NZ205000A - Treating virus infections using hexapyranose derivatives - Google Patents

Description

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Complete Specification Filed: *P.? Class: 4.y.*.V/l° Publication Dat*: ... ^. /? .....

P.O Jo.'i-nat. No: 205000 o "ON JUL 1983 .

Patents Form No. 5 NEK ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "Use of sugar derivatives for the prophylaxis and treatment of virus infections" WE, CIBA-GE1GY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which we pray that a patent may be granted to us,and the method by which it is to be performed, to be particularly described in and by the following statement (follcv.sd I v - 1ft- 2G5CQ0 Use of sugar derivatives for the prophylaxis and treatment of virus infections The present invention relates to the use of sugar derivatives, especially hexopyranose compounds of the formula I, R' 13 ■> (I) 3 1 4 R -°-R R5 R6 0=C-R 9 R' 0 II 11 C—N C C —N—CH—CH-— CH—C— R II 7 II 0 R in which each of X^" and X^ independently of the other, represents a group 205000 - 2 each of R1, R2, H12 and R13, N(R"^)-> R^ representing hydrogen or lower alkyl, independently of one another, represents a radical of the formula la -(z1-rL-x3)n-A1 (la) in which n represents 0 or 1, Z^ represents car-bonyl or thiocarbonyl, represents unsubstituted or substituted alkylene which may be interrupted by iminocarbonyl or oxy-•* carbonyl, 7S represents a group of the formula -0-or -N(R^)-, wherein R^ has the meaning given above, and represents a radical of the formula lb, 0 11 15 -P-O-R (lb) 1 OH in which R^ represents an aliphatic or cycloaliphat-ic radical having at least 7 carbon atoms, or A"'" represents a group of the formula Ic, i-- ....... .....:■ * 205000 0 R16 I! I -P - O - CH 1 1 17 OH R in which R represents 17 hydrogen and R ' represents 2-hydroxysthy1 or 1,2-dihydroxyethyl, wherein at least one hydroxy group is esterified or etherified by a radical having at least 7 carbon atoms, or in which each of R^ and R"^, independently of the other, represents esterified or etherified hydroxymethyl, the esterifying or etheri-fying radicals having at least 7 carbon atoms, or 1 2 12 l^ each of R , R , R and R , independently of one another, represents hydrogen, acyl other than a radical of the formula la in which n represents 1, or a radical that can be removed under physiological conditions, each of R3, R^", R^, R^ and R®, independently of one another, represents hydrogen or lower allcyl, R represents hydrogen or 205000 lower alkyl that is un-substituted or substituted by a group of the formula Id, -E-(Z2-Y2-X4)m-A2 (Id) in which m represents 0 or lf E represents a group of the formula -0-. -3- or R^* having the 2 meaning given above, Z represents carbonyl or 2 thiocarbonyl, Y represents unsubstituted or substituted alkylene which may be interrupted by iminocarbonyl or oxy-carbonyl, represents a group of the formula -0-or -N(R^)-, R ^ having the meaning given above, p and A represents a radical of the formula lb or Ic; or by free or etherified hydroxy or mercapto, by esterified hydroxy or mercapto other than a group of the formula Id, by free amino or substituted amino other than a group of the formula Id, by free, esterified or amidated carboxy, by cyclo-alkyl, by carbocyclic aryl or R5 and R6 each of Bp and R^\ 2 0 5 0 0 "0 - or by nitrogen-containing heteroaryl having 5 or 6 ring members in the heterocyclic ring, together represent un-substituted or substituted 1,3- or 1,4-lower alkylene, independently of the other, represents a radical of the formula Ie, -X5-y3-X6-A3 (Ie) in which X-* represents a group of the formula -0-, -S- or -N(R14)-, and X6 represents a group of the formula -0- or -N(R^)-, in each case R^4 having the meaning given above, •K represents unsub-stituted or substituted alkylene which may be interrupted by imino-carbonyl or oxycarbonyl, and A3 represents a radical of the formula lb or Ic, or free hydroxy or mercapto, etherified hydroxy or mercapto other than a radical of the formula Ie, or free amino or substituted amino 20500 other than a radical of the formula Ie, and R^® represents hydrogen or free, esterified or ami- dated carboxy, with the proviso that the compounds of the formula I 12 ^ have at least one radical A , A or A^( and the use of pharmaceutical^ acceptable salts of such compounds for the prophylaxis and (preferably) treatment of virus infections in warm-blooded animals, especially and including humans, and to novel pharmaceutical preparations that contain hexopyranose compounds of the formula I.

By contrast with the treatment of bacterial infections, agents available for the prophylaxis and treatment of virus infections are few and inadequate so that to overcome viral diseases it is in almost sill cases necessary that the organism itself has adequate powers of defence.

In accordance with the invention it has surprisingly been found that the above-mentioned hexopyranose compounds of the formula I and their pharmaceutically acceptable salts are excellently suitable both for the prophylaxis and treatment of virus infections, as demonstrated, for example, by animaT experiments such as those illustrated in the Examples. In these animal experiments animals, such as mice or guinea pigs, are infected by a wide variety of types of virus in a dose that is lethal for all or the large majority of untreated (control) animals, for example ^®a0-90' the course of the infection is observed in the untreated control animals compared with animals that are treated before, at the same time as, or after the infection, with one of the above-mentioned hexopyranose compounds or a salt thereof.

These experiments demonstrate that the antiviral 205000 action of the above-mentioned hexopyranose compounds of the formula I and their salts is not achieved by any hitherto knovm antiviral substance of any structure. It is especially remarkable that a prophylactic effect is produced when hexopyranose compounds of the formula I are administered from just a few days up to a few, for example four, weeks before infection, and a therapeutic effect still occurs on administration several days, for example 1 week, after infection.

Remarkable and hitherto unprecedented is also the broad viral spectrum against which the above-mentioned compounds are effective.

The hexopyranose compounds of the formula I can be used especially for the prophylaxis and treatment of diseases caused by the viruses specified in detail hereinafter [for nomenclature cf. J.L. Melnick, Prog. med. Virol. 26, 214-232 (1980) and 28, 208-221 (1982)]: DNA viruses with cubic symmetry and naked nucleocapsid, DNA viruses with enveloped virion and also RNA viruses with cubic, and those with helical, symmetry of the caps id.

Preferably, the compounds of the formula I are used in the case of DNA viruses with enveloped virion and cubic symmetry of the capsid, in the case of RHA viruses with cubic symmetry of the capsid and naked virion, and in the case of RNA viruses with helical symmetry of the capsid, in which the nucleo-capsid casing is located at the surface membrane, but also in the case of Adenoviridae, Poxviridae and Corona-viridae, such as, especially, human coronaviruses.

The compounds of the formula I are used especially in the case of Herpetoviridae, Picornaviridae and mixoviruses, but also in the case of mastadeno-viruses, such as, especially, human adenoviruses, in the case of Chordopoxvirinae, such as, chiefly, orthopoxviruses, such as, especially, for example, vaccinal 205000 viruses, in the case of Reoviridae, chiefly (especially human) rotaviruses, and also in the case of Calici-viridae and Rhabdoviridae, such as, especially, vesiculoviruses in humans as well as horses, cows and pigs.

The compounds of the formula I are mainly used in the case of Alphaherpesvirinae like Varicellaviruses, for example human varicellazoster viruses, rhinoviruses, cardioviruses and Orthomyxoviridae, but also in the case of Betaherpesvirinae, such as, especially, human cytomegaloviruses, in the case of aphthoviruses, especially aphthoviruses of cloven-hoofed animals, such as, chiefly, cows, and in the case of Paramyxoviridae, such as, especially, pneumoviruses, for example respiratory syncytial viruses in humans, and such as, in addition, morbilliviruses or paramyxoviruses, such as parainfluenza viruses, for example human parainfluenza viruses, including Sendai viruses, as well as in the case of arboviruses or vesiculoviruses, for example vesicular stomatitis viruses.

Above all the compounds of the formula I are used for simplex viruses, for example human herpes simplex viruses of types 1 and 2, and in the case of human encephalomyocarditis viruses, influenza viruses, such as mainly influenza A and influenza B viruses, and most especially in the case of the viruses mentioned in the Examples.

The hexopyranose compounds of the formula I can be used in accordance with the invention by administering them enterally or parenterally, especially together with suitable adjuncts or carriers. Preferably they are applied to the mucous membrane, for example intranasally, rectally, vaginally or to the conjunctiva of the eye, or orally. The antiviral effect occurs, however, also if administered in other ways, for example subcutaneously, intravenously, intramuscularly or if applied to the skin. 205000 The dosage of the active ingredient depends, inter alia, on the species of the warm-blooded animal, the defensive condition of the organism, the mode of administration and the nature of the virus. There is no especially pronounced relationship between dosage and action.

For prophylaxis, a single dose of from approximately 0.01 mg to approximately 25 mg, preferably from 0.05 to 7 mg, for example 0.5 mg, of active ingredient is administered to a warm-blooded animal of approximately 70 kg body weight, for example a human. The prophylactic effect of this dose lasts for several weeks. If required, for example at times of increased risk of infection, the administration of this dose can be repeated.

The therapeutic dose for warm-blooded animals of approximately 70 kg body weight is between 0.1 mg and 50 mg, preferably between 1 and 10 mg, for example 5 mg, especially when administered orally. The dosage in the case of topical, especially intranasal, administration is lower by up to a factor of 10. If required, the administration of the hexopyranose compounds of the formula I can be repeated until there is an improvement in the disease. Normally, however, one administration is adequate.

Preferably, the hexopyranose compounds of the formula I are used in accordance with the invention in the form of pharmaceutical preparations that contain a pharmacologically active amount of the active ingredient together with pharmaceutically acceptable carriers that are suitable for enteral, for example oral, or parenteral, administration and may be inorganic or organic, solid or liquid. For example, tablets or gelatin capsules that contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerin, 205000 and/or lubricants, for example siliceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, are used. Tablets may likewise contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat or rice starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescing mixtures, or adsorbents, colouring substances, flavouring substances and sweeteners. Furthermore, the pharmacologically active compounds of the present invention can be used in the form of parenterally administrable preparations, for example infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, and these, for example in the case of lyophilised preparations that contain the active ingredient alone or together with a carrier, for example mannitol, can be prepared before use. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations in question are produced in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and contain from approximately 0.001 up to approximately 95 # of active ingredient, an active ingredient content of less than 1 being suitable especially for preparations that are to be topically administered.

Pharmaceutical preparations for enteral or parenteral administration that contain an effective amount, but less than 1% by weight, of a hexopyranose 205000 compound of the formula I or a salt thereof together with a significant amount of a pharmaceutical carrier, are novel and the invention relates also to these.

The invention relates especially to pharmaceutical preparations containing a hexopyranose compound of the formula I that is mentioned below as being preferred for the use in accordance with the invention.

The following forms of administration, which have not been prior-published, of hexopyranose compounds of the formula I are especially suitable for the use in accordance with the invention: creams, ointments, pastes or a gel with an active ingredient content of from 0.001 % up to, but exclusive of, 1 % by weight, principally of from O.OOl % to 0.9 %, especially from 0.01 % to 0.1 %, for example 0.05 %, for example ointments for intranasal administration, vaginal or rectal suppositories or lipsticks, aqueous solutions having an active ingredient content of from 0.001 % by weight up to, but exclusive of, 1 % by weight, principally from 0.001 % to 0.9 %, especially from 0.05 % to 0.5 %, for example 0.1 %, preferably isotonic, sterile and physiologically tolerable solutions, for example eye drops, preferably in disposable micro-containers, or sprays for use in the mouth or pharyngeal cavity, or tablets or capsules having an active ingredient content of from 0.1 up to, but exclusive of, 1 % by weight, for example 0.9 %.

The pharmaceutical preparations described in the Examples are especially suitable.

Creams are oil-in-water emulsions that contain more than 50 % of water. There are used as oily base substances especially fatty alcohols, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, 205000 and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. There come into consideration as emulsifiers surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty-acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerin fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents that reduce the drying out of creams, for example polyalcohols, such as glycerin, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes etc.

Ointments are water-in-oil emulsions that contain up to 70 $>, preferably from approximately 20 % to approximately 50 $», of water or aqueous phase. There come into consideration as fatty phase especially hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which, in order to improve the water-binding ability, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerin, propylene glycol, sorbitol and/or polyethylene glycol, as well as preservatives, perfumes etc. 205000 Fatty ointments are anhydrous and contain as the base substance especially hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated peanut or castor oil, and fatty acid partial esters of glycerin, for example glycerin mono- and di-stearate, as well as, for example, the fatty alcohols that increase water-ab-sorbing ability, emulsifiers and/or additives mentioned in connection with the ointments.

Pastes are creams and ointments with secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, and also talc and/or aluminium silicates, the purpose of which is to bind any moisture or secretions present.

Foams are administered from pressurised containers and are liquid oil-in-water emulsions in aerosol form, halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, being used as propellants. There are used as oily phase, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopro-pyl myristate, and/or other waxes. There are used as emulsifiers, inter alia, mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition there are the customary additives, such as preservatives, etc.

Tinctures and solutions usually have an aqueous/ ethanolic base substance to which there are added, inter alia, polyalcohols, for example glycerin, gly- 205000 cols and/or polyethylene glycol,as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low polyethylene glycols, that is to say lipophilic substances soluble in aqueous mixture as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other adjuncts and additives.

The manufacture of the topically administrable pharmaceutical preparations is carried out din a manner known per se. for example by dissolving or suspending the active ingredient in the base substance, or in a portion thereof, if necessary. When processing the active ingredient in the form of a solution, it i3 usually dissolved in one of the two phases before emul-sification; when processing in the form of a suspension it is mixed with a portion of the base substance after emulsification and then added to the remainder of the formulation.

The above terms used for the definition of the compounds of the formula I have, within the scope of this application, preferably the following meanings: Acyl, for example aa R^", R2, R^2 and R"*"3, is especially the acyl radical of an organic carboxylic acid, especially an aliphatic, but also a cycloali-phatic, cycloaliphatic-aliphatic, aromatic or arali-phatic carboxylic acid, which may have, for example, up to 90 carbon atoms.

Aliphatic carboxylic acids are, inter alia, alkanecarboxylic acids that are unsubstituted or substituted, for example, by hydroxy or etherified or esterified hydroxy, such as lower alkoxy or lower alkanoyloxy, or by unsubstituted or substituted amino, such as lower alkylamino, di-lower alkylamino or acyl-amino, for example alkanoylamino, and corresponding alkene- or alkyne-carboxylic acids that may have one or more double or triple bonds. These acids may contain, 205000 2 for example, up to 90 carbon atoms, R as the radical of an aliphatic carboxylic acid, in the case when X1 represents a group of the formula -N(R^)-, preferably representing the acyl radical of an unsubstituted or hydroxy-substituted lower alkanecarboxylic acid.

Cycloaliphatic carboxylic acids may be monocyclic or polycyclic and as a cycloaliphatic radical contain monocyclic or polycyclic cycloalkyl that is unsubstituted or is substituted, for example by hydroxy, and corresponding cycloalkenyl.

In cycloaliphatlc-aliphatic radicals, the cycloaliphatic moiety and the aliphatic moiety have the meanings given above; such radicals are especially monocyclic or polycyclic cycloalkyl-lower alkyl.

Aromatic and araliphatic carboxylic acids are, inter alia, benzoic or phenyl-lower alkanecarboxylic acids that are unsubstituted or substituted, for example by lower alkyl, hydroxy, lower alkoxy or halogen.

Groups that can be removed under physiological conditions are especially organic silyl groups, especially aliphatically substituted silyl groups, such as tri-lower alkylsilyl.

Substituents of alkylene, which is represented by 12 "3 the radicals Y , Y and Y , are, inter alia, hydroxy, esterified or etherified hydroxy, such as acyloxy, for example lower alkanoyloxy, or lower alkoxy, amino or substituted amino, such as lower alkylamino, di-lower alkylamino or acylamino, for example lower alkanoyl-amino. In an alkylene radical that is interrupted by iminocarbonyl or oxycarbonyl, there may be one or more, for example two, such groups and these may be present as groups of the formula -N(R"^)-C(=0)- or -0-C(=0)-, and as groups of the formula -C(=0)-iJ(R^^)- or -C(=0)-0-, and R^ has the meaning given above and preferably represents hydrogen. An alkylene radical formed 205000 6 by the groups R and R and having 3 or 4 carbon atoms in the chain may be substituted, for example by hydroxy, which may be acylated, for example by a group of the formula la.

An aliphatic radical having at least 7 carbon IS atoms that is the group R ^ or etherifies a hydroxy 1 6 17 group in a radical R or R ' is especially a corresponding unsubstituted or substituted alkyl radical but may also represent a corresponding unsaturated radical, such as an unsubstituted or substituted alkenyl radical having one or more double bonds, such radicals having, for example, from 7 up to and including 90 carbon atoms, preferably from 7 up to and including 30 carbon atoms. Substituents of such aliphatic radicals are, for example, hydroxy, etherified or esterified hydroxy, such as lower alkoxy or lower alkanoyloxy and/or unsubstituted or substituted amino, such as lower alkylamino, di-lower alkylamino or alkanoylamino.

A corresponding cycloaliphatic radical that is IS the group R J or a radical etherifying a hydroxy group 16 17 in a radical R or R is especially monocyclic or polycyclic cycloalkyl, or also corresponding cyclo-alkenyl, which may contain one or more double bonds.

Such radicals contain at least 7, and preferably from 7 to 30, carbon atoms, and may, in addition, be substituted, for example by hydroxy, etherified or esterified hydroxy, such as lower alkoxy or lower alkanoyloxy, or by unsubstituted or substituted amino, such as lower alkylamino, di-lower alkylamino or alkanoylamino.

Etherified hydroxy or substituted amino as a radical ] 1 cal R^ or R^ is, for example, lower alkoxy, or, for example, lower alkylamino, in which lower alkyl may be substituted.

A radical esterlfying a hydroxy group in a radical 16 17 R or R is especially an acyl radical of an organic 205000 carboxylic acid, especially of one of the above-men-tioned aliphatic and cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic, carboxylic acids, preferably having from 7 to 90 carbon atoms.

Etherified hydroxy or mercapto or esterified hydroxy or mercapto other than a radical of the formula Id as substituent of lower alkyl R^ is, for example, lower alkoxy, acyloxy, such as alkanoyloxy, wherein alkanoyl contains up to 90, for example from 7 to 30, carbon atoms and may optionally be substituted, for example by hydroxy, or is halogen, lower alkylthio or acylthio, such as alkanoylthio, wherein alkanoyl contains up to 90, for example from 7 to 30, carbon atoms. Substituted amino other than a radical of the formula Id as substituent of a lower alkyl group R^ is, for example, lower alkylamino, guanylamino or acylamino, such as alkanoylamino, wherein alkanoyl may contain up to 90, for example up to 30, carbon atoms. Esterified carboxy as substituent of a lower alkyl radical R^ is preferably carboxy esterified by an aliphatic radical, such as alkyl having up to 30 carbon atoms, that is to say, for example, corresponding alkoxycar-bonyl, whilst corresponding amidated carboxy, is, for example, aminocarbonyl or lower alkylaminocarbonyl, wherein lower alkyl may be substituted, for example by carboxy, alkoxycarbonyl or aminocarbonyl. Esterified or amidated carboxy in a radical R^ may also be a radical of the formula o II -c- • E (Y^ ■X4) m (Ida) x,";:: i 205000 OA O in which m, E, Y , X and A have the meanings given above.

Aryl as substituent of a lower alkyl group is especially phenyl that is unsubstituted or substituted, for example by lower alkyl, hydroxy or etherified or esterified hydroxy, such as lower alkoxy, or halogen, whilst nitrogen-containing heteroaryl having 5 or 6 ring members in the heterocyclic ring as corresponding substituent of R^ is monocyclic or bicyclic heteroaryl containing one or two nitrogen atoms as ring members. q ]i Etherified mercapto as radical R^ or R is especially lower alkylthio, whilst in a lower alkylamino 9 11 radical R or R the lower alkyl group may be substituted, for example by carboxy, lower alkoxycarbonyl or aminocarbonyl.

Esterified carboxy R"*"® is especially lower alkoxy-carbonyl, whilst amidated carboxyl R^ may be carbamoyl or H-lower alkylcarbamoyl, wherein lower alkyl may be substituted, for example by carboxy, lower alkoxycarbonyl or aminocarbonyl.

In the context of the present description, the general terms used above have the following meanings, radicals and compounds that are termed "lower" containing up to and including 7, preferably up to and including 4, carbon atoms: Alkyl is, for example, lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tributyl, sec.-butyl or tert,-butyl, also n-pentyl, neopentyl, n-hexyl or n-heptyl, or higher alkyl, such as straight-chain or branched octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl or heneicosyl, and also higher alkyl of the triacontyl, tetracontyl, pentacontyl, hexacontyl, heptacontyl, octacontyl or nonacontyl series.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert.- 205000 butoxy.

Alkanoyloxy is lower or higher alkanoyloxy, lower alkanoyloxy being, for example, formyloxy, acetoxy, pro-pionyloxy or butyryloxy, whilst higher alkanoyloxy is, for example, lauroyloxy, myriatinoyloxy, palmitoyloxy, stearoyloxy or behenoyloxy. Alkanoyloxy substituted by hydroxy, for example higher alkanoyloxy, is, inter alia, mycoloyloxy.

Lower alkylamino is, for example, methylamino, ethylamino, n-propylamino or isopropylamino, Di-lower alkylamino is, for example, dimethylamino, diethylamino or di-isopropylamino. Alkanoylamino is lower alkanoylamino, for example formylaminof acetylamino or pro-pionylamino, or higher alkanoylamino, for example lauroylamino, palmitoylamino, atearoylamino or behen-oylamino.

An alkanecarboxylic acid is, for example, a lower alkanecarboxylic acid, such as acetic acid, propionic acid, butyric acid or caproic acid, or a higher alkanecarboxylic acid, such as lauric acid, myristic acid, palmitic acid, stearic acid or behenic acid, whilst, for example, an alkanoic acid substituted by hydroxy may be, inter alia, mycolic acid.

Alkene- and alkyne-carboxylic acids are, inter alia, lower alkene- and lower alkyne-carboxylic acids, such as acrylic acid, crotonic acid or tetrolic acid, or higher alkene- and higher alkyne-carboxylic acids, such as undecylenic acid, oleic acid or elaidic acid.

The acyl radical of a lower alkanecarboxylic acid, 2 1 which is the group R in the case when X represents the radical of the formula -N(R^)-, is especially acetyl or hydroxyacetyl, and propionyl.

Cycloalkyl is, for example, cyclopentyl, cyclo-hexyl or adamantyl, whilst cycloalkenyl may be, for example, 1-cyclohexenyl, and cycloalkyl-lower alkyl 205000 may be, for example, 3-cholanylmethyl or the acyl radical of cholanic acid.

Phenyl-lower alkanecarboxylic acids are, for example, phenylacetic acid or phenylpropionic acid, which may be substituted, for example as stated.

Halogen is preferably halogen having an atomic number of up to 35 and represents especially chlorine, but also fluorine or bromine.

Tri-lower alkylailyl is especially trimethylsilyl.

Alkylene is straight-chain or branched and is especially lower alkylene, for example methylene, ethylene, 1,2-propylene, 1,3-propylene or 1,6-hexylene, but also higher alkylene, such as 1,11-undecylene.

Alkenyl is lower alkenyl, for example allyl or methallyl, or higher alkenyl, for example decenyl.

Lower alkylthio is, for example, methylthio or ethylthio.

In an alkanoylthio radical, the alkanoyl radical represents lower alkanoyl, for example acetyl, propio-nyl, butyryl or hexanoyl, but may also represent higher alkanoyl, for example lauroyl, myristinoyl, palmitoyl, stearoyl or behenoyl, Alkoxycarbonyl is lower alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert.-butoxy-carbonyl, or higher alkoxycarbonyl, for example dodecyl-oxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycar-bonyl or heneicosyloxycarbonyl.

Lower alkylaminocarbonyl is, for example, methyl-aminocarbonyl or ethylaminocarbonyl, also carboxy-, lower alkoxycarbonyl- or carbamoyl-lower alkylaminocarbonyl, such as carboxymethylaminocarbonyl, 1-car-boxyethylaminocarbonyl, methoxycarbonylmethylamino-carbonyl or carbamoylmethylaminocarbonyl.

Nitrogen-containing heteroaryl having 5 or 6 ring members in the heterocyclic ring is, for example, 205000 imidazolyl, such aa 4-imidazolyl, or indolyl, such aa 3-indolyl.

The hexopyranose compounds of the formula I may be in the form of isomeric mixtures or pure isomers.

They may thua have the L- or DL-configuration in the sugar moiety, but have preferably the D-configura-tion. Furthermore, the hexopyranose moiety may be that of any hexose, but is preferably that of an alloae, galactose or mannoae, but especially of a glucose.

That is to say, the compounds of the present invention are especially corresponding alio-, galacto- or manno-pyranose compounds, but more especially corresponding glucopyranose compounds, having preferably the D-con-figuration.

The radical of the formula -C(R^)(R^)-C(=0)- linked to the oxygen atom, in the case where one of the groups B? and R^ is other than hydrogen, is preferably in optically active form and has especially the D-con- figuration, whilst the radical of the amino acid of the formula -N(R^)-C(R^)(R^)-C(=0)-, in the case where 6 7 one of the radicals R and R is other than hydrogen, is likewise preferably in optically active form, especially in the L-configuration, and the terminal a-aminoglutaric acid radical is preferably in optically active form, especially in the D-configuration. Furthermore, the optionally substituted 1-hydroxy group of the formula -0-R^" may have the a- or the 0-con-figuration; the novel compounds of the formula I may, however, also be in the form of a mixture of the l-a-and 1-p-isomers.

In the compounds of the formula I, the proton bonded to phosphorus via an oxygen atom can readily be replaced by a cation, that is to say, the compounds form salts. In this case, the compounds of the formula I may be in salt form or in the form of a mixture of 205000 the free compounds and their salts. These are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and ammonium salts, or salts with suitable organic amines, such as lower alkylamines, for example triethylamine. Compounds of the formula I having basic groups, for example amino groups, are in the form of internal salts but, when there are more basic than acidic groups in a molecule of the formula I, they may also form acid addition salts with external acids, such as salts with inorganic acids, such as mineral acids, for example hydrochloric, sulphuric or phosphoric acid, or organic carboxylic or sulphonic acids, for example acetic, maleic, fumaric, tartaric, citric, methanesulphonic or 4-toluenesul-phonic acid. Only the pharraaceutically acceptable, non-toxic salts are used therapeutically.

The above-mentioned hexopyranose compounds of the formula I and their salts and their preparation are described in New Zealand Patent Specification numbers 194432, 195235 and 199545, which are in the name of the Applicants of the present invention, and the last-mentioned Specification or foreign equivalents thereof were not published until after the priority date of the present Specification. The use in accordance with the invention of the phosphorylmuramyl peptides per se for the prophylaxis and treatment of virus infections is neither described in, nor made obvious by, the above-mentioned Specifications. The second paragraph on page 13 of the above-mentioned specification 194432 relates merely to their use as adjuvant in admixture with vaccines.

The present invention relates especially to the use of: 1 2 ^ (a) compounds of the formula I in which X and X have ^ 1 °-<\fche meanings given above, R represents a radical of the ^formula la in which n, Z1, Y1, X3 and A1 have the mean-N19867ings given above, each of R2, R12 and R13, independent- 205000 ly of one another, represents hydrogen, acyl other than a radical of the formula la in which n represents 1, or a group that can be removed under physiological conditions, R^, R^, R^, R^, R® and R^ have the meanings given above, R^ represents hydrogen or lower alkyl that is unsubstituted or substituted by free or etherified hydroxy or mercapto, by esterified hydroxy or mercapto other than a corresponding group of the formula Id or by free amino or substituted amino other than a corresponding group of the formula Id, by free, esterified or amidated carboxy, by cycloalkyl, by car-bocyclic aryl or by nitrogen-containing heteroaryl having 5 or 6 ring members in the heterocyclic ring, or 5 6 R and R together represent unsubstituted or substituted 1,3- or 1,4-lovrer alkylene, and in which each q of R and R , independently of the other, represents free hydroxy or mercapto, etherified hydroxy or mercapto other than a radical of the formula Ie, or free amino or substituted amino other than a radical of the formula Ie, it being possible for free functional groups to be in protected form, and of pharmaceutically acceptable salts of such compounds; (b) compounds of the formula I in which X and X p have the meanings given above, R represents a radical of the formula la in which n, z\ X-* and A"*- have "" 1 12 13 the meanings given above, each of R , R and R , independently of one another, represents hydrogen, acyl other than a radical of the formula la in which n represents 1, or a group that can be removed under physiological conditions, R^, R4, R^, R^, R® and R^ have the meanings given above, R^ represents hydrogen or lower alkyl that is unsubstituted or substituted by free or etherified hydroxy or mercapto, by esterified hydroxy or mercapto other than a corresponding group of the formula Id, by free amino or substituted amino 2Q5GOO other than a corresponding group of the formula Id, by free, esterified or amidated carboxy, by cycloalkyl, by carbocyclic aryl or by nitrogen-containing heteroaryl having 5 or 6 ring members in the heterocyclic 5 6 ring, or Jr and R together represent unsubstituted or substituted 1,3- or 1,4-lower alkylene, and in which q in each of R and R , independently of the other, represents free hydroxy or mercapto, etherified hydroxy or mercapto other than a radical of the formula Ie, or free amino or substituted amino other than a radical of the formula Ie, it being possible for free functional groups to be in protected form, and of pharmaceutical^ acceptable salts of such compounds; (c) compounds of the formula I in which X and X 13 have the meanings given above, R ' represents a radical of the formula la in which n, z\ X^ and A"*" have "" 12 12 the meanings given above, each of R , R and R , independently of one another, represents hydrogen, acyl other than a radical of the formula la in which n represents 1, or a group that can be removed under physiological conditions, R^, R4, R*', R^, R® and R^"® have the meanings given above, R^ represents hydrogen or lower alkyl that is unsubstituted or substituted by free or etherified hydroxy or mercapto, by esterified hydroxy or mercapto other than a corresponding group of the formula Id, by free amino or substituted amino other than a corresponding group of the formula Id, by free, esterified or amidated carboxy, by cycloalkyl, by carbocyclic aryl or by nitrogen-containing heteroaryl having 5 or 6 ring members in the heterocyclic ring, 5 6 or R^ and R together represent unsubstituted or substituted lower alkylene having 3 or 4 carbon atoms in Q 11 the chain, and in which each of RJ and R , independently of the other, represents free hydroxy or mercapto, etherified hydroxy or mercapto other than a radical of the formula Ie, or free amino or substituted 20500 0 amino other than a radical of the formula Ie, it being possible for free functional groups to be in protected form, and of pharmaceutically acceptable salts of such compounds; or 1 2 (d) compounds of the formula I in which X and X have 1 2 12 13 the meanings given above, each of R , R , R and R , independently of one another, represents hydrogen, acyl other than a radical of the formula la in which n represents 1, or a group that can be removed under physiological conditions, R3, R^, R"*, R7, R8 and R10 have the £ meanings given above, R represents lower alkyl substituted by a radical of the formula Id, in which m, E, 2 2 4 2 6 Z , Y , X and A have the meanings given above, or R represents lower alkyl substituted by a group of the OA 2 formula Ida in which m, E, Y , X and A have the mean- 9 11 ings given above, and m which each of R and R , independently of the other, represents free hydroxy or mercapto, etherified hydroxy or mercapto other than a radical of the formula Ie, or free amino or substituted amino other than a radical of the formula Ie, it being possible for free functional groups to be in protected form, and of pharmaceutically acceptable salts of such compounds, and to novel pharmaceutical preparations containing these compounds.

The invention includes especially the use of hexopyranose compounds, particularly D-glucopyranose 1 2 compounds of the formula I, in which X and X have 1 2 12 13 the meanings given above, each of R , R , R and R , independently of one another, represents hydrogen, the acyl radical of an aliphatic, cycloaliphatic, aromatic or araliphatic carboxylic acid, especially of an alkanecarboxylic acid having up to 90 carbon atoms that is unsubstituted or substituted, for example by hydroxy, amino and/or alkanoylamino, such as higher alkanoylamino, a tri-lower alkylsilyl group or a 205000 radical of the formula la in which n and have the meanings given above, represents thiocarbonyl or, _1 preferably, carbonyl, Y represents lower alkylene which may be interrupted by iminocarbonyl or oxycar- bonyl, and A^" represents a radical of the formula lb or Ic, in which R ^ represents an aliphatic radical having at least 7 carbon atoms, R"^ represents hydrogen 17 and R represents 2-hydroxyethyl or 1,2-dihydroxy-ethyl, in which at least one hydroxy group is etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or is esterified by a corresponding 16 17 aliphatic acyl radical, or each of R and R , independently of the other, represents hydroxymethyl etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or esterified by a corresponding aliphatic acyl radical, R^, R^f R^, R^ and R® have the meanings given above, R^ represents hydrogen or lower alkyl which is unsubstituted or substituted by a radical of the formula Id in which m, E and X^" 2 ~" have the meanings given above, Z represents thiocarbonyl or, especially, carbonyl, Y^ represents lower alkylene which may be interrupted by iminocarbonyl 2 or oxycarbonyl, and A represents a radical of the formula lb or Ic in which R represents an aliphatic radical having at least 7 carbon atoms, R"^ represents 17 hydrogen and R ' represents 2-hydroxyethyl or 1,2- dihydroxy ethyl, in which at least one hydroxy group is esterified by an aliphatic radical having at least 7 and up to 90 carbon atoms or by a corresponding ali- 16 17 phatic acyl radical, or each of R and R , independently of the other, represents hydroxymethyl etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or esterified by a corresponding aliphatic acyl radical, or R^ represents lower alkyl substituted by hydroxy or mercapto, by hydroxy or Z0500 0 mercapto etherified by an aliphatic radical containing up to 90 carbon atoms, by hydroxy or mercapto that is esterified by an aliphatic acyl radical containing up to 90 carbon atoms and is other than the group of the formula Id, by amino, by amino that is substituted by an acyl radical containing up to 90 carbon atoms and is other than a radical of the formula Id, by free carboxy, by lower alkoxycarbonyl, by carbamoyl, by lower alkylaminocarbonyl, by carboxy-lower alkylamino carbonyl or by amidated carboxy 1 of the formula Ida, by phenyl that is unsubstituted or substituted by hydroxy, lower alkoxy or halogen, or by imidazolyl or indolyl, or R** and R^ together represent 1,3- or 1,4-lower q alkylene, each of R and R , independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino, or a radical of the formula Ie, in which X^ and X° have the meanings 3 given above, 1 represents lower alkylene which may ■3 be interrupted by iminocarbonyl or oxycarbonyl, and A^ represents a radical of the formula lb or Ic, in which IS R ^ represents an aliphatic radical having at least 7 16 17 carbon atoms, R represents hydrogen and R represents 2-hydroxyethyl or 1,2-dihydroxyethyl, in which at least one hydroxy group is etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or is esterified by a corresponding aliphatic 16 17 acyl radical, or each of R and R independently of the other, represents hydroxymethyl etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or esterified by a corresponding aliphatic acyl radical, and R^"® represents hydrogen, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylaminocarbonyl or carboxy-lower alkylaminocarbonyl, it being possible for free functional groups to be in protected form, with the proviso that the compounds of the formula I 205000 12 "5 have at least one radical A , A or A% and of pharmaceutically acceptable salts of such compounds, and to novel pharmaceutical preparations containing these compounds.

The invention relates especially to (e) the use of the hexapyranose compounds mentioned under (a), (b), (c) and (d), especially D-glucopyranose compounds of the formula I in which one, several or all of the radicals X^ X2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R3"^, R^", R"*"2 and R^ have the meanings given in the preceding paragraphs, and of pharmaceutically acceptable salts of such compounds.

The invention relates more especially to (f) the use of D-glucopyranose compounds of the formula If R13-0-CU a , 2 l/' \ O-R1 R12-i>V ,/ 3 (If) ? / 02 R3—CH 2* 9 a \ R O-C-R 0 \ I a I a II il C— N— C—C—N—CH—CH-—CH,—C —R~ 'I H I 7 " H 0 n R' O a in which R represents hydrogen, lower alkanoyl or a 1 group of the formula la in which n represents 1, Z represents carbonyl, Y^ represents lower alkylene which may be interrupted by iminocarbonyl, represents a group of the formula -0- or -MH-, and A^ represents a 20500 0 ic radical of the formula lb or Ic, in which R represents an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, R^ 17 represents hydrogen and R represents 2-hydroxyethyl or 1,2-dihydroxyethyl, the hydroxy groups in a radical 17 R being etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms or being esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or each of R and R , independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 2 carbon atoms, Ra represents lower alkanoyl, hydroxy-lower alkanoyl, benzoyl or a group of the formula la, 113 i in which n, Z , T , Xv and A have the meanings given 12 13 above, R_ represents hydrogen or lower alkanoyl, R~ a a represents hydrogen, alkanoyl or hydroxyalkanoyl having up to 90 carbon atoms, alkanoylaminoalkanoyl having up to 30 carbon atoms or a group of the formula la in 1 1 1 which n, Z , Y , X and A have the meanings given *3 7 6 above, R^ and R' represent hydrogen or methyl, R_ re-a a a presents hydrogen or lower alkyl that is unsubstituted or substituted by free hydroxy or mercapto, lower alkoxy, lower alkylthio, alkanoyloxy or hydroxyalkan-oyloxy having up to 90 carbon atoms, phenyl, imidazo-lyl, indolyl or by a group of the formula Id, in which -30- 205000 m represents 1, E represents a group of the formula 2 0 -0- or -3-, Z represents carbonyl, Y1" represents lower alkylene which may be interrupted by iminocarbonyl, X4 represents a group of the formula -0-, and A2 represents a radical of the formula lb or Ic, in which R^ represents an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, 1 r *1 n R represents hydrogen and R represents 2-hydroxy- ethyl or 1,2-dihydroxyethyl, the hydroxy groups in a 17 radical R being etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms or being esterified by sua alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or 16 17 each of R and R , independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, and each of the radicals q in R„ and R„ , independently of the other, represents a a hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino or a radical of the formula Ie in which X^ represents a group of the formula -0- or -NH-, Y^ represents lower alkylene which may be interrupted by iminocarbonyl, X^ represents a group of the formula -0-, and A, represents a radical of the formula lb or Ic, in which R represents an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, R"^ 205 0 0 0 17 represents hydrogen and R represents 2-hydroxyethyl or 1,2-dihydroxyethyl, the hydroxy groups in a radical 17 R being etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or being esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or each of 16 17 R and R , independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 a carbon atoms, R„ preferably represents one of the amino 11 groups and Ra preferably represents hydroxy, with the proviso that the compounds have at least one, and pre- 12 1 ferably only one, radical A , A or A*', and of pharmaceutically acceptable salts thereof, and to novel pharmaceutical preparations containing these compounds, The invention relates especially to (g) the use of the D-glucopyranose compounds of the- formula I mentioned under (a), (b), (c) and (d) in which X1 represents a 2 group of the formula -NH-, X represents a group of the formula -0-, R4, R^, R® and R^® represent hydrogen, and R1, R2, R3, R6, R7, R9, R11, R12 and R13 have the meanings given in the foregoing section for the radicals R^", R2, Rj, R?, R7 R?, rJ1, Rq12 and R^5, res-a' a' a' a a' a' a ' a a ' pectively, and of pharmaceutically acceptable salts thereof.

The invention relates chiefly to h) the use of compounds of the formula I in which X^" represents a 2050 00 group of the formula -N(R )-, R 4 representing hydro- 2 1 gen or C^_^-alkyl, X represents oxygen, R represents hydrogen, lower alkanoyl, or a group of the formula la in which n represents 0 or 1, Z^ represents carbonyl, Y^" represents lower alkylene which may be interrupted "5 1 by iminocarbonyl, represents oxygen and A represents a radical of the formula lb or Ic in which R represents an alkyl or alkenyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 22 16 17 carbon atoms, R represents hydrogen and R represents 2-hydroxyethyl or 1,2-dihydroxyethyl, at least 17 one hydroxy group in a radical R ' being etherified by an alkyl or alkenyl radical having from 7 to 30 carbon atoms, or being esterified by an alkanoyl or alkenoyl radical having from 7 to 30 carbon atoms, or each of 16 17 R and R , independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl or alkenyl radical having from 7 to 30 carbon atoms, or is esterified by an alkanoyl or 2 alkenoyl radical having from 7 to 30 carbon atoms, R represents lower alkanoyl, hydroxy-lower alkanoyl, 1 12 13 benzoyl or, independently of R , R and R , a group of the formula la as defined hereinbefore, each of R-% R4, R^, b7 and R®, independently of one another, represents hydrogen, methyl or ethyl, R^ represents hydrogen, or lower alkyl that is unsubstituted or substituted by free hydroxy, free mercapto, lower alkoxy, lower alkylthio, alkanoyloxy having from 2 to 30 carbon atoms, alkenoyloxy having from 6 to 30 carbon atoms, phenyl, 4-hydroxyphenyl, or by a group of the formula Id in which m represents 0 or 1, E represents oxygen ~~p ? or sulphur, Z represents carbonyl, Y represents lower alkylene that is unsubstituted or substituted by phenyl and may be interrupted by iminocarbonyl, X4 represents 205000 2 13 oxygen and A , independently of A and A-% represents a radical of the formula lb or Ic as defined herein- Q 11 before in this Specification, each of R and R , independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino, lower alkoxycarbonyl-lower alkylamino, carba- moyl-lower alkylamino, or a radical of the formula Ie 3 in which X-^ represents oxygen or NH, represents lower alkylene which may be interrupted by iminocarbon- C -x "} yl, X represents oxygen and hP, independently of A 2 and A , represents a radical of the formula lb or Ic as defined hereinbefore in this Specification, R10 represents 12 hydrogen, R represents hydrogen, lower alkanoyl or 13 13 the same radical as R , and R ^ represents hydrogen, or alkanoyl or alkenoyl each having up to 30 carbon l 2 atoms or, independently of R and R , a radical of the formula la as defined hereinbefore in this Specification, with the proviso that the compounds contain at least one, and at most two, radicals selected from 12 3 the group A , A and kr , and the use of pharmaceutically acceptable salts of these compounds.

The invention relates especially to i) the use of compounds of the formula I in which X^" represents the 2 1 group NH, X represents oxygen, R represents hydrogen 2 or lower alkanoyl, R represents lower alkanoyl, benzoyl or a group of the formula la in which n represents 0 or 1, I?" represents carbonyl, Y^" represents lower alkylene which may be interrupted by one or two 3 1 iminocarbonyl groups, Xy represents oxygen, and A represents a radical of the formula lb or Ic in which 15 R y represents an alkyl radical having from 7 to 22 *16 17 carbon atoms, R represents hydrogen, and R represents 1,2-dihydroxyethyl in which each of the hydroxy groups, independently of the other, is esterified by an alkanoyl or alkenoyl radical having from 10 to 22 205000 3 4 carbon atoms, represents hydrogen or methyl, R , c 7 Q c R , R and R each represents hydrogen, R represents hydrogen, or lower alkyl that is unsubstituted or substituted by free hydroxy, alkanoyloxy having from 2 to 22 carbon atoms, alkenoyloxy having from 6 to 22 carbon atoms, phenyl or by a group of the formula Id 2 in which m represents 0 or 1, E represents oxygen, Z p represents carbonyl, Y represents lower alkylene that is unsubstituted or substituted by phenyl and may be interrupted by iminocarbonyl, X4 represents oxygen and 2 13 A , independently of A and , represents a radical of the above-defined formula lb or Ic, each of R9 and R^", independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, a-carboxy-lower alkylamino, a-lower alkoxycarbonyl-lower alkylamino, a-carbamoyl-lower alkylamino, or a radical of the formula Ie in which Xy represents the group NH, Yy represents lower alkylene which may be interrupted by one or two iminocarbonyl groups, X^ represents oxygen 3 12 and A , independently of A^ and A , represents a radical of the formula lb or Ic defined hereinbefore, R^ 12 represents hydrogen, R represents hydrogen, lower 13 13 alkanoyl or the same radical as R , and R represents hydrogen, alkanoyl having from 2 to 22 carbon atoms, alkenoyl having from 6 to 22 carbon atoms or, indepen- 2 dently of R , a radical of the formula la as defined hereinbefore, and the use of pharmaceutically acceptable salts of these compounds.

The invention relates most especially to j) the use of compounds of the formula I in which X repre- 2 1 sents the group NH, X represents oxygen, R represents 2 hydrogen or C2-4-alkanoyl, R represents C2_^-alkanoyl or a group of the formula la in which n represents 0 or 1, Z1 represents carbonyl, Y^" represents lower alkylene which may be interrupted by one or two iminocarbonyl 205QQQ groups, *3 represents oxygen, and represents a radical of the formula lb or Ic in which R^ represents an unbranched alkyl radical having from 12 to 18 carbon 16 17 atoms, R represents hydrogen and R1 represents 1,2- dipalmitoyloxyethyl or 2-oleoyloxy-l-palmitoyloxy- 3 A 7 ethyl, R^ represents hydrogen or methyl, R*, R^, R , R® and R^ each represents hydrogen, R^ represents methyl, ethyl or isopropyl, each of which is unsubstituted or substituted by a radical of the formula Id 2 in which jj represents 0 or 1, E represents oxygen, Z 2 represents carbonyl, T represents lower alkylene that is unsubstituted or substituted by phenyl and may be A interrupted by one or two Iminocarbonyl groups, X 2 1 "5 represents oxygen and A , independently of A and represents a radical of the formula lb or Ic defined q hereinbefore, R represents amino, R represents hydroxy or a radical of the formula Ie in which X represents the group UH, Y3 represents lower alkylene which may be interrupted by one or two iminocarbonyl groups, represents oxygen and independently of 1 2 A and A , represents a radical of the fonnula lb or 12 Io defined hereinbefore, R represents hydrogen, 13 13 acetyl or the same radical as R , and R represents 2 hydrogen, acetyl or, independently of R , a radical of the formula la as defined hereinbefore, and the use of pharmaceutically acceptable salts of these compounds.

The invention relates principally to k) the use of the above-mentioned compounds of the formula I in 1 ? 3 which the radicals A , A and kJ, if present, represent a radical of the formula Ic, and the use of pharmaceutically acceptable salts thereof.

The invention relates especially to 1) the use of the above-mentioned compounds of the formula I that carry only one phorphoryl substituent, that is in the 11 9 radical R or R , and the use of pharmaceutically /,. i\ I sosooo acceptable salts thereof.

The invention relates most especially to a) the use of the compounds of the formula I mentioned above under i) or k) that contain as the sugar moiety a derivative of D-glucose and that, in the case of asymmetric substitution, have at the C-R3 the (D)-configuration, at c ~ Q the C-R the (L)-configuration, auad at the C-N-R the (D)-configuration, and that carry (only) one phorphoryl 9 11 substituent, that is in the radical or R » wherein, in this phorphoryl substituent of the formula Ie, the ■3 radical kr represents a radical of the formula Ic, which is defined according to h) or j), and the use of pharmaceutically acceptable salts thereof.

The invention relates preferably to the use of compounds of the formula I that have at an asymmetrically substituted C(-R3)-atom the (D)-configuration, at an asymmetrically substituted C(-R^)-atom the (L)-con- Q figuration, and at the C(-N-R )-atom the (D)-configuration, and in which the sugar moiety is derived froa (D)-glucose, X represents the group NH, X represents oxygen, R1, R4, R5, R7, R8, R10, R12 and R13 each 2 represents hydrogen, R represents C. ,-alkyl or phenyl, * 6 R*^ represents hydrogen or C^_j-alkyl, R represents hydrogen, C^^-alkyl optionally substituted by hydroxy, methoxy, mercapto, methylmercapto or by halogen, phenyl or phenylmethyl each optionally substituted by hydroxy, methoxy or halogen, or heteroaryl or heteroaryl- methyl each containing one or two aza atoms and having c g ring members- or R and R together represent tri- Q ]1 methylene, one of the radicals R and R represents a radical of the formula Ie in which X^ represents the group NH or oxygen, Y3 represents Cg^-alkylene or a radical of the formula 0 2 3 2 " 3 -U-COO-U- or -U-C-NH-U- 205000 2 3 in which each of U and U , independently of the other, represents C^^-alkylene "that is unsubstituted or substituted by C^_^-alkyl optionally substituted by hydroxy, lower alkoxy, mercapto or by lower alkylmer-capto, or by phenyl or phenyl-lower alkyl each of which is optionally substituted by hydroxy, methoxy or halogen, or by heterocyclyl or heterocyclyl-CC^^-alkyl) each containing one or two aza atoms and having 5 or 6 6 3 ring members, X represents oxygen, and A. represents 16 a radical of the formula Ic in which R represents 17 hydrogen and R represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in each of which at least one of the hydroxy groups is esterified by an aliphatic Cl6-20-carboxylic aci,<i ^at is optionally singly or doubly unsaturated, or is etherified by an aliphatic Ci2_i8-alc°hol that is optionally singly or doubly unsaturated, and the other of the radicals R9 and R^" represents hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino, and the use of pharmaceutically acceptable salts of such compounds.

The invention relates most preferably to the use of compounds of the formula I that have at an asymmetrically substituted C(-R^)-atom the (D)-configuration, at an asymmetrically substituted C(-R^)-atom the (L)-configuration and at the C_(-N-R8)-atom the (JD) — configuration, and in which the sugar moiety is derived from (D)-glucose, X^ represents the group NH, X2 represents oxygen, r\ R4, R7, R8, R1^, R12 and R^ each 2 represents hydrogen, R represents lower alkyl or "5 5 phenyl, each of R^ and R , independently of the other, represents hydrogen or methyl, R^ represents C. .- 9 11 " alkyl, R represents amino and R represents a radical of the formula 205000 , ii ii (-nh-u -c)r-nh-ch2-ch2-0-p-0-ch2 oh ch-o-r ch2-o-r in which r represents 0 or lt U^" represents a radical of the formula 3 k ch, ch—ch, ch, i ch, \3 I \2 ch. ch—ch, ch, ch—ch, I I I I -ch- , -ch- , -ch- or -ch- (l) (l) (l) (l) a b and each of R and R , independently of the other, represents the acyl radical of an alkanoic carboxylic acid having from 12 to 22 carbon atoms or of an unsubstituted aliphatic carboxylic acid having from 12 to 22 carbon atoms and containing one or two double bonds, and the use of pharmaceutically acceptable salts of such compounds.

The invention relates above all to the use in accordance with the invention of the following compounds : 205000 the sodium salt of N-acetylmuramyl-L-alanyl-D-isogluta-mine-2- (1 ,2-dlpal Tnitoyl-an-glycero-4-hydroxyphosphoryl-oxy)-ethylamide, the 8 odium salt of N-acetyldesmethyl-muramyl-L-alariyl-D-is oglut amine-2-(1 ,2-d ipalmit oyl-sn-glycero-3-hydroxyphoaphoryloxy)-ethylamide, the sodium salt of N-acetyldeamethylmuramyl-L-alanyl-D-isogluta-mine-2-(1-palmitoyl-2-oleoyl-Bn-glycero-3-hydroxy-phosphoryloxy)-ethylamide, the sodium salt of N-acetyldesmethylmuramyl-L-alanyl-D-isoglutaminyl-L-aIanine-2- (1 ,2-dipal mi toyl-Bn-glycero-3-hydroxyphos-phoryloxy)-ethylamide, N-acetylmuramyl-Ir-alanyl-D-i s oglut aminyl-L-alanine-2- (3-palmit oyl-rac-glyc e ro-1 -hydroxyphosphoryloxy)-ethylamide, the sodium salt of N-ac e t ylmuramyl-L-g-am i nobutyryl-D-iaoglutamlnyl-Ir-alanine-2- (1 ,2-dipalmitoyl-sn-glyeero-3-hydroxyphos-phoryloxy)-ethylamide, the sodium salt of N-benzoyl-muramyl-L-alanyl-D-iB0glutaminyl-L-alariine-2- (1,2-d ipalmit oyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide, N-acetylmuramyl-L-alanyl-D-laoglutairi nyl-L-al anine-2-(te t rade cyloxyhydroxypho s phor yl oxy) -e thylamide, N-ac etylmuramyl-L-alanyl-D-is oglut am inyl-L-al anine-2-(hexadecyloxyhydroxyphosphoryloxy)-ethylamide, the sodium salt of N-acetylmuramyl-L-g-aniinobutyryl-D-isoglutaminyl-L-alanine-2-[ (3R)-hydroxy- (2S)-palmit oylamino-4t-octadecenyloxyhydroxyphosphoryloxy]-ethylamide, the sodium salt of N-acetylmuramyl-I^-g-ami nobutyryl-D-is oglut am iny1-L-alanine -2 - [ (3R) -hydroxy- (2S) -palmit oyl-aminooctadecyloxyhydroxyphosphoryloxyj-ethylamide, the sodium salt of N-ac etylmuramyl-L-alanyl-D-is oglut aminyl-L-alanine-2- (choleat—5-en-3P-oxyhydroxyphosphoryloxy]-ethylamide, the sodium salt of N-acetylmuramyl-L-0-£(N-[2-( 1 -palmitoyl-2-oleoyl-sn-glycero-3-hydroxyphosphoryl-oxy)-ethyl]-suecinamoyl)-glycylj-seryl-D-isoglutamine, 2Q5000 the sodium salt of N-acetylnormuramyl-l-0-(lf2-di-palmitoyl-rac-glycero-3-hydroxyphosphoryl)-seryl-D-isoglutamine, the sodium salt of N-acetyl-6-0-( [l, 2-dipalmitoyl-rac-glycero-3-hydroxyphosphoryloxy]-acetyl)-normuramy1-L-alany1-D-i s o glut amine, the sodium salt of N-acetyl-6-0-(l,2-dipalmitoyl-rac-glycero-3-hydroxyphosphoryloxy)-normuramyl-L-alanyl-D-isoglutamine, the sodium salt of n-[n-[2-(1,2-dipalmitoyl-sn-glycero)-3-hydroxyphosphoryloxy]-ethylj -succinamoylmuramyl-L-alanyl-D-isoglutaraine , the sodium salt of N-acetyl-6-0-[N-^-Cl^-dipalmi-toyl-sn-glycero-J-hydroxyphosphoryloxy )-ethyl]-auocinajnoyl^ -muramyl-L-a-aminobutyryl-D-isoglutamine, the sodium salt of N-acetylnormuramyl-L-0-[/I-[2-tetra-decyloxyhydroxyphosphoryloxy)-ethyl]-succinamoyl} -seryl-D-isoglutamine, the sodium salt of N-acetyl-muramyl-L-O- [_[N-( l-palmitoyl-2-oleoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethyl]-auccinamoyl-L-phenylala-nyl^-seryl-D-isoglutamine, the sodium salt of N-acetyl-muramyl-L-0-(hexadecyloxyhydroxyphosphoryl)-seryl-D-isoglutamine and the sodium salt of N-acetylmuramyl-L-0-(l,2-dipalmitoyl-3-sn-glycerohydroxyphosphoryl)-seryl-D-isoglutamine.

The invention relates especially to the use of the compounds of the formula I described in the Examples, and of the pharmaceutically acceptable salts thereof, and above all to the use of N-acetylmuramyl-l-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide, especially the sodium salt of this compound, referred to hereinafter as compound i, 205000 The following Examples illustrate the invention but do not limit the invention in any way.

Example 1: Groups of 30, 40 or 50 female MF-2f SPF mice each having a body weight of 14-16 g, or of 12-14 g in the case of tests with herpes simplex 1 viruses, are infected intranasally, under light anaesthesia using a mixture of equal parts of ether, ethanol and chloroform, with lethal doses (approximately LDgo-go; number of plaque-forming units [PFU] see Table 1) of the undermentioned virus strains in the form of 0.05 ml in each case of a suspension of the viruses.

At the time indicated below (days) in relation to the day of infection, 10 or 20 of these mice are administered once (single dose) the quantities indicated in Table 1 of the active ingredient, the sodium salt of N-acetylmuramyl-L-alanyl-D-isoglut-aminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide (compound I), in 0.05 ml or 0.1 ml of phosphate-buffered salt solution (PBS) or in 0.2 ml of a 0.05 % by weight solution of sodium carboxymethylcellulose in double-distilled water, by means of intranasal, intravenous or oral administration respectively, in the manner indicated in Table 1.

The remainder of the above-mentioned mice, that is 20 or 30, serve as the control, that is to say they either receive no treatment or are given a placebo.

The intranasal administration of compound I is effected under light anaesthesia using a mixture of equal parts of diethyl ether, ethanol and chloroform.

Table 1: Virus [PFU] Mode of administration Time of administration [days] Percentage of mice surviving 20 days after infection in dependence on the quantity of active ingredient [rag/kg] - : before infection statistical significance xP-0.05, xx„ ^ _ P - 0 .01 (Vierfelder test) + : after infection 500 lOO 1 O. 1 O = control Influenza A/ intravenous -7 80XX 90XX Victoria/3/75 (H3N2) -5 80XX SO** (mouse-adapted) -1 80XX 80XX 70X [2X103-1X104 PFU] O 90XX iooxx 70X +1 90XX 70X 60 intranasal -14 60 70(X) 80X 40 -7 10o1™ iooxx 09 o X oral +3 70XX 90XX 80** +7 iooxx 100** 70XX I -p.

N> I Table 1: (continuation) > Virus [ppu] I •lode of administration Time of administration [days] Percentage of mice surviving dependence on the quantity of days after infection in active ingredient [mg/kg] - : before infection statistical significance XP<0.05, YV P<0.01 (Vierf elder test) + : after infection 500 lOO 1 0.1 0 * control Influenza a/ USSR/92/77 (H1N1) (mouse- intravenous -7 66X 40 4o -2 60X 70** 5QX adapted) [3xl02-lxl03 PFU] -1 70x 70XX 50X lO O iooxx 80™ 60X +1 90XX 9DXX 60x +2 go1" 50XX 40 +6 60X 60X 40 Influenza a/ Texas/1/77(H^Nj (mouse-adapted) [2x10°—lxio1 PFU] intranasal -7 50^ 40X *X' o ! -7 iooxx 90X 70(X) i oral +7 es3" 0 Continuation of Table 1 1 Virus [PFU] Mode of administration Application time Percent 500 age surv lOO ivors 20 l 0.1 o Influenza B / Honq Konq/5/72 [3X105-1X106 PFU] intravenous -7 90X 70 70 42 -5 90x lOO3" 80(x5 -2 iooxx 90X iooxx -1 loo** 90X 80^X^ O loo** loo3" 90X +1 80^X^ 80*x) 60 +2 loo3" 70 90X +6 loo3" 80(X) 70 intranasal -7 loo3" 80X 80X oral +3 50* 50X +7 8QXX go3" 50X | Influenza B / Ann Arbor (Ms.Lu.25.Russ) (mouse-adapted) [lxlO1 PFU] intranasal -14 50X 0 -7 eoxx 50 ! 20 oral +3 loo304 go3" „„xx 80 +7 loo3" eo3" i so3" i O 1 Continuation of Table 1 Virus [pfu] Mode of administration Application time Percer 500 it age survi lOO vors 20 lo 1 0.1 O Encephalomyo-carditis [lxl01-lxl02 PFU] oral 0 X o CO loo** 60 +2 60 CD o X 90XX +4 iooxx 70(x) 90XX Herpes Simplex 1/TUP [2xl04 PFU] intranasal -7 70X 60* 60X Heroes Simplex 1/Virtue [2xl03 PFU] intranasal -7 90X ioox 70 40 N) O . Vi so o o 205000 The course of some of the above-described infections over a period of time is illustrated in Figures 1 and 2.

The great superiority of the phosphoryl compounds of the formula I over muramyl peptides, such as N-acetylmuramyl-L-alanyl-D-glutamine-n-butyl ester (compound II) is demonstrated, for example, by the fact that in the case of the above-mentioned tests carried out for comparison purposes, on oral administration of 10 mg of the latter compound on day +7 all the mice die from infection with Influenza A/Texas/1/77, whilst on administration of the same quantity of the phosphoryl-muramyl peptide compound I at the same time, as can be seen in the Table, 65 % of the mice survive the infection.

Furthermore, on intranasal administration of 1 mg/kg of compound II on day -7 it is not possible to detect any kind of protective action in the case of infection with Influenza A/Texas/1/77, whilst on administration of the same quantity of compound I at the same time 90 % of the mice survive the infection.

It is also not possible to detect any kind of protective action on intranasal administration of 10 mg/kg of compound II on day -7 in the case of intranasal infection with Herpesvirus hominis 1/TUP, as can be seen from Figure 3. 205000 Example 2 The number indicated in the following Table of female albino guinea pigs of the Pirbright strain (150-180 g body weight) are infected intravaginally with a/10^ PFU (plaque-forming units) of Herpesvirus hominis 2/Angelotti, cultivated in HEL (human / v' embryonal lungs) cells, as described in B. Lukas £t^ al., Arch. ges. Virusforsch. 44, 153-155 (1974).

At the time indicated in the following Table (the time difference in days in relation to the day of infection, - [minus] indicating a time before infection) the number N of guinea pigs indicated in Table 2 are treated intravaginally with a single dose of in each case 0.1 ml of a gel containing the concentration of compound I indicated in Table 2.

The gel without active ingredient has the following composition: 2.25 % sodium carboxymethylcellulose (Hercules, USA) % glycerine made up to 100 % with bi-distilled water.

The effect of the treatment can be seen in Table 2.

The symptoms occurring in untreated animals are described in B. Lukas' e_t al_., Arch. Virol. 49_, 1-11 (1975).

') Table 2: Effect on local symptoms in the topical chemotherapy of Herpes genitalis in guinea pigs X xx (statistical significance P< 0.05, P's.O.Ol in the Fisher test) Active ingredient Treatment N Animals [%] with regression of Symptom-free animals [%] on day concent rat ion time symptoms of > 66% on day [%] [days] 7 12 14 12 14 21 34 l.o -7 14 29 79XX 71XX 93XX 21 57x 86^ 86X 100x O.l -7 14 21 57X ee3" lOO™ 43X 64XX ee3" 86XX lOO304 l.o +4 14 79XX 79xx 86** 93xx 36 64XX 79xx 86™ iooxx 0.1 +4 13 62xx 85XX 1Goxx 93XX 7GXX 77 xx as5" iooxx 100XX 0 +4 14 0 0 0 O O O 0 O 0 (placebo) control 0 O 0 O O O 0 O (untreated) ND O Cn o £> <3 rs i 20500 0 Example 3: Eye drops Composition: compound I bor ic ac id sodium tetraborate. 1OH^O benzalkonium chloride 0.10 mg 30.00 mg 0.10 mg 0.20 mg water for injection to make up to 1.00 ml Preparation: The boric acid, sodium tetraborate and benzalkonium chloride are dissolved while stirring at room temperature under aseptic conditions in a portion of the above-mentioned quantity of water for injection. CGP 19835 is then dissolved in the resulting solution, and water for injection is added to make up to the final volume of 1.0 ml.

The solution, or a portion or a multiple thereof, is filtered through a membrane filter and introduced into cleaned containers. Suitable containers are, for example: - flexible plastics containers (5 ml or 10 ml) having a dropping attachment, - glass containers (5 ml or 10 ml) having a glass or plastics dropping pipette and an elastomeric pipette filler, or - plastics single-dose pipettes (contents 1 - 2 drops) .

-Y~' I 203000 50 Example 4; Non-aqueous single dose foe nasal administration.

Composition; compound I Miglyol 812 0.03 rag to make up to 30.00 rag Preparation; 0.03 rag of compound I is dissolved under aseptic conditions in 29.97 mg of Miglyol 812.

This solution is introduced into a commercially available single-dose nasal applicator, Eor example an applicator according to New Zealand Patent No. 166 585, which is attached to an aerosol-container before use.

I 205000 Example 5: Nose drops; Composition; I II compound I 0.15 mg 0.10 mg thiomersal 0.02 mg sodium monohydrogen phosphate.2H20 0.30 mg 0.30 mg sodium dihydrogen phosphate. 12H20 10.10 mg 10.10 mg benzalkonium chloride - 0.10 mg disodium salt of ethylenediaminetetra- acetic acid (EDTA) 0.50 mg 0.50 mg sodium chloride 3.70 mg 4.50 mg demineralised water 988.30 mg 987.60 mg pH value: 5.0 - 0.3 5.0 - 0.3 lowering of freezing point At - 0.51°C - 0.56°C Preparation: While stirring at room temperature, the sodium dihydrogen phosphate, disodium monohydrogen phosphate, sodium chloride, thiomersal and the disodium salt of EDTA are dissolved in a portion of the above-mentioned quantity of demineralised water Compound I is then dissolved in this solution and the whole is supplemented with the remaining demineralised water.

The solution, or a portion or a multiple thereof, is filtered through a membrane filter and introduced into cleaned containers.

Suitable containers are, for example: a) glass or plastics containers (5 ml or 10 ml) 2050 00 having a glass or plastics pipette with an elastomeric pipette filler b) compressible plastics bottles having a central tube and a plastics spraying head c) single-dose plastics containers (contents 2-3 drops), or d) glass or plastics bottles that are provided with a standardised pumpable dosing spray made of plastics (no propellant).

Example 6: Gel Composition; compound I 0.01 g glycerine 85 % 10.00 g methyl paraben 0.12 g propyl paraben 0.03 g sodium carboxymethylcellulose (high viscosity) 2.50 g demineralised water 87.34 g Preparation: The methyl paraben and propyl paraben are dissolved in a portion of the hot demineralised water. The sodium carboxymethylcellulose is then incorporated into the resulting solution while stirring vigorously. While stirring, the glutinous product is allowed to swell. After cooling, the glycerine and a solution of the active ingredient, compound I, in the remaining water are then added to this product. 2050 Example 7: Cream Composition: compound I 0.10 g sorbitan monostearate 0.60 g cetyl alcohol 3.00 g isopropyl palmitate 2.00 g methyl paraben 0.12 g paraffin oil, viscous 10.00 g PEG (20)-sorbitan monostearate 4.40 g propyl paraben 0.03 g 70 % solution of crystalline sorbitol 6.00 g in demineralised water stearic acid 9.00 g demineralised water 64.67 g Preparation: The fatty phase, comprising sorbitan monostearate, cetyl alcohol, stearic acid, PEG (20)-sorbitan monostearate, isopropyl palmitate and paraffin oil, is melted. The methyl paraben and propyl paraben are then dissolved in a portion of the hot demineralised water. The sorbitol solution is added to the aqueous phase. While stirring, the aqueous phase is then added at approximately 75°C to the fatty phase. The cream base is then allowed to cool while stirring. A solution of the active ingredient, compound I, in the remaining water is then added to the cream base at approximately 40°C. 20500 0 Example 8: Nasal ointment Composition: compound I paraffin oil, viscous white petroleum jelly wool fat, anhydrous demineralised water Preparation: The fatty phase, comprising paraffin oil, petroleum jelly and wool fat, is melted. The aqueous solution of the active ingredient is incorporated into the fatty phase at approximately 50°C.

Example 9: Skin ointment Composition compound I 0.25 g sorbitan sesquioleate 10.00 g white beeswax 5.00 g cetyl alcohol 2.50 g methyl paraben 0.15 g paraffin oil, viscous 20.00 g propyl paraben 0.02 g stearyl alcohol 2.50 g white petroleum jelly 40.00 g demineralised water 19.58 g Preparation: The fatty phase, comprising sorbitan sesquioleate, white beeswax, cetyl alcohol, paraffin oil, stearyl alcohol and white petroleum jelly is melted. The 0.03 g .00 g .00 g 40.00 g 19.97 g 205000 methyl paraben and propyl paraben are then dissolved in the main quantity of the water at elevated temperature. The aqueous phase is incorporated into the fatty phase at approximately 80°C. A solution of the active ingredient/ compound I, in the remaining water is added to the resulting ointment base at approximately 40°C.

Example 10: Lipstick Composition: compound I 1.00 g polyethylene glycol having an average molecular weight of 400 15.00 g polyethylene glycol having an average molcular weight of 1000 83.00 g polyethylene glycol having an average molecular weight of 4000 1.00 g Preparation: The active ingredient is finely dispersed in the molten polyethylene glycols. The viscous melt is poured into suitable lipstick cases and left to harden.

Example 11: Preparation of compound I A solution of 1.5 mmol of N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-N-hydroxysuccinimide ester in 5 ml of dimethyl acetamide is added dropwise to a solution of 1 mmol of 2-(1, 2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine and 3.5 mmol of N-ethylmorpholine in 25 ml of chloroform:methanol:water = 205000 65:25:4. After stirring for 8 hours at room temperature the reaction is complete. 130 ml of water are added to the reaction mixture. Chloroform and portions of the methanol are distilled off under reduced pressure. The aqueous solution is filtered through a millipore filter made of Teflon (pore size 5 urn)• The filtrate is dialysed, while stirring, in an Amicon ultrafiltration cell through an Amicon YM 10 membrane (consisting of polysaccharide, nominal molecula£ga^ngt weight cut off 10 000 dalton)in a diafiltration process firstly/ water (400 ml), then against 0.1M sodium phosphate buffer - 0.1M NaCI, pH 7 (200 ml), and subsequently against water (850 ml). The internal dialysate is filtered through a millipore filter, pore size 0.45 um, and freeze-dried, yielding the sodium salt of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide hydrate.

Example 12: Groups of 20 female Tif:MF-2f (SPF) mice each having a body weight of 14-16 g are infected intravenously, under light anaesthesia using a mixture of equal parts of diethyl ether, ethanol and chloroform, with 2 x 103 PFU vaccinal virus IHD in the form of in each case 0.1 ml of a suspension of the virus in beef heart infusion broth. of these mice from each of the above-mentioned groups are treated on the fourth or sixth day after infection, that is to say on day +4 or +6 (administration day), with a single oral administration of 1 mg/kg of compound I in 0.2 ml of a 0.05 % by weight aqueous solution of sodium carboxymethylcellulose.

The remaining 10 mice from each of the above-mentioned groups serve as the controls and receive a 2 05000 placebo.

On the seventh, ninth, tenth and twelfth day after infection the number of tail lesions in the mice is determined, this being carried out substantially as described by J.J. Boyle, R.F. Haff and R.C. Stewart in Antimicrobial Agents and Chemotherapy, 536-539 (1967), and it should be noted that the first tail lesions can' be identified only on the sixth or seventh day. The results can be seen in Table 3: 2050 O0 Table 3; Day of administration Number of standard +7 tail lesi deviation) +9 ons (mean on day +10 + +12 +4 0.9+0.7* 0.9+0.9* 0.9+1.4* 0.2+0.4* +6 1.1+1.4* 0.9+1.6* 0.3+0.7* 0.5+1.O* control 4.3+1.9 4.3+1.9 .9+1.9 4.6+1.8 * statistical significance P< O.Ol (Student's T-test) \ 500O Example 13: Groups of 50 - 54 female albino guinea pigs of the Pirbright strain (150-180 g body weight) are infected intravaginally with 1 x 103 PFU of the neurotropic virus strain Herpes simplex 2/MS in a manner analogous to Example 2. In the case of the Alabama strain, on the third day after infection 15 to 18 of these guinea pigs are administered orally a single dose, as indicated in Figure 4, of compound I in 0.2 ml of a 0.005 % by weight aqueous solution of sodium carboxymethylcellulose. In the case of the MS strain, on the seventh day before infection 17 to 19 of the above-mentioned guinea pigs, under light anaesthesia using a mixture of equal parts of diethyl ether, ethanol and chloroform, are administered intranasally a single dose, as indicated in Figure 5, of compound I in 0.2 ml of a 0.005 % by weight aqueous solution of sodium carboxymethylcellulose.

The control groups each comprise 35 animals and receive no treatment (Fig. 4) or are given a placebo (Fig. 5). The results are shown in Figures 4 and 5, respectively.

Example 14: Groups of 30 or 34 female Tif:MF 2f (SPF) mice each having a body weight of 14-16 g are infected intranasally under light anaesthesia with from 10 to 50 PFU of Parainfluenza Virus 1 (Sendai)/52 (mouse-adapted, stored at -70°C in the form of a mouse-lung suspension in ampoules). For the above-mentioned anaesthesia there is used a mixture of equal parts of diethyl ether, alcohol and chloroform.

At the time indicated in Figures 6 and 7, 10 (in the case of. Fig. 6) and 14 (in the case of Fig. 7) of these mice are administered once the quantities 2050 00 indicated in the Figures of compound I in 0.2 ml of 0.005 % by weight sodium carboxymethylcellulose in double-distilled water in the manner indicated in the Figures, in the case of intranasal administration of the active ingredient before infection under anaesthesia using a mixture of equal parts of diethyl ether, alcohol and chloroform and in the case of intranasal administration of the active ingredient after infection under anaesthesia using Nembutal (0.5 mg/mouse, intraperitoneal), followed after 20-25 minutes by intranasal administration by drip of 0.02 ml of 1 % aqueous cinchocaine hydrochloride solution.

The remaining 20 mice from each of the above-mentioned groups serve as the control. The control animals either receive no treatment or are given a placebo.

The action of compound I can be seen from Figures 6 and 7.

Example 15: Groups of 30 female Tif:MF-2f (SPF) mice having a body weight of 14-16 g are infected intranasally under light anaesthesia, using a mixture of equal parts by volume of diethyl ether, ethanol and chloroform, with lethal doses (approximately LOgg-go) °f the virus strains indicated in Table 4. At the time shown in Table 4 [days in relation to the day of infection] 10 of these mice in each case are administered once (single dose) with the quantity, the active ingredient, and in the manner of administration, all as indicated in Table 4.

The active ingredients are: the sodium salt of N-acetyl-6-0-£[N-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethyl]-succinamoylj-normuramyl-L-alanyl-D-isoglutamine (III) , 205000 the sodium salt of N-propionyldesmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-di-palmi toyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide (IV) , the sodium salt of N-acety1-1,4,6-0-triacetyl-muramyl-L^alanyl-D^isoglutaminyl-L-alanine-2-(1, 2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide (V), the sodium salt of N-acetylmuramyl-L-alanyl-D-isoglutamine-2-(t,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide (VI), and the sodium salt of N-acetylmuramy1-L^alanyl-£-isoglutaminyl-Y-oxymethylcarbonyl-2-(1,2-dipalmi toy1-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide (VII).

The remaining 20 mice in each group serve as the control, that is to say instead of the active ingredient they receive a placebo (0.005 % by weight of sodium carboxymethylcellulose in double-distilled water) .

The results of the test are shown in Table 4. y Table 4 Act. i v»» incrredient VI ru* Mode of admin i-nt-.r«t ion Tlmp of Admin i-* t r a f. i on Percentage of mice surviving 23 days after infection in dependence upon the quantity of active ingredient [mq/kq] lOO O. 1 (plncetoo) J TI tit TV V VT VII I n flu?n z a_A/Te x a a/1/7 7 ^h3N2) Influenza A/Tnxas/1/77 ''SV Influenza.A/Tex a a/1/77 "W Influenza A/Texae/1/77 (ll3N2) Influenza A/Texaa/1/77 (H3HJ) Influenza A/Texas/1/77 <h3N2) oral i nt-rnnnsn 1 oral oral oral oral + 7 +7 +7 +7 •47 60 60 60 60 50 60 40 60 40 80 60 AO ,5 K> O —en- CD Q <3 2050 0 0 Example 16: Manufacture of 1000 tablets containing 0.5 % of active ingredient Composition for 1000 tablets: compound I lactose, ground corn starch Pharmacoat 603® (hydroxypropyl-methylcellulose containing 28-30 % methoxy groups, supplied by Shinetsu Chemical Company, Tokyo, Japan) Aerosil® (colloidal silica, supplied by Degussa, Frankfurt, Federal Republic of Germany) magnesium stearate Preparation: Compound I and 15 g of lactose are premixed. The resulting premix is mixed with 28 g of lactose and 47 g of corn starch. Using the resulting mixture and an aqueous solution of the Pharmacoat a composition suitable for granulation is prepared and is granulated, dried and ground. 5 g of corn starch, the Aerosil and magnesium stearate are mixed in and the whole is pressed to form 1000 tablets each weighing 100 mg.

The compacts can be provided with a coating that is resistant to gastric juices in a manner known per se.

Example 17: Active ingredient in the form of a dry lyophilised substance 0.5 mg of compound I and 500 mg of mannitol 0.5 g 43.0 g 52.0 g 3.0 g 1.0 g 0.5 g 20500 0 (pyrogen-free) are dissolved in water for injection and sterile-filtered through a membrane filter. The sterile-filtered solution is introduced under aseptic conditions into a sterilised glass ampoule or into a glass phial and freeze-dried. After lyophilisation the ampoule is sealed or the phial is sealed with a rubber-elastomeric seal and aluminium cap.

Example 18: Single-dose pipette with nose drops A 0.05 % solution of compound I in 1,2-propylene glycol, benzyl alcohol or ethanol or in a mixture of 1,2-propylene glycol and polyethylene glycol having an average molecular weight of 300 is prepared.

The solution is filtered and introduced into single-dose pipettes made of deformable plastics. The single-dose pipettes contain the quantity of nose drops required for one application, that is to say they each contain 0.1 ml of the above solution.

Claims (29)

- 65 - 205000 WHAT t!WE CLAIM IS:-Potent. C-lriimc--

1. Use of hexopyranose compounds of the formula I, 13 2 R - X CH2 S » o R1 / ^.^vO-R1 \ / / 2 * x-r' \3 i-R4 11 ' I 'I 11 ~ N— C— C — N CH—CH-— CH— C —R -- -R (I)' O R5 R6 o=C-R9 R10 0 0 R7 O R8 in which 1 2 each of X and X , independently of the other, represents a group of the formula -0- or -N(R^}-, R^4 representing hydrogen or lower alkyl, 1 2 12 13 each of R , R j R and R , independently of one another, represents a radical of the formula la, 113 1 "(Z )n"A (la) in which n. represents 0 or 1, represents carbonyl or thiocarbonyl, Y*' represents unsubstituted or substituted alkylene which may be interrupted by iminocarbonyl or oxycarbonyl, X3 represents a group of the formula -0- or -N(R^4)-, - 66 - 205000 wherein R^4 has the meaning given above, and A^ represents a radical of the formula lb, 0 I' 15 -P-0—R (lb) OH 15 in which RIJ represents an aliphatic or cycloaliphatic radical having at least 7 carbon atoms, or A^ represents a group of the formula Ic, 0 R16 II 1 P - 0 - CH (Ic) AH R17 in which R^® represents hydrogen and R^7 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, wherein at least one hydroxy group is esterified or etherified by a radical having at least 7 carbon atoms, 1 fi 17 or in which each of R1 and R , independently of the other, represents esterified or etherified hydroxymethyl, the esterifying or etherifying radicals having at least 7 carbon atoms, or 1 2 12 13 each of R , R , R and R , independently of one another, represents hydrogen, acyl other than a radical of the formula la in which n_ represents 1, or a radical that can be 205000 - 67 - removed under physiological conditions, 7 8 and R , independently of one another, represents hydrogen or lower alkyl, represents hydrogen or lower alkyl that is unsubstituted or substituted by a group of the formula Id, 2 2 4 2 —E—(Z —Y -X ) —A (Id) in which jn represents 0 or 1, E represents a group of the formula -0-, -S- or -N(R*'4)-, R^4 having the meaning given above, Z^ represents carbonyl or thiocarbon-yl, Y represents unsubstituted or substituted alkylene which may be interrupted by iminocarbonyl or oxycarbonyl, X4 represents a group of the formula -0- or -N(R^4)-, R^4 having the meaning given above, and A' represents a radical of the formula lb or Ic; or by free or etherified hydroxy or mercapto, by esterified hydroxy or mercapto other than a group of the formula Id, by free amino or substituted amino other than a group of the formula Id, by free, esterified or amidated carboxy, by cycloalkyl, by carbocyclic aryl or by nitrogen-containing heteroaryl having 5 or - 68 - 6 ring members in the heterocyclic ring, or R^ and R® together represent unsubstituted or substituted 1,3- or 1,4-lower alkylene, 9 11 each of R and R , independently of the other, represents a radical of the formula Ie, -X5 - Y3 - X6 - A3 (ie) in which represents a group of the formula -0-, -S- or -N(R^)-, and X® represents a group of the formula -0- or -N(R^)-, in each case R1* having the meaning given above, Y3 represents unsubstituted or substituted alkylene which may be interrupted by iminocarbonyl or oxycarbonyl, and A3 represents a radical of the formula lb or Ic, or free hydroxy or mercapto, etherified hydroxy or mercapto other than a radical of the formula Ie, or free amino or substituted amino other than a radical of the formula Ie, and represents hydrogen or free, esterified or amidated carboxy, with the proviso that the compounds of the formula I have at least one radical A^, A2 or A3, and the use of pharmaceutically acceptable salts of such compounds in warmblooded animals except humans for the - 69 - prophylaxis or treatment-, of diseases caused by viruses..

2. Use according to claim 1 of compounds of the 1 2 12 13 formula I in which each of R , R , R and R , independently of one another, represents hydrogen, the acyl radical of an aliphatic, cycloaliphatic, aromatic or araliphatic carboxylic acid having up to 90 carbon atoms, tri-lower alkylsilyl, or a radical of the formula la in which n^ and X3 have the meanings given in claim 1, Z ^ represents carbonyl, Y^ represents lower alkylene which may be interrupted by iminocarbonyl or oxycarbonyl, and A^ represents a radical of the formula lb or Ic in which R^ represents an aliphatic radical having at least 7 carbon atoms, R^® represents hydrogen and R17 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, in which at least one hydroxy group is etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or is esterified by a corresponding aliphatic acyl radical, or each of R^® and R17, independently of the other, represents hydroxymethyl etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or esterified by a corresponding aliphatic acyl radical, R^ represents hydrogen or lower alkyl that is unsubsituted or substituted by a radical of the formula Id in which m, E and X4 have the meanings given in claim 1, Z^ represents carbonyl, Y* represents lower alkylene which may be interrupted by iminocarbonyl or oxycarbonyl, and A2 represents a radical of the formula lb or Ic in which R15 represents an aliphatic radical having at least 7 carbon atoms, R^® represents hydrogen and R^7 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, in which at least one hydroxy group is esterified by an aliphatic radical having at least 7 and up to 90 carbon atoms or by a corresponding aliphatic acyl radical, or" S . )\ 1 f I ZQsepi - 70 - 2050 0 0 each of and R^7, independently of the other, represents hydroxymethyl esterified by an aliphatic acyl radical having at least 7 and up to 90 carbon atoms, or R6 represents lower alkyl substituted by hydroxy or mercapto, by hydroxy or mercapto etherified by an aliphatic radical containing up to 90 carbon atoms, by hydroxy or mercapto that is esterified by an aliphatic acyl radical containing up to 90 carbon atoms and is other than the group of the formula Id, by amino, by amino that is substituted by an acyl radical containing up to 90 carbon atoms and is other than a radical of the formula Id, by free carboxy, by lower alkoxycarbonyl, by carbamoyl, by lower alkylaminocarbonyl, by carboxy-lower alkylaminocarbonyl or by amidated carboxyl of the formula 0 " 2 4 2 —C-E-(Y-X)m-A 2 4 2 in which jjj, E, Y , X and A have the meanings given in claim 1, by phenyl that is unsubstituted or substituted by hydroxy, lower alkoxy or halogen, or by imidazolyl or indolyl, or R5 and R6 together represent 1,3- or 1,4- Q 11 lower alkylene, each of R* and R1 , independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino, or a radical of the formula Ie, in which X^ and have the meanings given in claim 1, YJ represents lower alkylene which may be interrupted by iminocarbonyl or oxycarbonyl, and represents a radical of the 1 ^ formula lb or Ic, in which RIJ represents an aliphatic radical having at least 7 carbon atoms, R^ represents hydrogen and R^7 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, in which at least one hydroxy group is etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or is esterified by a - 71 - 2060QO corresponding aliphatic acyl radical, or each of R1® and R17, independently of the other, represents hydroxymethyl etherified by an aliphatic radical having at least 7 and up to 90 carbon atoms or esterified by a corresponding aliphatic acyl radical, and R^ represents hydrogen, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylaminocarbonyl or carboxy-lower alkylaminocarbonyl, with the proviso that the compounds 12 3 of the formula r have atlaast one radical A , A or A , and the use of pharmaceutically acceptable salts of such compounds.

3. Use according to claim 1 of compounds of the 1 * 2 formula I in which X represents the group NH and X represents oxygen, R^ represents hydrogen, lower alkanoyl, or a group of the formula la in which ti represents 1, Z^ represents carbonyl, represents lower alkylene which may be interrupted by iminocarbonyl, X3 represents a group of the formula -0- or -NH-, and A ^ represents a radical of the formula lb or Ic in which R^ represents an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, R^® represents hydrogen and R^7 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, wherein each of the hydroxy groups in a radical R^7, independently of the other, is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or each of R^® and R^7, independently of the other, represents hydroxymethyl in which the 205000 hydroxy group is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, R2 represents lower alkanoyl, hydroxy-lower alkanoyl, benzoyl, or a group of the formula la in which n, Z1, Y , X and A1 have the meanings given hereinbefore in 12 this claim, R represents hydrogen or lower alkanoyl, R^ represents hydrogen, alkanoyl or hydroxyalkanoyl having up to 90 carbon atoms, alkanoylaminoalkanoyl having up to 30 carbon atoms, or a group of the formula la in which ru Z^, Y^, X^ and have the meanings given hereinbefore in this claim, R^ and R7 each represents hydrogen or methyl, R4, R5, R® and R^° each represents hydrogen, R6 represents hydrogen, lower alkyl that is unsubstituted or substituted by free hydroxy or mercapto, lower alkoxy, lower alkylthio, alkanoyloxy or hydroxyalkanoyloxy having up to 90 carbon atoms, or by phenyl, imidazolyl or indolyl, or by a group of the formula Id in which rn represents 1, E represents a group of the formula -0- or -S-, Z2 represents carbonyl, Y represents lower alkylene which may be interrupted by iminocarbonyl, X4 represents a group of the formula -0-, and A2 represents a radical of the formula lb or Ic in which R^ represents an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, R^ represents hydrogen, and R*'7 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, wherein each of the hydroxy groups in a radical R ^7, independently of the other, is etherified by an alkyl radical having from 7 to 30 carbon atoms that is - 73 - 20 5000 unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or each of R16 and R*17, independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, and each of the radicals R9 and R^1, independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino, or a radical of the formula Ie in which represents a group of the formula -O- or -NH-, Y^ represents lower alkylene which may be interrupted by iminocarbonyl, X® 'i represents a group of the formula -0- and AJ represents a radical of the formula lb or Ic in which R^ represents an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 16 17 carbon atoms, R1 represents hydrogen and R1 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, wherein 1 7 each of the hydroxy groups in a radical R , independently of the other, is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 - 74 - 2Q500Q> carbon atoms, or each of R1® and R17, independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, or is esterified by an alkanoyl radical having from 7 to 90 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 30 carbon atoms, with the proviso that the compounds contain at least one radical selected from the group a\ A2 and A3, and the use of pharmaceutically acceptable salts of these compounds.

4. Use according to clair. 1 of compounds of the formula I in which represents a group of the formula -N(R14)-, R14 representing hydrogen or Cj_4-alkyl, 2 1 X represents oxygen, R1 represents hydrogen, lower alkanoyl, or a group of the formula la in which repesents 0 or 1, represents carbonyl, Y^ represents lower alkylene which may be interrupted by iminocarbonyl, X3 represents oxygen, and A^ represents a radical of the formula lb or Ic in which R^ represents an alkyl or alkenyl radical having from 7 to 30 carbon atoms that is unsubstituted or substituted by hydroxy, amino and/or alkanoylamino having up to 22 carbon atoms, R^ represents hydrogen and R^7 represents 2-hydroxyethyl or 1,2-dihydroxyethyl, at least one hydroxy group in a radical R^7 being etheriEied by an alkyl or alkenyl radical having from 7 to 30 carbon atoms, or being esterified by an alkanoyl or alkenoyl radical having from 7 to 30 carbon atoms, or each of R^® and R^7, independently of the other, represents hydroxymethyl in which the hydroxy group is etherified by an alkyl or alkenyl radical having from .7 - 75 - 205000 to 30 carbon atoms, or is esterified by an alkanoyl or alkenoyl radical having from 7 to 30 carbon atoms, R2 represents lower alkanoyl, hydroxy-lower alkanoyl, benzoyl or, independently of R1, R12 and R13, a group of the formula la as defined hereinbefore in this claim, 3 4 5 7 8 each of R , R , R , R and R , independently of one another, represents hydrogen, methyl or ethyl, R6 represents hydrogen, or lower alkyl that is unsubstituted or substituted by free hydroxy, free mercapto, lower alkoxy, lower alkylthio, alkanoyloxy having from 2 to 30 carbon atoms, alkenoyloxy having from 6 to 30 carbon atoms, phenyl, 4-hydroxyphenyl, or by a group of the formula Id in which m represents 0 or 1, E represents oxygen or sulphur, Z2 represents carbonyl, Y2 represents lower alkylene that is unsubstituted or substituted by phenyl and may be interrupted by iminocarbonyl, X4 represents oxygen and A2, independently of A1 and A , represents a radical of the formula lb or Ic as defined hereinbefore in this Q 11 claim, each of R5 and R , independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino, lower alkoxycarbonyl-lower alkylamino, carbamoyl-lower alkylamino, or a radical of the formula Ie in which X^ represents oxygen or NH, Y3 represents lower alkylene which may be interrupted by iminocarbonyl, X^ represents oxygen and A3, independently of A^ and A2, represents a radical of the formula lb or Ic as 10 defined hereinbefore in this claim, R,u represents 1 ? hydrogen, R represents hydrogen, lower alkanoyl or 1 "3 1 ^ the same radical as R , and R1 represents hydrogen, or alkanoyl or alkenoyl each having up to 30 carbon atoms or, independently of R' and R , a radical of the formula la as defined hereinbefore in this claim, with the proviso that the compounds contain - 76 - 20500$ at least one, and at most two, radicals selected from 12 3 the group A , A and A , and the use of pharmaceutically acceptable salts of these compounds.

Use according to claim 4 of compounds of tha 1 2 formula I in which X represents the group NH, X represents oxygen, R^ represents hydrogen or lower alkanoyl, R represents lower alkanoyl, benzoyl or a group of the formula la in which n^ represents 0 or 1, Z^ represents carbonyl, Y1 represents lower alkylene which may be interrrupted by one or two iminocarbonyl •j i groups, X represents oxygen, and A1 represents a radical of the formula lb or Ic in which R^ represents an alkyl radical having from 7 to 22 carbon atoms, represents hydrogen, and R^7 represents 1,2-dihydroxyethyl in which each of the hydroxy groups, independently of the other, is esterified by an alkanoyl or alkenoyl radical having from 10 to 22 carbon atoms, R3 represents hydrogen or methyl, R4, R^, R7 and R® each represents hydrogen, R® represents hydrogen, or lower alkyl that is unsubstituted or substituted by free hydroxy, alkanoyloxy having from 2 to 22 carbon atoms, alkenoyloxy having from 6 to 22 carbon atoms, phenyl or by a group of the formula Id in which m represents 0 or 1, E represents oxygen, Z2 represents carbonyl, represents lower alkylene that is unsubstituted or substituted by phenyl and may be interrupted by iminocarbonyl, X4 represents oxygen and A2, independently of A^ and A3, represents a radical of the above-defined formula lb or Ic, each of R9 and R11, independently of the other, represents hydroxy, lower alkoxy, amino, lower alkylamino, a-carboxy-lower alkylamino, a-lower alkoxycarbonyl-lower alkylamino, o-carbamoyl-lower alkylamino, or a radical of the formula Ie in which represents the group NH, Y3 represents lower alkylene - 77 - 2©500fi) which may be interrupted by one or two iminocarbonyl groups, Xs represents oxygen and A^, independently of A' and A , represents a radical of the formula lb or Ic defined hereinbefore, R^ represents hydrogen, R^2 represents hydrogen, lower alkanoyl or the same radical as R^3, and R^ represents hydrogen, alkanoyl having from 2 to 22 carbon atoms, alkenoyl having from 6 to 22 carbon atoms or, independently of R , a radical of the formula la a3 defined hereinbefore, and the use of pharmaceutically acceptable salts of these compounds.

6. Use according to claim 5 of compounds of the 1 2 formula I in which X represents the group NH, X represents oxygen, R1 represents hydrogen or C2_4~ alkanoyl, R2 represents C2_4-alkanoyl or a group of the formula la in which n_ represents 0 or 1, represents carbonyl, Y^ represents lower alkylene which may be interrupted by one or two iminocarbonyl groups, X^ represents oxygen, and A^ represents a radical of the formula lb or Ic in which R^ represents an unbranched alkyl radical having from 12 to 18 carbon atoms, R^® represents hydrogen and represents 1,2-dipalmitoyloxyethyl or 2-oleoyloxy-1-palraitoyloxy-ethyl, R^ represents hydrogen or methyl, R4, R"3, R7, R® and R^° each represents hydrogen, R® represents methyl, ethyl or isopropyl, each of which is unsubstituted or substituted by a radical of the formula Id in which jn represents 0 or 1, E represents oxygen, Z2 represents carbonyl, Y' represents lower alkylene that is unsubstituted or substituted by phenyl and may be interrupted by one or two iminocarbonyl groups, X4 represents oxygen and A , independently of A' and A3, represents a radical of the formula lb or Ic defined hereinbefore, R9 represents amino, 20 S£pj - 78 - 205000 represents hydroxy or a radical of the formula Ie in which x5 represents the group NH, represents lower alkylene which may be interrupted by one or two iminocarbonyl groups, X® represents oxygen and A^, 1 2 independently of A' and A', represents a radical of 1 ? the formula lb or Ic defined hereinbefore, R represents hydrogen, acetyl or the same radical as R1^, and R13 represents hydrogen, acetyl or, independently of R , a radical of the formula la as defined hereinbefore, and the use of pharmaceutically acceptable salts of these compounds.

7. Use according to any one of claims 1 to 6 of com- 1 2 pounds of the formula I in which the radicals A , A and A3, if present, each represents a radical of the formula Ic, and of pharmaceutically acceptable salts of these compounJs.

8. Use according to any one of claims 1 to 7 of compounds of the formula I in which the sugar moiety is derived from (D)-galactose or (D)-mannose, and of pharmaceutically acceptable salts of these compounds.

9. Use according to any one of claims 1 to 7 of compounds of the formula I in which the sugar moiety is derived from (D)-glucose, and of pharmaceutically acceptable salts of these compounds.

10. Use according to any one of claims 1 to 9 of compounds of the formula I that have at an asymmetrically substituted C(-R3)-atora the (D)-configuration, at an asymmetrically substituted C(-R6)-atom the (L)-configuration, and at the C(-N-R8)-atom the (DJ-configuration, and of pharmaceutically acceptable salts of these compounds

11. Use according to any one of claims 1 to 9 of com - 79 - 205000 pounds of the formula I that have at an asymmetrically substituted C(-R^)-atom the (L)-configuration, at an asymmetrically substituted C(-R6)-atom the (L)-configuration, and at the C(-N-R®)-atom the (D)-configuration, and of pharmaceutically acceptable salts of these compounds.

12. Use according to any one of claims 1 to 11 of compounds of the formula I that carry only one phosphoryl substituent, that is in the radical R^3, and of pharmaceutically acceptable salts of these compounds.

13. Use according to any one of claims 1 to 11 of compounds of the formula I that carry only one phosphoryl substituent, that is in the radical R®, and of pharmaceutically acceptable salts of these compounds.

14. Use according to any one of claims 1 to 11 of compounds of the formula I that carry only one phosphoryl substituent, that is in the radical R^, and of pharmaceutically acceptable salts of these compounds.

15. Use according to claim 1 of N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1, 2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide.

16. Use according to any one of claims 1 to 15 of pharmaceutically acceptable salts of compounds of the formula I.

17. Use according to claim 16 of sodium salts of compounds of the formula I.

18. Use according to claim 1 of compounds of the formula I that have at an asymmetrically ■ • • •• ^ ,4 v - 80 - 205000 substituted C(-R3)-atom the (D)-configuration, at an asymmetrically substituted C(-R®)-atom the (LJ-configuration, and at the C(-N-R®)-atom the (D)-configuration, and in which the sugar moiety is derived from (D)-glucose, X1 represents the group NH, X* represents oxygen, R1, R4, R5, R7, R8, R10, R12 and R13 each represents hydrogen, R2 represents C^j-alkyl or phenyl, R3 represents hydrogen or C^.^-alkyl, R® represents hydrogen, C^-alkyl optionally substituted by hydroxy, methoxy, mercapto, methylmercapto or by halogen, phenyl or phenylmethyl each optionally substituted by hydroxy, methoxy or halogen, or heteroaryl or heteroarylmethyl each containing one or two aza atoms and having 5 ring members, or R^ and R® together represent trimethylene, one of the radicals R9 and R^ represents a radical of the formula Ie in which X5 represents the group NH or oxygen, Y3 represents C2_3-alkylene or a radical of the formula 0 2 3 2 'I 3 -U-COO-U- or -U -C-NH-U -, in which each of U2 and U3, independently of the other, represents C^-alkylene that is unsubstituted or substituted by C^-alkyl optionally substituted by hydroxy, lower alkoxy, mercapto or by lower alkyl-mercapto, or by phenyl or phenyl-lower alkyl each of which is optionally substituted by hydroxy, methoxy or halogen, or by heterocyclyl or heterocyclyl-(C^.j-alkyl) each containing one or two aza atoms and having 5 or 6 ring members, X® represents oxygen, and A3 represents a radical of the formula Ic in which R^® represents hydrogen and R^7 represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in which at last one of the hydroxy - 81 - 205000 groups is esterified by an aliphatic Cj6_2g-carboxylic acid that is optionally singly or doubly unsaturated/ or is etherified by an aliphatic C^2_ jg-aloohol that is optionally singly or doubly unsaturated, and the other Q 11 of the radicals R' and R1' represents hydroxy, lower alkoxy, amino, lower alkylamino or aminocarbonyl-lower alkylamino, and the use of pharmaceutically acceptable salts of such compounds.

19. Use according to claim 1 of compounds of the formula I that have at an asymmetrically substituted C (-R-*)-atom the (D)-configuration, at an asymmetrically substituted C(-R®)-atom the (L_) -conf iguration and at the C (-N-R®)-atom the (^-configuration, and in which the sugar moiety is derived from (D)-glucose, 2 14 represents the group NH, X represents oxygen, R , R , 781012 13 0 R , R , R , R and R each represents hydrogen, R represents lower alkyl or phenyl, each of R^ and R^, Independently of the other, represents hydrogen or methyl, R® represents C^_4-alkyl, R9 represents amino and R^ represents a radical of the formula 0 0 1 H " (-NH-U -C)r-NH-CH2-CH2-0-P-0-CH2 oh ch-o-r3 I h ch2-o-r° in which r represents 0 or 1, represents a radical of the formula /V" *-v - 82 - 205000 CH, V1 nch-ch, h,c \ CH-CH- CH. CH. V CH. \ CH-CH, -CH- . -CH- -CH- or -CH- (L) (L) (D (k) and each of Ra and R*5, independently of the other/ represents the acyl radical of an alkanoic carboxylic acid having from 12 to 22 carbon atoms or of an unsubstituted aliphatic carboxylic acid having from 12 to 22 carbon atoms and containing one or two double bonds, and the use of pharmaceutically acceptable salts of such compounds.

20. Use according to any one of claims 1 to 17 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by DNA viruses with enveloped virion or by RNA viruses with cubic or helical capsid symmetry.

21. Use according to claim 20 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by DNA viruses with enveloped virion and cubic capsid symmetry, by RNA viruses with cubic capsid symmetry and naked virion or by RNA viruses with helical capsid symmetry in which the nucleocapsid - 83 - 20500CP casing is located at the surface membrane.

22. Use according to claim 21 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by Herpetoviridae, Picornaviridae or myxoviruses.

23. Use according to claim 22 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by Alphaherpesvirinae, car-dioviruses or Orthomyxoviridae.

24. Use according to claim 23 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by simplex viruses, encephalo-myocarditis viruses or Influenza A or Influenza B viruses.

25. Use according to any one of claims 1 to 17 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treat-, ment of diseases that are caused by Adenoviridae.

26. Use according to claim 20, of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases tnat are caused by Poxviridae, Caliciviridae, Reoviridae, Rhabdoviridae or Coronaviridae.

27. Use according to claim 26 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment^Ofr 5? - 84 - 205000 OKJ diseases that are caused by Orthopoxviruses/rotaviruses

28. Use according to claim 22 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by — rhinoviruses, aphthoviruses of cloven-hoofed animals, or Paramyxoviridae. /.)). use according CU Lldliu 28 uf uuiupuunda of fehe_ formula I, including the pharmaceutj salts thereof, fort]j£_-prai5fiylaxis or treatment of diseases__tba-t^Srecaused by human parainfluenza viruses hy «nrp<nynyH.l .flying j n h'lmi"-. 13 Off. Use according to claim 20 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or treatment of diseases that are caused by vaccinal viruses or parainfluenza viruses. I*, Vc&u*, I 3D Use according to claim 20 of compounds of the formula I, including the pharmaceutically acceptable salts thereof, for the prophylaxis or t diseases that are caused by arboviruses viruses. treatment of or vesiculo- Pharmaceutical preparation for enteral or parenteral administration that contains an active amount/ but less than 1» by weight, of an active ingredient of the formula Iyyand/or of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and a pharmaceutical carrier. 27 MAYI986 205000 - 85 - 32 Topically admi^istrable pharmaceutical preparation according to claim that contains from 0.001% up to, but exclusive of, 1% of active ingredient. 33 22. Eye drops according to claim 34 3* ^5. Aqueous nose drops according to claim^53'. 35" ^>6. Anhydrous nose drops according to claim^M. 3Q> 32. Gel according to claim/>3. s7 30 ^>6. Cream according to claimJtf. 38 3a

29. Nasal ointment according to claim JA. 35 3ft. Skin ointment according to claim yi. Ac 3Q. >frf. Lipstick according to claim 4l 31 Pharmaceutical preparation according to claim^f for oral administration in the form of tablets or capsules with an active ingredient content of fr9m 0.1 to 0.9% by weight. BALDWIN* SON/& CAREY i / v./.... ATTOnNEYS FOR THE APPLICANTS V.o\. 'Aj. y