Journal of Virology (1987) 61 (5) 1325-1331]).

In cell cultures which are infected with Visna virus, pronounced virus-induced, cytopathic effects appear 5 to 10 days after infection. By treatment of the infected cell cultures with the compounds according to the invention, the appearance of these cytopathic effects could be prevented.

The Visna virus test was carried out by the method of O. Narayan et al., Journal of Infectious Diseases 135, 5, 1977, 800-806. For this, the compounds according to the invention were diluted to non-cytotoxic concentrations in culture medium in 96-well microtiter plates. Subsequently, sheep fibroblast cells (5.times.10.sup.4 cells per well) in production medium were added to each well. Each well then contained 50 .mu.l of a Visna virus solution having a titre of about 2.5.times.10.sup.4 TCID.sub.50 (TCID=tissue culture infectious dose). This virus dose corresponds to an MOI (multiplicity of infection) of about 0.05.

Under these infection conditions, a virus-induced cytopathic effect resulted in one infection control without substance between day 5 and day 10. The infected and treated cells and the controlled cells were incubated for 7 days at 37.degree. C. and 5% CO.sub.2.

On appearance of the virus-induced cytopathogenic effect in the untreated virus control, the cultures were fixed using formalin and subsequently stained with a Giemsa solution. The inhibitory concentration (IC.sub.50) was determined microscopically as the concentration at which the cytopathic effect was inhibited by 50% in comparison to the untreated virus control which exhibited 100% cell destruction.

It was found, for example, that N-(4-ethoxyphenyl)-3-(1,5-didesoxy-1,5-imino-D-glucit-N-yl)propionamide protects the cells infected with Visna virus from virus-induced cell destruction in a concentration range from 500 .mu.g/ml to 15 .mu.g/ml.

Typical actions which were found for the compounds according to the invention are listed in Table 1. Herein, MCC denotes cytotoxicity and MIC denotes the minimum concentration at which an inhibition of virus multiplication was still observed. ______________________________________ Examp. 1 MCC   2 MIC   Examp.   1 MCC 2 MIC No.    .mu.g/ml .mu.g/ml No.      .mu.g/ml .mu.g/ml ______________________________________ 4     >1000   125     60       >1000 500 7     >1000   500     66        1000 500 10     >1000    30     68         500 250 11     >1000   500     72       >1000 500 12      1000   250     76       >1000 500 14     >1000   125     82       >1000 500 16     >1000   250     87       >1000 250 17      1000   125     89        1000 500 18     >1000   500     90        1000 250 19     >1000   125     92       >1000 250 23       150    75     93       >1000 500 24     >1000   125     94       >1000 500 25     >1000   250     96       >1000 500 27     >1000   250     99       >1000 125 28     >1000   500     00       >1000 500 29     >1000   125     89        1000 500 31     >1000   125     90        1000 250 32     >1000   250     92       >1000 250 34     >1000    15     93       >1000 500 35       250     15    94       >1000 500 38      1000   250     96       >1000 500 40     >1000    15     99       >1000 125 41      1000   125     100      >1000 500 43     >1000   500     101       1000 125 50      1000   250     102      >1000 125 51      1000   250     103      >1000 125 53       500   250     104      >1000 250 54      1000   250     107      >1000 500 55      1000   250 ______________________________________

Since they change the glycosylation pattern of the virus proteins, the compounds according to the invention can also be used in the production of attenuated or noninfectious virus particles which in turn can be employed for vaccine production.

The compounds to be used according to the invention therefore represent valuable active compounds in human and veterinary medicine for the treatment and prophylaxis of diseases produced by retroviruses.

Indication areas which may be mentioned in human medicine, for example, are:

(1) The treatment or prophylaxis of human retrovirus infections.

(2) The treatment or prophylaxis of diseases (AIDS) caused by HIV (Human Immunodeficiency Virus; formerly named HTLV III/LAV) and the stages such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome) associated with it, and also the hypoimmunity and encephalopathy caused by this virus.

(3) The treatment or the prophylaxis of an HTLV I or HTLV II infection.

(4) The treatment or the prophylaxis of the AIDS carrier condition.

Indications in veterinary medicine which may be mentioned, for example, are:

Infections with

The present invention includes pharmaceutical preparations which contain one or more compounds of the formula (I) or which consist of one or more active compounds of the formula (I) in addition to non-toxic, inert pharmaceutically suitable excipients, and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparation is present in the form of individual parts, for example tablets, dragees, capsules, pills, suppositories and ampoules, whose active compound content corresponds to a fraction or a multiple of an individual dose. The dosage units may contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose preferably contains the amount of active compound which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose.

Non-toxic, inert, pharmaceutically suitable excipients are taken to mean solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any type.

Preferred pharmaceutical preparations which may be mentioned are tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, dragees, capsules, pills and granules may contain the active compound(s) in addition to the customary excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatin and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrants, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retardants, for example paraffin, and (f) absorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) absorbants, for example kaolin and bentonite and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols or mixtures of the substances mentioned under (a) to (i).

The tablets, dragees, capsules, pills and granules may be mixed with the customary coatings and shells, if appropriate containing opacifying agents, and may also be composed so that they release the active compound(s), if appropriate with a delay, only or preferably in a certain part of the intestinal tract, for which purpose, for example, polymeric substances and waxes can be used as embedding materials.

If appropriate, the active compound(s) may also be present in microencapsulated form with one or more of the abovementioned excipients.

In addition to the active compound(s), suppositories may contain the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C.sub.14 -alcohol with C.sub.16 -fatty acid), or mixtures of these substances.

Ointments, pastes, creams and gels may contain the customary excipients in addition to the active compound(s), for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixture of these substances.

Powders and sprays may contain the customary excipients in addition to the active compound(s), for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances, and sprays may additionally contain the customary propellants, for example chlorofluorohydrocarbons.

Solutions and emulsions may contain the customary excipients, such as solvents, solution retardants and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoates, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cotton seed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances in addition to the active compound(s).

For parenteral administration, the solutions and emulsions may also be present in sterile and blood-isotonic form.

Suspensions may contain the customary excipients, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances in addition to the active compound(s).

The formulation forms mentioned may also contain colorants, preservatives and also odor-improving and flavor-improving additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.

The active compounds of the formula (I) should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably 0.15 to 95% by weight, of the total mixture.

The abovementioned pharmaceutical preparations may also contain further pharmaceutically active compounds in addition to the compounds of the formula (I).

The production of the abovementioned pharmaceutical preparations takes place in a customary manner by known methods, for example by mixing the active compound(s) with the excipient(s).

The preparations mentioned may be used either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powders, ointments, drops) in humans and animals and for the therapy of infections in hollow spaces and body cavities. Suitable preparations are injection solutions, solutions and suspensions for oral treatment, gels, formulations for pouring on, emulsions, ointments or drops. For local treatment, ophthalmological and dermatological formulations, silver salts and other salts, ear drops, eye ointments, powders or solutions may be used. In animals, the administration can also take place in suitable formulations via the feed or drinking water. Furthermore, gels, powders, tablets, delayed-release tablets, pre-mixes, concentrates, granules, pellets, boli, capsules, aerosols, sprays and inhalants can be used in humans and animals. Furthermore, the compounds according to the invention can be incorporated in other excipients such as, for example, plastics (plastic chains for local treatment), collagen or bone cement.

In general, it has proved advantageous both in human and veterinary medicine to administer the active compound(s) of the formula (I) in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to obtain the desired results. An individual dose preferably contains the active compound(s) in amounts from about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to deviate from the dosages mentioned depending on the species and the body weight of the subject to be treated, the nature and severity of the disease, the type of the preparation and the administration of the medicament and also the time period or interval within which the administration takes place.

Thus, in some cases it may be sufficient to manage with less than the abovementioned amount of active compound, whereas in other cases the abovementioned amount of active compound must be exceeded. The optimum dosage required in each case and the type of administration of the active compound can easily be established by one skilled in the art on the basis of his expert knowledge.

The compounds to be used according to the invention can be given in the customary concentrations and preparations together with the feed or with feed preparations or with the drinking water. ##STR8##

2 g (8.5 mmol) of N-(2-carboxyethyl)-1-desoxynojirimycin are dissolved in a mixture of 11 ml of water and 22 ml of pyridine. The solution is cooled to 0.degree. C. A solution of 1.9 g (9.4 mmol) of dicyclohexylcarbodiimide in pyridine is added and the mixture is left at 0.degree. for 120 minutes. 1.3 g (10.2 mmol) of p-methoxy aniline are then added. The cooling is removed and the reaction mixture is stirred at room temperature. After 8 hours, substantial reaction is detected by thin-layer chromatography (chloroform:methanol:ammonia solution=4:3:1 v/v system).

The solid material is filtered off, the solvent is evaporated in high vacuum and the residue is chromatographed on 200 g of silica gel (mobile phase methylene chloride:ethanol:triethylamine=4:1:0.005). 2.5 g (7.2 mmol, 85%) of product are isolated. R.sub.f =0.60 (chloroform:methanol:ammonia=4:3:1) N-yl)propionamide ##STR9##

In accordance with the directions for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-oxymethylenemethoxycarbonylaniline.

Yield: 1.45 g.

Melting point: 103.degree. C., R.sub.f =0.60.

[.alpha.].sub.D.sup.20 =-36.degree. (c=1, methanol). ionamide ##STR10##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-(4-pyridylmethoxy)aniline.

Yield: 0.86 g.

Melting point: 172.degree. C., R.sub.f =0.6.

[.alpha.].sub.D.sup.20 =-38.degree. (c=1, methanol). ##STR11##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-benzyloxyaniline.

Yield: 1.26 g.

Melting point: 124.degree. C., R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-25.degree. (c=1, methanol). onamide ##STR12##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-trifluoromethoxyaniline.

R.sub.f =0.64. ##STR13##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-hydroxyaniline.

R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-25.degree. (c=1, methanol). ##STR14##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-tert.-butylaniline.

Yield: 1.97 g.

Melting point: 76.degree. C., R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-35.degree. (c=1, methanol). pionamide ##STR15##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-(6-methylheptyloxy)aniline.

Yield: 1.39 g.

Melting point: colorless resin, R.sub.f =0.72.

[.alpha.].sub.D.sup.20 =-29.degree. (c=1, methanol). -yl)propionamide ##STR16##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-(2-N,N-diethylaminoethoxy)aniline.

Yield: 1.44 g.

Melting point: colorless resin, R.sub.f =0.67.

[.alpha.].sub.D.sup.20 =-28.degree. (c=1, methanol). ##STR17##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-allyloxyaniline.

Yield: 1.0 g.

Melting point: 139.degree. C., R.sub.f =0.66.

[.alpha.].sub.D.sup.20 =-36.degree. (c=1, methanol). amide ##STR18##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-trifluoromethylaniline.

Yield: 0.72 g.

Melting point: colorless resin, R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-24.degree. (c=1, methanol). ucit-N-yl)propionamide ##STR19##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-(2-chloro-1,1,2-trifluoroethoxy)aniline.

Yield: 1.36 g.

Melting point: colorless resin, R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =27.degree. (c=1, methanol). ##STR20##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-isopropylaniline.

Yield: 1.7 g.

Melting point: colorless resin, R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-38.degree. (c=1, methanol). ##STR21##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-isopropylaniline.

Yield: 1.05 g.

Melting point: 156.degree. C., R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-32.degree. (c=1, methanol). ##STR22##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-fluoroaniline.

Yield: 1.7 g.

Melting point: colorless resin, R.sub.f =0.58.

[.alpha.].sub.D.sup.20 =-31.degree. (c=1, methanol). ##STR23##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-fluoroaniline.

Yield: 0.92 g.

Melting point: 169.degree. C., R.sub.f =0.66.

[.alpha.].sub.D.sup.20 =-23.degree. (c=1, methanol). ##STR24##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2,3-dihydroindole.

Yield: 1.2 g.

Melting point: 198.degree., R.sub.f =0.7.

[.alpha.].sub.D.sup.20 =-42.degree. (c=1, methanol). ##STR25##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2,4-difluoroaniline.

Yield: 1.03 g.

Melting point: 166.degree. C., R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-24.degree. (c=1, methanol). ##STR26##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3,4-difluoroaniline.

Yield: 1.33 g.

Melting point: colorless resin, R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-26.degree. (c=1, methanol). amide ##STR27##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are needed with 10 mmol of 2-trifluoromethylaniline.

Yield:.

R.sub.f =0.62. ##STR28##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2,6-difluoroaniline.

R.sub.f =0.62. ##STR29##

In accordance with the description of Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-aminoadamantane.

R.sub.f =0.62. mide ##STR30##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethy)desoxynojirimycin are reacted with 10 mmol of 3,4,5-trimethoxyaniline.

Yield: 2.16 g.

Melting point: colorless resin, R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-29.degree. (c=1, methanol). e ##STR31##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3,4-dimethoxyaniline.

Yield: 1.78 g.

Melting point: 157.degree. C., R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-43.degree. (c=1, methanol). e ##STR32##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3,5-dimethoxyaniline.

Yield: 1.82 g.

Melting point: 106.degree. C., R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-35.degree. (c=1, methanol). de ##STR33##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2,4,6-tribromoaniline.

Yield: 0.98 g.

Melting point: 194.degree. C., R.sub.f =0.62.

[.alpha.].sub.D.sup.20 =-16.degree. (c=1, methanol). ##STR34##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3-cyanoaniline.

Yield: 0.86.

Melting point: 177.degree. C., R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-22.degree. (c=1, methanol). ##STR35##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-cyclohexylaniline.

Yield: 1.9 g.

Melting point: 206.degree. C., R.sub.f =0.71.

[.alpha.].sub.D.sup.20 =-34.degree. (c=1, methanol). amide ##STR36##

In accordance with the description of Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3,4-ethylenedioxyaniline.

Yield: 2.98 g.

Melting point: colorless resin, R.sub.f =0.62.

[.alpha.].sub.D.sup.20 =-35.degree. (c=1, methanol). ##STR37##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-bromoaniline.

Yield: 0.89 g.

Melting point: 201.degree. C., R.sub.f =0.6.

M+1=390. namide ##STR38##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3,4-methylenedioxyaniline.

Yield: 1.59 g.

Melting point: colorless resin, R.sub.f =0.62.

[.alpha.].sub.D.sup.20 =-37.degree. (c=1, methanol). ##STR39##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-methylthioaniline.

Yield: 0.8 g.

Melting point: 201.degree. C., R.sub.f =0.68. yl)piperazine ##STR40##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(4-trifluoromethylphenyl)piperazine.

Yield: 2.83 g.

Melting point: 179.degree. C., R.sub.f =0.67.

[.alpha.].sub.D.sup.20 =-11.degree. (c=1, methanol). ##STR41##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of aniline.

Melting point: 145.degree. C., R.sub.f =0.52. ##STR42##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-ethoxyaniline.

Melting point: 195.degree. C., R.sub.f =0.52. de ##STR43##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-dimethylaminoethylamine.

Melting point: 0.9 g.

Melting point: colorless resin, R.sub.f =0.59.

[.alpha.].sub.D.sup.20 =-2.degree. (c=1, methanol). namide ##STR44##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-(3-methoxyphenyl)ethylamine.

Yield:

R.sub.f =0.61. ##STR45##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-aminomethylpyridine.

Yield: 0.75 g.

Melting point: colorless resin, R.sub.f =0.51.

[.alpha.].sub.D.sup.20 =-15.degree. (c=1, methanol). ##STR46##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-cinnamylpiperazine.

R.sub.f =0.67. onamide ##STR47##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-(2-hydroxyethoxy)aniline.

Yield:

Melting point: 149.degree. C., R.sub.f =0.43. azine ##STR48##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-fluorophenyl)piperazine.

Yield: 1.2 g.

Melting point: 155.degree. C., R.sub.f =0.64.  [.alpha.].sub.D.sup.20 =-12.degree. (c=1, methanol). ##STR49##

2 g (8.5 mmol) of N-(2-carboxyethyl)-1-desoxymannonojirimycin are dissolved in a mixture of 11 ml of water and 22 ml of pyridine. The solution is cooled to 0.degree.. A solution of 1.9 g (9.4 mmol) of dicyclohexylcarbodiimide in pyridine is added and the mixture is left at 0.degree. C. for 120 minutes. 1.3 g (10.2 mmol) of p-methoxyaniline are then added. The cooling is removed and the reaction mixture is stirred at room temperature. After 8 hours, substantial reaction is detected by thin-layer chromatography (chloroform:methanol:ammonia solution 4:3:1 v/v system).

The solid material is filtered off, the solvent is evaporated in high vacuum and the residue is chromatographed on 200 g of silica gel (mobile phase methylene chloride:ethanol:triethylamine=4:1:0.005). 1.9 g of product are isolated.

R.sub.f =0.60 (chloroform:methanol:ammonia=4:3:1). amide ##STR50##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-methoxycarbonylaniline.

R.sub.f =0.60.

[.alpha.].sub.D.sup.20 =-27.degree. (c=1, methanol). ionamide ##STR51##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannojirimycin are reacted with 10 mmol of 4-(4-pyridylmethoxy)aniline.

R.sub.f =0.6. ##STR52##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-benzyloxyaniline.

R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-42.degree. (c=1, methanol). amide ##STR53##

[.alpha.].sub.D.sup.20 =-38.degree. (c=1, methanol).

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-trifluoromethoxyaniline.

R.sub.f =0.64. ##STR54##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-hydroxyaniline.

R.sub.f =0.65. e ##STR55##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-tert.-butylaniline.

R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-39.degree. (c=1.0, methanol). pionamide ##STR56##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-(6-methylheptyloxy)aniline.

R.sub.f =0.72.

[.alpha.].sub.D.sup.20 =-33.degree. (c=1.0, methanol). -yl)propionamide ##STR57##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-(2-N,N-diethylaminoethoxy)aniline.

R.sub.f =0.67.

[.alpha.].sub.D.sup.20 =-32.degree. (c=1.0, methanol). ##STR58##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-allyloxyaniline.

R.sub.f =0.66.

[.alpha.].sub.D.sup.20 =-45.degree. (c=1.0, methanol). amide ##STR59##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-trifluoromethylaniline.

R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-38.degree. (c=1.0, methanol). nnit-N-yl)propionamide ##STR60##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-(2-chloro-1,1,2-trifluoroethoxy)aniline.

R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-38.degree. (c=1.0, methanol). ##STR61##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-isopropylaniline.

R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-41.degree. (c=1.0, methanol). ##STR62##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-isopropylaniline.

R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-36.degree. (c=1.0, methanol). ##STR63##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-fluoroaniline.

R.sub.f =0.58.

[.alpha.].sub.D.sup.20 =-42.degree. (c=1.0, methanol). ##STR64##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-fluoroaniline.

R.sub.f =0.66.

M+1=329. ##STR65##

R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-43.degree. (c=1, methanol).

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2,3-dihydroindole.

R.sub.f =0.7. ##STR66##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2,4-difluoroaniline.

R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-35.degree. (c=1.0, methanol). ##STR67##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 3,4-difluoroaniline.

R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-39.degree. (c=1.0, methanol). amide ##STR68##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-trifluoromethylaniline.

R.sub.f =0.62. ##STR69##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2,6-difluoroaniline.

R.sub.f =0.62. ##STR70##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 1-aminoadamantane.

R.sub.f =0.62. mide ##STR71##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 3,4,5-trimethoxyaniline.

R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-32.degree. (c=1.0, methanol). de ##STR72##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 3,4-dimethoxyaniline.

R.sub.f =0.65.

[.alpha.].sub.D.sup.20 =-48.degree. (c=1.0, methanol). e ##STR73##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-mannonojirimycin are reacted with 10 mmol of 3,5-dimethoxyaniline.

R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-41.degree. (c=1.0, methanol). de ##STR74##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2,4,6-tribromoaniline.

R.sub.f =0.62. ##STR75##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 3-cyanoaniline.

R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-49.degree. (c=1.0, methanol). ##STR76##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of cyclohexylaniline.

R.sub.f =0.71.

[.alpha.].sub.D.sup.20 =-38 (c=1.0, methanol).

N-(3,4-Ethylenedioxyphenyl)-3-(1,5-didesoxy-1,5-imino-D-mannit-N-yl)propion amide ##STR77##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 3,4-ethylenedioxyaniline.

R.sub.f =0.62.

[.alpha.].sub.D.sup.20 =-43.degree. (c=1.0, methanol. ##STR78##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-bromoaniline.

R.sub.f =0.6. ##STR79##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 3,4-methylenedioxyaniline.

R.sub.f =0.62.

[.alpha.].sub.D.sup.20 =-43.degree. (c=1.0, methanol). ##STR80##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-methylthioaniline.

R.sub.f =0.68.

[.alpha.].sub.D.sup.20 =-50.degree. (c=1.0, methanol). yl)piperazine ##STR81##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 1-(4-trifluoromethylphenyl)piperazine.

R.sub.f =0.67. ##STR82##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of aniline.

R.sub.f =0.52. ##STR83##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-ethoxyaniline.

R.sub.f =0.52.

[.alpha.].sub.D.sup.20 =-46.degree. (c=1.0, methanol). e ##STR84##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-dimethylaminoethylamine.

R.sub.f =0.59. namide ##STR85##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-(3-methoxyphenyl)ethylamine. R.sub.f =0.61. ##STR86##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 2-aminomethylpyridine.

R.sub.f =0.51.

[.alpha.].sub.D.sup.20 =-15 (c=1.0, methanol). ##STR87##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 1-cinnamylpiperazine.

R.sub.f =0.67. onamide ##STR88##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-(2-hydroxyethoxy)aniline.

R.sub.f =0.43.

3-(1,5-Didesoxy-1,5-imino-D-mannit-N-yl)-propionyl-1-(4-p-fluorophenyl)pipe razine ##STR89##

In accodance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-1-desoxymannonojirimycin are reacted with 10 mmol of 4-fluorophenyl)piperazine.

R.sub.f =0.64.

[.alpha.].sub.D.sup.20 =-23.degree. (c=1.0, methanol). ##STR90##

326.4 g (2 mol) of 1-desoxymannonojirimycin are dissolved in 5 l of an 0.1M aqueous potassium hydrogen phosphate solution and as much 1N sodium hydroxide solution is added as is necessary to give a pH of 7.5. 80 ml of acrylonitrile are added to the solution. This mixture is stirred at 50.degree. C. for 48 hours. After this time, the educt can no longer be detected. (Thin-layer chromatography: CH.sub.2 Cl.sub.2 :MeOH:NH.sub.3 solution=4:3:1, R.sub.f =0.4). For working up, reagent and solvent are evaporated in high vacuum, the residue is taken up in 5 l of a mixture of pyridine aand acetic anhydride in the ratio 2:1 and stirred for 8 hours. After evaporating the solvent, the residue is taken up in 3 l of chloroform, and the solution is extracted repeatedly with water, dried over sodium sulphate and concentrated again. A syrup is obtained which is chromatographed on 2 kg of silica gel 60 in the system CH.sub. 2 Cl.sub.2 :EtOH=60:1. After evaporation of the eluent, the residue is taken up in 3 1 of anhydrous methanol to which 0.1% sodium methoxide is added. After 8 hours at 40.degree. C., the deblocking reaction has proceeded to completion. The mixture is neutralized by the addition of 50 g of a strongly acidic ion exchanger, filtered off and concentrated slowly. 362 g (84%) of product crystallize.

R.sub.f =0.4.

[.alpha.].sub.D.sup.20 =-59.degree. (c=1.0, methanol). ##STR91##

50 g (0.23 mol) of the compound from Example 83 are dissolved in 1000 ml of water, 8 g of barium hydroxide are added and the mixture is stirred for 120 minutes at 80.degree. C. After cooling, the mixture is rendered neutral by the addition of 2N sulphuric acid. The precipitate is separated off by centrifuging and 44.4 g (82%) of product are isolated after evaporation of the solvent.

R.sub.f =0.1.

[.alpha.].sub.D.sup.20 =-41.degree. (c=1, H.sub.2 O). ##STR92##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-phenylpiperazine.

R.sub.f =0.65. ine ##STR93##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-cyclopropylpiperazine.

R.sub.f 0.6. ##STR94##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(4-methylphenyl)piperazine.

R.sub.f 0.66. hyl])piperazine ##STR95##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of N-pyrrolyl piperazinoacetamide.

R.sub.f 0.65. amide ##STR96##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-trifluoromethylbenzylamine.

R.sub.f 0.65. ide ##STR97##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of .beta.-aminoacetophenone.

R.sub.f 0.59. ##STR98##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 3-aminoquinuclidine.

R.sub.f 0.65. azine ##STR99##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(2-fluorophenyl)piperazine.

R.sub.f 0.7. ine ##STR100##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(3-methylphenyl)piperazine.

R.sub.f 0.65. zine ##STR101##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(2-nitrophenyl)piperazine.

R.sub.f 0.65. zine ##STR102##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirmycin are reacted with 10 mmol of 1-(2-cyanophenyl)piperazine.

R.sub.f 0.65. azine ##STR103##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(2-methylphenyl)piperazine.

R.sub.f 0.6.

3-(1,5-Didesoxy-1,5-imino-D-glucit-N-yl)propionyl-1-(4-[3-trifluoromethyl-4 -chlorophenyl])piperazine ##STR104##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-desoxynojirimycin are reacted with 10 mmol of 1-(3-trifluoromethyl)-4-chlorophenyl)piperazine

R.sub.f 0.65. ethyl])piperazine ##STR105##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of piperazinoacetomorpholine.

R.sub.f 0.66. azine ##STR106##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 1-(2-pyrimidyl)piperazine.

R.sub.f 0.65. ##STR107##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of thiomorpholine.

R.sub.f 0.6. mide ##STR108##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 2-aminomethylthiophene.

R.sub.f 0.59. ##STR109##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of L(-)-1-phenethylamine.

R.sub.f 0.65. ##STR110##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of D(+)-1-phenethylamine.

R.sub.f 0.65. ##STR111##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of butylamine.

R.sub.f 0.62. ##STR112##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of t-butylamine.

R.sub.f 0.6. ##STR113##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)desoxynojirimycin are reacted with 10 mmol of 4-decyloxyaniline.

R.sub.f 0.8. ##STR114##

1 mol of 1-desoxynojirimycin is dissolved in 1 l of N,N-dimethylformamide, 0.5 mol of potassium carbonate is added and the 1.0 mol of ethyl .omega.-bromo-butanoate is added dropwise to this suspension with stirring. As soon as no more evolution of gas can be observed, the mixture is filtered off from the solid material and concentrated. The residue is taken up in 1.05 l of 1N sodium hydroxide solution and stirred at 90.degree. C. for 8 hours. The solution is then stirred with 1000 ml of a strongly acidic ion exchanger and filtered off.

After evaporating the solvents, 0.75 mol of product is isolated.

R.sub.f 0.25 CH.sub.2 Cl.sub.2 :MeOH:NH.sub.3 solution. ##STR115##

In accordance with the description for Example 1, 8.5 mmol of N-(3-carboxypropyl)desoxynojirimycin are reacted with 10 mmol of 4-ethoxyaniline.

R.sub.f 0.68. ##STR116##

In accordance with the description for Example 1, 8.5 mmol of N-(3-carboxyphenyl)desoxynojirimycin are reacted with 10 mmol of 4-t-butylaniline.

R.sub.f 0.6. ucit-N-yl)butanamide ##STR117##

In accordance with the description for Example 1, 8.5 mmol of N-(3-carboxypropyl)desoxynojirimycin are reacted with 10 mmol of 4-(2-chloro-1,1,2-trifluoroethoxy)aniline.

R.sub.f 0.65. ##STR118##

In accordance with the description for Example 1, 8.5 mmol of N-(3-carboxypropyl)desoxynojirimycin are reacted with 10 mmol of 4-cyclohexylaniline. R.sub.f 0.7. quinoline ##STR119##

In accordance with the description for Example 1, 8.5 mmol of N-(2-carboxyethyl)-desoxynojirimycin are reacted with 10 mmol of 1,2,3,4-tetrahydroisoquinoline.

R.sub.f 0.65. ##STR120##

To a suspension of 163 g (1 mol) 1-desoxynojirimycin in 2000 ml of dry N,N-dimethylformamide, 69,1 g (0.5 mol) potassiumcarbonate were added. The suspension was cooled to 0.degree. and 153 g (1 mol) of 2-bromo-methylacetate were added over a period of 1 hour.

The reaction mixture was stirred at 0.degree. for a further 10 hours. For workup the salts then were separated off by filtration with suction and the solvent was evaporated. The crude product was directly submitted to the next reaction step.

R.sub.f 0.6. CH.sub.2 Cl.sub.2 MeOH H.sub.3 N=4:3:1 vvv. ##STR121##

23.5 g (0,1 mol) of the compound described in Example 113 and 9.3 g (0,1 mol) of freshly distilled aniline were heated for five hours to 180.degree. under an atmosphere of inert gas.

After that time the reaction product was absorbed on silica gel and purified by chromatography with Toluene=Ethanol=40:1 1:1 as the eluent.

R.sub.f 0.45. ##STR122##

In accordance with the description for Example 114 0.1 mol of 2-(1,5-didesoxy-1,5-imino-D-glucit-N-yl) ethanemethylate are reacted with 0.1 mol of 4-ethoxyamiline.

R.sub.f 0.45. ##STR123##

In accordance with the description for Example 114 0.1 mol of 2-(1,5-didesoxy-1,5-imino-D-glucit-N-yl) ethanemethylate are reacted with 0.1 mol of 4-tert.-butylaniline.

R.sub.f 0.6. eamide ##STR124##

In accordance with the description for Example 114 0.1 mol of 2-(1,5-didesoxy-1,5-imino-D-glucit-N-yl) ethanemethylate are reacted with 0.1 mol of 4-(2-Hydroxyethoxy)-aniline.

R.sub.f 0.35. ##STR125##

In accordance with the description for Example 114 0.1 mol of 2-(1,5-didesoxy-1,5-imino-D-glucit-N-yl) ethanemethylate are reacted with 0.1 mol of 4-hydroxyaniline.

R.sub.f 0.55.

## Claims

1. A compound of the formula ##STR126## in which R or R' stands for a hydroxyl group and in which the other R' or R in each case stands for hydrogen, benzyl, and which is substituted by aryl having 6 to 10 carbon atoms, where the aryl is radical is unsubstituted or substituted by up to 4 identical or different substituents selected from the group consisting of fluorine; chlorine; bromine; iodine; cyano; nitro; alkyl, alkoxy, alkylthio and arylthio each having up to 6 carbon atoms; dioxymethylene; dioxyethylene; trifluoromethyl; trifluoromethoxy; difluoromethoxy; carboxyl and alkoxycarbonyl having up to 4 carbon atoms, or which can be substituted by pyridyl; thienyl; furyl; pyrimidyl; pyridazinyl; pyrazinyl or quinolyl, or unsubstituted or monosubstituted to tetrasubstituted by fluorine, chlorine, bromine, iodine, cyano, alkyl having up to 6 carbon atoms, alkoxy having up to 12 carbon atoms, alkylsulphonyl having up to 4 carbon atoms, trifluoromethyl, difluoromethylene, trifluoromethylthio, dioxymethylene, dioxyethylene, by cycloalkyl having 3 to 7 carbon atoms, by carboxyl or alkoxycarbonyl having up to 4 carbon atoms, by aryloxy having 6 to 10 carbon atoms, where the aryl radical of the aryloxy is unsubstituted or is substituted by up to 4 identical or different substitutents selected from the group consisting of fluorine; chlorine; bromine; iodine, cyano, hydroxyl; nitro; alkyl, alkoxy, alkylthio having up to 6 carbon atoms; dioxymethylene; dioxyethylene; trifluoromethyl; trifluoromethoxy; or difluoromethoxy; or by halogenoalkoxy having up to 6 carbon atoms and up to 5 fluorine and/or 3 chlorine atoms; or by hydroxyalkoxy, hydroxyalkyl and cyanoalkyl each having up to 8 carbon atoms; and alkenyloxy having up to 6 carbon atoms; or by a group --XR.sup.3, the substituents being identical or different, where up to 8 carbon atoms, and where different substituents selected from the group consisting of fluorine; chlorine; bromine; iodine; cyano; alkyl, alkoxy, alkylthio having up to 6 carbon atoms; nitro; dioxymethylene; dioxyethylene; trifluoromethyl; trifluoromethoxy; difluoromethoxy; and trifluoromethylthio, or R.sup.3 can be fused to benzene and which can contain oxygen, sulphur or up to 2 nitrogen atoms as hetero atoms, or alkylcarbonyloxy having up to 18 carbon atoms, or R.sup.3 alkylamino or dialkylamino each having up to 6 carbon atoms per alkyl group, or R.sup.3 6-membered ring which can be anellated, which can be interrupted by oxygen, sulphur or the group --NR.sup.4, and which can be substituted by alkyl having up to 4 carbon atoms, hydroxyl, phenyl, carboxyl or alkoxycarbonyl having up to 4 carbon atoms, where unsubstituted or substituted by up to 4 identical or different substituents selected from the group consisting of fluorine; chlorine; bromine; iodine; cyano; nitro; hydroxyl; alkyl, alkoxy, alkylthio having up to 6 carbon atoms; dioxymethylene; dioxyethylene; trifluoromethyl; trifluoromethoxy and difluoromethoxy, or R.sup.4 quinolyl, or R.sup.4 or monosubstituted or disubstituted by phenyl which is unsubstituted or substituted by chlorine, dioxymethylene or trifluoromethyl, hydroxyl, amino, alkylamino, dialkylamino each having up to 3 carbon atoms per alkyl group, fluorine, bromine, cycloalkyl having 3 to 6 carbon atoms, by carboxyl or alkoxycarbonyl having up to 6 carbon atoms, by pyridyl, pyrimidyl, pyrazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl or pyrrolidinocarbonyl, by morpholinocarbonyl, by alkylaminocarbonyl, dialkylaminocarbonyl or phenylalkylaminocarbonyl each having up to 6 carbon atoms per alkyl group, the substituents being identical or different.

2. A compound according to claim 1, where which is substituted by pyridyl, thienyl or by phenyl, where the phenyl radical is unsubstituted or substituted by up to 3 identical or different substituents selected from the group consisting of fluorine; chlorine; bromine; hydroxyl; alkyl, alkoxy having up to 4 carbon atoms; dioxymethylene; dioxyethylene and carboxyl, or R.sup.2 or trisubstituted by fluorine; chlorine; bromine; cyano; alkyl having up to 4 carbon atoms; hydroxyalkyl or hydroxyalkoxy having up to 4 carbon atoms; trifluoromethyl; trifluoromethoxy; dioxymethylene; dioxyethylene; by phenyl which is unsubstituted or substituted in the aromatic part by fluorine; chlorine; bromine; hydroxyl; alkyl, alkoxy having up to 9 carbon atoms; dioxymethylene; trifluoromethyl or carboxyl, or by straight-chain or branched alkenyloxy having up to 4 carbon atoms, or by a group --XR.sup.3, the substituents being identical or different, where atoms and fluorine; chlorine; bromine; hydroxyl; alkyl, alkoxy having up to 4 carbon atoms; dioxymethylene; trifluoromethyl or carboxyl, the substituents being identical or different, or R.sup.3 cyclopropyl, cyclopentyl or cyclohexyl or R.sup.3 per alkyl group, ##STR127## where R.sup.4 trisubstituted by fluorine; chlorine; bromine; hydroxyl; alkyl, alkoxy having up to 4 carbon atoms; dioxymethyl; trifluoromethyl or carboxyl, the substituents being identical or different, or R.sup.4 atoms, which is unsubstituted or monosubstituted or disubstituted by phenyl which is unsubstituted or substituted by chlorine, trifluoromethyl or dioxymethylene, hydroxyl, amino, methylamino, dimethylamino, fluorine, chlorine, cyclopropyl, cyclopentyl, cyclohexyl or alkoxycarbonyl having up to 4 carbon atoms, by morpholinyl or pyrrolidinyl, or by morpholinocarbonyl, dialkylamino or phenylalkylamino each having up to 4 carbon atoms, the substituents being identical or different.

3. A compound according to claim 1, in which atoms, which is substituted by thienyl or phenyl, or R.sup.2 or trisubstituted by fluorine, chlorine, bromine, cyano, alkyl having up to 4 carbon atoms, hydroxyalkyl, alkoxy having up to 9 carbon atoms, hydroxyalkoxy having up to 4 carbon atoms, alkylthio having up to 4 carbon atoms, trifluoromethyl or trifluoromethoxy, the substituents being identical of different, or R.sup.2 ##STR128## where R.sup.4 by fluorine; chlorine; bromine; hydroxyl; alkyl or alkoxy having up to 4 carbon atoms, the substituents being identical or different, or R.sup.4 atoms, which is unsubstituted or monosubstituted or disubstituted by chlorine, trifluoromethyl or dioxymethylene, by hydroxyl, amino, dimethylamino, cyclopropyl or alkoxycarbonyl having up to 4 carbon atoms, by morpholinyl, pyrrolidinyl or pyrrolidinocarbonyl, the substituents being identical or different.

4. A compound according to claim 1 selected from the group consisting of amide, ionamide, namide, namide, e, pionamide, -yl)propionamide, amide, lucit-N-yl)propionamide, amide, mide, e, e, de, amide, namide, yl)piperazine, de, namide, onamide, amide, ionamide, namide, opionamide, e, opionamide, -yl)propionamide, amide, nnit-N-yl)propionamide, amide, mide, e, e, de, amide, namide, yl)piperazine, de, namide, onamide azine, ine, de, razine, ne, ne, ine, -chlorophenyl])piperazine, ethyl])piperazine, zine, mide, ucit-N-yl)butanamide, noline.

5. An antiviral composition comprising an antivirally effective amount of one or more compounds according to claim 1 and a pharmaceutically suitable excipient.

6. An antiviral composition according to claim 5 in dosage unit form.

7. A method of combating viral infections comprising administering to a patient having a viral infection an antiviral effective amount of one or more compounds according to claim 1.

8. A method according to claim 7 wherein the viral infection is an infection of a DNA virus or an RNA virus.

9. A method for the treatment and prophylaxis of diseases produced by retroviruses comprising administering to a patient in need of such treatment or prophylaxis an effective amount therefor of one or more compounds according to claim 1.