CH683920A5 - New alpha-lipoic acid ester(s) with antitumour and bio-surfactant activity - formulated as spontaneously dispersible concentrate with other surfactants, opt. contg. pharmaceutical or cosmetic active ingredients - Google Patents

Abstract

Lipoic acid esters of formula (I) are new. Where, R1 = borneyl (endo-(1R or 1S)-1,7,7- trimethylbicyclo (2,2,1)heptan-2-yl); citronellyl; farnesyl; geranyl; menthyl ((1R,2S,5R or 1R,2S,5S)-2- isopropyl-5-methyl-cyclohexyl); myrtenyl; (iso)phytyl; thymyl or one of the gps. (II)=(VI); (dotted lines all single or all double; R2-R4=H or Me. Also new are spontaneously dispersible concentrates contg. (I). USE/ADVANTAGE - (I) have antitumour and biosurfactant activities, i.e. they can be used to prepare dispersible concentrates contg. pharmaceutical and cosmetic active ingredients. (I) are better co-surfactants for concentrate prepn. then known cpds. The concentrates when mixed with water form microemulsions of excellent phase stability and good permeation and spreading properties. They form micelles of radius 1.2-2.4 mm which penetrate the plasma membrane of tumour cells easily by a diffusion process independent of cellular metabolism.

Description

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description

The present invention relates to antitumor and biosurfactant esters of DL-a-lipoic acid {1,2-dithio-ian-3-pentanoic acid; 6,8-dithiooctanoic acid; DL-6,8-thioctic acid, 8- [3- (1,2-dithiacyclopentyl)] pentanoic acid}; Processes for their manufacture; spontaneously dispersible concentrates containing such esters, and a therapeutic system preparation as an agent for the treatment of tumors, which contains spontaneously dispersible concentrates with active pharmaceutical ingredients.

In German laid-open publication No. 4 000 397 A1, the cholesteryl and Paimitoylester of DL-a-lipoic acid are described as lipid-selective antioxidants. In contrast, it has now surprisingly been found that the newly synthesized esters of DL-a-lipoic acid have a very good antitumor effect, especially when they have been incorporated into spontaneously dispersible concentrates.

In addition, it was found that the esters of DL-a-lipoic acid with special alcohols are significantly better than cosurfactants for the production of spontaneously dispersible agents with pharmaceutical and cosmetic active ingredients than the compounds hitherto usually used for this purpose.

The new antitumor and bio-surfactant esters of DL-a-lipoic acid with vitamin D and vitamin E compounds, as well as with ergosterol and with special alcohols correspond to the general formula in which Ri

Borneyl [endo- (1 R) -1,7,7, -trimethyl-bicyclo [2,2,1] heptan-2-yl]

Borneyl [endo- (1S) -1,7,7, -trimethyl-bicyclo [2,2,1] heptan-2-yl]

Citroneiiyl [3,7-dimethyl-6-octenyl-1yl; ß-rhodinyi; 2,3-dihydrogeranyl]

Farnesyl [3,7,11-trimethyl-2,6,10-dodecatrien-1yl]

Geranyl [(E) -3,7-dimethyi-2,6-octadien-1yl]

Menthyl [(1 R, 2S, 5R) -2-isopropyl-5-methylcyclohexanyi]

Menthyl [(1R, 2S, 5S) -2-isopropyl-5-methyl-cyclohexanyl]

Myrteny {(1 R) -6,6-dimethy! Bicyclo [3.1.1] hept-2-en-2-methanyi; (1 R) -2-pinene-10-yl} phytyl [3,7,11,15-tetramethyl-2-hexadecen-1 yl]

isophytyl [3,7,11,15-tetramethyl-1-hexadecen-1 yl]

Thymyl [2-isopropyl-5-methylphenyl]

s — s

(I)

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CH 683 920 A5

means or represents one of the radicals of the formulas (II) to (VIII):

* 4

(H)

* 4

(hd

(IV) (V)

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CH 683 920 A5

(VI) (VII)

(VII!)

wherein in formulas (II) and (III) R2, R3 and R4 denote hydrogen or methyl. Vitamin D compounds are understood to mean the following compounds: cholecalciferol: (5Z, 7E) - (3S) -9.10-seco-5.7,7.10 (19) -cholestatrien-3-oi 25-hydroxychoIecaiciferol [calcidiol] : (5Z, 7E) - (3S) -9,10-seco-5,7,10 (19) -cholestatrien-3,25-dioi 1a-dihydroxy-cholecalciferol [calcitriol]:

(5Z, 7E) - (1 S, 3R) -9,10-seco-5,7,10 (19) -cholestatrien-1,3,25-triol Ergocalciferol [CaIciol]:

(5Z, 7E, 22E) - (3S) -9,10-seco-5,7,10 (19), 22-ergostatetraen-3-ol

Tachysterol: (6E) - (3S) -9,10-seco-5, (10) -6,8-choiestatrien-3-ol

Dihydrotachysterol: (5E, 7E) - (3S, 10S) -9,10-seco-5,7-cholestatrien-3-ol

All Tocoi and Tocotrienol compounds, such as:

Tocol [2-methyl-2 (4,8,12-trimethyitridecyl) chroman-6-ol]

a-tocopherol [5,7,8-trimethyltocol],

which can be in the following configurations:

12,12,12-a-tocopherol

2-epi-a-tocopherol

2-ambo-a-tocopherol all-rac-a-tocopherol

4-ambo-8-ambo-a-tocopheroi

ß-tocopheroi [5,8-dimethyltocol]

Y-tocopherol [7,8-dimethyitocol]

8-tocopherol [8-methyltocol]

Tocotrienol [2-methyl-2- (4,8,12-trimethyldeca-3,7,11-trianyl) chroman-6-ol]

pi- or p2-tocophero! [5,7,8-trimethyitocotrienol] and e-tocopherol [5,8-dimethyltocotrienol or e-tocotrienol]

to understand.

Examples of novel esters of the formula (I) according to the invention include:

DL-a-lipoic acid borney ester

DL-a-lipoic acid citroneliester

DL-a-lipoic acid farnesyl ester

DL-a-lipoic acid geranyl ester

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DL-a-lipoic acid menthyl ester

DL-a-lipoic acid myrtenyl ester

DL-a-lipoic acid phytylester

DL-a-lipoic acid isophyte ester

DL-a-lipoic acid thymate

DL-a-lipoic acid 2-methyl-2 (4,8,12-trimethyltridecyl) chroman-6yl ester

DL-a-lipoic acid cholecalciferylester

DL-a-Lipoic Acid Ergocalciferylester DL-a-Lipoic Acid Ergosterylester

The new esters of the formula (I) can generally be prepared by the following, known processes:

a) Reaction of the DL-a-lipoic acid with N, N'-carbonyl-diimidazole or dicyclohexylcarbodiimide at 20 to 70 ° C in an indifferent solvent, such as e.g. Tetrahydrofuran, benzene, toluene or chloroform and subsequent alcoholysis of the intermediate products formed - with the addition of an alcoholate in a catalytic amount - with borneol, citronelloi, farnesol, geraniol, menthol, myrtenol, phytol, isophytol, thymol, and with a vitamin D or vitamin -E compound or with ergosterol.

b) formation of the chloride or the bromide of DL-a-lipoic acid with a chlorination or bromination agent such as e.g. Thionyl chloride, oxalyl chloride or oxalyl bromide and subsequent reaction of the resulting chlorides or bromides with borneol, citronelloi, farnesol, geraniol, menthol, myrtenol, phytol, isophytol, thymol, as well as with a vitamin D or vitamin E compound or with ergosterol at a temperature of 40 to 120 ° C in an inert solvent, such as Tetrahydrofuran, benzene, toluene or chloroform and in the presence of a catalyst such as e.g. Dimethylformamide.

The new esters of formula (I) surprisingly have an excellent antitumor effect, especially when they have been incorporated into spontaneously dispersible concentrates in accordance with the invention.

The present invention therefore also relates to spontaneously dispersible concentrates with the new esters of the formula (I). Such concentrates, when mixed with water, result in microemulsions with excellent phase stability and an extremely high permeation and spreading capacity. Control measurements carried out at the Institute for Polymers / Supermolecular Chemistry at E.T.H., Zurich, have shown that the hydrodynamic radii for the micelles that form are around 1.2-2.4 nm. (Prof. Dr. Pier Luigi LUISI and Prof. Dr. Peter SCHURTENBERGER).

All experimental observations on ultramicroemulsions designed in this way can be interpreted uniformly by the assumption that the selected surfactants and cosurfactants, taken as a balanced system, form organized aggregates, so-called micelles, in the aqueous phase. They have a more or less spherical shape, with a hydrodynamic radius of 1.2 to 3 nm. The surfactants and hydrotropes (cosurfactants) leave between the outer, aqueous phase and the inner, oily phase of the microemulsion [containing the lipoic acid esters of the formula (I) dissolved in the biosensitive solubilizer], an interface is formed, which means that these two phases are not mixed. In the oily inner phase, the molecules of the lipoic acid esters are in monomeric or in oligomeric agglomerated form.

The micelles of the inner phase containing lipoic acid esters of the ultramicroemulsions according to the invention are protected at the boundary layer with a surfactant coat, which makes them easy to diffuse through the cell membrane into the interior of the tumor cell. The diffusion through the plasma membrane of tumor cells occurs exclusively due to thermal molecular movements.

The direction that a specific diffusion process takes is determined by the difference in concentration that exists on the plasma membrane between outside and inside the tumor cell. The diffusion continues along the concentration gradient until it is broken down. Between the extracellular zone and the interior of the individual tumor cell, the concentration of active substance or of the active substance system (“multiple drug system”) is balanced, whereby delayed release effects (“slow release effects”) can also occur. Such diffusion processes take place independently of any energy supply. They have no relation to cellular metabolic energy.

The diffusion rate obeys Fick's law for diffusion processes in the direction of a concentration gradient:

where dm is the amount in moles of the active substance molecules penetrating a cell membrane surface q (in cm2) per time dt (in seconds). D is the diffusion coefficient and de is the concentration difference over the distance dx.

dm 1

EQUATION (A)

dt q

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According to Nernst, the diffusion coefficient depends on the absolute temperature and the frictional resistance f

R T kT

D = - - = EQUATION (B)

N f f

The frictional resistance depends on Stoke's law f = 6 n n r EQUALIZATION (C)

on the viscosity of the diffusing solution and on the radius of the diffusing particles. Substituting f with 6 k ti r in the Nernst equation gives the Sutherland-Einstein equation for the diffusion coefficient

RT 1 kT

D = - = EQUATION (D)

N 6 ic r] r 6 jt ri r where k is the Boltzmann constant.

If there is a uniform drop in concentration in the membrane of the

dc A c mor cell assumed, the expression in the diffusion law can be replaced by

dx x den. (Concentration difference ac over the cell membrane of thickness x). x is a constant size for a certain cell membrane, which is why it can be combined with the diffusion coefficient to form a new constant, the permeability coefficient P.

D

P = - EQUATION (E)

X

dm 1

The expression - in the diffusion equation, the flux is called J and has the di-

dt q dimension moles per second per cm2. The negative sign on the right side of the diffusion equation indicates that the transport of the active substance molecules or the active substance system takes place in the direction of the decreasing concentration. So it is

RT 1 4 kT 1

J = -FAc = ——— Ac = - —Ac

Nx 6 7t tj r x 6 tc ti r

EQUATION (F)

It follows from this equation that the speed of the diffusion process or the strength of the active substance transport through the membrane of the tumor cell is determined:. 1. of the difference in concentration ac in the two compartments. 2. of the particle radius of the diffusing drug molecule or drug system. 3. the viscosity of the diffusing aqueous solution (emulsion)

. 4. on the temperature.

The concentrates which are spontaneously dispersible according to the invention contain:

0.001 to 25% by weight of individual DL-a-lipoic acid esters of the formula (I), or combinations of such esters, and

0.1 to 40% by weight of a pharmaceutically acceptable solvent or solvent mixture serving as a hydrotrope or co-emulsifier

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0.1 to 90% by weight of a pharmaceutically compatible surfactant or surfactant mixture 0 to 10% by weight of a vitamin or provitamin

0 to 10% by weight of a free fatty or fruit acid or an amino acid and pharmaceutically approved carriers and / or diluents.

In addition, the esters of formula (I) with special alcohols, such as the Borneyl, Citronel-lyl, Farnesyl, Geranyl, Menthyl, Myrtenyl, Phytyl, Isophytylester and Thymylester of DL-a-Lipoic acid also Suitable as solubilizers or cosurfactants (ie hydrotropes) for the preparation of spontaneously dispersible concentrates which contain pharmaceutical and / or cosmetic active ingredients. The present invention accordingly also relates to spontaneously dispersible concentrates of pharmaceutical and cosmetic active ingredients which contain the new biosurfactant esters of the formula (I) as solubilizers or cosurfactants (hydrotropes).

If these concentrates, which are true to the invention, are diluted with water, surprisingly, micromicells are formed spontaneously, the particle radius of which is significantly below the mass which was previously customary for such micelles.

Thanks to the small particle radius of the micromicells that form, the resulting “ultra-microemulsion” has excellent phase stability, a considerably increased permeability (“transfusion”) and very good spreading. The described properties of the microemulsions prepared from concentrates according to the invention with incorporated pharmaceutical and cosmetic active ingredients have the result that their biological mode of action is surprisingly significantly increased.

The concentrates which are spontaneously dispersible according to the invention contain:

0.001 to 30% by weight of one or more pharmaceutical or cosmetic active ingredients 0.001 to 50% by weight of an ester of formula (I) according to the invention, or combinations of such esters, as solubilizers, or hydrotrope

0.001 to 90% by weight of a pharmaceutically compatible surfactant or surfactant mixture 0 to 10% by weight of a vitamin or provitamin

0 to 10% by weight of a free fatty or fruit acid or an amino acid and optionally conventional carriers and / or diluents.

In the present case, pharmaceutical active ingredients are to be understood as all active ingredients that can normally be used in human medicine. These include, for example:

Beta blocker

Pindolol [1- (4-indolyloxy) -3-isopropylamino-2-propanol]

Propanolol [1-isopropylamino-3- (1-naphthyloxy) -2-propanol] oxprenolol [1- (o-allyloxyphenoxy) -3-isopropylamino-2-propanol]

Metoprolol [di - {(+ -) - 1 - (isopropylamino) -3- [p- {2-methoxyethyl) phenoxy-2-propanol] -L (+) tartrate}] labetalol [5- [1-hydroxy-2 {(1-methyl-3-phenylpropylaminoethyl} salicylamide]

Diuretic

Acetazolamide [5-acetamido-1,3,4-thiadiazo! -2-sulfonamide]

Hydrochlorothiazide [6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide]

Chlorotalidone [1-oxo-3- (3-sulfamyl-4-chlorophenyl) -3-hydroxyisoindoline]

Metolazone [7-chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-o-tolyl-6-quinazoline sulfonamide]

Weak sedatives

Diazepam [7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one] medazepan [7-chloro-2,3-dihydro-1-methyl-5- phenyl-2H-1,4-benzodiazepin-2-one]

Strong sedative

Sulpiride [N- (1-ethyl-2-pyrrolidinyl-methyl) -2-methoxy-5-suifamoylbenzamide]

Muscle relaxant

Baclofen [ß- (Aminoaethyl) -p-chlorohydrocinnamic acid]

Antibiotics

Sulfamethoxazole [5-methyl-3-sulfanilamido-isoxazole] trimethoprim [2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine] chloramphenicol [D (-) - threo-2-dichloroacetamido-1 - (4-nitrophenyl) -1,3-propanediol] cefaclor [3-chloro-7-D (2-phenyl-glycinamido) cephalosporanic acid monohydrate]

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Cefradin [7- {D-2-amino-2- (1,4-cyclohexadien-1-yl) acetamido} -3-methyl-cephalosporar) acid]

Bacampicillin [1-ethoxycarbonyloxyethyl 6- (D-a-aminophenylacetate-amido) penicillinate]

Minocycline [7-diethylamino-6-deoxy-6-desmethyltetracycline]

Sulfadoxin [N '- (5,6-Dimethoxy-4-pyrimidinyl) sulfaniamide]

Sulfamethoxazole [3-methyl-3-suifanil-amido-isoxazole]

SulfisoxazoI [3,4-dimethyl-5-sulfanil-amido-isoxazoI]

Sulfadimethoxin [2,4-dimethoxy-6-sulfanilamido-1,3, diazine]

Dermatologica

Chloroquinaldol [5,7-dichior-8-hydroxy-chinaIdin]

Crotamiton [N-Crotonyl-N-ethyI-o-toIuidin]

Diamthazole [6 (-) 2-dimethylamino-ethoxy- (ß-diaethylamino-) benzothiazole dihydrochloride] flumethasone pivalate [6a, 9-difluoro-11ß, 17,21-trihydroxy-16a-methyl-pregna-1 , 4-diene-3.20, dione-21 pivalate] T retinoin [vitamin A acid]

Corticosteroids

Cortisone [17a-21, dihydroxy-pregn-4-en-3,11,20-triene-21-acetate] prednisone [11ß-17,21-trihydroxy-pregna-1,4-diene-3,20-dione] Dexamethasone [9-fluoro-11ß, 17,21-dihydroxy-16cx-methyl-pregna-1,4-diene-3,20-dione] deoxycortone acetate [21-hydroxy-pregn-4-en-3.20- dione acetate]

Coronary

Pentaerythrityitetranitrate (PETN)

Nitroglycerin (glyceryl trinitrate)

Pindolol [1- (4-indolyloxy-3-isopropylamino-2-propanoI]

Cytostatica

Melphalan [p-di- (2-chloroethyi) amino-L-phenylalanine] procarbazine [p- (N'-methyl-hydrazinomethyi) -N-isopropyl-benzamide]

Dactinomycin [actinomycin D]

Polyestradiol phosphate

Cyciophosphamide [N, N-bis (ß-chloroethyl) amino-1-oxa-3-aza-2-phosphocyciohexane-2-oxide] Anti-inflammatory agents Mefenamic acid [3-xylyl-2-aminobenzoic acid]

Dexamethasone [9-fluoro-11β, 17,21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione] hydrocortisone [17a-hydrocorticosterone]

Coronary dilators

Nifedipine [1,4-dihydro-2,6-dimethyl-4- (o-nitrophenyl) pyridine-3,5-dicarboxylic acid dimethyl ester] isosorbide dinitrate [1,4; 3,6-dianhydrosorbitol-2,5- dinitrate]

Nitroglycerin (glyceryi trinitrate)

DipyramidoI [2,6-bis- (diethanoiamino) -4,8-dipiperidino (5,4-dipyrimidine)]

Peripheral vasodilators

Cinepazide [4 - (- 3,4,5-trimethoxy-cinnamoyl) -1-piperazineacetic acid pyrroiidide] cyclandelate [3,3,5-trimethyl-cyclohexyimandelate] cinnazarin [1-trans-cinnamyl-4-diphenylmethyl-piperazine] pentoxyfyliine [3,7-dimethyl-1- (5-oxo-hexyi) xanthine]

Antirythmic

Procainamide [4-aminobenzoic acid-ß-diethylaminoethyliamide] disopyramide [4-diisopropylamino-2-phenyl-2- (2-pyridyl) -butyramide]

Anti-gout agent

Aliopurinol [1H-pyrazoio- (3,4-d) pyrimidin-4-oi]

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Antiepileptics

Phenytoin {diphenylhydantoin}; [5,5-diphenyl-2,4-imidazolidinedione] carbamazepine [5-carbamoyl-5H-dibenz (b, f) azepine]

Antihistamines

Chlorophenamine [{3- (p-chlorophenyl) -3- (2-pyridyl) propyldimethylamine]

Clemastine {hydrogen fumarate}; [1-Methyl-2- {2- (a-methyl-p-chloro-di-phenylmethoxy) ethyl} pyrrolidine] mequitazine [10- (3-quinuclidinylmethyl) phenothiazine] alimemazine [10- (3-dimethylamino-2-methyl -propyi) -phenothiazine]

Anti-nausea and dizziness medication

Domperidone [5-chloro-1- {1- (3- [2-oxo-1-benzimidazolinyl] propyl) -4-piperidyl} 2-benzimidazolinone] betahistine [2- {2-methylaminoethyl} pyridine]

Metoclopramide [4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxy-benz-amide]

Antihypertensive agents

Reserpine [3,4,5-trimethoxybenzoyl-methylreserpat]

Rescinnamine [3,4,5-trimethoxy-methylreserpat]

Methyldopa {L-a-methyopa}; [L-3- (3,4-dihydroxyphenyl) -2-methyl-alanine] ciomidine hydrochloride [2,6-dichloro-N-2-imidazoidinylidene-benzamine hydrochloride]

Sympathomimetica

Isoprotereno! [N-isopropyl-nor-adrenaline]

Etilefrin [DL-1- {a-ethylaminomethyl} m-hydroxy-benzyl alcohol]

Expectorants

Carbocysteine [(S-carboxymethyl) cysteine]

Bromhexine [N-Cyclohexyl-N-methyl- (2-amino-3,5-dibromo-benzyl) amine HCL]

L-ethyl cysteine

L-methylcysteine

Oral antidiabetics

Glibenclamide [N-4-2- (5-chloro-2-methoxybenzamido) ethylphenylsulfonyl-N'-cyclohexylurea] tolbutamide [N- (4-tolylsulfonyl) -N'-n-butyl- urea]

Cardiovascular agents

Ubidecarenone

Adenosine [6-amino-9-ß-D-ribo-furanosyl-9H-purine]

Immunosuppressant ciclosporin

The new biosurfactant esters of the formula (I) are preferably suitable as solubilizers or cosurfactants (hydrotropes) for the production of spontaneously dispersible concentrates of the following antitumor agents:

Ergosta-5,7-dien-3-ol-9-hexadecenoate

(Ergosta 5,7-dienyl palmitoelate)

Ergosta-8,22-diene-3-OI14-methyl-4,9-octadecenoate

(14a-methylergosta-8,22-dienyl oleate)

Lanost-8-en-3-ol-9-octadecenoate

(Dihydrolanosterol oleate)

Ergost-5-en-3-ol-9,12,15-octadecatrienoate

(Dihydrobrassicasteryi linolenate)

Ergost-5-en-3-ol-9,12-octadecadienoate

Ergost-5-en-3-ol-9-octadecenoate

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(Dihydrobrassicasteryl olaet)

Ergosta 7,24 (28) dien-3-ol-4-methyl-9-octadecenoate

(Gramisteryl oleate)

Stigmasta-8.24 (28) -dien-3-ol-9.12-octadecadienoate (A7-Avenasteryl-linoleate)

Ergosta 7,24 (28) -dien-3-ol-4-methyl-9,12-octadecadienoate (gramisteryl linoleate)

Stigmast-24 (28) -en3-oi-9,12-octadecadienoate

Ergosta-5,22-dien-3-ol-4,23-dimethyi-9-octadecenoate

Ergostan-3-ol-4-methyl-9-octadecenoate

5a-stigmastan-3-ß-ol linolenate

5a-stigmastane-3-ß-oi-oleate

Stigmastan-3-ol-9,12-octadecadienoate

(5a-stigmastane-3-ß-oi-iinoleate)

22-dihydrospinasteryl iinoleate

Ergosta-5,7,22-trien-3-oi-9,12-octa-decadienoate

(Ergosteroi Linoieat)

Stigmasta 5.24 (28) dien-3-ol 9-octadecenoate

Stigmasta-5.24 (28) -3-ol-9.12-octadecadienoate

Stigmasta-5-en-3-ol-5,8,11,14-eicosatetraenoate

(ß-sitosterol arachidonate)

Ergost-5-en-3-ol-5,8,11,14-eicosatetraenoate

Stigmasta 7.24 (28) -dien-ol-4-methyl-9.12-octadecadienoate

Cholest-5-en-3-oi (3ß) -9-hexadecenoate

(Choiesteryi-trans-9-hexadecenoate)

Ergost-7-en-3-oi-9,12,15-octadecatrienoate

Ergost-5-en-3-oi-9,12,15-octadecatrienoate

(Campesteryl iinolenate)

Ergostan-3-ol-9,12-octaoctadecadienoat

Choiest-7-en-3-oi-9.12-octaoctadecadienoat

Ergosta-5,24- (28) -diene-3-oi-9-hexadecenoate

Choiestan-3-oi-9-hexadecenoate

Ergosta-5,22-dien-3-oi-octadecenoate

(Brassicasteryl oleate)

Cholest-7-en-3-ol-9-octadecenoate

(Lathosteryi-oieat)

Lanosta-8,24-dien-3-ol-9-octadecenoate (Lanosteroi-oieat)

Stigmasta-5.24 (28) -dien-3-ol-9-octadecenoate (Fucosteryi-oieat)

Cholesta-5,22-dien-3-ol-9-octadecenoate

(Desmosteryl oleate)

Ergost-5-en-3-ol-12-octadecadienoate

(Campesteryl iinoelate)

Ergosta-5,22-dien-3-ol-9-octadecenoate

Ergost-22-en-3-oi-9-hexadecenoate

Choiesta 5,22-diene-3-oi-9-hexadecenoate

Ergosta-5,22-dien-3-ol-9,12-octadecadienoate

(Brassicasteryi-iinoleat)

Ergosta-7.24 (2ß) -diene-3-oi-9.12-octadecadienoate stigmasta-5.22-dien-3-ol-9.12.15-octadecatrienoate (stigmasteryl linolenate)

Stigmasta-5,22-dien-3-ol-9,12-octadecadienoat (Stigmasteryi-linoleat)

Choiest-5-en-3-ol- (3ß) -5,8,11,14-eicosatetraenoate

Cholest-5-en-3-ol- (3ß) -4,7,10,13,16,19-docosahexaenoate

Cholest-5-en-3-ol- (3β) -9,12-octadecadienoate

Cholesta-8, (14), 24, dien-3-ol-9-octadecenoate

(Zymosteryl oleate)

Ergost-5-en-3-ol-9-octadecenoate

(Campesteryl oleate)

Cholest-5,7,9 (11) -trien-3-ol-9-octadecenoate (Cholesta-5,7,9 (11) -trien-3ß-yl-oleate) Ergosta-5,7,22-triene- 3-ol-9-hexadecenoate (ergosteryl-9-hexadecenoate)

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CH 683 920 A5

Cholest-5-en-3-ol- (3ß) -11-octadecenoate (Cholesteryl I-11-octadecenoate) Cholest-5-en-3-ol- (3ß) -9,12-octadecadienoate (Cholesteryl-9,12- octadecadienoate) cholest-5-en-3-ol- (3ß) -9-octadecenoate (cholesterol-elaidate) 5a-stigmasta-7,22-dien-3ß-ol-oleate (a-spinasterol-oleate) cholest-5- en-3-ol- (3ß) -9-hexadecenoate (cholesterol palmitoleate) cholestan-3-ol-9,12,15-octadecatrienoate (cholestanol linolenate)

Cholest-5-en-3-ol- (3ß) -11-octadecenoate (Choiesteroi-11-octadecenoate) Cholesta-5,7-dien-3-ol-9-octadecenoate Cholesta-5,7-dien- (3ß) -ol-linoleate (Choiecaiciferon-linoleate; Cholecaiciol-linoleate)

Ergosta-5,7,22-trien-3-oi-9-octadecenoate (Ergosterol-oieat)

Stigmast-5-en-3-oi-9-octadecenoat (ß-Sistosteroi-oieat)

Stigmast-5-en-3-ol-9,12-octadecadienoate (ß-sistosterol linoleate)

Stigmast-5-en-3-ol-9,12,15-octadecatrienoate (ß-Sistosteroi-linolenat)

Cholest-5-en-3-ol- (3β) -9,12,15-octadecatrienoate

(Cholesteryl linienate)

Cholestan-3-ol-9-octadecenoate

(Choiestanoi oleate)

Cholestan-3-ol-9,12-octadecadienoate

(Cholestanol iinoate)

Cholest-5-en-3-ol- (3β) -9-hexadecenoate

(Cholesterol-9-hexadecenoate)

Cholest-5-en-3-oi (3ß) -5,8,11,14-eicosatetraenoate

(Cholesterol arachidonate)

Cholest-5-en-3-ol- (3β) -9,12-octadecadienoate

(Cholesterol linoleate)

Choiest 5-en-3-oi (3ß) -9-octadecenoate

(Cholesterol oieate)

β-sitosterol undecenoate

ß-Sitosteroi-lau roylat

ß-Sitosterol-pal mitât

Stigmasterol undecenoate

Stigmasteroi-Iaurat

Stigmasterol palmitate y-sitostanoi oleate v-sitostanol linoieate

7-Sitostanol-iinoienat rSitosteroi-oieat

Cholest-5-en-3a-ol oleate

5-a-stigmastan-3ß-ol-oleate

5-a-stigmastan-3ß-ol-iinoienate

Choiesta-5,7-diene-3β-ol linoleate

Cholecalciferol linolenate (Cholecaiciol linoleate)

10-a-Ergosta-5,7,22-triene-3ß-ol-linoleate

Stigmast 5-en-3-ol dodecenoate

(ß-sitosterol-2-dodecenoate)

Ergost-5-en-3-ol-dodecenoate

(Campesteryl-10-dodecenoate)

Cholest-7-en-3-ol dodecenoate

Stigmasta-5,22-dien-3-ol dodecenoate

(Stigmasterol-2-dodecenoate)

ySitosterol dodecenoate

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Cholest-5-en-3-oi-10-undecenoate Cholest-5-en-3-ol-2-dodecenoate 5-cholestan-3ß-ol-2-dodecenoate Ergosta-5,7,22-trien-3-ol -all-trans-retinate Ergosta-5,7,22-trien-3-ol-13-cis-retinate Cholest-5-en-13-cis-retinate Stigmast-5-en-3-ol-all-trans- retinate (ß-sitosterol-ali-trans-retinate)

Stigmast-5-en-3-oi-13-cis-retinate (ß-sitosterol-13-cis-retinate)

Stigmast-5-en-3-ol-azafrinate Stigmasta-5,22-dien-3-ol-al! -Trans-retinate (Stigmasteroi-ali-trans-retinate) Stigmasta-5,22-dien-3-oI- 13-cis-retinate (Stigmasterol-13-cis-retinate) Stigmasta-5,22-dien-3-ol-arachidonate Stigmasta-5,22-dien-3-oi-azafrinate

Stigmasta-5,22-dien-3-oi-1,2-dipaimitoyi-glycerophosphatide Stigmasta-5,22-dien-3-ol-1,2-dipalmitoyl-glycero-thiophosphatide Ergosta-5,7,22- trien-3-ol-1,2-dipaimitoyi-glycerophosphatide

Ergosta-5,7,22-trien-3-oi-crotonate Ergosta-5,7,22-trien-3-oi-caproyiat Ergosta-5,7,22-trien-3-oi-10-undecenoate Ergosta-5 , 7,22-trien-3-oi-2-trans-dodecenoate Ergosta-5,7,22-trien-3-ol-paimitat Ergosta-5,7,22-trien-3-ol-oleate Ergosta-5, 7.22-triene-3-oi-iinoieat Ergosta-5,7,22-triene-3-oi-iinolenate Ergosta-5,7,22-triene-3-oi-arachidonate Ergosta-5,7,22-triene -3-oi-azafrinate

β-oestradiol-3,17-di-all trans-retinate β-oestradiol-3-benzoate-17-retinate

Cholecalciferoi-caproylat Ergocaiciferoi-caproylat ChoiecaIciferoi-10-undecenoyiat Ergocalciferol-10-undecenoylat Cholecalciferoi-iaurat Ergocalciferoi-iaurat Choiecalciferol-paimitat Ergocalciferol-pal

Choiecalciferoi-linoieat Ergocalciferoi-linoleate Cholecalciferol-linolenate Ergocaiciferol-linolenate Cholecalciferol-all trans-retinate Ergocalciferol-all trans-retinate

Cholecalciferol-3-ol-1,2, -dipalmitoylglycerophosphatide

Cholecalciferol-3-ol-1,2, -dipalmitoylglycero-thiophosphatide

Cholecalciferol geranyl phosphatide

Cholecalciferol farnesyl phosphatide

Ergocalciferol-3-ol-1,2, -dipalmitoyl-glycerophosphatide

Ergocalciferol-3-ol-1,2, -dipalmitoyl-glycero-thiophosphatide

Ergocalciferol geranyl phosphatide

Ergocalciferol farnesyl phosphatide

DL-a-tocopherol-10-undecenoate DL-a-tocopherol palmitate DL-a-tocopherol-all trans-retinate DL-a-tocopherol-13 cis-retinate

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Malonic acid bis-stigmasteryl ester

Succinic acid bis-stigmasteryl ester

Glutaric-acid-to-stigmoid esters

Adipic acid bis-stigmasteryl ester

Pimelic acid bis-stigmasteryl ester

Suberic acid bis-stigmasteryl ester

Azelaic acid bis-stigmasteryl ester

Sebacic acid bis-stigmasteryl ester

Azelaic acid-to-β-sitosteryiester

Sebacic acid bis-ß-sitosteryl ester

Azelaic acid bis-ergosteryl ester

Sebacic acid bis-ergosteryl ester

Azelaic acid bis-cholesteryl ester

Bis-cholesteryl sebacic acid

Maleic acid bis-stigmasteryl ester

Fumaric acid bis-stigmasteryl ester

Maleic acid bis-ß-sitosteryl ester

Fumaric acid bis-ß-sitosteryl ester

Maleic acid bis-ergosterylester

Fumaric acid-to-ergosterylester

Maleic acid bis-cholesteryl ester

Fumaric acid bis-cholesterol esters

Azelaic acid calciferyl diester sebacic acid calciferyl diester Azelaic acid cholecalciferyl diester sebacic acid choleclaciferyl diester

Azelaic acid DL-a-tocopheryl diester Sebacic acid DL-a-tocopheryl diester

DL-a-lipoic acid 2-methyl-2 (4,8,12-trimethyltridecyl) chroman-6-yl ester DL-a-lipoic acid cholecalciferylester DL-a-lipoic acid ergocalciferylester DL-a-lipoic acid ergosterylester

The surfactants or surfactant mixtures to be used according to the invention can be anionic, cationic, amphoteric or non-ionic. They are best non-ionic or amphoteric and have an HLB ratio (i.e. a «hydrophilic-lipophilic balance») between 2 and 18; this value is preferably between 2 to 6 on the one hand and 10 to 15 on the other. HLB ratios provide information about the hydrophilic and lipophilic properties of an emulsifier. See “Hydrophile-Lipophiie Balance: History and recent Developments” by Paul Becher in the Journal of Dispersion Science and Technology. 5 (1), 81-96 (1984).

Suitable anionic surfactants can be both so-called water-soluble soaps and water-soluble synthetic compounds.

Suitable soaps are the alkali, alkaline earth or optionally substituted ammonium salts of higher fatty acids (Ciò to C22), such as the natural Na or K salts of oleic or stearic acid, or of natural fatty acid mixtures, which among other things Made from coconut or tallow oil. The surfactants also include the fatty acid methyl taurine salts and modified and unmodified phospholipids.

However, so-called synthetic surfactants are used more frequently, in particular fatty sulfonates, fatty sulfates, sulfonated benzimide azole derivatives or alkylarylsulfonates.

The fatty sulfonates and sulfates are generally present as alkali, alkaline earth or optionally substituted ammonium salts and generally have an alkyl radical having 8 to 22 carbon atoms, alkyl also including the alkyl part of acyl radicals. Examples of these are the Na or Ca salt of Li gninsulfoic acid, dodecylsulfuric acid ester and sulfonic acids of fatty alcohol-ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain two sulfonic acid groups and a fatty acid residue with about 8-22 carbon atoms. Alkylaryl sulfonates are e.g. the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid or a naphthalenesulfonic acid / formaldehyde condensation product.

The nonionic surfactants available are primarily the polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and aikylphenols, which contain 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon radical and

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May contain 6 to 18 carbon atoms in the alkyl radical. Also suitable as nonionic surfactants are the water-soluble polyethylene oxide adducts containing 20 to 250 ethylene glycol ether groups and 10 to 100 propylene ether groups on polypropylene glycol and alkylpolypropylene glycol with 1 to 10 carbon atoms in the alkyl chain. The compounds mentioned usually contain 1 to 5 ethylene glycol units per propylene glycol unit.

Examples of non-ionic surfactants are:

Nonylphenolpolyäthoxyäthanole, castor oil polyglycol ether, polypropylene-polyethylene oxide adducts, tri-butylphenoxy-polyethylenethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyoxyethylene sorbitan, such as polyoxyethylene sorbitan trioleate, are also suitable.

The cationic surfactants are primarily quaternary ammonium salts which contain at least one alkyl radical having 8 to 22 carbon atoms as N substituents and, as further substituents, have low, optionally halogenated alkyl, benzyl or low hydroxyalkyl radicals. The salts are previously in the form of halides, methyl sulfates or ethyl sulfates, e.g. the stearyl trimethyl ammonium chloride or the benzyl di (2-chloroethyl) ethyl ammonium bromide. On the one hand, highly preferred for the production of spontaneously dispersible concentrates according to the invention are phosphoric acid ester surfactants, such as:

Tristyrylphenol polyoxyethylene 18 mono / dimethyl phosphoric acid ester (Soprophor® FL, Rhone-Poulenc); Nonylphenol-10-polyoxyethylene mono / dimethyl phosphoric acid ester (Diphasol® 3873, CIBA-GEIGY), or the identical Sermul® EA 188 (SERVO)

(—Ch2 — ch2 — o) 2

-och,

oh,

(Surfactant 508, CIBA-GEIGY);

Tinovetin® JU (CIBA-GEIGY), a hydroxybiphenyl-10-ethoxy phosphoric acid ester; Butyl mono-4-ethoxy phosphoric acid ester (Zerostat® AT, CIBA-GEIGY), or

ch3- {ch2) 3- <j: h-ch2-o (-ch2-ch2-O) 6 «

c2h5

■ oh,

oh,

(Zerostat ® AN, CIBA-GEIGY)

and on the other hand betaine compounds, i.e. amphoteric, salt and water-free imidazole derivatives, such as:

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CH2 OH

CH2

CH2

[-] [+1

CH2 eoo Me where Me [+] stands for hydrogen, alkali and alkaline earth atoms and Rx for Cr to C32 alkyl or C2 to C32 alkenyl groups.

Pharmaceutical-compatible solvents which serve as hydrotropes or co-emulsifiers can be used, e.g .:

Esters of an aliphatic alcohol (C3-C18) with an aliphatic carboxylic acid (C10-C22) such as isopropyl laurate, hexyl laurate, decyl laurate, isopropyl myristate, isopropyl palmitate and lauryl myristate; Hydrocarbons with a straight carbon chain (C12-C32) which is substituted with 6 to 16 methyl groups and can have up to 6 double bonds, of which terpenes such as polymethylbutanes and poly-methylbutenes may serve as examples.

Monoesters of ethylene glycol or propylene glycol with an aliphatic carboxylic acid (C6-C22), such as propylene glycol monolaurate and propylene glycol monomyristate.

Esters of an aliphatic alcohol (C12-C22) with lactic acid, e.g. Myristyl or preferably lauryl lactate; Mono-, di- or triesters of glycerol with an aliphatic carboxylic acid (C6-C22), e.g. Glyceryl caprylate, or Miglyol® 812 neutral oil (oleum neutral).

Esters of a poly (2-7) ethylene glycol glycerol ether with at least one free hydroxyl group with an aliphatic carboxylic acid (C6-C22), e.g. aliphatic alcohols (C12 to C22), including Do-decanol, tetradecanol, oleyl alcohol, 2-hexyldecanol and 2-octyldecanol.

Esters with at least one free hydroxyl group, from poly (2-10) glycol with an aliphatic carboxylic acid (C6 to C22), monoethers from a polyethylene glycol with an aliphatic alcohol (C12 to C18), e.g. Polyoxyethylene (Cio) octyl ether.

Heterocyclic compounds, e.g. 1-methyl-2-pyrrolidone.

Before being added to the spontaneously dispersible concentrates, all technical surfactants were filtered or chromatographed over neutral aluminum oxide using an inert solvent such as e.g. Tetrahydrofuran, ethyl alcohol or methylene chloride cleaned.

Suitable light stabilizers, vitamins and provitamins (such as vitamin A, retinol, carotenes, tocopherols) and free fatty acids such as: valeric acid, isovaleric acid, sorbic acid, isocaproic acid, pelargonic acid are suitable as additives in the spontaneously dispersible concentrates according to the invention , Lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, hexacosanoic acid, octacosanoic acid, pentadecanoic acid, decenylic acid, undecenylic acid, dodecenylic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, erucic acid, etc. Also suitable are benzoic acid, malic acid, citric acid, etc. or dicarboxylic acids such as Malonic acid, succinic acid, glutaric acid, azelaic acid, sebacic acid, or ß-glycyrrhetic acid.

The daily dose required for pharmaceutical use is 0.001 to 25 mg / kg body weight, if possible divided into 2-3 single doses. For this purpose, the dicarboxylic acid esters of sterols, vitamin D and vitamin E compounds, as well as of special alcohols or the spontaneously dispersible concentrates with these esters can be used in the common pharmaceutical preparations and dosage forms such as pills, tablets, capsules, powders, granules, pellets Incorporate solutions, ampoules, emulsions, creams or suppositories together with the usual carriers and / or diluents and stabilizers.

The active ingredients forming the subject of the invention, as well as the spontaneously dispersible concentrates, which contain these active ingredients or active ingredient mixtures, can be administered to humans orally, by injection (intravenously, subcutaneously or intramuscularly) or in another way. When prepared as solid dosage forms for oral use, this can take the form of tablets, granules, pellets, powders or capsules, etc. The preparations can contain additives, e.g. a drug carrier such as a saccharide or cellulose base, a binder such as starch paste or methyl cellulose, a filler or a disintegrant, etc. - using additives which are usually used in the manufacture of medical or paramedical formulations. When the active compounds according to the invention are administered orally as liquid dosage forms, they can have any form selected from aqueous preparations for internal use, from suspensions, emulsions and syrups etc.

CHj

I.

N

Rx— Cj [+]

N

I.

CH,

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and they can also be in the form of dried preparations which are put into solution or emulsion before use.

If the active compounds or active compound mixtures according to the invention are prepared in the form of aqueous solutions, suspensions or oily or aqueous emulsions, preferably as microemulsions from the spontaneously dispersible concentrates in accordance with the invention, they can also be injected. However, the injection solutions are usually prepared shortly before use by dissolving or suspending the extracts or concentrates in aqueous, liquid media such as sterile water, glucose solution or physiological saline.

If necessary, commonly used solvents, stabilizers, preservatives and additives for the preparation of isotonic solutions can be added to an injection preparation. The injection preparations obtained in this way are administered intravenously, intramuscularly, subcutaneously or in another suitable manner.

The present invention also relates to pharmaceutical preparations which contain the active substances and / or the described, spontaneously dispersible concentrates for combating the growth of tumor cells. The pharmaceutical preparations according to the invention are those for enteral (such as oral or rectal) as well as for parenteral or topical administration to warm-blooded animals, which contain the spontaneously dispersible concentrate alone or together with a pharmaceutically usable carrier material.

The dosage of the concentrates according to the invention depends on the warm-blooded species, the age and the individual condition, and on the mode of administration. For example, to achieve a killing effect of tumor cells on warm-blooded animals with low body weight, such as Mice, rats and hamsters, doses in the range of approximately 0.1-50 mg / kg of body weight when administered by succession, and doses in the range of 0.05-5 mg / kg of body weight by intraperitoneal administration.

The oral and rectal forms of the new pharmaceutical preparations contain between 1-95%, preferably between 10-95%, in particular between 20-95% of the spontaneously dispersible concentrate according to the invention. You can e.g. Available in unit dose form, i.e. as dragees, micropellets, tablets, suppositories or ampoules and above all as capsules.

Suitable pharmaceutically usable excipients for the oral forms are mainly fillers, such as sugar (e.g. lactose, sucrose, mannitol or sorbitol), cellulose preparations and / or calcium phosphates (e.g. tricalcium or calcium hydrogen phosphate), as well as binders such as starch paste using, among others. Corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose, hydroxyl methyl cellulose, sodium carboxymethylceilulose and / or polyvinylpyrrolidone and / or disintegrants (if desired), such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt of it, such as Sodium silicate.

The flow regulating agents are e.g. the polyethylene glycols No. 200 to 600 are suitable. The gelatin capsules preferred as a dosage form in humans are provided with suitable coatings, one of the things being: concentrated sugar solutions - which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide - lacquer solutions (aqueous or those which have been prepared using organic solvents), or enteric-acid-resistant coatings from solutions of suitable cellulose preparations, such as microcrystalline cellulose ( Avicel ™), acetyl cellulose phthalate, hydroxymethyl cellulose phthalate, Metolose®, AQOAT ™ or a copolymer such as Eudragit® L 30 D is used.

Plug-in capsules made of gelatin and a plasticizer, such as glycerol or sorbitol, are suitable as a pharmaceutical dosage form which is particularly suitable according to the invention and can be used orally. Push-fit capsules made of hydroxylpropyl methyl cellulose acetate succinate also had excellent suitability. The soft or hard gelatin capsules can contain the spontaneously dispersible concentrate according to the invention in a mixture with fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and optionally with stabilizers and antioxidants such as e.g. contain a-, ß-, y-tocopherol. The use of suitable liquids such as liquid polyethylene glycols No. 200-600 can be recommended as a diluent, whereby stabilizers, antioxidants or light stabilizers or radical scavengers can also be added.

For parenteral administration, the concentrates according to the invention are mixed with distilled water. The resulting aqueous injection microemulsion can contain viscosity-increasing substances, e.g. Na carboxymethyl cellulose, sorbitol, mannitol and / or dextran, and optionally also stabilizers and antioxidants are added.

The pharmaceutical preparations for parenteral use preferably contain between 0.1 to 60%, in advance between 1 to 40% of the spontaneously dispersible concentrate according to the invention.

As topically applicable preparations, which are primarily suitable for the prophylaxis of skin cancers, come e.g. Gels, creams, ointments, pastes, foams, tinctures and solutions into consideration, which contain between 0.01 and 100% of the concentrate according to the invention.

For creams and oil-in-water emulsions which contain more than 50% water, primarily fatty alcohols, e.g. Lauryl, cetyl or stearyl alcohol, liquid to solid waxes, e.g. Isopropyl myristate, wool or beeswax and / or hydrocarbons such as Vaseline (petrolatum) or paraffinoel. Li16 is primarily suitable for emulsifying these oily bases

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never surface-active, pharmaceutically compatible substances with predominantly hydrophilic properties, e.g. Non-ionic emulsifiers, especially fatty acid esters of polyalcohols or ethylene oxide adducts (such as polyglycerol fatty acid esters or polyethylene sorbitan fatty acid esters) with an HLB ratio of less than 8. Agents which reduce the drying out of the creams, e.g. Polyalcohols such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols No. 200-600, also preservatives, fragrances, etc.

Ointments are water-in-oil emulsions that contain up to 70%, but preferably between 20 and 50% water or aqueous phases. The fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffinoel and / or hard paraffins in question, which suitable hydroxide compounds to improve water retention, such as Fatty alcohols or esters, including cetyl alcohol or wool wax alcohols.

In some cases, emulsifiers with an HLB value of 8 to 16, e.g. Sorbitan fatty acid esters (such as sorbitan isostearol) are added. Additions to the water phase include Humectants, such as polyalcohols (glycerol, propylene glycol, sorbitol and / or polyethylene glycols No. 200, 400, 600); also preservatives, fragrances, etc.

Fatty ointments are anhydrous and mainly contain hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins; also natural or partially synthetic fats such as Co-fatty acid triglyceride, further: fatty acid partial esters of glycerin, e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments, which increase the water absorption capacity. So-called "multi-functional glucose derivatives" are also used, e.g. Glucate® SS (methyl glucose sesquistearate) and Glucamate® SSE-20 (PEG-20 methyl glucose sesquistearate) from Amerchol, Edison, N.J.

Pastes are creams and ointments with secretion-absorbing powder components, such as metal oxides (such as titanium oxide or zinc oxide), talc and / or aluminum silicates, which have the task of binding moisture or secretions.

Foams are administered from pressure containers and are aerosol-form oil-in-water emulsions of the spontaneously dispersible concentrates according to the invention, with halogenated hydrocarbons (such as chlorofluoro-lower alkanes: e.g. dichlorodifluoromethane and dichlorotetrafluoroethane) being used as blowing agents. In addition, there may be the usual additives such as preservatives, etc.

PROCESS EXAMPLES for the production of the DL-a-lipoic acid esters according to the invention 1. Preparation of DL-a-lipoic acid cholecalciferylester

200 mg of oxalyl chloride in 30 ml of toluene are added dropwise to 200 mg of DL-a-lipoic acid in 30 ml of toluene at 10 ° C. The reaction solution is left to stand at 20 ° C. for 24 hours. 30 ml of toluene and the excess oxalyl chloride are then distilled off under vacuum and then 300 mg of cholecalciferol (cholecalciol; D3) and 50 mg of dimethylformamide are added. After heating at 70 ° C. for 2 hours, the solvent is removed by vacuum distillation.

The residue is chromatographed on a silica gel column using n-hexane / ethyl acetate (80:20) as the eluent. The DL-a-lipoic acid cholecalciferylester is obtained with a refractive index (B1) no 20 ° C. of 1.51 932 and a UV absorption Arnax. at 369.6 nm.

IR 2935 cm-1 v (CH)

1727 cm-1 v (C = 0) ester

1461 cm-1 g (CH) 1371 cm-1 5 (CH3)

1181 cm-1 v (C-O) ester

The following compounds of the formula (I) are also prepared in a corresponding manner:

DL-a-Lipoic Acid Citrone DL-a-Lipoic Acid Phytylester DL-a-Lipoic Acid Calciferylester (D2) DL-a-Lipoic Acid Ergosteryl

UV xmax. 272.4 nm

Bl 1.50 130 Bl 1.47 346 Bl 1.49 520

N.B. Bl = refractive index measured on the DUR refractometer Schmidt + Haensch, Berlin UV spectra measured on the Shimadzu UV-160A spectrophotometer IR = infrared spectra measured on the Perkin-Elmer 983G spectrometer.

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Composition examples for spontaneously dispersible agents according to the invention which contain new DL-a-lipoic acid esters of the formula (I) as antitumor active ingredients:

a) 2.5 to 25% by weight of one or more DL-a-lipoic acid esters of the formula (I)

0.1 to 40% by weight isopropyl myristate, isopropyl palmitate or Miglyol® 812 (Dynamit Nobel)

20 to 45% by weight of Diphasol® 3873 (CIBA-GEIGY), or the identical product Sermul EA 188

(SERVO)

20 to 45% by weight Invadin® JFC 800% (CIBA-GEIGY)

0 to 50% by weight of multifunctional giucose derivatives such as Glucate® SS and Glucamate® SSE-20 (Amer-chol)

b) 2.5 to 25% by weight of one or more DL-a-lipoic acid esters of the formula (I)

0.1 to 40% by weight isopropyl myristate, isopropyl palmitate or Miglyol® 812 (Dynamit Nobel)

20 to 45% by weight Invadin® JFC 800% (CIBA-GEIGY)

20 to 45% by weight SOPROPHOR® FL (Rhône-Poulenc)

0 to 50% by weight of multifunctional giucose derivatives such as Glucate® SS and Glucamate® SSE-20 (Amer-chol)

Miglyol® 812 neutral oil is a neutral oil (oleum neutral) from Dynamit Nobel, which corresponds to a mixed acid triglyceride of the fractionated coconut fatty acids Cs to C10.

Diphasol® 3873 = Sermul® EA 188 is a mixed emulsifier, each consisting of 50% of the two compounds with the formulas:

c) 2.5 to 25% by weight of one or more DL-a-lipoic acid esters of the formula (I)

0.1 to 40% by weight isopropyl myristate, isopropyl palmitate or Miglyol® 812 (Dynamit Nobel)

20 to 60% by weight Invadin®ID JFC 800% (CIBA-GEIGY)

20 to 40% by weight Amphonyl® CAA, or CA-AA (Oranienburger Chemicals A.G., or Christ A.G., Aesch / BL)

Invadin® JFC 800% (CIBA-GEIGY) is a tert. Octylphenylpolyoxyethylene ether with 9 to 10 oxyaethylene groups.

Soprophor® FL (Rhone-Poulenc) is a tristyrylphenol polyoxyethylene 18 mono / dimethyl phosphoric acid ester.

Amphonyl® CAA, or CA-AA (Oranienburger Chemicals A.G.) is an amphoteric, salt and water-free imidazole derivative based on coconut fatty acids with the formula:

o oh

O

och3

CH2 CH2-OH

CH2 CH

'2

, COO U

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COMPOSITION EXAMPLES of spontaneously dispersible CONCENTRATES according to the invention with the new biosurfactant esters of formula (I) as solubilizers, or hydrotropes (co-emulsifiers).

a) 0.5 to 30% by weight of one or more pharmaceutical or cosmetic active ingredients 1 to 40% by weight of one or more of the biosurfactant esters of the formula (I) according to the invention 0 to 45% by weight of a phosphoric acid ester surfactant, such as e.g. DIPHASOL® 3873 (CIBA-GEIGY), or SERMUL® EA 188 (SERVO), tenside 508 (CIBA-GEIGY), ZEROSTAT® AN or AT (CIBA-GEIGY), TINOVETIN® JU (CIBA-GEIGY), SOPROPHOR® FL (Rhone-Poulenc) 5 to 90% by weight INVADIN® JFC 800% (CIBA-GEIGY)

Invadin® JFC 800% (CIBA-GEIGY) is a pharmaceutically compatible tert. Octylphenyl polyoxyethylene ether with 9 to 10 oxyethylene groups.

Diphasol® 3873 (CIBA-GEIGY), or the identical Sermul® EA 188 (SERVO) is a mixing emulsifier, each consisting of 50% of the two compounds with the formulas:

O

II

(—Ch2-ch2-0 p — och3 oh o

II

(—Ch2-ch2-0) 10 p och3

och3

Surfactant 508 (CIBA-GEIGY) is an emulsifier of the formula:

O

(—Ch2 — ch2 — o) 2— p och3

och3

(Surfactant 508, CIBA-GEIGY);

Tinovetin® JU (CIBA-GEIGY), is a hydroxybiphenyl-10-ethoxy phosphoric acid ester; Zerostat® AT (CIBA-GEIGY) is a butyl mono-4-ethoxy-phosphoric acid ester; Zerostat® AN (CIBA-GEIGY) is an emulsifier of the formula:

O

ch3- (ch2 ch2-o (-ch2-ch2-o) s-P och3

och3

(Zerostat ® AN, CIBA-GEIGY)

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Soprophor® FL (Rhone-Poulenc) is a tristyrylphenol polyoxyethylene 18-phosphoric acid ester of the formula:

O

II

, 5-P-0CH3

OH

b) 0.5 to 30% by weight of one or more pharmaceutical or cosmetic active ingredients 1 to 40% by weight of one or more of the biosurfactant esters of the formula (I) according to the invention

0 to 45% by weight of a betaine compound, i.e. an amphoteric, salt and water-free imidazole derivative of the formula

CHz CK, COO1 ^ Me ^

where Me [+] stands for hydrogen, alkali and alkaline earth atoms and Rx for Cr to C32-alkyl or C2 to C32-alkenyl groups, the Amphonyl® CAA (Oranienburger Chemicals A.G.) being explicitly mentioned as an example. [Imidazole derivative based on coconut fatty acids],

c) 10% by weight of an oily active ingredient, selected from the lists on pages 8ff. and 12ff., e.g. 10-undecenyl-ergocalciferol ester

20% by weight of a biosurfactant ester of the formula (I) according to the invention

35% by weight Invadin® JFC 800%

35% by weight of Diphasol® 3873

d) 5% by weight of a crystalline active ingredient, selected from the lists on pages 8ff. and 12ff., e.g. 10-undecenyl-3-ergosterylester

15% by weight of a biosurfactant ester of the formula (I) according to the invention

40% by weight Invadin® JFC 800%

40% by weight Soprophor® FL or Amphonyl® C-AA

Example of the pharmaceutical production of a system preparation with concentrates according to the invention in the form of “multiple units”.

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a) Granulation

Metolose® 90 SH-4000 (Shin-Etsu Chemical) 90.0 g

Avicel® PH-101 80.3 g

CONCENTRATE according to the invention 139.4 g

Aerosil® 200 80.3 g

2,390.0 g

Granulate / form in a high-speed mixer or in a rotary bed with the addition of 110 g of ethanol, break, sieve 18 to 42 mesh, dry for 24 hours at 40 ° C.

b) MSR and RETARD equipment in a rotary bed with AQOAT® AS-HG (Shin-Etsu Chemical) and talc c) Composition of the finished granulate / resp. finished micropellets

Core material 44%

CONCENTRATE according to the invention 25%

MSR coating 31%

Z 100%

N.B .: MSR = gastric juice resistance. The pellets / granules according to a) can also be filled directly into capsules, which are made from AQOA ™ (HPMC-AS-M or HPMC-AS-N), and sealed with acetone / ethanol 1: 1, and so the functions adequately control the MSR and the delayed release (retard).

BIOLOGICAL TESTS

The antitumor effect of spontaneously dispersible concentrates with active ingredients according to the processing example is confirmed on the basis of the following test results:

In vitro tests with suitable tumor cell lines

A biological assay system has been developed that works with microtiter plates and dilution series. Prepare 104 / ml tumor cells in culture medium RPMI 1640 with 10% fetal calf serum (GIBCO); they are sown so leaky that they can grow during the assay in so-called non-confluent monolayers. The sample is added after 6-24 hours, with 100 nl per row, which is mixed with 100 ml of medium in the 1st hole. Half of this is removed and placed in the next hole, again mixed with 100 nl of medium, etc. A geometric dilution series nVfe is formed.

The samples are incubated in the plaque assay for 3-5 days at 37 ° C with 31/2% CO2. Then dye / fix with 0.1% crystal violet (Fluka, Buchs) in a solution of 70% methanol, 1% formaldehyde, 29% water. The evaluation is carried out on a microscope: magnification 300 times. The largest cytotoxic dilution is determined. The quantitative evaluation can also be carried out by means of scanning and absorption measurement on the spectrophotometer.

CYTOTOXICITY

CONCENTRATE

Highest cytotoxic dilution 1:

DL-a-lipoic acid - (+) - ß-CITRONELLYL-ESTER

2,560,000

DL-a-lipoic acid-PHYTYL-ESTER (ice + trans-)

2,560,000

DL-a-lipoic acid D2 ESTER

1 280 000

DL-a-lipoic acid D3 ESTER

1 280 000

DL-a-lipoic acid ERGOSTERYL ESTER

1 280 000

Concentration / dilution: calculated on the active substance content tumor cell line: Py6, virus-transformed 3T3 mouse fibroblast incubation: 72 h

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Claims (1)

Claims 1. Antitumor and bio-surfactant esters of DL-a-lipoic acid with vitamin D and vitamin E compounds, as well as with ergosterol and with special alcohols, according to the general formula (I) where Ri Borneyl [endo- (1R) -1,7,7, -trimethyl-bicyclo [2,2,1] heptan-2-yi] Borneyl [endo- (1 S) -1,7,7, -T rimethyl-bicyclo [2,2,1] heptan-2-yl] Citronellyl [3,7-dimethyl-6-octenyl-1 yl; β-rhodinyl; 2,3-dihydrogeranyl] Farnesyl [3,7,11-trimethyl-2,6,10-dodecatrien-1 yl] Geranyl [(E) -3,7-dimethyl-2,6-octadien-1yl] Menthyl [(1 R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanyl] Menthyl [(1R, 2S, 5S) -2-isopropyl-5-methyl-cyclohexanyl] Myrtenyl {(1 R) -6,6-dimethyl-bicyclo [3.1.1] hept-2-en-2-methanyl; (1 R) -2-pinene-10-yl} phytyl [3,7,11,15-tetramethyl-2-hexadecen-1yl] isophytyl [3,7,11,15-tetramethyl-1-hexadecen-1yl] thymyl [2-isopropyl-5-methylphenyl] means or represents one of the radicals of the formulas (II) to (VIII): s — s (I) & CHg (II) 22 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 683 920 A5 (VI) (IH) (VII) CHg CH3 (VIII) wherein in formulas (II) and (III) R2, R3 and R4 denote hydrogen or methyl. 23 5 10th 15 20th 25th 30th 35 40 45 50 55 60 CH 683 920 A5 2. The following compounds according to claim 1 DL-a-lipoic acid-Borneylester DL-a-lipoic acid-Citronellylester DL-a-lipoic acid farnesyl ester DL-a-lipoic acid geranyl ester DL-a-lipoic acid menthyl ester DL-a-lipoic acid myrtenyl ester DL-a-lipoic acid phylyl ester DL-a-lipoic acid isophylyl ester DL-a-lipoic acid thymyl ester DL-a-lipoic acid 2-methyl-2 (4,8,12-trimethyltridecyl) chroman-6-yl ester DL-a-lipoic acid cholecalciferylester DL-a-lipoic acid ergocalciferylester DL-a-lipoic acid ergosterylester 3. A process for the preparation of the compounds according to claim 1, characterized in that first the DL-a-lipoic acid is converted into the chloride or the bromide with a chlorinating or brominating agent and then the resulting lipoic acid chloride or bromide with borneol, Citronelloi, Farnesol, Geraniol, Menthol, Myrtenol, Phytol, Isophytol, Thymol or with a vitamin D or vitamin E compound or with ergosterol at a temperature of 40 to 120 ° C in an inert solvent and in the presence of a catalyst . 4. Spontaneously dispersible concentrate, characterized in that it 0.001 to 25% by weight of individual DL-a-lipoic acid esters of the formula (I) according to Claim 1, or combinations of such esters, and 0.1 to 40% by weight of a pharmaceutically acceptable solvent or solvent mixture serving as a hydrotrope or co-emulsifier 0.1 to 90% by weight of a pharmaceutically compatible surfactant or surfactant mixture 0 to 10% by weight of a vitamin or provitamin 0 to 10 wt .-% of a free fatty or fruit acid or an amino acid and pharmaceutically approved carriers and / or diluents. 5. Spontaneously dispersible concentrate, characterized in that it acts as a solubilizer or as a hydrotrope 0.001 to 50% by weight of a compound of the formula (I) according to Claim 1, or combinations of such compounds, and 0.001 to 30% by weight of one or more pharmaceutical or cosmetic active ingredients 0.001 to 90% by weight of a pharmaceutically acceptable surfactant or surfactant mixture, 0 to 10% by weight of a vitamin or provitamin 0 to 10 wt .-% of a free fatty or fruit acid or an amino acid and carriers and / or diluents. 6. Spontaneously dispersible concentrate according to claim 4, characterized in that it 2.5 to 25% by weight of one or more DL-a-lipoic acid esters of the formula (I) according to Claim 1, and 0.1 to 40% by weight of isopropyl myristate, isopropyl palmitate or miglyol, 20 to 40 wt .-% of a mixed emulsifier of the formulas o OH O OCH3 20 to 40 wt .-% tert. Octylphenylpolyoxyäthylenäther with 9 to 10 oxyethylene groups, and 0 to 50 wt .-% of a multifunctional glucose derivative contains. 7. Spontaneously dispersible concentrate according to claim 5, characterized in that it 1 to 40% by weight of one or more of the biosurfactant esters of the formula (I) according to Claim 1, and 24th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 683 920 A5 0.5 to 30% by weight of one or more pharmaceutical or cosmetic active ingredients 0 to 45% by weight of an emulsifier of the formula o II p — ochg oh CHg and 5 to 90 wt .-% tert. Contains octylphenyl polyoxyethylene ether with 9 to 10 oxyethylene groups. 8. Spontaneously dispersible concentrate according to claim 7, characterized in that it contains 1 to 40% by weight of DL-a-lipoic acid citronellyl ester, DL-a-lipoic acid farnesyl ester, DL-a-lipoic acid geranyl ester or DL-a-lipoic acid -Phytylester and 0.5 to 30% by weight of DL-a-lipoic acid ergosterylester, DL-a-lipoic acid cholecalciferylester or DL-a-Li ponic acid ergocalciferylester 0 to 45% by weight of the emulsifier of the formula 0 to 90 wt .-% tert. Contains octylphenyl polyoxyethylene ether with 9 to 10 oxyethylene groups. 9. Therapeutic system preparation which contains 1 to 95% of a spontaneously dispersible concentrate according to one of claims 5 to 8 and which is in unit dosage form as micropellets, granules, dragees, suppositories, ampoules or as capsules. 10. Therapeutic system preparation according to claim 9, which contains 44 parts of core material for granulate or pellet formation, 25 parts of a concentrate according to the invention according to one of claims 5 to 8 and 31 parts of enteric coating and retardant coating with hydroxylpropyl methyl cellulose acetate succinate contains or which consists of 64 parts of core material for granulate or pellet formation and 36 parts of a concentrate according to the invention according to one of claims 5 to 8 and is filled into pharmaceutically suitable capsules made of hydroxylpropyl methyl cellulose acetate succinate. ch2 ch2 - oh n ch2 ch2 ch2 coo m and 25th