CA2026278C

CA2026278C - Use of alkylphosphoric acid compounds for combatting psoriasis disorders

Info

Publication number: CA2026278C
Application number: CA002026278A
Authority: CA
Inventors: Hansjorg Eibl; Clemens Unger; Jurgen Engel
Original assignee: Asta Medica GmbH; Max Planck Gesellschaft zur Foerderung der Wissenschaften
Current assignee: Asta Medica GmbH; Max Planck Gesellschaft zur Foerderung der Wissenschaften
Priority date: 1989-09-27
Filing date: 1990-09-26
Publication date: 1996-04-30
Anticipated expiration: 2010-09-26
Also published as: RU1837877C; EP0419998A3; FI904726A0; MC2150A1; HU209589B; UA19335A; IE903464A1; EP0916343A1; NO904184D0; JPH03130228A; HUT55992A; NO904184L; CA2026278A1; ZA907702B; PT95422B; LV10391A; EP0419998A2; LT3804B; FI904726A7; LV10391B

Abstract

The use of alkylphosphoric acid compounds of formula I

where in formula I R represents a saturated or unsaturated hydrocarbon radical with 12 to 24 carbon atoms or where R
represents the group -CH2-CHR3-CH2-Z-R4 and R3 is a C1-C6-alkoxy group or a C1-C6-alkoxymethyl group, Z represents oxygen or sulphur and R4 represents a C1-C24-alkyl radical, X is an oxygen atom, NH or NR2 and Y is an oxygen atom or NH, R1 is a C1-C8-alkyl group, or where R1 represents a C2-C8-alkyl group which is unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl for the preparation of a medicament for combatting psoriasis disorders.

Description

~2~3~7~

~he invention relates to agents for combatting psoriasis disorders such as psoriasis and psoriasis related disorders, and more particularly to the use of alkylphosphoric acid compounds for combatting psoriasis disorders.

Alkylphosphoric acid compounds of formula I are known substances having an anti-tumour effect. It has now been found that compounds of this type of formula I or salts therQof with physiologically acceptable acids are also effective against psoriasis and related disorders.

According to the invention, the term psoriasis disorders covers skin disorders associated with hyperkeratoses, such as in particular psoriasis, Arthropathia psoriatica and parapsoriasis disorders.

Corticosteroids are currently the most frequently used treatment for psoriasis. Severe cases of psoriasis may even be treated with cytostatics (for example methotrexate).
However, all these substances have pronounced and serious side effects.

In contrast, the compounds of formula I in the dosages used show no or only negligible side effects. For example the effect of topical therapy using compounds of formula I is clearly superior to that of conventional dermatological agents used in psoriasis (keratolytic agents and corticoids).

The pharmaceutical formulations for use in psoriasis disorders and disorders related thereto generally contain between 1 to 1000, preferably 5 to 500 mg, in particular 10 to 100 mg per individual dose of component I (component I =
sum of the weights of the individual compounds of formula I) in oral, parenteral, rectal, vaginal or inhalable forms.

7 ~

Should a formulation contain two or more single compounds of formula I, these figures always apply to the total amount of component I. This applies by analogy to the following amounts which relate to component I (component I = sum o the individual compounds of formula I) in connection with dosage data and their weights in the corresponding pharmaceutical formulations and to corresponding amounts in the claims.
Compound I is in each case understood to refer to the single substance represented in formula I or its physiologicall~
acceptable salt.

For formulations for local application to the skin and mucous membranes the amount of component I is for example between 0.1 mg and 1000 mg, preferably 0.1 to 500 mg.
Administration may for example be in the form of tablets, capsules, pills, coated tablets, suppositories, ointments, gels, creams, powder, dusting powder, aerosols or in liquid form. Liquid forms which may for example be used are: oily or alcoholic or a~ueous solutions as well as suspensions and emulsions. Pre~erred forms of application are tablets containing between 10 and 100 mg or solutions containing between 0.01 and 10 percent by weight of component I~

~he individual dose of component I ~i.e. the total amount of compounds I) can for example lie a) in oral medicinal forms between 1 - 1000 mg, preferably 10 - 500 mg;
b) in parenteral medicinal forms (for example intravenous, intramuscular) between 1 - 1000 mg, preferably 10 - 500 mg;
5 c) in medicinal forms for inhalation (solutions or aerosols) between 1 - 1000 mg; preferably 10 - 500 mg;

2~ 27~

d~ in medicinal forms for rectal or vaginal application between 1 - 1000 mg, preferably 10 ~ 500 mg;

e) in the case of medicinal forms for local application to the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, ointments and the like) between 0.1 mg 1000 mg, preferably 0.1 - 500 mg, the concentration of the components I (i.e. the total amount of compounds I) in such formulations being for example 0.01 to 12, in particular 0.1 - 8 percent by weight.

It is for example possible to recommend 1 to 3 tablets containing 1 to 100 mg of component I (i.e. total amount I) 3 times daily or for example in the case of intravenous injection one ampoule containing 1 to 10 mg with 1 to 100 mgl of component I (i.e. total amount I) 1 to 3 times daily. In the case of oral administration the minimum daily dose is for example l mg; the maximum daily dose for oral administration should not exceed 1000 mg.

For the treatment of dogs and cats the oral individual dose of component I generally lies between about 0.01 and 60 mg/kg body weight; the parenteral dose about between 0.01 and 60 mg/kg body weight.

For the treatment of horses and cattle the oral individual dose o~ component I generally lies between about 0.05 and 100 mg/kg; the parenteral individual dose about between 0.05 and 100 mg/kg body weight.

The acute toxicity of compounds I in the mouse (expressed by the LD 50 mg/kg; method after Miller and Tainter: Proc. Soc.
Exper. Biol. a. med. 57 (1944) 261) is for example between 300 and 1000 mg/kg for oral application.

2~ 7~

The medicaments of the invention are characterized in that they contain as active substance at least one compound of the general formula I

R - Y - PO2 - X - Rl or a physiologically acceptable salt thereof, optionally together with conventional pharmacological additives and diluents.
The following may preferably be used as active substances:
hexadecylpho~phocholine, oleylphosphocholine, hexadecylphosphoric acid-(N,N)-bis-(2-chloroethyl)-amideO

Formula I also comprises possible enantiomers and diastereomers. Should the compounds be racemates, these can be split in a method known per se, for example using an optically active acid, in which the optically active isomers are split. Preference is, however, also given from the outset to use of enantiomeric or optionally diastereomeric starting substances, resulting in a correspondingly pure optically active or diastereomeric compound as end product.

In the context of the invention, R is preferably an alkyl group of the given chain length which is combined with the oxygen of the glycol radical via a terminal carbon atom or also via a carbon atom within the alkyl chain (for example via the carbon atom 2 or carbon atom 3 or another central carbon atom). This alkyl chain may be straight or branched.
The alkyl chain R may have one, two or three carbon double bonds or triple bonds which may also be present in mixed form and/or contain halogen substituents. Halogen atoms that may be used are: fluorine, chlorine or bromine. One to three of such halogen atoms may be present in the chain R, whereby these may be located at one or at different carbon atoms of the radical R. Apart from the saturated, straight-chain 2~27~

alkyl radicals, preference may also be given to those with one or two carbon double bonds in the molecule~ Particularly preferred are those substituents R which contain an alky]
radical with 14 to 20, preferably 15 to 20, in particular 16 to 20 carbon atoms or a corresponding alkenyl radical with 14 to 20, preferably 15 to 20, in particular 16 to 20 carbon atoms.

Examples of halogen-substituted radicals R are:
chlorohexadecyl, bromohexadecyl, fluorohexadecyl, 9,10-dibromooctadecyl, 2,3-dibromooctadecyl, 15,16-dibromohexadecyl, bromotetradecyl.

Examples of unsaturated radicals R are:
9-octadecenyl radical (oleyl alcohol radical, R in formula I
represents in particular this g-octadecenyl radical), 15-hexadecenyl radical, 9,12-octadecadienyl radical (linoleyl radical~.

Should more than one double or triple bond be present/ these are conjugated.

Examples of saturated and unsubstituted radicals R are:
tetradecyl radical, hexadecyl radical, octadecyl radical.
R preferably means for exampls the group -CH2-CHR3-CH2-Z-R4 when Y and X are oxygen and Rl is a Cl-C6-trialkylamino group (in particular trimethylamino) which is associated with X via -:
a C2-C3-alkyl chain and where the positive charge of the trialkylamine cation is neutralized by the phosphoric acid anion.

The alkoxy groups R3 and R4 are preferably methoxy groups.
The C1-C24-alkyl radical R4 preferably consists of 10 to 20, in particular 12 to 18 carbon atoms and is preferably not branched.

~ 3 ~ ~3 ~

Should Rl or R2 represent an unsubstituted alkyl group, this consists for example of 1 - 6, preferably 1 - 4 carbon atoms.
Should Rl or R2 represent an unsaturated alkyl group, this consists in particular of 3 to 6 carbon atoms, it being necessary to have at least one simple C-C bond between the unsaturated function of such an unsaturated alkyl group and X. These are in particular C3-C6-alkenyl groups. Examples hereof are: allyl, butenyl, pentenyl, hexenyl.

Should Rl or R2 be substituted, this is in particular a straight chain alkyl or alkenyl radical, in this case Rl preferably consists of 2 - 6 carbon atoms, whereby the given substituents are preferably in the ~-position oE the alkyl or alkenyl group Rl or R2; this is for example the ethyl or straight propyl radical with one of the mentioned substituents in -position (i.e. in 2-position in the case of ethyl and 3-position in the case of propyl).

Should Rl be a 2-tert.-butyloxycarbonylaminoethyl radical or a 2-tert.-butyloxycarbonylethyl radical, this is preferably the D- or L-form.

Of the substitutents of Rl the trialkylammoniumethyl radical is preferred, in particular when X is an oxygen atom, whereby the trialkyl radicals preferably consist in each case of one, two or three carbon atoms, preference being given to methyl groups. The trimethylammoniumethyl xadical is therefore particularly preferred. In this particularly preferred embodiment the compounds of formula I are phosphatidylcholine derivatives.

In the case of the C3-C8-cycloalkyl substituents, these consist in particular of 3 - 6 carbon atoms (for example cyclopropyl to cyclohexyl). In the case of the 2,3-dihydroxypropyl~ group this is in particular the sn-1,2-2 ~ 2, ~ 2 rl 8 dihydroxy-propylamino-(3)-structure or the sn-2,3-dihydroxy-propylamino-(1)-structure.

Other examples of preferred compounds of formula I are:

oleyl-phospho-(N,N,M-trimethyl)-propanolamine, oleyl-phospho-(N,N,N-trimethyl)-butanolamine, oleyl-phospho-(N,N,N-trimethyl~-pentanolamine, oleyl-phosphoserine, oleyl-phosphoethanolamine, oleyl-phosphopropanolamine, oleyl-phosphobutanolamine, oleyl-phosphoglycerol, hexadecyl-phospho-(N,N,N-tri- methyl)-propanolamine, l-octadecyl-2-methyl-sn-glycero-3-phosphocholine (for example ET-18-OCH3, see German Patent 26 19 686).
1-Hexadecylmercapto-2-methoxymethyl-propanol-3-phosphocholine (Ilmo~osin).

The salts may be inner salts (for example if R1 represents a trimethylammonio-alkyl group) or salts with physiologically acceptable cation~. The medicaments of the invention or the compounds I may be present as inner salts, for example if R
contains an amino group. Should no inner salts be present, or should the radical R1 contain no basic group, the negative charge of the phosphoric acid group is saturated by a physiologically acceptable cation. Physiologically acceptable cations of this type may for example be: alkali cations (Na, K), alkaline earth cations (Mg, Ca) or the cations of organic amines, such as for example guanidinium-, morpholinium, cyclohexylammonium cation, ethylene diammonium cation, piperazonium cation (in both latter cases one or two basic) or the cation derived from an amine of formula NRaRbRC
wherein the radicals Ra to Rc are the same or different and represent hydrogen, Cl-C2-alkyl groups or oxyethyl groups.

Should cations be involved derived from an amine of formula NRaRbRC, this is preferably the ammonium cation or an ammonium cation substituted by one to ~hree Cl-C2-alkyl groups or an ammonium cation substituted by one to three 2-hydroxyethyl groups.

The negative charge of the compounds of formula I is thus for example saturated by a basic amino group present in the molecule or a low molecular weight mono-, di- or tri-C1-C6-alkylamino group or by an additional physiologically acceptable cation.

The preparation of the active substances according to the general formula I is basically known and can for example take place using methods known per se or analogous methodsO The basic skeleton may easily be obtained by reacting a compound of formula ROH or a functional derivative thereof with phosphorus o~ychloride and triethylamine, reaction of the product with a co~pound HXRl and acid splitting, where R, R
and X have the above meaning.

The pharmaceutical compositions or medicaments of the invention contain as acti~e substance at least one compound (component) of formula I, optionally mixed with other pharmacologically or pharmaceutically active substances. The preparation of the medicaments occurs in known manner, it being possible to use known and conventional pharmaceutical auxiliary substances and other conventional carriers and diluents.

Carriers and diluents of this type that may be used are for example substances recommended or listed in the following literature references as auxiliary substances for pharmaceutical, cosmetic and related fields: Ullmanns Encyklopadie der technischen Chemie, Volume 4 (1953), page 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq.: H.v.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind. issue 2 r~

(1961), paye 72 et seq.; Dr. ~.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmaæie, Kosmetik und angrenzende Gebiete, cantor KG, Aulendorf in Wurttemberg 1981.

Examples hereof are gelatine, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch), cyclodextrines and cyclodextrine derivatives, polyvinylpyrrolidone, polyvinyl acetate, gelatine, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic oxyalcohols, for example methoxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulosephthalate); fatty acids as well as magnesium, calcium or aluminium salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also hydrated; mono-, di- and triglycerides of saturated fatty acids C12H242 to ClgH36O2 and their mixtures, pharmaceutically acceptable single or multivalent alcohols and polyglycols such as polyethylene glycols as well as derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 - 18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent al~ohols such as glycols, glycerol, diethylene glycol, pentaerythritol, soxbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, benzylbenzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol ethers with Cl-C12 alcohols, dimethylacetamide, lactamides, lactates, ethyl ~ $ ~ ~ ~3 carbonates, silicones (in particular medium viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Other auxiliary substances that may be considered are substances promoting disintegration (so-called disinte~rants) such as: cross-linked polyvinylpyrrolidone, sodium carboxy methyl starch, sodium carboxy methyl cellulose or microcrystalline cellulose. It is also possible to use known coating substances such as for example: polymerisates as well as copolymerisates of acrylic acid and/or methacrylic acid and/or their esters; copolymerisates o~ acrylic and methacrylic acid esters with a low ammonium group content (for example Eudragit~ RS), copolymerisates o~ acrylic and methacrylic acid esters and trimethylammonium methacrylate (for example EudragitR RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropylmethylcellu].osephthalate or -acetate succinate; cellulose-, starch as well as polyvinylacetate phthalate; carboxymethyl cellulose;
methylcellulosephthalate, -succinate, -phthalate succinate as well as -phthalate acid half ester; zein; ethyl cellulose as well as -succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride-copolymer;
maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerisate; 2-ethyl-hexyl- acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer;
glutaminic acid/glutaminic acid ester copolymer;
carboxymethylethyl-cellulose glycerol monooctanoate;
cellulose acetate succinate; polyarginin.

Plasticizing agents for coating substances that may be considered are:

Citric and tartaric acid esters (acetyltriethyl-, acetyltributyl-, tributyl-, triethyl citrate); glycerol and .

2 ~ 2 ~

glycerol esters (~lycerol diacetate; -triacetate, acetylated monoglycerides, castor oil~; phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl phthalate), D-(2-methoxy- or ethoxy ethyl)-phthalate, ethylphthalyl-, butylphthalyl ethyl- and butyl glycolate; alcohols ~propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl-adipate, di(2-methoxy- or ethoxyethyl adipate); benzophenone; diethyl- and dibutylsebacate, succinate, -tartrate; diethylene glycol dipropionate;
ethylene glycol-diacetate, dibutyrate, -dipropionate;
tributyl phosphate, tributyrin; polyethylene glycol sorbitane monooleate (polysorbates such as Polysorbat 80); sorbitane monooleate.

To prepare solutions or suspensions it is for example possible to use water or physiologically acceptable organic solvents such as for example ethanol, propanol, isopropanol, 1,2-propylene glycol, glycerol-Cl-C12-alkyl ethers, in particular l-glycerol-Cl-Cg-alkyl ethers such as for example glycerol-1-n-propyl ether, glycerol-1-n-hexyl ether, glycerol-1-n-nonylether polyglycols and their derivatives, dimethylsulfoxide, fatty alcohols, triglyc~rides, partial esters of glycerol, paraffins and the like.
For injectable solutions or suspensions it is for example possible to use non-toxic parenterally acceptable diluents or solvents such as for example: water, 1,3-butane diol, ethanol, 1,2-propylene glycol, polyglycols in a mixture with water, Ringer's solution, isotonic sodium chloride solution or also hardened oils including synthetic mono- or diglycerides or fatty acids such as oleic acid.

Known and conventional solubilizers or emulsifiers may be used in the preparation of formulations. Solubilizers and emulsifiers that may for example be considered are:
polyvinylpyrrolidone, sorbitane fatty acid esters such as sorbitane trioleate, phosphatides such as lecithin, acacia, ~&7~2~

tragacanth, polyoxyethylated sorbitane monooleate and other ethoxylated fatty acid esters of sorbitane, polyoxyethylated fats, polyoxye~hylated oleotriglycerides, linolisated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl) imidazolidone (2).
Polyoxyethylated here means that the substances in question contain polyoxyethylene chains the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20. Polyoxyethylated substances of this type may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as for example those containing oleic acid radicals) with ethylene oxide (for example ~0 Mol ethylene oxide per Mol glyceride.
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil.
See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" 1971, p. 191-195.

It is also possible to add conserving agents, stabilizers andbuffer substances, for example calcium hydrogen phosphate, colloidal aluminium hydroxide, flavour enhancers, sweeteners, colourants, antioxidants and complex formers (for example ethylenediaminotetraacetic acid) and the like.
It is optionally also necessary to adjust to a pH range of ca. 3 to 7 using physiologically acceptable acids or buffers to stabilize the active substance molecule. Generally speaking, as neutral to weakly acid (up to pH 5) a pH value as possible is preferred.

To prepare dermally applicable formulations it is possible to use the previously mentioned substances and spreadable or liguid hydrocarbons such as Vaseline or paraffin or gels of alkanes and polyethylene, fats and oils of plant or animal 7 ~

origin, which may in part also be hydrated, or synthetic ~ats such as glycerides of fatty acids C8-C18, as well as beeswax cetyl palmitate, wool wax, wool wax alcohols, fatty alcohols such as cetyl alcohol, stearyl alcohol, polyethylene glycols of molecular weight 200 to 20,000; liquid waxes such as isopropyl myristate, isopropyl stearate, ethyloleate;
emulsifiers such as sodium, potassium, ammonium salts of stearic acid or palmitinic acid as well as triethalolamine stearate, alkali salts of oleic acid, castor oil acid, salts of sulfurated fatty alcohols such as sodium lauryl sulphate, sodium cetyl sulphate, sodium stearyl sulphate, salts of gallic acid, sterols such as cholesterol, partial fatty acid esters of multivalent alcohols such as ethylene glycol monostearate, glycerol monostearate, pentaerythritol monostearate, partial fatty acid esters of sorbitane, partial fatty acid esters of polyoxyethylene sorbitane, sorbitol ethers of polyoxyethylene, fatty acid esters of polyoxyethylene, fatty alcohol ethers of polyoxyethylene, fatty acid esters of saccharose, fatty acid esters of polyglycerol, lecithin.

Antioxidants that may ~or example be used are sodium metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl ester, butylhydroxyanisol, nordihydroguaiacic acid, tocopherols as well as tocopherols + synergists (substances that bind heavy metals through complex formation, for example lecithin, ascorbic acid, phosphoric acid). The addition of synergists substantially enhances the antioxygenic effect of the tocopherols.
~onserving agents that may for example be considered are sorbic acid, p-hydroxybenæoic acid esters (for example lower alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and formalin derivatives.

rJ~

The pharmaceutical and galenic treatment of the compounds of formula I is according to conventional standard methods. For example active substance(s) and auxiliary or carrier substances are well mixed by stirring or homogenization (for example using conventional mixing devices), working generally being at temperatures between 20 and 80C, preferably 20 to 50C, in particular at room temperature. Reference is made in this context to the following standard work: Sucker, Fuchs, Speiser, Pharmaæeutische Technologie, Thieme Verlag Stuttgar~, 1978.

Application may be to the skin or mucous membrane or to the inside of the body, for example oral, enteral, pulmonal, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intracardial, intramuscular, intraperitoneal, intracutaneous, subcutaneous.
In the case of parenteral formulation forms, these are in particular sterile or sterilized products.
The concentration of compound I (component I, i.e. the total amount) in the medicinal forms for local application is 0.01 to 12, preferably 0.05 to 10, in particular 0.1 to 8 or also 0.5 to 6 percent by weight.

For the treatment of psoriasis the compounds I ~component I) ~5 are used in particular locally, for example in the form of solutions, tinctures t suspensions, emulsions, ointments, gels, creams, pastes, lotions or shampoos. Preference is given to anhydrous formulations, facilitating the simultaneous use of salicylic acid and/or urea. Formulations of this type, which can also be made resistant to scrubbing through the addition of surfactants, are described for example in German Published Patent 36 03 859. The urea may either be present as surfactant-urea inclusion compound or also in free for~. Formulations containing neither urea nor salicylic acid may of course also be used.

The concentrations of compound I used (in each c.ase the total amount) are in this case for example 0.1 to 10 %
(weight/weight), preferably 0.5 to ~ %, in particular 1 to 6%. The concentrations of use of salicylic acid are for example 0.1 to 10%, preferably 0.2 to 8%, in particular 0.5 to 5%. The concentrations of use of urea are for example 1 to 20%, preferably 3 to 18~, in particular 5 to 15%.

For topical application it has for example been found beneficial to use the compounds I (component I) together with at least one alkyl glycerol with 2 to 12 carbon atoms in the alkyl radical which may be present in the form of an ether yroup bound to on~ of the primary or secondary OH groups of the glycerol. Alkyl glycerols of this type enhance or improve the effect of the compounds I. Preference is given here to alkyl glycerols with 3 to 9 carbon atoms alone or mixed.

Particularly favourable effects are thus possessed by a medicament which contains a) one or several compounds of formula I (component I) and b) an alkyl glycerol of the general formula II
H2C ~ R5 ~2C - OH, in which one of the radicals R5 and R6 represents an alkyl group with 2 to I2 carbon atoms and the other radical represents a hydrogen atom, as well as optionally other conventional pharmacological additives and diluents.

$

Use may preferably be made of a mixture of water and an alkylglycerol mixture of nonyl or octyl glycerol, hexyl or pentyl glycerol and propyl- or ethylglycerol. A
corresponding formulation for topical use contains for example 1 to 100 mg of compound I (component I, i.e. total amount I) per ml of alkyl glycerol of formula II or of a corresponding alkylglycerol mixture with water.

A mixture of this type will hereinafter also be referred to as a cascade.
The content of component I in mg/ml cascade is designated by a suffixed index in such a way that for example a cascade mixture containing 10 mg/ml of component I is termed a cascade 10 and a mixture containing 60 mg of component I per ml of cascade is referred to as cascade 60.

The preparation of alkyl glycerols is known, for example from German Published Patent 33 43 530.8.
For example alkyl glycerol-water mixtures containing for example nonyl glycerol, octyl glycerol, hexyl glycerol, pentyl glycerol, propyl glycerol and ethyl glycerol are preferred. Aqueous mixtures of this kype preferably contain 3 of the named glycerol ethers, namely one lower (ethyl, propyl), one medium (pentyl, hexyl) and one higher (octyl, nonyl) one where the amount by weight of the lower ether is about the same as the sum of the amounts by weight of the two other glycerol ethers. The amount of water is about the same as the amount of the lower glycerol ether and is for example half ~he total amount of the glycerol ethers present.
Examples of such glycerol ether-water mixtures are listed below:

~2~2~

Water Glycerol-propyl- Glycerol-hexyl- Glycerol-nonyl-ether ether ether Parts 2 : 2 : 1 : 1 by weight Water Glycerol-ethyl- Glycerol-pentyl- Glycerol-octyl-ether ether ether Parts 2 : 2 by weight Medicaments with the alkyl glycerols of formula II are particularly suitable for topical application. In order for example to treat psoriasis and disorders related thereto, the skin areas in question are for example rubbed twice to three times daily with cascade 10 to cascade 80. No harmful side effects have been observed to date.

The mode of preparation of the compounds I (component I) in the form of the cascade (for example in the form of solutions of cascade 10 to cascade 100, in particular cascade 40 to 60) is also suitable for the preparation of suppositories for rectal insertion. Psoriasis or psoriasis disorders may be effectively treated herewith.
A particularly favourable carrier mixture for the component I
consists of a mixture of about 4 parts by weight of water, 4 ~parts by weight o* propyl glycerol and 2 parts by weight each of hexyl glycerol and nonyl glycerol.

i3 2 ~ ~

To prepare medicaments containing the component I in the presence of a glycerol ether of formula II or a mixture of glycerol ethers of this type of formula II, the component I
is for example used with lo,Ooo to 7, in particular 100 to 10, preferably 30 to 16 parts by weight (related in each case to one part by weight) o~ at least one glycerol ether of formula II or a mixture of glycerol ethers of this type as well as optionally 7,700 to 0.05, in particular 400 to 2, preferably 20 to 3 parts by weight of water (also related to one part by weight of component I, that is in each case the total amount of the compounds I)o This mixing with the glycerol ethers may be carried out at the beginning of the preparation of the corresponding medicament, but optionally also at a later stage in the preparation.
Examples:

Example 1 (solution for topical use) Hexadecylphosphocholine solution is prepared by dissolving hexadecylphosphocholine in a solvent referred to as cascade 0.

Preparation of cascade 0 1000 g of water, 1000 g of glycerol-l-n~propyl ether, 500 g of glycerol-l-n-hexyl ether and 500 g of glycerol-1-n-nonyl ether are mixed in a suitable vessel.

Preparation of the solution Ca. 2 litres of cascade 0 are filled into a suitable vessel and 1~0 g of hexadecylphosphocholine dissolved therein with stirring. The mixture is then filled up to 3 litres with cascade 0. The density of the solution is 1.003 g/ml at 26C.

~ ~ t~

This solution is filtered under aseptic conditions in a sterile collecting vessel through a membrane filter o~ pore size 0.2 um and filled into sterile dropping bottles of 10 ml each. 1 ml of the solution contains 60 mg of hexadecylphosphocholine.

Example 2 (capsules) 50 mg Hexadecylphosphocholine hard gelatine capsules ~-250 g of hexadecylphosphocholine, 435.5 g of lactose monohydrate DAB 9, 241.5 g of microcrystalline cellulose DAB
9, 14 g of talcum DAB 9, 7 g of highly disperse silicon dioxide DAB 9 and 2 g of magnesium stearate DAB 9 are passed through a sieve of mesh size 0.8 mm and then homogenized in a suitable mixer ~or 30 mins.
This capsule mass is filled in 190 mg batches into size 2 hard gelatine two-piece capsules in a capsule filling machine.
1 capsule contains 50 mg of hexadecylphosphocholine.

Example 3 (tablets3 100 mg hexadecylphosphocholine tablets 300 g o~ hexadecylphosphocholine and 600 g of lactose monohydrate DAB 9 are passed through a 0,8 mm sieve, mixed in a fluidized air bed granulating unit and granulated with 180 g of a 10% gelatine solution.
The fluidized air bed granulate, 82.8 g of microcrystalline cellulose DAB 9, 120 g of corn starch, 16.8 g of talcum and 2.4 g of magnesium stearate are passed through a sieve of 0.8 mm mesh size. This tablet mass is pressed into tablets weighing 380 mg and having a diameter of 10 mm using an appropriate tablet press.

f~

1 tablet contains 100 mg of hexadecylphosphocholine.

An example of the method of application used for the compounds according to the present invention will now be given.

The effect was tested in the course of ambulatory treatment of six subjects suffering from psoriasis vulgaris. These subjects had inflamed skin, encrustations on the skin, scaley skin (over the whole body). Treatment consisted of topical application of a 6-~ solution of hexadecylphosphocholin in a mixture of water, glycerine propylether, glycerin hexylether and glycerine nonylether in a proportion of 2~ 2 (parts by weight). One ml of the above glycerine-ether-water mixture thus contains 60 mg of the hexadecylphosphocholin (Kascade 60) This solution was applied twice daily (morning and evening) for a week. Application was in drops applied to the affected areas of skin, which were massaged in ueing very light pressure (with a finger stall or glove of polyvinylchloride (PVC)). After one week, in all the patients, the scaling on the lesions had improved and the thickness of the lesions had been reduced.

,

Claims

1. The use of compounds of the general formula R - Y - PO2?- X - R1 I

or a physiologically acceptable salt thereof where in formula I R represents a saturated or unsaturated hydrocarbon radical with 12 to 24 carbon atoms which may also be halogen substituted or where R represents the group -CH2-CHR3-CH2-Z-R4 and R3 is a C1-C6-alkoxy group or a C1-C6 alkoxymethyl group, Z represents oxygen or sulphur and R4 represents a C1-C24-alkyl radical, X is an oxygen atom, NH or NR2 and Y is an oxygen atom or NH, R1 is a C1-C8-alkyl group, or where R1 represents a C2-C8-alkyl group, which is unsaturated and/or substituted by halogen, amino, C1-C6-alkyl amino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl, and where R1 may also represent 2-tert.-butyloxycarbonylaminoethyl, 2-tert.-butyloxycarbonylethyl, 2,3-isopropylidendioxy-propyl-(1),

2,3-dibenzyloxy-propyl-(1), 1,3-dibenzyloxy-propyl-(2) or N-C1-C6-alkylamino-C2-C6-alkyl when X is an oxygen atom and where R1 may also represent 2,3-dihydroxypropyl-(1) when X is the NH group, and R2 represents a 2,3-dihydroxypropyl-(1)-group, a C1-C8-alkyl group or a C2-C8-alkyl group which is unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl; for the preparation of a medicament for combatting psoriasis disorders.

2. An agent for the topical treatment of psoriasis disorders containing as active substance at least one compound of the general formula or a physiologically acceptable salt thereof, where in formula I R represents a saturated or unsaturated hydrocarbon radical with 12 to 24 carbon atoms which may also be halogen substituted, or where R represents the group -CH2-CHR3-CH2-Z-R4 and R3 is a C1-C6-alkoxy group or a C1-C6-alkoxymethyl group, Z represents oxygen or sulphur and R4 represents a C1-C24-alkyl radical, X is an oxygen atom, NH or NR2 and Y an oxygen atom or NH, R1 is a C1-C8-alkyl group or where R1 represents a C2-C8-alkyl group which is unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl, and where R1 may also represent 2-tert.-butyloxycarbonylaminoethyl, 2-tert.-butyloxycarbonyl ethyl, 2,3-isopropylidendioxy-propyl-(1), 2,3-dibenzyloxy-propyl-(1), 1,3-dibenzyloxy-propyl-(2) or N-C1-C6-alkylamino-C2-C6-alkyl, when X is an oxygen atom, and where R1 may also represent 2,3-dihydroxypropyl-(1) when X is the NH group, and R2 represents a 2,3-dihydroxypropyl-(1)-group, a C1-C8-alkyl group or a C2-C8-alkyl group which is unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl.

3. An agent according to claim 2, containing conventional pharmaceutical carriers, auxiliary agents and/or diluents.

4. An agent according to claims 2 or 3, further containing an alkyl glycerol of the general formula II

where one of the radicals R5 and R6 in formula II represents an alkyl group with 2 to 12 carbon atoms and the other radical represents a hydrogen atom as well as optionally other conventional pharmaceutical carriers, additives and/or diluents.

5. A process for the preparation of a medicament for combatting psoriasis disorders wherein at least one compound of the general formula or a physiologically acceptable salt thereof, where in formula I R represents a saturated or unsaturated hydrocarbon radical with 12 to 24 carbon atoms which may also be halogen substituted, or where R represents the group -CH2-CHR3-CH2-Z-R4 and R3 is a C1-C6-alkoxy group or a C1-C6-alkoxymethyl group, Z represents oxygen or sulphur and R4 represents a C1-C24-alkyl radical, X is an oxygen atom, NH or NR2 and Y is an oxygen atom or NH, R1 is a C1-C8-alkyl group, or where R1 represents a C2-C8-alkyl group which may be unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxy, C3-C8-cycloalkyl or phenyl, and where R1 may also represent 2-tert.-butyloxycarbonylaminoethyl, 2-tert.-butyloxycarbonylethyl, 2,3-isopropylidendioxy-propyl-(1), 2,3-dibenzyloxy- propyl-(1), 1,3-dibenzyloxy-propyl-(2) or N-C1-C6-alkylamino-C2-C6-alkyl when X is an oxygen atom, and where R1 may also represent 2,3-dihydroxypropyl-(1) when X is the NH group, and R2 is a 2,3-dihydroxypropyl-(1)-group, a C1-C8-alkyl group or a C2-C8-alkyl group which is unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxy, carboxyl, C3-C8-cycloalkyl or phenyl is processed with conventional pharmaceutical carriers, auxiliary and/or diluting agents to form a medicament for the treatment of psoriasis disorders.

6. A process for the preparation of a medicament according to claim 5, wherein during preparation is added an alkyl glycerol of formula II

in which one of the radicals R5 and R6 represents an alkyl group with 2 to 12 carbon atoms and the other radical represents a hydrogen atom, or a mixture of alkyl glycerols of this type as well as optionally water, using 10,000 to 7 parts by weight of alkyl glycerol of formula II or an appropriate alkyl glycerol mixture and optionally 7,700 to 0.05 parts by weight of water, in each case related to one part by weight of component I.