DE3726101A1 - Pharmaceutical preparations - Google Patents

Abstract

The preparation and use of N(1)-n-alkylated pyridinium salts is described which have a low critical micelle concentration (CMC) of 10<-5>-10<-7> mol/litre. These N(1)-alkylated pyridinium compounds have a pharmacodynamic effect and can act as antimetabolites.

Description

Pharmaceutical preparations

The present invention relates to pharmaceutical preparations known cationic surfactants as components pharmaceutical preparation, new chemical compounds (cationic surfactants), especially as an ingredient of the pharmaceutical preparations used are, processes for the manufacture of pharmaceutical Preparation and method for producing the known and new chemical compounds (cationic surfactants).

State of the art and its disadvantages:

Micelles in aqueous solution, both non-ionic, cationic and anionic are in the literature numerous publications have been described. (Mittal, K.L. (1977) Micellization, Solubilization and microemulsions, Plenum Press, New York. - Mittal, K.L. (1979), Solution Chemistry of Surfactants, Plenum Press, New York. - Menger, F.M. (1977). In Bioorganic Chemistry III. Macro and multicomponent systems (E. E. Van Tanelen, Ed.), Academic Press, New York. - Menger, F. M. (1979a) Acc. Chem. Res. 12, 111-117. On the Structures of Micelles. - J.H. Fendler, E.J. Fendler (1975) Catalysis in micellar and macromolecular Systems, Academic Press.) Your structure and their pharmaceutical, medical and technical uses has been the subject of numerous investigations. That's how it is antiseptic effect of cetylpyridinium chloride, Benzethonium chloride and benzalkonium chloride or their Bromides known. Also that they are in low concentrations bactericidal activity in vitro against a large Number of gram-positive and gram-negative bacteria show, the gram-negative much more sensitive than the gram positive respond. Also are certain gram-negative bacteria resistant to these quaternaries Ammonium bases, e.g. B. Pseud. Cepalia, Mycobakt. tuberculosis.

Normally, cationic micelles in the aqueous phase additionally have in their hydrophobic core, which is largely determined by the aliphatic chain and their length, a hydrophobic-hydrophilic boundary layer (star layer) which is hydrated and e.g. T. houses the counterions. The size of this boundary layer is generally between 7-10 Å. They are also surrounded by the Guy-Chapman layer of 10-20 Å, which is not electrostatically bound counterions, e.g. B. Cl ^- , Br ^- , HSO₄ ^- and contain unstructured water. Only the concentrations of the counterions as well as other ions bring about a reduction in the critical micelle formation concentration (KMK) at constant temperature, pressure and chemical potential, the nature of the counterions being able to determine the shape and size of the micelles in the aqueous phase. However, this only causes the fraction of counterions that are in the star layer near the quaternary nitrogen.

The pure, previously known cationic quaternaries Ammonium bases - officially also known as invert soaps - have limited and non-specific antimicrobial Effect (see e.g. W. Forth, D. Henschler, W. Hype, general and special pharmacology and toxicology, 4th edition. B. I. Wissenschaftsverlag, 1983, p. 616). Therefore, their applicability z. B. as a preservative or as a disinfectant in the operative Subjects in medicine or on infection stations (antiseptics) limited, despite their low toxicity. Domagk recognized in 1935 (see Wallhäusers, K.H .: Sterilization, Disinfection, preservation, germ identification, Industrial hygiene. 2nd ed., Thieme, Stuttgart, 1978) that the quaternary ammonium bases are only bactericidal are when at least one of the substituents on the nitrogen from a linear alkyl chain with 8-18 carbon atoms exists, the optimal chain length is C₁₂-C₁₆. The best known representatives of these classes of substances are Benzalkonium salts (chlorides and bromides). Furthermore are hexadecylpyridinium chloride and benzethonium chloride known and have medical and pharmaceutical Gained meaning. The effect of these invert soaps is as is known, strongly dependent on the milieu. Soap z. B. will the effect largely canceled, as in acid pH range. Also lead blood, pus, stool and dirt also for inactivation. They also have one  Protein-falling effect, even at low levels Concentrations of the N⊕ surfactants, d. H. in the Range of 1-2% by weight of aqueous solutions. At Concentrations of these known surfactants, which only amount to 2-3 times the critical KMK although no protein-binding effect (denaturation), a reversible inactivation of enzyme systems and supporting proteins by unfolding the active three-dimensional structure. ("loss of activity through unfolding ".)

Antibacterial and non-specific are also known Effect of quaternary ammonium compounds and their surface-active effect, from dequalinium acetate, Cetyldimethylammonium bromide (CTAB) and Hexadecyl pyridinium chloride (CPCl), (see e.g. Goodman and Gilman's, The Pharmacological Basis of Therapeutics, EDS. A.G. Goodma, L.S. Goodman, W. Rall, F. Murad, 1985, 7th Edition, Collier, MacMillan Publishing Company, N.Y., p. 971; Merck Index, 1985). The micellar properties of this Connections are with their surface activity and antimicrobial properties in relationship (see Attwood, D., and Florence, A. T., Surfactant Systems, Chapman and Hall, London u. New York, 1983). However, the non-specific Surface activity of this quaternary aliphatic and aromatic ammonium bases not a priori as Requirement for the antibacterial, antifungal and keratolytic effects are considered because nonionic detergents, e.g. B. Brÿ, Triton X 100, Lubrol etc. do not become reactive.  

Organic quaternary ammonium bases of the type
(R _n , R₂, R _m , N⊕) Y⊖,
(HET≡N⊕- (CH₂) _x -CH₃) Y⊖ and
[H₃C) ₃ · C-CH₂-C (CH₃) ₂-X₁- [O- [CH₂) ₂] ₂-N⊕ (CH₃) ₂-CH₂X₂] Y⊖
are only partially known, e.g. Example, hexadecyltrimethylammonium chloride and bromide (cetyltrimethylammonium), hexadecylpyridinium chloride or bromide (cetylpyridinium chloride) and N, N'-dimethyl N-2,2-4- (1,1,3,3-tetramethylbutyl) phenoxyethylphenyl methanium chloride (benzethonium chloride, methylbenzethonium chloride, methyl benzene) ) and the benzalkonium chlorides with alkyl radicals from C₈H₁₇ to C₁₈H₃₇. These N⊕ surfactants mentioned all have a small critical micelle formation constant (KMK) in the range of 10 ^-4 -10 ^-5 mol, depending on the environmental conditions, such as. B. ionic strength, temperature, pressure and addition of organic solvents of certain dielectric constants. The influence of an anion, Y⊖, such as fractional bonds, the number of anions on the micelle surface (star layer) and their influence on the geometric shape of the entire cationic micelle of the above-mentioned quaternary organic ammonium bases has so far been little investigated. This also applies to the form of the above-mentioned surfactants in the presence of potentiating mixtures such as glycerol, dimethyl sulfoxide, ethanol, propanol and their stability to the temperature and absorption capacity of hydrophobic (lipophilic) active pharmaceutical ingredients. There are no quantifiable investigations of the above-mentioned N⊕ surfactants.

Surfactants of the general form (Het≡N⊕- (CH₂) _x -CH₃) Y⊖, where the heterocycle is a benzimidazole, pyrimidine, imidazole, thiazole, benzothiazole or purine radical have not been described, and her micellar behavior in aqueous solutions in the presence and absence of potentization mixtures. This also applies to substituted pyrimidinium compounds which, as will be shown later, can also form vesicles of a particular size and shape in aqueous solution.

The relatively broad and undifferentiated mechanism of action the already known quaternary organic ammonium bases and the related field of application as antiseptics and their toxic effects at higher therapeutic levels  Cans, has the application of these organic quaternaries Pharmaceutical limited ammonium bases. Is also for 1% by weight or higher aqueous solutions, creams and ointments hypersensitive, allergic and topical irritations been observed, so that a targeted therapeutic Use is only possible to a limited extent.

The bactericidal effect of chlorhexidine is known gram-positive and gram-negative bacteria, but resistant against gram-negative bacilli.

Pharmaceutical preparations, which are more targeted Therapy with micellar included pharmaceutical Active ingredients, e.g. B. antiviral, antifungal, antineoplastic Nature in therapeutically effective doses and a suitable pharmaceutical composition (Galenik) not available.

A major disadvantage of the previously known pharmaceutical Preparations of quaternary organic ammonium bases, also in the presence of potentization mixtures, is in the polydispersity of the colloidal micellar solutions. Depending on the pharmaceutical preparation, pH value, Ionic strength, counter anion Y⊖ and temperature are all in one pharmaceutical preparation so far micelles of various Shape and size, as well as stability and absorption capacity of active pharmaceutical ingredients.  

In the broadest sense one understands by micelles Association formed aggregates of dissolved molecules. Described in the narrower sense that is mainly used today one as micelles those aggregates that are made up of surfactant molecules in aqueous solutions above a certain one Temperature (Krafft point) or a characteristic Form concentration. This concentration is called critical micelle concentration (KMK; English: critical micellization concentration, cmc): When exceeded the KMK, the monomer concentration remains practical constant and the excess surfactant molecules form micelles. These can take various forms (Balls, chopsticks, slices) occur depending on the chemical constitution of the surfactant both from temperature, Concentration or ionic strength of the solution. The Micelles have characteristic aggregation numbers mostly a narrow distribution range. Reaching the KMK gives itself up by sudden changes in the surface tension, (which is used to measure the KMK) des osmotic pressure, electrical conductivity and Detect viscosity.

The micelles are thermodynamic stable association colloids of surfactants, where the hydrophobic residues of the monomers inside of the aggregates and through hydrophobic interaction (van der Waals forces) are held together; the hydrophilic Groups face the water and mediate the solubility of the colloid by solvation.

More information on micelles can be found in Römpps Chemistry lexicon, 8th edition, Franckh'sche Verlagbuchhandlung Stuttgart, 1985, page 2600ff.  

An object of the present invention is to provide a pharmaceutical preparation to create the active ingredient contains in the most stable form possible and in which the Active ingredient at the location of the pathological event if possible is released quickly and completely.

This object is achieved according to the invention by a pharmaceutical preparation which is characterized in that it is composed of a micelle, consisting of a cationic surfactant with a monovalent anion and a hydrophobic pharmaceutical active ingredient, dispersed in a solvent whose pH is less than 7 , the critical micelle concentration (KMK) being in the range of 1.0 x 10 ^-7 to 1.5 x 10 ^-4 mol / liter.

This pharmaceutical preparation is preferably composed of a micelle, consisting of a cationic surfactant with a monovalent anion in an amount of 0.01 to 1.0% by weight, based on the entire pharmaceutical preparation, and a hydrophobic active pharmaceutical ingredient in an amount of 0.001 to 0.5% by weight, based on the entire pharmaceutical preparation, dispersed in a solvent whose pH is 7.0, in an amount of 99.40 to 99.989% by weight, based on the total pharmaceutical preparation, the critical micelle concentration (KMK) is in the range of 1.0 x 10 ^-7 to 1.5 x 10 ^-4 mol / liter.

These micelles described here have an aqueous phase with a hydrophobic chain length of 15- (CH₂) groups including their quaternary nitrogen in the aromatic  Form a diameter of ∼50-100 Å, depending on the nature the counterions.  

Description and preparation of the quaternary ammonium bases

The cationic surfactant according to the invention is preferably a compound of the general formula

preferably

R₁ is an alkyl radical with 1-12 C atoms or an aralkyl radical, R₂ is an alkyl radical with 1-12 C atoms or an aralkyl radical, R _{n is} a straight-chain or branched alkyl radical, substituted or unsubstituted, with 1-22 C atoms, preferably 10- 20 carbon atoms or an alkenyl radical with 8-20 carbon atoms, preferably 8-10 carbon atoms or a 5- or 6-membered aromatic heterocycle with one or 2 nitrogen atoms, and optionally a sulfur atom or an oxygen atom and R _{m is} a straight-chain or branched Alkyl radical, substituted or unsubstituted, with 1-22 carbon atoms, preferably 10-20 carbon atoms or an alkenyl radical with 8-20 carbon atoms, preferably 8-10 carbon atoms or a 5- or 6-membered aromatic heterocycle with one or 2 nitrogen atoms, and optionally a sulfur atom or an oxygen atom or a quinolinium radical and y⊖ is a monovalent anion.

Further preferred embodiments are:

The straight chain or branched alkyl radicals are preferably those with C₆-C₂₂, but especially C₁₂-C₂₀, carbon atom, is for example n-heptyl, 2-methylhexyl, 3-methylhexyl, 3-ethylpentyl, 2,2-, 2,3-, 2,4- or 3,3-dimethylpentyl, n-octyl, 4-methylheptyl, 2,2,2-, 2,2,4-, 2,3,3-, 2,3,4-trimethylpentyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl (cetyl), n-heptadecyl, n-octadecyl, n-nonadecyl or n-eicosyl (arachinyl).

A straight-chain alkyl with a even number of 10-20 carbon atoms, e.g. B. n-dodecyl, n-tetradecyl, n-hexadecyl (cetyl), n-octadecyl or n-eicosyl. You have all of them equal binding and absorption capacity of inorganic and organic (hydrophobic) Active substances, for example Hg (CN) ₂, ZnEDTA, ZnO, and K₁₈ (KW₂₁Sb₉O₈₆) ₁₇ as an inorganic antiviral Active ingredients, and azathioprine, nystatin, Amphotericin, idoxuridine, cytarabine and Trifluorothymidine as an organic active ingredient.

An alkenyl having 12-20 carbon atoms for R _n is preferred if R _{m is} a methyl, ethyl to hexyl radical, especially an alkenyl with a double bond, e.g. B. 9-cis-dodecenyl, 9-cis-tetradecenyl, 9-cis-hexadecenyl, 6-cis-octadecenyl 6-trans-octadecenyl and 9-cis-octadecenyl.

R₁, R₂ and R _m is preferably methyl, ethyl or hexyl.

An aromatic heterocycle for R _n of formula (I) is a 5- or 6-membered heterocycle, with one or two nitrogen atoms and optionally one nitrogen and one sulfur atom, e.g. B. a pyridine, a pyrimidine, a pyrazine (1,4-diazine), a pyrazole, an imidazole, a thiazole and purine residue (7N-imidazolium [4,5-d] pyrimidine) or a benzo-condensed Thiazole and imidazole residue z. B. N₃-benzimidazole or benzothiazole.

Substituents of this heterocycle are on the nitrogen atom and optionally on a carbon atom a lower alkyl, e.g. B. methyl or ethyl, or a hydroxy lower alkyl, e.g. B. hydroxymethyl or 2-hydroxyethyl, oxo, hydroxy or halogen, e.g. B. chlorine or bromine.

A heterocycle is preferably 2- or 4-lower alkyl pyridinium e.g. B. 2- or 4-methyl or 2- or 4-ethyl pyridinium, di-lower alkyl pyridinium e.g. B. 2,6-dimethyl, 2-methyl-3-ethyl, 2-methyl-4-ethyl, 2-methyl-5-ethyl- or 2-methyl-6-ethyl-pyridinium, 2-, 3- or 4-halopyridinium, e.g. B. 2-, 3- or 4-chloropyridinium or 2-, 3- or 4-bromopyridinium, 2-lower alkylimidazolinium, oxazolinium or -thiazolinium z. B. 2-methyl or 2-ethylimidazolinium, oxazolinium or thiazolinium or 2-lower alkyl-8-haloquinolinium e.g. B. 2-methyl-8-chloroquinolinium.

Y⊖ is an anion, preferably chloride, bromide, Iodide or ethyl sulfate, a lower alkonate, such as Formate, acetate, propionate, hydrogen sulfate (HSO₄-), malate or fumarate, salicylate, alginate  or gluconate.

A cationic surfactant of the general formula (I) is preferably N-benzyl-N, N-dimethyl-N-2- [2- (4- (1,1,3,3-tetramethylbutyl) phenoxy) ethoxy] - ethyl ammonium chloride, N-benzyl-N, N-dimethyl-N-2 [2- (3-methyl-4- (1,1,3,3-tetramethylbutyl) phenoxy) - ethoxy] ethylammonium chloride (methylbenzethonium chloride), n-dodecyl-trimethylammonium chloride or bromide, Trimethyl-n-tetradecyl ammonium chloride or -bromide, n-hexadecyltrimethylammonium chloride or -bromide (Cetyltrimethylammonium chloride or bromide), Trimethyl-n-octadecylammonium chloride or bromide, Ethyl-n-dodecyldimethylammonium chloride or bromide, Ethyldimethyl-n-tetradecylammonium chloride or bromide, ethyl-n-hexadecyl-dimethylammonium chloride or bromide, ethyldimethyl-n-octadecylammonium chloride or bromide, n-alkyl-benzyldimethylammonium chloride or bromide (benzalkonium chloride or bromide), e.g. B. Benzyl-n-dodecyldimethylammonium chloride or bromide, benzyldimethyl-n-tetradecalammonium chloride or bromide, Benzyl-n-hexadecyldimethylammonium chloride or bromide or benzyldimethyl-n-octadecylammonium chloride or bromide, N- (n-decyl) pyridinium chloride or bromide, N- (n-dodecyl) pyridinium chloride or bromide, N- (n-tetradeyl) pyridinium chloride or bromide, N- (n-hexadecyl) pyridinium chloride or bromide (Cetylpyridinium chloride) or N- (n-octadecyl) pyridinium chloride or bromide or one Mixture of these surfactants.  

A cationic surfactant of the general formula (I) R _n N⊕ (R₁, R₂) R _m Y⊖ is preferably with R _n = R₁ = R₂ z. B. R _n N⊕ (CH₃) ₃Y⊖ or as a substance z. B. n-heptyl-trimethyl-ammonium chloride (bromide), 3-methyl-hexyl-trimethyl-ammonium chloride, n-nonyl-trimethyl-ammonium bromide, n-undecyl-trimethyl-ammonium chloride, n-hexadecyl-trimethyl-ammonium chloride, n-octadecyl or n-eicosyl trimethyl ammonium bromide with an even number of 12-20 carbon atoms.

Based on a micro-emulsion and / or ointment e.g. B. in the presence of up to 10% (g / g) DMSO have these N-surfactants same antifungal, antibacterial and keratolytic Properties like the non-covalently bound pharmaceutical Active ingredients.

The preparation of the surfactants of the general formula R _n N⊕ (R₁, R₂) R _m Y⊖ are analogous to that described in the standard work "Cationic Surfactants" by E. Jungermann, Dekker, NY, 1970, see also the annually new one Manual "Mc Cutcheon's Emulcifiers and Detergents" Manufacturing Cofectioner Publishing Co. Other alkyl-pyridinium halides can be obtained in good yield by reacting stoichiometric amounts of the pyridine derivative with long-chain alkyl halides. Other processes are based on the corresponding, ultra-cyclic N compounds and 1,3-propane methane, such as. B. FJ Fendler et al, J. Chem. Soc., Perkin Trans III., 1097 (1977). Other processes which lead to a similarly good yield are e.g. B. Attwood, D., Elwarthy, PH, and Kaye, SB, J. Phys. Chem. 74, 3529 (1970), they can be used analogously for the synthesis of the substances of the formula II. The active pharmaceutical ingredients are commercially available.

The synthesis of the compounds of the general formula R _n , R _m , R₁, R₂N⊕Y⊖ or R _n , R _m N⊕ (CH₃) ₂Y⊖ in particular are represented according to the following instructions:

• a) The corresponding alkyl iodide or bromide is with a Excess of trimethylamine (halide: amine = 1: 1.45) for 24 hours at 20 ° C to produce the corresponding quaternary ammonium base left in the autoclave. No solvent other than methanol, which with the Trimethylamine or R₁, R₂-alkylamine has been saturated, was used. The reaction mixture is 5 times Volume of ether stirred in and abundant for 20 min heated. The solid residue, which after cooling in Forms ether, is filtered off. It is recrystallized Chloroform. The crystals are repeated with washed anhydrous ether. The recrystallization until to constant melting point were from ethanol / ether (1: 1,% w / w) in the presence of activated charcoal. The crystals were at 80 ° C over calcium chloride dried under vacuum at 1 mm / Hg overnight.
• b) For the preparation of R _n , R _m , R₁, R₂N⊕Y⊖ the corresponding amines R₁, R₂-N⊕ amines with the stoichiometric amounts of the R _n , R _m iodides in absolute ethanol-hexane (1: 2 % g / g) refluxed for 48 hours. The reaction is then cooled and poured into a 5-fold excess of ether and filtered off. The recrystallization was carried out as indicated under a).
• c) In order to convert the quaternary ammonium halides into the corresponding bromides, chlorides or iodides, the following procedure is available: 300 g of Amberlite IRA-400 (4 mequiv / g) as a chloride form are filled in a column (45 × 5 cm) and washed with 1 liter of a 20% aqueous solution of potassium chloride or potassium bromide or potassium iodide or KY⊖ at a very slow flow time. The matrix was then washed with deionized water until no reaction to chloride or bromide or iodide occurred. The column matrix was then loaded with a 10% aqueous solution of a quaternary ammonium bromide. The subsequent elution was carried out with water at a flow rate of 1 ml / min. The corresponding quaternary ammonium bromide or halide was obtained by concentrating the eluate on a rotary evaporator. The recrystallization was carried out as described under a). The following Table 4 shows some cationic surfactants of the form R _n N⊕ (CH₃) ₃Y⊖, which have been prepared by this process.

A subclass of the compounds of the general formula (I) is the compound of the general formula

These are descendants of the benzethonium halides. By substitution of the radicals X₁ and X₂ where X₁ = X₂ can be produced in the same way as already in the US patent 21 15 250 from (1938) or also according to US patent 21 70 111 from (1939) and 22 29 024 from (1941) are. These special N-surfactants are particularly stable even in the presence of a potentiation mixture and have Surprisingly, a high absorption capacity for micellar Inclusion of active pharmaceutical ingredients. Besides, they are independent of the environment in the case of production according to the process. Y⊖ is an anion z. B. chloride, bromide and also iodide, a lower alkonate, such as formate, acetate, propionate, malate or fumarate, Salicylate, alginate or gluconate.  

Table 4

Preparation and melting point, as well as elementary analysis of the quaternary ammonium compounds of the type RN⊕ (CH₃) ₃Y⊖ from R _n , R _m , R₁, R₂N⊕Y⊖ with R₁ = R₂ and R _n = R _m .

The cationic surfactant according to the invention is preferred a compound of the general formula

[HET≡N⊕- (CH₂) _x -CH₃] y⊖

in which

HET≡N⊕-a substituted or unsubstituted pyridinium residue or a substituted or unsubstituted pyrimidinium residue or
a substituted pyrazine (1,4-diazinium) residue or an imidazolium residue (4,5-d) pyrmidine residue substituted or unsubstituted, or a substituted or unsubstituted imidazolium residue or
a substituted or unsubstituted pyrazolium residue, or
a substituted or unsubstituted thiazolium radical, or
a substituted or unsubstituted benzothiazolium radical, or
a substituted or unsubstituted benzimidazolium residue, x 8 to 20 and y⊖chloride, bromide, iodide, formate, acetate, propionate, hydrogen sulfate, malate, fumarate, salicylate, alginate, gluconate or ethyl sulfate

mean.

Preferred embodiments of this cationic surfactant are the following connections:  

In the following embodiments, in which y⊖ occurs, this y⊖ means one of the above thirteen Anions.

N-alkyl pyridinium of the formula

Hexadecyl pyridinium of the formula

N-alkyl-4-hydroxypyridinium of the formula

Hexadecyl-4-hydroxypyridinium of the formula

2,5,6 substituted N₁-alkyl-pyrimidinium compounds of the formula

R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = R₁ = OH; R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = F

2,5,6 substituted N₁-hexadecylpyrimidinium of the formula  

R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = R₁ = OH; R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = F

4-n-alkyl-pyrazinium-2-carboxamide of the formula

4-Hexadecylpyrazinium-2-carboxamide of the formula

7-n-alkylimidazolium [4,5-d] pyrimidine of the formula  

R₁ = OH; R₂ = OH
R₁ = H; R₂ = H
R₁ = F; R₂ = NH₂
R₁ = F; R₂ = OH
R₁ = NH₂; R₂ = H
R₁ = NH₂; R₂ = NH₂

7-Hexadecylimidazolium [4,5-d] pyrimidine of the formula

R₁ = OH; R₂ = OH
R₁ = H; R₂ = H
R₁ = F; R₂ = NH₂
R₁ = F; R₂ = OH
R₁ = NH₂; R₂ = H
R₁ = NH₂; R₂ = NH₂

3-n-alkyl-5,6-substituted benzimidazolium compounds of the formula

R₁ = OH

4-substituted 2-hexadecylpyrazolium compounds of the formula

R = H; CH₃; OH

1-n-alkyl-4-substituted imidazolium compounds

R = H; CH₃;

1-Hexadecyl-4-substituted imidazolium compounds of the formula

R = H; CH₃;

3-n-Alkyl-5,6-substituted thiazolium compounds of the formula

R₁ = H;
R₁ = CH₃;

3-n-Hexadecyl-5,6-substituted thiazolium compounds of the formula

R₁ = H;
R₁ = CH₃;

3-n-Alkyl-5,6-substituted benzothiazolium compounds of the formula

R₁ = R₂ = H
R₁ = CH₃
R₁ = R₂ = OH
R₁ = R₂ = CH₃

4- [1,1bis n-alkyl (lower alkyl)] N-hexadecylpyridinium compounds of the formula

3.5 to [(n-alkyloxy) carbonyl-] N-hexadecylpyridinium compounds of the formula

4- (17-tritriacontyl) -n-methyl-pyridinium chloride of the formula

3,5bis [(n-hexadecyloxy) carbonyl)] - N-methyl-pyridinium chloride

Cationic surfactants of the general formula  

in which

x₁ein a phenyl radical which is unsubstituted or substituted in the 4-position or in the 3,5-position or in the 1,2,4,5-position, x₂ein an unsubstituted or in the 4-position or in the 3,5-position or in the 1,2,4,5-substituted phenyl radical and Y _- mean the anions according to claim 78.

General information on the preparation of the (HET≡N⊕- (CH₂) _x -CH₃) Y⊖ compounds II:

The cationic surfactants according to the invention of the general Formula II, except hexadecylpyridinium halide, are new.

In the cationic surfactant of general formula II HET≡N⊕ preferably a substituted or unsubstituted Pyridiniumrest or a substituted or unsubstituted pyridinium radical or  substituted pyrazine (1,4-diazinium) residue or an imidazolium residue (4,5-d) pyrimidine residue substituted or unsubstituted, or a substituted or not substituted imidazolium residue or a substituted one or unsubstituted pyrazolium, or a substituted or unsubstituted thiazolium radical or a substituted or unsubstituted benzothiazolium radical, or a substituted or unsubstituted Benz imidazolium residue.  

These cationic surfactants are characterized in that they have a very small micelle formation constant (KMK) of approximately 1.5 × 10 ^-7 mol, are very strongly antimicrobial, antifungal, have no polydispersity in the presence of inorganic anions or potentiating mixtures, and z . T. themselves are microbial metabolites (antimetabolites) that are not toxic to the host cell.

The formation of the salt-like structure of this class of cationic surfactants of the form (HET≡N⊕- (CH₂) _x -CH₃) Y⊖ is based, among other things, on the electron density distribution of the heteroaromatic nuclei or their basicity, including the influence of the substituents. A necessary condition which leads to the formation of quaternary salts of this five- and six-membered heteroaromatic class is that the electron density on the nitrogen, which is quaternized, according to MO-SCF calculations an amount of -0.08 (e.g. Pyrazine-N₄) to -0.159 (e.g. Imidazole-N₁, Purin-N₇) must have. The stability of the individual heterocyclic cationic surfactants described here is also determined by their symmetry and chain length of the alkyl chain on the quaternary nitrogen:

In the case of imidazole, benzimidazole z. B. is by the Formation of the salt on the quaternary nitrogen N₁ and that free pair of electrons at N₃ and the resulting high Stabilized symmetry. The same applies to the H₉ tautomer of purine and its symmetrically arranged substituents, which the negative charges at N₁ (-0.124), N₃ (-0.108) and N₉ (-0.149) influence the quaternization at N₉ is preferred by the above. line N₁ → N₃ → N₉ reverses. By choosing suitable solvents you can increase the yields. While for pyridine, Pyrimidine and imidazole residues have symmetrical effects on the nucleus play an important role is e.g. B. in pyrazine the electronic Significant effect in the 2 position, but there is there are also very strong inductive effects (e.g. 2-amino group), less than mesomers. This also applies to pyrazole.

The length of the alkyl chain on the quaternary nitrogen atom is determined not only melting point and hydrophobicity of the later in aqueous Solutions formed cationic micelles, but also the Yields decrease with increasing chain length, while the Response times e.g. B. in nitrobenzene or 2-ethoxyethanol increase.

Stable and easily crystallizable compounds are used for C₁₂-C₁₈ obtained, the counterion Y⊖ without exception bromide and is chloride. The other connections can easily be made Acetone or chloroform can be recrystallized. The corresponding Iodine compounds are sensitive to temperature and light.  

Special preparation of the (HET≡N⊕- (CH₂) _x -CH₃) Y⊖ compounds.

a) The corresponding compounds of pyridine or substituted Leave pyridines as a six-membered heterocycle resulting from the corresponding alkyl bromides or iodides in methanol at 35 ° C and pyridine or substituted pyridines produce with a yield of 70%. The corresponding molar amounts of the alkyl bromide, which is almost all are commercially available, but by high pressure liquid chromatography (HPLC) preparative cleaned must first be in methanol (10-fold volume excess measured on pyridine) dissolved, and under nitrogen the stoichiometric amount of pyridine, which is also dissolved in methanol, added dropwise with stirring. It is refluxed for 6 hours with stirring heated at 70 ° C, so that the reaction yield almost is quantitative. So z. B. the yield of hexadecyl-4-hydroxy-pyridinium chloride or bromide in methanol as a solvent 95%, with ethanol 80% and in ether / ethanol only 40%. Dodecylpyridinium chloride is obtained with a yield of almost 70% received. 3,5-dihydroxy-dodecylpyridinium bromide forms quantitatively according to the previous regulation from dodecyl bromide and 3,5-dihydroxypyridine in boiling Chloroform after 4 hours (melting point 180 ° C).

Purification of the corresponding pyridinium compounds. - By repeated recrystallization from mixtures of methanol / ether, starting with 40/60 (v / v); 50/50 (v / v) and finally 90/10 (v / v), the desired products are obtained with a constant melting point, uniform molecular weight and specific surface-active properties (measured by the concentration dependence of the surface tension). In addition, these compounds show the typical 1 H-NMR signals described above. The numerous CH₂ groups and the CH₃ group produce a clearly visible absorption vibration in the IR spectrum at 2930 cm ^-1 and 2850 cm ^-1 (methylene group) a medium weak band at 2960 cm ^-1 and a weak band at 2870 cm ^-1 , which can be assigned to the methyl group.

A quick and quantitative separation of the n-alkyl-pyridinium halides of unreacted n-alkyl bromides and pyridine is by preparative high pressure liquid chromatography on an RP18 column using the Elution mixture consisting of 60% (v / v) methanol (ethanol) and acetonitrile 40% (v / v) isocratic at 9.52 atm column pressure reached (UV detection at 260 nm).

b) pyrimidine compounds

1. Hexadecyl pyrimidinium bromide. - 0.01 mol of 5-aminopyrimidine (0.95 g) and hexadecyl bromide, 0.01 mol (3.05 g) are in 20 ml of methanol with stirring and nitrogen at 20 ° C for 24 hours in the presence of catalytic Amounts (0.5 mg) of sodium amide converted. The resulting N₁-hexadecyl-5-aminopyrimidinium bromide is in acetone dissolved at 76 ° C, and after cooling to room temperature crystallizes the N₁-hexadecyl aminopyridinium bromide with melting point 122 ° C. Yield 35%.

0.01 mole of this N₁-hexadecyl-5-aminopyrimidinium bromide (3.20 g) become 50/50 (v / v) in methanol / water Concentrated at 0 ° C in an ice bath with 1 g NaNO₂ and 0.1 ml Hydrobromic acid stirred under nitrogen for 6 hours. The mixture is then brought to room temperature and then at 80 ° C under reflux for 2 hours Nitrogen and stirring heated. The resulting hexadecyl pyrimidinium bromide is extracted with 2-ethoxyethanol and crystallized at 10 ° C. Yield 30%, Melting point 105 ° C (bromide) 189 ° C (chloride).  

Preparative separation of unreacted products can also be done by high pressure liquid chromatography can be achieved, as with the pyridinium derivatives described.

2. Pyrimidinium compounds substituted in the 2,5,6-position are under pressure by reaction in 2-ethoxyethanol in an autoclave at 100 ° C with a reaction time of 8 hours from the corresponding n-alkyl bromides or Iodides and the substituted pyrimidinium compounds obtained with yields between 30 and 40%. The recrystallizations are for all substituted pyrimidinium compounds made from chloroform.

Preparative separation of unreacted products can as described above by high pressure liquid chromatography can be achieved.

3. N₁-n-alkyl compounds of pyrimidine can by Conversion of n-alkyl-Mgx (x = Br, Cl) in good yields Pyrimidine or 2,6,5,6-substituted pyrimidines in Presence of 1,2-dimethoxyethane and / or n-heptane be preserved. No hetarin or addition-elimination or elimination-addition mechanism instead of.

0.01 mol (1.0 g) of 5-fluoropyrimidine are dissolved in 1,2-dimethoxymethane (100 ml) with stirring in a three-necked flask and under nitrogen. 0.08 mol (same order of magnitude as above) of n-decylmagnesium chloride (or 0.09 mol of 29.6 g of n-hexadecylmagnesium bromide) dissolved in 20 ml of heptane is slowly added dropwise at 20 ° C. from a dropping funnel. This solution is brought to 40 ° C., stirred for 12 hours and, after the reaction has ended, 20 ml of 50% by weight hydrobromic acid are added dropwise from a dropping funnel at a constant temperature. The excess Grignard reagent is reacted after 1 hour. It is cooled to 0 ° C and any excess Grignard reagent which may still be destroyed by adding methanol and the quaternary N 1 -pyrimidinium bases are extracted by 2-ethoxyethanol. The first recrystallization is carried out from chloroform / methanol at 0 ° C, the further recrystallizations at room temperature.
Melting point: 5-fluoro-N₁-decylpyrimidinium bromide 199 ° C (dec.)
Melting point: 5-fluoro-hexadecylpyrimidinium bromide 175 ° C (dec.)

c) Preparation of the 7-n-alkyl-imidazolium 4,5-d pyrimidine derivatives (Purine), e.g. B. 7-Hexadecyl-imidazolium-2,6-dihydroxy [4,5-d] pyrimidine bromide

1.5 g of 2,6-dihydroxy-purine (0.01 mol) are dissolved in 100 ml of acetone dissolved in a four-necked flask at 35 ° C. From two dropping funnels triethyl oxonium borofluoride (Et₃O⊕F₄) in triple excess (5.7 g = 0.03 mol) versus n-hexadecyl bromide (3.3 g, 0.01 mol) found in the second dropping funnel, simultaneously with n-hexadecyl-Br dripped. The reaction is carried out with constant stirring Maintained at 40 ° C for 6 hours and then at 10 hours Boiled at reflux at 65 ° C. After the reaction is complete 100 ml of ethanol are added, the quaternary that is formed is filtered Ammonium base over a glass sinter crucible (1G4) and crystallized from a mixture consisting of 2-ethoxyethanol / chloroform, 1: 1 um. Yield: 0.5 g, melting point: 122 ° C.

The compound is hygroscopic and forms a crystalline one Adduct with two parts of chloroform.

The UV spectra show the typical absorption properties of the purine derivatives. The same applies to the ¹ H-NMR spectra, measured in d₆-Me₂SO₄.

d) The corresponding benzothiazoles and benzimidazole n-alkyl Compounds, especially if they are halogenated in the 2 position are formed with a yield by this method of 50% and are very easy to recrystallize from chloroform.

e) The corresponding quaternary salts of pyrazole can be also produce according to method c). Can also after Process b3) by using n-hexyl magnesium bromide or n-Alkylmagnesiumchlorid work, since neither an additive Elimination or an elimination-addition mechanism expires. Form the 4-H-pyrazolium salts with R = CH₃, OH, H. themselves with high yield of 60%.

Since the n-alkyl radical on both N₁ and N₂ or both can be localized, it is necessary the reaction product by high pressure liquid chromatography on a RP-18 column in an acetone / acetonitrile elution mixture separate as described above. This is also necessary if the corresponding n-alkyl bromide in the bomb tube or Autoclave with a pyrazole derivative at 100 ° C in the presence are reacted by piperidine. The relationship from di-N-substituted to mono-N-2-substituted Pyrazolium derivatives behave like 1.5: 1.

The imidazolium compounds, the N₁-substituted such the N₁, N₂-disubstituted can be like the corresponding Prepare pyridinium compounds.

For the preparation of the N₁-substituted imidazolium compounds one proceeds as described under b3). The yields are 30%. As a suitable reaction medium acetone is recommended.  

g) The quaternization of the pyrazine at the N₄ when in the 2-position is substituted takes place in 50% yield if in 2-position z. B. a chlorine or a carboxamide (carbamoyl) Group is located. If proceed according to regulation b1) is obtained, yields of 20-30% depending on the size of the Alkyl radical. One proceeds according to the known production The yields of pyridinium compounds (a) increase to 50%.

As usual and described above, the (CH₂) _x chain with X = 10-20 determines the size and the KMK in aqueous solutions. The size, shape and molecular weight distribution of the micelle formed in aqueous solution at pH <7.0 is determined by the nature of the counterion Y⊖.

The covalently bound active pharmaceutical ingredients can e.g. B. to 9- β- arabino-1,4-adenine, 5-fluorocytosine, acaturidine, 6-mercaptopurine or thioguanine. This also includes the nucleosides or nucleotides of the thymidine series, which inhibit the growth of neoplastic tumors, inter alia by inhibiting DNA synthesis. The entiviral substances of 1,3,5-triazines, e.g. B. the 2-acetamido-4-morphino-1,3,5-triazine, which has virustatic properties against herpes zoster, should be mentioned.

Table 2

Characteristic properties of the N⊖ surfactants of the general formula HET N⊖≡ (CH₂) _x -CH₃ Y⊖

Table 3

Yields and hydrodynamic radius of N-surfactants of the formula HET ≡ N- (CH₂) _x -CH₃ and benzethoium derivatives depending on Y⊖

The following Figure 6 shows the variance of the hydrodynamic radius of benzethonium chloride and N- Hexadecyl-4-cetyl-imidazolium salicylate depending of the hydrodynamic radius according to different ultrasound treated times in minutes, measured by inelastic laser light scattering.  

Further preferred embodiments of the invention

While the total range of critical micelle concentration (KMK) is in the range of 1.0 · 10 ^-7 to 1.5 · 10 ^-4 mol / liter, the KMK is preferably in the range of 1.0 to 8.5 · 10 ^-7 /Liter.

The cationic surfactant is preferably monovalent Anion in an amount of 0.05 to 0.1 wt .-%, based on the entire pharmaceutical preparation.

Particularly good results are achieved if the cationic Surfactant with the monovalent anion in an amount of 0.08-0.1% by weight, based on the total pharmaceutical Preparation that is included.

The hydrophobic active pharmaceutical ingredient is preferred in an amount of 0.06-0.05 wt .-%, based on the entire pharmaceutical preparation.

Particularly good results are achieved if the hydrophobic active pharmaceutical ingredient in an amount of 0.001-0.005 wt .-%, based on the total pharmaceutical Preparation that is included.

Solvents are preferably water or water + Glycerin or water + glycerin + ethanol.

Preferably the monovalent anion is a monobasic one or dibasic fatty acid residue.  

The monovalent anion is preferably acetate, propionate, Fumarate, maleate, succinate, aspartate or glutamate.

The monovalent anion is preferably a sugar residue.

Preferably the monovalent anion is gluconate, galacturonate or alginate.

Preferably the monovalent anion is chloride, bromide Iodide or hydrogen sulfate.

The hydrophobic active pharmaceutical ingredient is preferred an antimicrobial agent or an antifungal Drug or an antiproliferative drug or antiviral agent.

The hydrophobic pharmaceutical active ingredient is preferably an inorganic compound of the elements zinc or mercury or tungsten and / or antimony. Preferably, the inorganic compound Z _n SO₄ or Z _n O or Hg (CN) ₂ or (HN₄) ₁₈ (NaW₂₁ Sb₉O₈₆) ₁₇ or an alkali or alkaline earth metal salt of the phosphonic acid ROP (O) Me₂ or an N-phosphonoacetyl l-aspartate.

The hydrophobic active pharmaceutical ingredient is preferred an antibiotic or an antiviral agent or a antifungal agent or an antineoplastic agent.

The solvent is preferably water and / or ethanol and / or glycerin. Preferably the solvent is Water and / or ethanol and / or dimethyl sulfoxide.  

In any case, while the pH of the solvent is 7 must be the preferred pH of the solvent = 5 or near 5.

According to the invention, the pharmaceutical preparation can be essentially be produced by first in the solvent is placed in a reaction vessel, then the cationic surfactant with stirring at room temperature is then added to the resulting isotropic micellar Solution of the hydrophobic active pharmaceutical ingredient under Stirring at room temperature is added and to it complete solution is stirred.

Particularly favorable results are achieved with the cationic surfactants of the general formula II when x = 14, ie when the alkyl chain has 15 carbon atoms.

This straight-chain C₁₅ descendants of the N-surfactants are particularly characterized by a simple chemical production. In addition, they surprisingly have the lowest KMK (this is approximately 2.5 · 10 ^-7 mol / liter). They are still very easy to control with Y⊖ (shape, molecular weight distribution, polydispersity). They are also variable due to their size of the alkyl chain and therefore with regard to the absorption of the active pharmaceutical ingredients. Finally, they are characterized by easy crystallizability.

As already mentioned, the remainder is hexadecylpyridinium known (as a pure chemical compound). Not the influence of the associated is known according to the invention Anions (Y⊖) on the micelle size and shape of the micelle. With regard to the independent claimed according to the application Fabric protection for all new disclosed  Connections is therefore a generic term in the following disclosed, preferably the new invention Connections includes. This generic term is "isoelectronic heterocyclic nitrogen bases with 5- or 6- Rings containing either 2 N atoms in the 1,2 position or 1,3-position or 1,4-position or an S atom in 1 position with an N atom in 3 position ".  

Manufacturing process for pharmaceutical preparation: General information on the preparation of the aqueous phase:

To preferably a monodisperse, homogeneous and isotropic aqueous solution of the N⊕ surfactants both in terms of shape (spherical, oval, elongated) and size as well To achieve molecular weight distribution, the listed solutions including their included hydrophobic active pharmaceutical ingredients

• a) be treated with ultrasound, e.g. B. at 100 watts, a mint, then possibly by b)
• b) by column chromatography, e.g. B. on an agarose A 0.5 m, Sepharose 2 B, Sephadex G 200, DEAE-Sepharose C1-6B at pH 6.0 or on an Ultragel AcA44 (pH 6.0-6.5) or BiO gel 1.5 m at pH 7.0; or
• c) on a linear density gradient, e.g. B. from 1- 30% by weight subrose, in a preparative Ultracentrifuge in a SW-27 rotor at 25,000 rpm centrifuged for 12 hours. When using a zonal centrifugation with the same gradient (20 ° C) can at 10,000 rpm large amounts of homogeneous Centrifuged populations of micelles and vesicles will.
• d) DEAE cellulose column chromatography at pH 5.0 6.5 (pH7) e.g. B. by a phosphate gradient (linear from 0.01M, KH₂PO₄ / 0.01M K₂HPO₄, pH 6.5 up to 0.05M KH₂PO₄ / 0.05M K₂HPO₄ in total elution volume of 1000 ml) are cleaned until the corresponding  desired population of micelles or vesicles has been obtained.

So it is possible to get the desired homogeneous populations of micelles or visicles including their included active pharmaceutical ingredients, in the form of repeatable constant molecular weights and geometric To get shapes. This enables monomers the surfactants from the micelles as well as from not trapped pharmaceutical ingredients quantitatively to separate.

Preparation of the homogeneous, micellar solution in aqueous phase

The aqueous phase can be pure water. Usually however, an aqueous solution of an electrolyte is chosen. For example, an aqueous solution of NaCl or CaCl₂ (MgCl₂) be used. In addition, active pharmaceutical Active substances of the type mentioned are then introduced Micellar can also be solved under sonication.

Most procedures are more hydrophilic on encapsulation Active substances limited. With the present invention it is possible to use hydrophobic z. B. lipophilic inorganic (Hg (CN) ₂) and organic substances (amphotericin B) include micellar. Hydrophilic anions, have pharmaceutical importance, e.g. B. salicylate, each according to the nature of the N-surfactant (especially formula II) trapped on the external surface of the micelle will.

The invention can be used to either hydrophilic or lipophilic substances or both  Include substances. In the case of hydrophobic These then become active ingredients together with the N-surfactant of the formula I and II in a glycerol / ethanol mixture, consisting of 15% by weight glycerin, 15% by weight ethanol and 70 % By weight water or 50% by weight ethanol and 50% by weight water dissolved, possibly shaken or sonicated and then on the aqueous phases containing of glycerin / ethanol of maximum 15 g glycerin, 5 g ethanol diluted in 100 g water. Subsequent gel permeations Chromotography or preparative HPLC can be undesirable Remove material and a homogeneous, isotropic solution deliver. While hydrophobic substances primarily over an organic phase (50%) and subsequent dilution (Water) are made, are hydrophilic pharmaceutical Active substances preferably in the aqueous Liquid used to disperse the micellar Solution can be used. If necessary, any active ingredients not absorbed from the dispersion using known techniques, e.g. B. Dialysis, centrifugation, gel permeation chromatography be removed.

The shape and size, as well as the degree of hydration of the micellar solutions of the N-surfactants depends, among other things, on Y⊖, less on the structure of the heterocycle, but on the hydrophobic chain length (CH₂) _x . So z. B. in the presence of Br⊖ or Salizylat⊖ large rod-shaped micelles of hexadecylpyridinium are obtained of an order of magnitude of L = 10,000 Å and a diameter of 100-500 Å, while in the presence of chloride micelles of the order of 50-100 Å in aqueous solution. In this case, the shape and size of the micelle indicates the concentration of the (micellar) active substance to be encapsulated and is therefore the reverse of liposomes.

The advantage of the invention over encapsulation Liposomes

• 1. in the tightness of these N-surfactants, which the micellar-bound pharmaceutical ingredient due do not release the forces listed above can and
• 2. by controlling the shape and size of the micelles Y⊖ to control the absorption capacity of hydrophobic or hydrophilic active ingredients, without large, profound influence of the heterocycle on the KMK.

The formation of the small and large micelles of the N-surfactants in the aqueous phase can be demonstrated using physical measurement methods, e.g. B. with freeze-dried samples ("freeze fracture") in the electron microscope or by X-ray small-angle scattering, by dynamic light scattering, by nuclear magnetic resonance spectroscopy (1 H, 13 C and 31 P), as well as by transmission electron microscopy. Fig. 2 and 99999 00070 552 001000280000000200012000285919988800040 0002003726101 00004 99880d 3 show e.g. B. electron micrographs of micellar trapped Hg (CN) ₂ in hexadecylpyridinium and benzethonium chloride.

In the nuclear magnetic resonance spectrum there are sharp signals with a weak line width, which gives an indication of the formation of micelles with a diameter of less than 600 Å. Sharp signals at δ about 0.89 ppm (-CH₃), δ about 1.28 ppm (-CH₂-) and δ about 3.23 ppm (-N- (CH₃) ₂ are e.g. for the Micelles of the N-surfactants of the general formulas I and II are characteristic: For active substances included in these micelles of the N-surfactants, a methyl signal at δ is approximately 0.87-0.89 ppm, which is, however, split into a triplet and is essential has a smaller line width than the methyl signal, which occurs as a singlet at δ = 0.89 ppm, which, however, originates only from the micelle.

These aqueous phases, which are those obtained according to the invention Contain micelles with enclosed active substances, are administration systems, which may vary according to Concentration, e.g. B. by ultrafiltration, ultracentrifugation or lyophilization with subsequent dissolution in an aqueous phase, for oral (p. o.) or topical Administration.

When administered orally, the micellar bound active pharmaceutical ingredients of the N-surfactants of the aqueous Phase with pharmaceutically acceptable diluents or carriers or with usual additives, e.g. B. dyes or flavorings, mixed and as a syrup or in Form of capsules to be administered.

A homogeneous isotropic micellar aqueous solution preferably consists of an N-surfactant of the formula II and I with an antiviral active ingredient, in particular with Hg (CN) ₂, or ZnSO₄, ZnEDTA, idoxuridine, 5-ethyl-2'-deoxyuridine or trifluorothymidine, Amantadine, rimantadine ( α- methyladamantane) and viderabine (9- β- arabino <1.4 <-adenine) and ribavirin (1- b -D-ribofuranosyl-1,2,4-triazole-3-carboxamide) as well as with 2,6-Di-amini-kuban 1,1 ': 3,3'-bis-cyclobutane or simply substituted 2,6-di-amino compounds (CF₃, Cl, OCH₃) dispersed in the presence or absence of glycerol / ethanol (20 ° C; ionic strength <0.2 M).

A homogeneous, isotropic micellar aqueous solution exists from an N-surfactant of formula II and / or formula I. preferably with an antifungal agent, preferably with 5-fluorocytosine, clotrimazole, econazole, miconazole or Oxyconazole (Z-form) as well as with Amphotericin B, Nystatin and ZnOEDTA as an inorganic antifungal active ingredient, and Hg₂ (CN) ₄ (Hg (CN) ₂ is present here as a polymer, where the dimer is the basic construction principle (in aqueous Solution) dispersed.

A homogeneous, isotropic aqueous solution consists of a N-surfactant of the formula I and / or the formula II preferably with an antineoplastic agent, especially 5- Fluorocyanide, Hg (CN) ₂ · 4 (ascorbate or acetylacetonate), Azauridine, cytarabine, azaribine, 6-mercaptopurine, Deoxycoformycin, azathioprine, thioguanine, vinblastine, Vincristine, daunorubicin, doxorubicin in the presence or Absence of glycerin / ethanol dispersed.

A homogeneous, isotropic aqueous solution consists of a N-surfactant primarily of formula II or formula I. preferably with aminoglycosides such. B. canamycin, Gentamycin, neomycin etc. or tetracyclines, Chloramphenicol or erythromycin as bacteriostatic (gram-positive) or clindamycin (against non-spore-forming anaerobic bacteria) or rifampicin as bactericidal, as well as bacitracin, tyrotricin and polymycine in the presence or absence of glycerol / ethanol dispersed.

The homogeneous mixture can then also in gels based on alginate, hydrogel structures such as B. Sephadex agarose, propyl cellulose, propyl hydroxy cellulose, be dispersed in the presence of DMSO, glycerol,  the active pharmaceutical ingredients micellar in the desired concentrations are included.

It is dispersed e.g. B. by shaking, stirring the aqueous Phase or by ultrasound treatment, which the previously prepared homogeneous isotropic mixture contains. The Formation of the micellar structures with the included ones Active ingredients, pH 7.0, 20 ° C, takes place spontaneously, d. H. without great additional energy supply from the outside and with great Speed instead. The concentration of N-surfactant Formula I and II and inclusion compound can be increased if the KMK is exceeded by at least ten times is in the aqueous phase at constant chemical Potential and temperature.

The KMK is a variable size for the amount of monomers the N-surfactants, which can be found in a certain volume Dissolve water using pH fluctuations 7.0 can. The KMK, which according to the invention is not very dependent is of the nature of the counter ion, which is only the form determined, since work can be done far above the KMK through electrochemical processes (conductivity, Potentiometry) by measuring the transfer cells in the Connection with counterions, surface tension, Vapor pressure reduction, freezing point reduction and osmotic pressure, measurement of density, refractive index, elastic and inelastic light scattering (Diffusion coefficient, Stokes' radius) and the Viscosity, as well as by gel filtration and Small angle X-ray scattering measurements can be determined. Nanosecond fluorescence as well as measuring the Fluorescence polarization leaves additional determinations the location of the included pharmaceutical active ingredients by the N-surfactants of the formula I and II, for. B. by  ZnEDTA or Hg (CN) ₂ as quencher and amphotericin B as Amplifier. Positronium annihilation measurements on these described micellar solutions with the included Active ingredients also leave statements about the amount (Concentration) of the included pharmaceutical Active ingredient depending on the nature and concentration from Y⊖ to.

Aqueous phases with a pH <7.0 are after the Centrifuged dispersion. Neutralization to pH 7.0 is necessary to destroy the heterocycle in Formula II as well as the active ingredient and / or the micelles to prevent under basic conditions. Physiologically Common and compatible acids are e.g. B. dilute aqueous Mineral acids and hydrochloric acids. Sulfuric acid or phosphate acid or organic acid, e.g. B. Lower alkanoic acids such as Acetic acid or propionic acid. Most of the time they react aqueous phases of the cationic N-surfactants of the formula I. and II acidic to neutral, but can also be Buffers or organic inert buffers such as e.g. B. HEPES, MOPS or MES precisely adjusted to pH values between 3 and 7.0 will.

Preparation of the homogeneous, micellar solution in non-aqueous phases

The choice of solvents concerned is from Solubility of the active pharmaceutical ingredient concerned dependent on it. Suitable solvents are e.g. B. methylene chloride, Chloroform, alcohols, e.g. B. methanol, ethanol and propanol, lower alkane carboxylic acid esters, (acetic acid Ethyl ester), ether or mixtures of these solvents. After preparing the micellar solution and adding the active pharmaceutical ingredient, dissolved in organic  Solvent, the organic solvent becomes either by the above-mentioned methods a) -d) or by Blow off with inert gas, e.g. As helium or nitrogen, removed.

example 1

10 mg of hexadecylpyridinium chloride are dissolved in 100 ml of one Water / ethanol mixture (85:15; w / w) at 25 ° C with stirring and add 10 ml glycerol. The pH should be around 6.5, can, however, with HCl at this or another pH (= 7.0) can be set. This solution is then set to 20 ± 0.01 ° C cooled, then treated with ultrasound (Bronson Sonifier, Mass., U.S.A.) for two minutes at 10 watts. The Micelle formation is achieved by measuring the diffusion coefficient determined by means of inelastic light scattering and then after the relationship

the Stokes' radius (R _H ) is calculated. In the presence of Cl⊖ as Y⊖ it should not be larger than 50 Å, of Br⊖ it should not be larger than 1000 Å. To form microemulsions of micelles of a certain size, a film-like residue, which is obtained by evaporating the above-mentioned solution in a rotary evaporator, is dispersed at room temperature (20 ° C.) in 1/10 of the volume by shaking for 10 minutes. A slightly opalescent, aqueous solution is obtained. For the inclusion of an active pharmaceutical ingredient, e.g. B. 5-fluorourazil, cytarabine or idoxuridine, these sparingly water-soluble substances directly, ie in solid form or as an aqueous suspension. So you give z. B. trifluoridine, 1.0-3.0 mg, at 20 ° C with stirring either as a microemulsion (suspension) or to the aqueous micellar solution of the quaternary ammonium base directly. - A quantitative dosage of these nucleoside and adenine nucleoside compounds can also be achieved by dialysis:

The micellar solution of the above-mentioned concentration (buffered, unbuffered, pH ≅ 6.0, ionic strength variable, T = 293 ° K) is filled into a dialysis tube (from Servant or Pharmacia), closed and, with constant stirring, at room temperature against a set one Solution of pH 7.0, containing the above-mentioned pyridine or / and adenine nucleoside of a certain concentration, dialyzed for 2 hours. The decrease in the absorbance at 260 nm with the time of dialysis allows the micellar incorporation of the above-mentioned active substances into the hydrophobic core of the hexadecylpyridinium chloride to be checked (Tab. 1).

Table 1

(20 ° C, pH 5.5)

The formation of small micellar structures in the solution mentioned above can be recognized in the NMR spectrum by the signals δ = 1.25 (methylene), δ = 0.86 (methyl). By incorporation of the pharmaceutical active ingredients mentioned above, depending on the saturation in the hydrophobic core, there is a shift of δ = 1.25 (methylene), but not of δ = 0.86 (methyl).

The size of the micelles can easily be determined by inelastic light scattering according to formula (1) (Table 1). The size, including the shape and to maintain a homogeneous and monodisperse solution can also be achieved by HPLC chromatography, gel permeation and agarose chromatography ( Fig. 7).

A concentration of the micelles produced in this way can be Pressure dialysis can be achieved using fiberglass cartridges Pore size. So it is possible not just a defined one Concentration of active pharmaceutical ingredient, but also the micelle size, aggregation rate, Keep hydration (solvation) constant because there is no fusion the micelles ("intermicellar growth") occurs. This means the number of micelles per unit volume with their included active pharmaceutical ingredient increases (concentration hydrodynamic particles with the same molecular weight), not the aggregation rate, nor the number of possibly present monomers, separated by ultrafiltration will.  

Example 2

Analogously to Example 1, 15 mg of benzethonium chloride are dissolved per experiment in 150 g water / ethanol (85/15; w / w) at 25 ° C below Stir and add 0.5 ml glycerin. The pH is normal between 4.8 and 5.5. To be clear, not opalescent To get solution, this solution is kept at 25 ° C for two minutes at 20 watts treated with ultrasound. The formation of the micelles defined size is after five minutes after cooling to 20 ° C completed. For incorporating the above-mentioned antivirals Active ingredients, e.g. B. trifluoruridine, idoxuridine, can like procedure under Example 1.

For the inclusion of miconazole (Z form), the micellar solution thus prepared is dispersed in the presence of miconazole of a certain concentration, treated with ultrasound (2 minutes), then chromatographed over agarose, the micelles being eluted with the hydrophobically enclosed Z-miconazole as a uniform, monodisperse peak can. The size and concentration of active ingredient can be determined by inelastic light scattering and UV spectroscopy. ( Fig. 8)

Analogously to Example 1, 10 mg of benzethonium chloride and a desired concentration of Z-miconazole can be dissolved in 5 ml of a chloroform / methanol (3: 1) mixture, then concentrated by "hollow fiber pressure dialysis" and then dispersed in water or the desired buffer . A clear aqueous solution is obtained which consists of micelles of the order of magnitude of R _H = 60-80 Å in the presence of Cl⊖ or R _H = 100-1000 Å in the presence of salicylate with the active ingredient included.

By adding 1% (g / g) alginate and / or 5% (g / g) Dimethyl sulfoxide can also use tixotropic gels with the front included active ingredients mentioned. By increasing the benzethonium chloride concentration, including of the included active substances, up to 2% (g / g) Effective oils can also be produced.  

Example 3

Analogously to Examples 1 and 2, the counterions Y⊖ = Cl⊖, Br⊖ etc. after production according to the process by ion exchanger Chromatography on DEAE-Sephadex A 50 or DEAE- Sepharose or by re-dialyzing against that or desired counterion Y⊖ are exchanged.

• a) an aqueous micellar prepared according to Examples 1 and 2 Solution is brought to pH = 7.0 with 0.01 N NaOH (20 ° C). This can be done either by titration or dialysis against 0.01 N NaOH over 10 hours. Subsequently there is dialysis against 1N fumarate or maleate solution, where the Na salts of fumaric or maleic acid are used can be. Dialysis ends after 12 hours. A loss of antiviral active ingredients up front are not mentioned.
• b) an aqueous micellar prepared according to Examples 1 and 2 Solution, pH 6.0, is on a DEAE-Sephadex A 50 (1.0 × 100 cm) column previously buffered (0.01 M K₂HPO₄ buffer) 0.1 N salicylate solution was, with a flow rate of 10 ml / 30 min eluted (20 ° C). The excess salicylate is removed by Dialysis against a large excess of water / ethanol / Glycerol (90/5/5; g / g) removed from the column eluate. DEAE-Sephadex A 50 chromatography can also be found at Countercurrent printing with the same solvent system be performed. It results in the Exchanger chromatography (DEAE-Sephadex A 50, DEAE- Sepharose 2B, 5B, DEAE cellulose, hilly) a homogeneous Peak according to the criteria in Examples 1 and 2 have been shown, can be analyzed. DEAE- Sephadex and DEAE-Sepharose have the advantage of being significant Amounts of micellar quaternary ammonium bases both cleaned and tested for mono-dispersity can be.

Example 4

Analogously to example 1, a micellar solution of Hexadecylpyridinium chloride with the following pharmaceutical Active ingredients manufactured:

100 g solution contain:

Hexadecylpyridinium chloride 0.10 g Atropine hydrochloride (±) 0.002 g Zinc II chloride 0.004 g Glycerol 10.0 g Ethanol 4,894 g Water 85.0 g pH 6.2

This preparation has a hydrodynamic radius of 35.0 ± 5.0 Å and an aggregation rate of N = 35, at a molecular weight of the monomer of hexadecylpyridinium chloride of 393.0. Every micelle of this Diameter contains on average 100 µg zinc and / or 50 µg atropine (-).

Fig. 9 shows the variance in the hydrodynamic radius, R _H , of this preparation. It also shows the separation of the racemate atropine according to the invention described above into the optical antipodes z. B. Hyocyamine (-). The micellar size distribution is not changed by ZnII chloride.

Fig. 10 shows the variance in the hydrodynamic radius, R _H , the N-hexadecyl-4-methyl-pyridinium chloride and N-hexadecyl-4-methyl-pyridinium chloride + atropine-HCL.

Example 5

5 mg of 4- (17-tritriacontyl) -N-methyl-pyridinium- chloride, 1-2.0 mg amphotericin B in 10 ml chloroform / Methanol mixture (2: 1) under nitrogen at 25 ° C and evaporates this solution in a rotary evaporator. The film-like residue is distilled in 5 ml Shaken water for five to ten minutes. This solution is then sonicated for three minutes until it is no longer opalescent. You can do this, depending as required, then by adding 0.5 ml of a five-fold concentrate of phosphate-buffered, isotonic Bring saline to pH 5.5-6.5.

This solution prepared in this way is poured into a stirred ultrafiltration cell (e.g. Amicon®), which instead of the ultrafilter is provided with a straight-pored filter with a pore diameter of 0.05 µm, in the absence of Me ²⁺ ions (Me ²⁺ = Ca ²⁺ , Mg ²⁺ ,) filtered so that the volume in the cell does not drop below 30 ml. This produces vesicles of a uniform size of <50,000 Å.

Shape, size and molecular weight distribution can be like can be determined in Examples 1 and 2. The pyridinium Amphiphile is made from the corresponding iodides Silver chloride made in 10% (v / v) ethanol water. The colorless crystals have an mp = 64 ° C. (from acetone recrystallized) and crystallize with one Molecule of water.

1 H-NMR (CDCl₃ / Me₄Si): δ 0.93, (6H, t, J∼4Hz), 1.28 (60 H, m) 2.8 (1H, q, J <2Hz, not resolved), 4.75 (3H, s), 7.7-9.5 (4H, m). An H₂O-dependent signal at δ 4.4 is characteristic.
Anal: Calc. for C₃₉H₇₄NCl · H₂O (MW 610.50) C, 76.72; H, 12.55; Cl, 5.81; found: C 76.53, H, 12.42; Cl, 5.78.

Example 6

Analogously to Example 5, 10 mg of 3,5-bis [(n-hexadecyloxy) carbonyl] -N-methyl-pyridinium chloride (mp = 102-102.5 °) with 2.0 mg of amantidine or rimantadine in 10 ml of an ethanol / Water mixture (1: 2) dissolved under nitrogen at 20 ° C. After ultrasound treatment (5 min, 20 ° C., 10 watts), the vesicles formed with their active ingredients amantidine or rimantadine can be separated on a Sepharose 2B according to size and molecular weight in order to obtain a homodisperse solution of vesicles with low molecular polydispersity. The 1 H NMR spectrum shows the clear signals of the methylene ( w = 1.28) and methyl protons ( δ = 0.86).

These unilamellar vesicles formed in Examples 5 and 6 can be made visible in the electron microscope. For this purpose, the vesicle dispersion is first called the "freeze" fracture "method. Also," negative staining "using the two drop method on Formvar or coal grids. Through these two Techniques, it is also possible to identify possible populations of vesicles visible.

The inelastic light scattering method used in Examples 1 and 2 also makes it possible to determine the shape and size of these vesicles and their enclosed pharmaceutical active ingredients ( Fig. 11).

3,5-bis [(n-hexadecyloxy) carbonyl] -N-methylpyridinium chloride, m.p. 102.0-102.5 ° (acetone). 1 H-NMR (CDCl₃ / Me₄Si): δ 0.85 (6H, t, J 5Hz), 1.30 (56H, m), 4.40 (4H, t, J <7Hz), 5.03 (3H, s) 9.20 (1H, t, J <2Hz), 10.00 (2H, d, J <2Hz).
Analyte. Calc .: C₄₀H₇₂NO₄Cl (MW 666.47): C 72.10, H 10.88, C 15.32; found C 71.44, H 10.84, Cl 5.23.

Example 7

3 ml of gentamycin are dissolved analogously to Examples 1 and 2 or in one of the surfactants mentioned in Table 3 quaternary ammonium bases in 1 ml of a chloroform / methanol Mix (3: 1) and evaporate this solution to one thin film. This is then dispersed in 10 ml of water. Then you can the solution to the desired Adjust pH <3 <6.5 with buffer. You get a clear solution.

Depending on the use of the surfactant according to Table 3, this clear solution contains a monodisperse distribution of micelles loaded with gentamycin in the desired size and yield ( Fig. 12).

Example 8

A micellar solution of hexadecylpyridinium chloride (Cetylpyridinium) is analogous to Example 1 (20 ° C) prepares and contains the following active ingredients:

100 g solution contain:

Cetylpyridinium chloride 0.10 g atropine hydrochloride (±) 0.004 g mercury II cyanide 0.004 g glycerol 10.892 g ethanol 5.0 g water 84.0 g p / h, T = 293 ° K 5.7

According to the invention, this preparation has a hydrodynamic radius of 35.0 ± 10.0 Å and an aggregation number, n , of 35 with a molecular weight of the monomer of cetylpyridinium chloride of 393.0. Each micelle of this diameter contains an average of 5 µg Hg (CN) ₂ and / or ∼5.0 µg atropine (-) ( Fig. 14).

This preparation is a homogeneous solution containing micelles on the order of 30-50 Å ( R _H ) . It inhibits the growth of influenza A virus as shown in Table 6 below ( Fig. 13).

Table 6

Fig. 7 shows the variant in hydrodynamic radius, R _H , of this preparation. It also shows the separation of atropine according to the invention described above into its optimal antipodes in the presence of Hg (CN) ₂.

Example 9

5 mg of one in Table 3 (primarily No. 1.2 or 4) indicated N-quaternary ammonium base and 2.0 mg 5-fluorourazil or 1.5 mg 5-fluorodeoxyuridine in 10 ml of one Chloroform / methanol / ether (mixture (3/1/1) and dispersed this micro-emulsion by shaking vigorously for two hours at 25 ° C. There are two ways of further processing:

• a) The suspension is evaporated to a thin film (under N₂ and UV protection). The film-like residue is then in water or buffer, e.g. B. 0.01 M to 0.001 M KH₂PO₄ adjusted to pH 4.5-6.5 or dispersed. Subsequently you separate the clear, micellar solution after going before to increase the yield of this z. T. opalescent solution treated with ultrasound (10 watts, 2 min) on a Bonderpak I-250 or an RP 18 column through high pressure liquid time chromatography (HPLC) of any monomers present and non-included pharmaceutical ingredients. It is in a stirred ultrafiltration cell (Amicon®) with a filter made of polycarbonate with a pore diameter of 0.015 µm concentrated.
• b) 10% (g / g) dimethyl sulfoxide (DMSO) and 2.5% (g / g) alginate are stirred into this suspension at 25 ° C. The gel formed forms spontaneously. In the small-angle X-ray diagram, a unit distance of d = 125 Å is found, which is very different from alginate gels (d = 25.45 Å). The gel has tixotrophic properties and becomes liquid at 45 ° C. The gel regresses at 42 ° C and reaches its constant rheological parameters at 20 ° C or 37 ° C after 2 hours.

The final concentrations per 100 g of pharmaceutical Preparation result as follows:

a) 100 g of solution contain:

N⊕ surfactant (Table 3, No. 4) 0.01 g 5-fluorodesoxyuridine 0.10 g glycerol 11.89 g water 88.00 g T = 293 ° K, pH = 5.5

b) N⊕ surfactant (Table 3, No. 2) 0.05 g 5-fluorodeesoxyuridine 0.05 g dimethyl sulfoxide 10.00 g alginate 2.50 g water 86.50 g T = 293 ° K, pH = 5.5

Example 10

15 mg (0.02 mmol) of benzethonium chloride, 2 mg, are dissolved 2-Acetamido-4-morpholino-1,3,5-triacine in 30 ml of one Water / ethanol mixture (80:20 or 90:10) at 20 ° C below Ultrasonic treatment in 0.01 M K₂HPO₄, pH 6.5 below N₂ current on. An opalescent, aqueous is obtained Phase. By separating the "reverse micelles" (reversed micelle) from the micelles in aqueous phase on a Sepharose 2B column (1.5 × 100 cm) a uniform, monodisperse micelle formation with an average hydrodynamic radius of 50 Å. The chromatographed solution can be as in Example 9 be concentrated by ultrafiltration. The solution is stabilized by using 5% (w / w) Glycerin or by adding 2% (w / w) salicylate. The solutions thus produced change their hydrodynamic Radius, their partially specific volume and molecular weight distribution in the temperature range from 15-45 ° C not.

100 g solution contain:

Benzethonium chloride 0.15 g 2-acetamido-4-morpholino-1,3,5-triazine 0.006 g salicylic acid 0.05 g glycerol 5.00 g water 94.894 g T = 239 ° K, pH = 5.5

Example 11

30 mg (0.020 mmol) of 3,5-bis [(n-hexadecyloxy) carbonyl] - N-methyl-pyridinium chloride and 1.0 mg (∼0.005 mmol) of polyoxin A are dissolved in 10 ml of 0.01 M KH₂PO₄, pH 6 , 5 at 20 ° C, the 1 ml of a mixture of tert. Contains butanol / methanol / ethanol (2: 1: 1). The solution is treated with ultrasound (20 watts, 5 min) in an ice bath at 0 ° C. and then made up to 20 ml with phosphate buffer, pH 7.0. The clear, non-opalescent solution is chromatographed on a Sepharose 2B column at pH 7.0 in the presence of phosphate at room temperature. The vesicles doped with the active pharmaceutical ingredient are concentrated in an ultrafiltration cell (Amicon®) with a pore diameter of 0.05 µm under slight excess pressure. After 0.3-0.5 ml of filtrate has passed through, all vesicles with a diameter of 350 Å are separated and the supernatant dispersion can be ampouled and used for treatment experiments. Fig. 15 shows the inhibition of chitin synthetase in digitonin-treated cells (Sacchamyces cerivisiae and Candida albicans) after addition of this preparation depending on the polyoxin A concentration, Fig. 16: Image of the "freeze-etch".

Example 12

Analogously to Example 2, 10 mg Hg (CN) ₂ and 40 mg Na ascorbate at pH 7.0 are dissolved in 10 ml phosphate buffer. The suspension is sonicated at 0 ° C for 5 min, slowly warmed to 20 ° C and centrifuged on a 10% (w / w) linear glycerol gradient in a preparative ultracentrifuge at 1000 × g for 6 hours (20 ° C, polyolomer Tubes). After dripping, the UV-active fractures are combined in an Amicon flow cell and then analyzed for mercury, ascorbate (HPLC; eluent CH₂OH / H₂O (50/50) mercury detection with sodium diethylthiocarbamate, hexadecyl pyridinium-Cl, e.g. B. by UV detection at 251 nm; N ascorbate by UV detection at R = 245 nm at pH 2.0 and R = 265 nm at pH 7.0). These micellar-enclosed Hg (CN) ₂-ascorbate complexes (MW ≃ 1,500) have the following representative inhibitor concentrations compared to B. subtilis DNA polymerase III according to Table 5.

Table 5

The inhibitor concentrations are 50% complete Inhibition indicated. The assay that has been used is the according to Clements, J; D'Ambrosio, J; Brown, N.C .; J. Biol. Chem. (1975) 250, 522 and Wright, G.E .; Brown, N.C .; Biochem. Biophys. Acta (1976) 432, 37.  

Pharmacodynamic trials

The importance of highly reactive oxygen molecules (superoxide radicals O _2₁ , peroxides H₂O₂, hydroxyl radicals ⁰OH, singlet oxygen ¹O₂) in the inflammatory process is known (see e.g. McCord, J. M, K. Wong: Phagocytosis-produced free radicales: roles in cytotoxicity and inflammation. In: Oxygen Free Radicales and Tissue Damage, Excepter Medica, Amsterdam-Oxford-New-York, 1979, 343-360; General and Special Pharmacology, Herg. W. Forth, D. Henschler, W. Rummel, Bio-Scientific Publisher, 1983) . They arise, among other things, in phagocytosis through activated leukocytes (monocytes, macrophages, polymorphonuclear, neutrophilic granulocytes) and can be used to kill foreign cells such as bacteria, bacilli and other viruses, if the immune system and the receptors specific for IgG or the complement C₃ the phagocytes are functional, serve. The phagocytic cells themselves are protected intracellularly by a system consisting of several enzyme systems against damage by these particularly active forms of oxygen.

It has now been found that quaternary ammonium bases of general formulas I and II

where Y⊖ is a counter ion both inorganic, z. B. Cl⊖, Br⊖, H₂PO₄ ^- or organic nature, for. B. fumarate, malate, salicylate, acetate, propionate, gluconate and alginate, the heterocycle can be either pyridine, pyrimidine, pyrazine, imidazole, thiazole or purine - but can be a π excess or π- deficient aromatic system - all are able to eliminate these oxygen radicals at pH 7.0 according to the following reaction mechanism:

In all reactions that occur in the inflammatory region between pH 5.0 and 6.0, what is guaranteed by the process preparation of this invention requires a pH range of 7.0. As a result, the aggressive oxygen radicals formed are reacted according to reaction 1-4 by the N-surfactant, e.g. B. Cetylpyridinium chloride, as well as the resulting hydrated, short-lived electrons, which can arise from collision · O₂ ^- radicals with H₂O. As a result, the N-surfactants in the pH range 7.0 have a membrane-protective effect according to the invention, so that inflammatory reactions according to a prostaglandin mechanism cannot occur. The high capture rate · O₂ ^- radicals in these N-surfactants of k = 5 × 10¹²N ^-1 sec ^-1 and their dependence on the ionic strength, which can be kept constant by adding ethanol / glycerol, is due to the electrostatic double layer structure quaternary ammonium bases explainable.

Thus, according to the invention, misdirected lytic reactions, in which aggressive oxygen radicals are involved, are prevented as pathogenic mechanisms of the inflammatory diseases caused by microorganisms and viruses. Thus, among other things, the cytotoxic effects of the secondary products of these aggressive · O₂ ^- radicals are prevented by the N-surfactants according to the invention, as shown by the example of cetylpyridinium halide, and inter alia depolymerizations of hyaluronic acids, proteoglycans, collagen fibrils, cytoskeletons etc. and also in muscular and membrane-like ones Fabrics (outer surfaces) prevented.

Furthermore, according to the procedural described Preparation found that compounds of structure I and II the infection of human cells is reduced in vitro, so that those produced according to the invention micellar solutions from I and II provide protection represent for the cells or their external surface.

It was further found that this protection by incorporation of Hg (CN) ₂, ZnEDTA and / or antiviral, antifungal and antibacterial agents is reinforced:

It has been found that when incubated with influenza virus, Subgroup A₂, infected monolayer cell cultures of Vero cells as well as herpes simplex virus HSV I-III in vitro more than 60% of the cells before infection by the affected Virus protected.

It was further found that the effect of the protection by the N⊕ surfactants according to the general formulas I and II for monolayer cell functions in vitro is not enhanced by the antiviral active ingredients, but the inhibitory concentrations of the antiviral active ingredients of cytarabine, idoxuridine , Trifuorthymidine as well as herpes simplex virus type 1 or influenza virus type A₂ infected monolayer cells reduced by 30% compared to applications that did not contain quaternary ammonium bases according to formula I and II. The combination of N⊕-surfactant according to the general formula I and II thus proved to be the effective antiviral in combination with micellar-bound antiviral agents ( Fig. 4).

It was also found that the N⊕ surfactants according to general formula I and II the antifungal effect in Combination with antifungal agents such as econazole, Clotrimazole, miconazole enhanced (≈35%) because of the N⊕ base with a suitable counter ion is able to cholesterol out the external membrane of the fungus or hyphae forming extract from mixed micelles and then the antifungal agents that are bound again are able to inject into the cell interior of the fungus.

It was further found that the antifungal activity by amphotericin B and an N-surfactant of the formula II, preferably hexadecylpyridinium bromide, decyl and Hexadecyl-1-pyridinium chloride or hexadecyl-4-hydroxy pyridinium chloride by a previously unknown Mechanism is strengthened tenfold. this includes according to the invention that a much lower Concentration of the active pharmaceutical ingredient sufficient to have the same therapeutic effects to reach.

It was u. a. found the fungistatic effect through micellar incorporation of ZnEDTA and ZnO, in particular also by Hg (CN) ₂ in the N-surfactants of the formula I and II, especially with hexadecyl-pyridinium chloride and hexadecyl-4- hydroxy-pyridinium bromide is enhanced, especially in Concentrations of the inorganic active substances, where they are are not yet effective.  

It has been found that, according to the invention, the micelles of N-surfactants in aqueous phase at pH 7.0 therapeutic Amounts of benzoyl peroxide that are poorly water-soluble and alcohol-soluble is able to bind micellar. So z. B. 1 g of benzoyl peroxide in 20 ml of benzethonium chloride or in 25 ml of hexadecyl pyridinium chloride, but especially in 3-hexadecylbenzothiazonium be dissolved bromide. When used locally solves the micellar solution similar to peeling effects on the Skin like tretinoin. Because of its additional very good bacteriostatic properties, both of the benzoyl peroxide as well as the N-surfactant, is according to the invention this combination is particularly useful for inflammatory forms of acne suitable, e.g. B. Acne comedonica, Acne papulo-pustulosa and Acne conglobata.

It has been found that those produced according to the invention Micelles in the aqueous phase of the N-surfactants, in which Hg (CN) ₂ or ZnO, ZnSO₄, ZnEDTA micellar is included in the Cell culture irreversible and virus-specific proliferation of herpes simplex viruses due to inhibition of viral DNA Inhibit polymerase. The non-infected cells remain largely unaffected so that those described in this invention Process, e.g. B. for hexadecyl pyridinium chloride, 3-hexadecyl benzothiazolium bromide (sulfate) including the front mentioned inorganic active ingredients, at a risk-free Therapeutic leads. The astringent properties of Hg (CN) ₂, ZnO, ZnSO₄, ZnEDTA, do not matter because there are no free ions in the hydrophobic core of the micelles, a) there z. B. Hg (CN) ₂ (more correctly Hg₂ (CN) ₄) undissociated is, b) the inorganic active substances through their Lipophilia are included and c) almost no water in the hydrophobic core is present.

The combined effect, the formation of mixed micelles ("mixed micelles") of the N-surfactants according to the general formula I and II with the virus-infested membrane and the phospholipid double membrane of the virus itself and the subsequent antiviral effect on the virus DNA - Polymerase due to the above-mentioned inorganic and organic active ingredients such as the nucleoside analogue, 5-ethyl-2'-deoxy-uridine and viderabine, could be detected according to Fig. 4a, b.

This mechanism could also be used in rhino and Influenza viruses are detected. Similar Effects, however at lower active substance concentrations were for 1,1 ′: 3,3′-biscyclobutane and for 1,1 ′: 3,3′-amine-substituted cubans found.

It was found that the enhanced antiviral Effect on phospholipid viruses, adeno viruses and Herpes simplex I through the N-surfactant and Active substances included in micellar according to the following biochemical mechanisms work synergistically unfold:

• a) binding to DNA, RNA-forming enzyme systems, Unfolding of the polypeptide chain by the N- Surfactant (denaturing),
• b) (reinforced) "template" binding, e.g. B. daunomycin, Adriamycin,
• c) binding to nucleoside analogs, e.g. B. the front mentioned ara-CTP-C5'-triphosphate of cytosine arabinosids, azathioprine,
• d) binding of inorganic active ingredients, e.g. B. ZnSO₄, ZnO, Hg (CN) ₂, tungstic acid antimonates, e.g. B. (NH₄) ₁₈ (NaW₂₁Sb₉O₈₆) ₁₇ and K₁₈ (KW₂₁- Sb₉O₈₆) ₁₇, and Hg-substituted cubans of type mentioned above. In connection with the antiviral effect of the micellar enclosed antiviral agents according to the procedural processing is one Reduction of ED₅₀ by 20-25% in vitro compared to the pure active ingredient, so the same molecular biological Effect at an approx. 20% dose by the micellar effect can be achieved. this applies especially for micellar trapped Rubaricin in hexadecyl pyridinium bromide, Hexadecyl-benzothiazolium chloride and  Benzethonium chloride. DNA viruses, herpes viruses are most sensitive in these examples in Contrary to rimantadine + N-surfactants of the formula I and II, which are primarily in vitro against RNA Viruses are effective.

It was further found that the anti-tumor activity of adenosine deaminase inhibitors that are micellar according Formula I and II are solved according to the process, for. B. Erythro- 9- (2-hydroxy-3-nonyl) adenine, deoxycoformycin to do this Is amplified tenfold. The same could be done for Aspartate transcarbamylase inhibitors are found; N- (phosphono-acetyl) - enclosed by micellar aspartate the biosynthesis of pyrimidine by blocking the carbamylation of aspartate is increased 20-fold.

It was also found that both micellar trapped Hg (CN) ₂, ZnSO₄, ZnO or ZnEDTA, as well as 5-trifluoromethyl 2′-deoxyuridine, which is derived from trifluoromethyl uracil in vitro arises, the thymidine synthetase - a key enzyme of DNA synthesis - irreversibly inhibits.

Pyrimidine biosynthesis is accomplished by pyrazofurin, a naturally occurring antibiotic, which included micellar is irreversibly inhibited by 20% while at the same time Reduction of cell toxicity.

It has also been found that the diffusion barrier for antibiotics, e.g. B. tetracyclines, aminoglycosides also for β- lactam antibiotics (penicillin) after a certain time in E. coli bacteria for the micellar trapped active ingredients are reduced. This diffusion barrier is concentration-dependent for the active substances mentioned above, but not for the N-surfactants produced according to the process. These are folding processes on the outer membrane, primarily to change the structure of the porins within the outer membrane of E. coli, so that, for. B. the inorganic active ingredients Hg (CN) ₂, ZnSO₄, ZnEDTA can diffuse into the periplasm of the outer cell membranes of gram-negative bacteria.

The porins are membrane-like, water-filled pores, through which hydrophilic pharmaceutical agents can diffuse into the interior of the cell. Hydrophobic active pharmaceutical ingredients cannot pass through these porins. The N⊕ surfactants in particular of the general formula HET≡N- (CH₂) _x -CH₃Y⊖ as well as benzetonium derivatives can pass through these water-filled pores. Thus, micellar-enclosed pharmaceutical, hydrophobic (lipophilic) active substances, in particular of an inorganic nature, can pass through the hydrophilic, external form of the N⊕ surfactants through passive diffusion into the cell interior.

Here they also react with the cell wall-synthesizing enzymes, in particular with Hg (CN) ₂ at concentrations of 10 µg / ml, ZnEDTA at c = 5 µg / ml.

The rate of diffusion enclosed by micellar Active ingredients increase with increasing hydrophobic character, this is usually the other way around, e.g. B. decreases the rate of diffusion in Gram-negative bacteria with increasing hydrophobic character. Favored further a positive charge the diffusion and formation of "Mixed micelles" of these to be produced according to the invention N-surfactants.

The validity of these findings could be checked the diffusion and dissolution rates of various radioactive (C¹⁴) labeled N-surfactants on the membrane (Periplasma) can be detected depending on the concentration.

It was also found in vitro that the thymidilate Synthesis (TS) (EC2.1.1.45) both by Hg (CN) ₂ in aqueous Solution as well as in micellar solution of an N-surfactant Formula I and II, in which Hg (CN) ₂ is dissolved hydrophobically, inhibited becomes. TS catalyzes the conversion of dUMP and CH₂-H₄- Folate to dTMP and H₂ folate. Because this enzyme is for the Synthesis of dTMP is essential, i.e. for DNA synthesis par excellence, it also represents a target for pharmaceuticals Active substances against neoplastic cells. It has now been found that e.g. B. a manufactured according to the invention Solution of hexadecylpyridinium chloride, the Hg (CN) ₂ holds hydrophobic bound, listed in Table 1 cytostatic activity against leukemia cells (L1210 cells). So u. a. being found,  that TS, DUMP and Hg (CN) ₂ as an inorganic pharmaceutical Active ingredient a ternary complex according to (A, B)

(cl UMP)
R = DESOXy RiBOSE

form, which can be isolated by column chromatography on Sephadex G-25 and BiO-Gel P10. The formation of the complex according to equation A has a formation constant of k ₁ = 0.51 h ^-1 , in the case of hexadecylpyridinium chloride, and k _-1 = 0.79 h ^-1 in the case of benzethonium chloride and micellar-enclosed Hg (CN) ₂. The dissociation constants are k _-1 = 0.015 h ^-1 (CPCl) and k _-1 = 0.02 h ^-1 , both very slow, although the formation and the dissociation of the complex. In contrast, the formation of the dimer according to B is much faster: k ₁ = 0.02 h ^-1 and k _-1 = 0.015 h ^-1 for CPCl and k ₁ = 0.01 h ^-1 , 0.03 h ^-1 for benzethonium chloride . This means that micellar solutions of quaternary ammonium bases according to formulas I and II at pH 7.0, which keep Hg (CN) ₂ bound hydrophobically, are therefore therapeutic in slow-growing tumors, where other inhibitors are ineffective in TS and counter the observed cytotoxicity the normal cells of other antimetabolites in rapidly growing, proliferating cells can therefore be slowed down.

Ribavirin, which is a synthetic 1,2,4-triazole nucleoside, has a broad antiviral spectrum for DNA and RNA viruses. Micellar-enclosed ribavirin through cationic surfactants of the form (Het≡N⊕- (CH₂) _x -CH₃) Y⊖ passes the membrane barrier very quickly, faster than the active pharmaceutical ingredient itself. The conversion of ribavirin to monophosphates, diphosphates and triphosphates by the specific cellular enzymes is also increased, so that the inhibition of the virus-induced enzymes, which are necessary for viral nucleic acid biosynthesis, is accelerated. While ribavirin alone has only a moderate effect on cellular DNA synthesis and is cytotoxic in the range of 200-1000 µg / ml in normal cell lines, the cytotoxicity in the presence of cationic micelles, if micellar included, drops to 50 µg / ml (in vitro tests), measured against cells infected with herpes simplex (DNA virus).

Amantadine (l-adamantanamine HCl) has a special pharmacodynamic effect against influenza viruses (class A). Replication of most influenza A strains is inhibited between 0.2-0.6 µg / ml in vitro. Micellar-enclosed amantadine in cationic micelles, in particular in the form (HET≡N- (CH₂) _x -CH₃) Y⊖ bring about a reduction in the concentration of active pharmaceutical ingredient to 0.05 µg / ml amantadine measured according to Hayden at. Al inhibition assay for drug susceptibility resting of influenca viruses. Antimicrob. Ag. Chermother. 1980, 17: 865-70; Grunert et al .; Sensitivity of influenza A / New Jersey 18/76 / (Hswl-N1) virus to amantadine HCl , J. Inf. Dis. 1977, 136, 297-300). While amantadine has almost no activity against influenza virus type B, micellar-enclosed amantadine is inhibited in the cationic surfactants of the formula

Y⊖ = fumaric acid residue
(2-hydroxy-5-fluoro-hexadecylpyrimidinium fumarate)

Y⊖ = fumaric acid residue
(2-hydroxy, 5-methyl-6-amino-hexadecylpyrimidinium fumarate)

At a concentration of 0.01% by weight of amantadiene Influenza virus type B corresponding to a concentration of 0.5 µg / ml active pharmaceutical ingredient in vitro.

A surprising effect of micellar trapped Amantadine in the two cationic surfactants of the above Formulas have been found to fight type A influenza virus Amantadiene does not become resistant in vitro while it does Amantadine alone is the case.

Rimantadine HCl ( α- methyl-l-adamantanmethylamine hydrochloride) has the same pharmacodynamic effects in vitro as amantadiene, but is more effective at the same dose. Here too, it was surprisingly found that micellar-enclosed rimantadine was found in a cationic surfactant, in particular of the two formulas above, to have the same in vitro effect as with the pure pharmaceutical active ingredient, but at a much lower dose of 0.05 μg / ml.

Among the inorganic active pharmaceutical ingredients, Hg₂ (CN) ₄ and micellar-bound Hg (CN) ₂ develops a surprising antiviral, interferon-induced spectrum in cationic micelles. In cell cultures of lymphocytes and fibroblasts it was possible to induce interferon α 1 and interferon β after incubation with micellar-enclosed Hg (CN) 2 in a cationic surfactant of the formula

Y⊖ = chloride
Hexadecylpyridinium chloride

Y⊖ = salicylate
2-carboxamide hexadecylpyrazinium salizylate
at a concentration of Hg (CN) ₂ of 5 µg / ml up to 15 µg / ml of a 0.1% (g / g) cationic surfactant. It was determined in the case of interferon α ₁ concentrations of 20-50 units / ml, in the case of interferon β 10-20 units / ml. Due to the micellar incorporation of the mercury cyanide, the release of the interferon α ₁ is increased in particular by the interferon β in fibroblast cultures by 10 to 100 times compared to simple aqueous, buffered solutions of mercury II-canide.

Secondary effects

The observed side effects of interferon α ₁, such as. B. headache, lymphocytopenia, mild to moderate illness are not present in the pharmaceutical preparations described here, especially against influenza and rhinoviruses, or have not been observed. This is primarily due to the fact that significantly lower units / ml of interferon α , induced by the inorganic pharmaceutical active ingredient, are used therapeutically than in therapy with interferon α alone. So no toxic effects, e.g. B. gastrointestinal disorders, weight loss, alopecia, peripheral convulsions, paraesthesia and bone marrow depression were observed, which are, however, reversible.

The haematological toxicity, which is dose-dependent in the case of interferon α ₁ (Thershold dose 3 × 10⁶ units / ml), is not present in these pharmaceutical preparations for mercury cyanide, rimantadine, amantadine and ribavirin.

b) The pharmaceutical preparation consisting, for. B. from hexadecylpyridinium chloride or a pyrimidinium derivative and a hexadecyl residue in the presence of micellar trapped mercury cyanide cause interferon production in cell culture. It is an interferon induction by released mercury cyanide, which occurs locally in high concentrations and with a relatively high molecular weight of 4500 due to the formation of polymeric structures. (Paradise, oligomeric structure of mercury cyanide in solution, lecture German-Austrian Chemical Society, Innsbruck, May 1986.) Thus, this pharmaceutical preparation belongs to the substances of defined interferon inducers of high molecular weight such as. B. synthetic double-stranded RNA: PolyI: PolyC as well as low molecular weight such. B. 10-carboxymethyl-9-acridanone. Despite this heterogeneity of the interferon effect, it has an antiviral effect. This effect served for the biological detection of this pharmaceutical preparation. It can be said that the interferon treatment of cells in cell culture is changed in such a way that subsequent virus replication in these cells is inhibited. Thereby, interferons differ fundamentally in their mechanism of action from antivirals that inhibit the metabolism of the viruses themselves. Since interferons act on the cells, it is not surprising that they can also have other effects on the cells. This not only applies to cell cultures but also has an impact on the whole organism. It is known from various studies that interferon inhibits a multiplicity of viruses in their reproduction. The extent of the inhibition depends on the respective virus system. The proliferation of almost all viruses seems to be inhibitable by interferon treatment of the cell. There are obviously various mechanisms by which interferons can be effective. So z. B. affects the multiplication of retroviruses on the formation of "budding" ie the removal of newly formed virions. A similar mechanism appears to apply to the pharmaceutical preparation with micellar-encapsulated Hg (CN) ₂. Thus, in the context of the invention, the so-called β- proteins were detected in the herpes simplex virus (HSV 1-3) by the pharmaceutical preparation consisting of cetylpyridinium chloride and mercury cyanide (see example) on the synthesis of early virally coded HSV proteins. In the SV40 virus, interferon also appears to act on a very early step of reproduction, which is before the primary transcription.

The pharmaceutical preparation according to the invention, specially included micellar Mercury cyanide in 7-hexadecylimidazolium-2,6- diamino [4,5-d] pyrimidine chloride left the interferon Observe conditional inhibition in various lytic RNA viruses. The inhibition takes place at the level of regulation of viral proteins. It is caused by Induction of certain cellular enzymes. Upon closer examination it was found that the enzymes of the 2 ′, 5′-oligoadenylate Synthetase, the 2.5 A dependent endoribonuclease and inhibit the dsRNA-dependent protein kinase. For both the former could be done through correlation studies and through characterization of cell mutants play a role in antiviral Activity against lytic RNA viruses by micellar bound Hg (CN) ₂ can be detected.

In these experimentally proven effects, an antiproliferative effect of this pharmaceutical preparation on the interferons could also be demonstrated in a variety of ways on the membranes and the cytoskeleton of cells. So they continue to affect the expression of a number of important genes, e.g. B. the main histocompatibility focus, the so-called transplantation antigens. Thus, immunoregulatory effects are also emerging (interleukin-1 synthesis). This results in the following aspects therapeutically and pharmacodynamically: The induction of the interferons by this pharmaceutical preparation leads to increased expression of the cell surface proteins, which play the most important role in the immune response. These are the so-called transplantation antigens. It should also be mentioned that at least two important cellular components of the body's defense are activated, namely the macrophages and the natural killer cells. In addition, especially with regard to interferon γ , the functions of the B lymphocyte seem to be significantly influenced by this pharmaceutical preparation.

Thus, for the pharmaceutical preparation according to the invention, in particular consisting of hexadecylpyridinium chloride and micellar-enclosed mercury cyanide or of 7-hexadecylimidazolium-2,6-diamino [4,5-d] pyrimidine chloride or also the bromide, there is an induction, if not a specific one , from interferon. There can be no doubt that interferons are not only antiviral but also immunoregulatory, not only in vitro but also in vivo. Although the direct antiviral effect can also be significant in vivo, other indirect mechanisms play a role in the organism in the interferon effect, as recorded above, e.g. B. the activation of macrophages especially with influenza virus A and B. The fact that interferon γ can activate macrophages also seems to be important with regard to bacterial and parasitic infections, since macrophages play a crucial role in their defense.

Posology and therapeutic indications

The therapeutic indications as well as the dose result itself by the micellar enclosed concentrations of active pharmaceutical ingredients:

• - So there are indications for emerging and existing Colds, which are mainly caused by influenza and rhinoviruses are caused;
• - catarrhal inflammation of viruid genesis;
• - skin infections and infectious dermatoses;
• - persistent, antiseptic wound treatment;
• - dermatomycoses;
• - mycoses;
• - Prophylaxis and therapy of bacterial skin lesions such as B. pyoderma, otitis media;
• - microbial and secondary infected eczema;
• - Hypersensitivity to macrolide antibiotics;
• - acne, especially inflammatory forms with papules and pustules;
• Bacterial infections and secondary infections of the skin, provided that they are sensitive to gram-positive and / or gram-negative meklocycline Germs are caused;
• - acne vulgaris;
• - prevention of umbilical infections;
• - surgical and traumatic wounds;
• - Local protection against infections and sensitive to antibiotics Germ infected wounds;
• - boils, carbuncles, abscess;
• - dermatomycoses caused by dermatophytes, yeast, Mold and other fungi, Pityriasis versicolor,
• - erythrasma by cornebacteria;
• - Candidiasis of the skin and mucous membranes
• - Herpes simple I-III, herpes keratitis  
• - solar and senile keratoses, premalignant changes and superficial basaliomas, even in those damaged by radiation Skin;
• Squamous cell carcinomas of the skin and mucosa in the head and neck area; dermatological malignancies;

Depending on the indication and active pharmaceutical ingredient depends on the special dose. Since the maintenance and starting dose of the pharmaceutical described herein Active ingredients are known, depending on the type of application and galenical preparation e.g. B. creams, suppositories, drops, Tablets, capsules and liposome-like encapsulations only 50% of the normal therapeutic total dose is required depending on the concentration of the micellar enclosed active pharmaceutical ingredient.  

Description of the dose reduction due to the potentiating (synergistic) effect

Micelles in aqueous solution, including those included lipophilic active ingredients are dynamic Equilibrium with their monomeric surfactants, i.e. H. the micelles change shape, size and hydration. Among others monomeric cationic surfactants leave one single micelle to join another micelle reinstall in aqueous solution so that - even if the concentration of the surfactant is well above the KMK lies - always a certain concentration of fluctuating monomers. By adding this dynamic becomes the potentiation mixture disturbed in that

• 1. at constant temperature and chemical Potentials the shape, size and monodisperse Obtain homogeneity of the isotropic solution remains, so there is no loss micellar enclosed lipophilic (hydrophobic) active pharmaceutical ingredient.
• 2. The concentration of monomers which destabilizing to the geometric shape of the Micelle works in favor of installation into the "full" micelle in isotropic Restricted solution. This causes the System including the micellar enclosed hydrophobic pharmaceutical Active ingredients "licks". This will be primarily thereby preventing the potentiation mixture, especially glycerin and dimethyl sulfoxide, the water structure at the external Freeze the surface of the micelle ("Tridy with structure ") that they are ice-like structures assume and the water molecules very  become immobile.
• 3. The pharmaceutical preparation works due to the potentiating effect of glycerin, such as B. can be shown in vitro, less cytotoxic, d. H. it mainly damages the damaged (infected) cell, less that healthy cell in the cell cluster.

The invention has the following advantages in particular:

The N-surfactants produced in this invention, including their procedural inclusion of the Active ingredients, requires a significant z. T. up to 80% Reducing the toxicity of the inorganic active substances, e.g. B. at Hg (CN) ₂, (also HgCl₂, Hg₂Cl₂, HG (NH₂) Cl [precipitate], ZnEDTA) and Zn salts in general, as well nephrotoxic, ototoxic antibiotics, in particular for polymixins, erythromycin, gentamycin, tetracycline, of about 30% there

• 1. the micelles, as well as their enclosed ones Active ingredients, not - because of their size - absorbed will,
• 2. The micellar trapped active ingredients only unfold locally - mostly topically - so that little Concentrations of active ingredient are sufficient, since additional there is still the synergistic effect of the N-surfactant.

It has been found, inter alia, that the inhibitory effect of saliva secretion of atropine by hexadecylpyridinium chloride and also by benzothiazolium sulfate is increased tenfold by micellar catalysis when the N-surfactants, pH 7.0, are produced in accordance with the process. The increased effect on the periphery is partly due to the micellar separation of the racemate into L (-) hyocyamine (see Fig. 1).

Also stabilized e.g. B, hexadecyl benzothiazolium sulfate the atropine by including the hydrophobic molecular regions of atropine in the micellar nucleus.

This content of the patent claim also extends on the anti-inflammatory properties of here  described quaternary organic ammonium bases. The Counterion Y⊖ influences the size due to the process, Form and micellar stability, but can also be one be an active pharmaceutical ingredient, so that a Drug effects are pharmacodynamically enhanced can. The surfactants described here have the big one Advantage that they are intrinsic pharmacodynamic Properties dependent on the environment and also in acid pH range are stable. The procedural available Micelles included as a pharmaceutical preparation lipophilic (hydrophobic) active pharmaceutical ingredients act as carriers for antimicrobial, antiviral, keratolytic, antifungal and antineoplastic agents, but can u. a. itself antimicrobial, antifungal and be antiviral and anti-inflammatory (topical).

In particular, the present invention describes one pharmaceutical preparation for the production of micellar dissolved hydrophobic inorganic substances such as mercury II-cyanide, zinc, tungsten and antimony compounds and salts of phosphonic acid. It was found that these inorganic compounds both antiviral and also have antineoplastic effects.

Also the formation of vesicular structures of the quaternary Ammonium bases of 4- and 3,5-substituted hexadecyl pyridinium-Y⊖ occurs spontaneously at constant temperature, Pressure, ionic strength including in the presence of used stoichiometric active pharmaceutical ingredients, which are both vesicular (cavity) and micellar (double membrane type) can be bound.

In particular, the invention relates to improved manufacturing process for the production of multilamellar lipid vesicles based on cationic Surfactants that can be used for this, in particular  lipophilic (hydrophobic) active pharmaceutical ingredients encapsulate.

Most of the processes known to date either suffer due to an insufficient encapsulation effect or due to Limitation of material types, which included should be, or both. As is known most of these processes involve the inclusion of hydrophilic Materials and active pharmaceutical ingredients limited and cannot effectively include lipophilic make active pharmaceutical ingredients. In contrast all procedures currently available are exceptions to this that of Banghan et al. (Biochim.Biophys.Acta 443: 629- 634, 1976) only for encapsulation more biologically active Substances in oligo-multilamellar or unilamellar Suitable for liposomes.

A particular advantage of this pharmaceutical preparation is based on vesicular structures of N⊕ surfactants the hydrophobic encapsulation of pharmaceutical Active ingredients. A particularly advantageous consequence of the Ultrasonic treatment and counter-ions produced large-caliber Vesicles can be seen in the danger the exit of the active pharmaceutical ingredient from the Blister skin of the approach is reduced or eliminated. Therefore, this form of the quaternary N⊕ surfactants on the Basis of six-membered heterocycles, especially for encapsulating hydrophobic active pharmaceutical ingredients that can be used to to local z. B. localized instead of systemic To have effects.

During most of the known methods on encapsulation hydrophilic active ingredients can be limited with this invention the encapsulation of hydrophobic active pharmaceutical ingredients are made. tries have shown that even inorganic lipophilic pharmaceutical  Active ingredients such as B. with mercury-II cyanide high effectiveness can be included and their pharmacodynamic effect through the potentiation mixture can still be reinforced.

This disadvantage is compounded by the new N-surfactants Formula II and new benzethonium compounds as well as the vesicles based on N⊕ surfactants either by micellar inclusion of the pharmaceutical active ingredients or by covalently linking the active ingredients with the N⊕ surfactant while maintaining the outer morphological Shape of the entire micelle removed.

The bactericidal effect of chlorhexidine is known gram-positive and gram-negative bacteria, but resistant against gram-negative bacilli. It was found that micellare Solutions of quaternary ammonium bases according to the general Formula I and in particular II the 2-4% by weight chlorhexidine Keep hydrophobic in the micellar core, the resistance against gram-negative bacilli and theirs therapeutic efficacy in relation to chlorhexidine amplify alone. The observed side effects of Chlorhexidine like contact dermatids, skin effects more topical Type, photosensitivity of the skin, see process-based production of micellar solutions the N-surfactants of the formula I and II do not take place.

It is the subject of the present invention that mentioned heterogeneity of shape and size of the micelles also in the presence of potentization mixtures. It is thus ensured that a monodisperse form of cationic organic ammonium bases even in the presence of active pharmaceutical ingredients and potentiating mixtures is achieved in the manufacture.

These quaternary organic ammonium bases according to the invention eliminate the disadvantages of  hitherto conventional invert soaps. So there is also great interest in both therapeutic use of quaternary ammonium bases, both as pharmaceutical Active ingredient act and as a carrier of active ingredients different types, e.g. B. antimicrobial, antiviral, antifungal or antineoplastic, micellar be able to record. You should therefore use the especially not have environmental-related disadvantages.

The inventive, with pharmaceutically covalently linked Active ingredients, such as B. pyrimidine and purine derivatives at N₁ or N₇, based on quaternaries Ammonium bases have the advantage

• 1. that these masked antimetabolites from the pyrimidine or purine series, no intramolecular interactions anionic or cationic in nature come in. They are charged neutrally (e.g. none Nucleotide dianion through the phosphate) and can therefore unimpeded in the pro or eukaryotic Diffuse cell so that high intracellular Antimetabolite (e.g. 5'-nucleotide) concentrations be achieved;
• 2. that the active pharmaceutical ingredients by N-C- Hydrolysis using the existing enzyme systems from germinal or eukaryotic cells, only on Target or topically released;
• 3. by increasing the hydrophobicity of the alkyl or aryl chain or the rest of the N⊕ surfactant Membrane permeability increased, so that the pharmaceutical Active ingredients quantitatively passive in the cytosol can cross. In contrast to di anions or Cations which cover the membrane under physiological pH conditions and ionic strengths are difficult to pass  can, this is the case with the process N⊕ surfactants unhindered;
• 4. The high hydrophobicity also means a high one Partition coefficient in the system CHCl₃-H₂O at pH 8.0;
• 5. through the concentrated absorption of hydrophobic or hydrophilic active pharmaceutical ingredients in addition to the covalently anchored and the Drug concentration after penetration through the germinal membrane, fungal cell wall (inhibition of Chitin synthetase) or viral phospholipid double membrane through a concentration gradient (extracellular - intracellular) increased. This results a short flooding time.

In contrast to liposomes as carriers of pharmaceutical Active ingredients such as z. B. in U.S. Patent 3,993,754 or called in the European patent specification 01 02 324 are described here according to the invention Micelles of quaternary ammonium bases the advantages

• 1. that they micellar water-insoluble active substances in so-called "liquid core", and thereby both topically and enterally by opening the Micelle controls these water-insoluble active ingredients can release, e.g. B. Rimantadin, Amantadine, tromantadine, which are used in influenza viruses or Herpes simplex viruses of both the skin and the Are effective.
• 2. Water-soluble active ingredients can be found both in the star layer as well as micellar be solved if they themselves have hydrophobic areas, e.g. B. Polyen Compounds, tetracyclines, aminoglycosides and aromatic Antimetabolites, e.g. B. trifluorothymidine, Viderabine, cytarabine, 5-iodine and 5-fluoro-deoxyuridine, 5-ethyl-2'-deoxyuridine, erythromycin and nalidixic acid.  
• 3. The cationic N-surfactants described here according to the invention have two specific binding sites with high binding constants (K _B = 10-15 μM) and large binding capacity (capacity 100 μg / micelle): one is due to the hydrophobic interactions between the “liquid core” "the micelle and the hydrophobic region of the active substance (G = 15-20 kcal / mol) as well as the π - π interactions of the active substances described here between the N-heterocycles of the N-surfactants and the pharmaceutical active substances, the second binding site is more non-specific The species is located at the interface between the star layer and the hydrophobic core. The binding constant is in the range of K _B = 20 mM, the binding capacity 100-200 µg / micelle. The non-specific binding sites are almost exclusively in the Guy-Chapman layer. In contrast to liposomes, where the number of non-specific binding sites is significantly higher, the number of non-specific binding sites can be eliminated by adding ethanol / glycerol, since the forces acting in the Guy-Chapman camp are caused by concentrations of ethanol, glycerol up to 30-35% by weight can be switched off without influencing the binding capacity, strength of the hydrophobic forces or in the star layer (only polarity and configuration).
• 4. The invention described here has the advantage that the micellar included pharmaceutical Active substances do not leave the micellar dressing again, such as B. in liposomes, according to the previously known methods "lick". The "tightness" ("sealing") the present invention by micellar included active ingredients is e.g. B. using the example  of micellar-bound radioactively labeled trifluorothymidine, Detect cytarabine and indoxuridine. So u. a. found that idoxuridine only after 200 days 5% by weight of its original micellar included concentration (2000 µg) in the case of hexadecyl pyridinium or benzethonium chloride Micellen loses. The corresponding values for radioactively labeled trifluorothymidine and catarabine are 210 and 300 days (20 °).
• 5. Leave by the method of the present invention these micelles with the enclosed inorganic and organic active ingredients at pH = 7.0 in a simple manner without great expenditure on equipment produce in aqueous phase, which small, simple Micelles with a diameter of approx. 50-100 Å and large micelles with a diameter of 600-10,000 Å - depending on the counter ion - included. Also be by a mixture of glycerol / ethanol in the ratio of 2 wt .-%: 15 wt .-% compared to water both micelles of different sizes both in their form (Ball, hemicylinder, rod, disc) as well as in their compactness by lowering the KMK, as well by reducing the free energy of the whole Micelle in the aqueous phase due to dilution the electron density on the external surface, stabilized. Using suitable separation methods e.g. B. HPLC, ultrafiltration, gel filtration and / or preparative centrifugation can be done by small preparative separate large micelles.
• 6. The stability, durability and shelf life of this micelles thus produced from quaternary organic Ammonium bases, pH = 7.0, versus temperature, Tightness ("sealing and leaking") and shelf life is through the storage of pharmaceutical Active substances in the hydrophobic core of the micelles in the ratio  to the micelles without active ingredients at the same Y⊖ increased. In contrast to the liposomes occurs here no melting at a higher temperature (<40 ° C), but change with process-based production the hydrodynamic conditions only change <60 ° C. Because with increasing temperature these are manufactured Micelles from quaternary ammonium bases rather a reduction in the hydrodynamic radius enter, therefore become more compact, are these types Micelles thermodynamically more stable than artificial ones Liposomes or liposomes + quaternary ammonium bases. These operations are easy in the routine process due to inelastic light scattering during manufacture to consider.
• 7. The hydrophobicity or the penetration of the H₂O molecules in these micelles thus produced and their influence by inorganic pharmaceutical agents, for. B. Hg (CN) ₂, ZnEDTA, ZnSO₄, ZnO, tungstic acid antimonate, K₁₈ (KW₂₁Sb₉O₈₆) ₁₇, as well as the organic substances could be detected by NMR spectroscopy:
  The example of 8-ketohexadecylpyridinium chloride (8-KHPCl) can be used to demonstrate the use according to the invention of the absorption of active pharmaceutical ingredients. Consequently, it has now been found that a chemical shift of 146.6 ppm occurs for a 0.1 molar micellar solution in water, which, however, is caused by e.g. B. Hg (CN) ₂ is shifted to 147.2 ppm. Micelles in aqueous solution which are 0.05 molar in 8-KHPCl and 0.2 molar in CPCl (cetylpyridinium chloride), however, gave a chemical shift of 147.2 ppm for the 13 C-carbonyl signal of 8-KHPCl. If you compare these two numbers with the shifts of 8-KHPCl in methanol (145.7 ppm) and acetonitrile (144.0 ppm) it becomes clear that the CO group in this micelle occupies a largely aqueous environment. Hg (CN) ₂ plays a double role here, which also determines the therapeutic range in vitro: the hydrophobic character of Hg (CN) ₂ causes a high solubility in the hydrophobic core of z. B. hexadecylpyridinium chloride as a monomer and requires a chemical shift from δ _{C 8} 27.5 ppm ¹³C the CH₂ chain to 32.5 ppm, while in 8-KHPCl micelles mercury II cyanide near the ketone group (C₈) as Hg₂ (CN) ₄ is dissolved in H₂O (see above) and this H₂O solubility limits the concentration of H₂ (CN) ₄.

Fig. 5 shows the dependence of the extinction of the micellarly enclosed inorganic active substances and the N-phosphono-acetyl-L-aspartate in hexadecylpyridinium chloride.

Legends for the illustrations, insofar as they are not yet in the description are included.

Fig. 12:

• 1) Dependence of the Stokes' radius (hydrodynamic radius) of N-Cetyl-4-methyl-imidazolium chloride with micellar trapped rimantadine measured by inelastic Laser light scatter from temperature
• 2) Dependence of the Stokes' radius on N-hexadecyl-5- carboxamide chloride with micellar trapped 5-fluorine cytosine by temperature
• 3) Dependence of the Stokes' radius on 2, -4-dihydroxy-5- methyl-hexadecyl-pyridinium chloride with micellar trapped gentamycin by temperature

Fig. 8:

• 1) Dependence of the Stokes' radius on benzyldimethyl [2- [2- (p-1,1,3,3, tetramethylbutyl-p, p′-dimethyl-phenoxy) ethoxy] ethyl] ammonium chloride with micellar trap Viderabin on the temperature
• 2) Dependence of the Stokes' radius on benzyldimethyl [2- [2- (p-1,1,3,3, tetramethylbutyl-p, p′-dimethyl-phenoxy) ethoxy] ethyl] ammonium chloride with 5-tri-fluoro-thymedin on the temperature

Fig. 7:

• 1) Dependence of the Stokes' radius on 8-ketohexadecyl pyridinium chloride with micellar trapped Z-miconazole on temperature
• 2) Dependence of the Stokes' radius on 8-ketohexadecyl pyridinium chloride with micellar trapped Z-Miconazole + Hg (CN) ₂ on temperature

Fig. 11:

• 1) Dependence of the Stokes' radius on 3,5-bis [(n-hexadecyloxy) carbonyl] -N-methyl-pyridinium chloride with lamellar trapped amantidine by temperature; Not treated with ultrasound
• 2) Dependence of the Stokes' radius on 3,5-bis [(n-hexadecyloxy) carbonyl] -N-methyl-pyridinium chloride with lamellar trapped amantidine by temperature; treated with ultrasound  
• 3) Dependence of the Stokes' radius on 3,5-bis [(n-hexadecyloxy) carbonyl] -N-methyl-pyridinium chloride with lamellar trapped rimantadine by temperature; treated with ultrasound

Fig. 13:

• 1) Dependence of the Stokes' radius on N-hexadecyl-pyridinium chloride and micellar trapped Hg (CN) ₂ from the Temperature; not treated with ultrasound
• 2) Dependence of the Stokes' radius on N-hexadecyl-pyridinium chloride and micellar trapped Hg (CN) ₂ from the Temperature; treated with ultrasound

Fig. 16
350 Å

"Freeze fracture" electron micrograph of Vesicles of the N⊕ surfactant 3,5-bis (n-hexadecyloxy) carbonyl N-methyl-pyridinium chloride including those included Polyoxin A according to working instructions.

It shows the different sizes of the vesicles, if not separated by order of magnitude.  

The following is a modification of the invention described, in particular the N-alkylated affects quaternary nitrogen-containing heterocycles.

State of the art

The quaternary ammonium bases are also known surfactant-like effect of the general structure (I)

being in general

R¹ is an alkyl radical with 1-12 C-atoms R² is an alkyl radical with 1-12 C-atoms R _{n is} a straight-chain or branched alkyl radical with 10-20 C-atoms or an alkenyl radical with 8-10 C-atoms or a 5- or 6-membered aromatic heterocycle with one or 2 nitrogen atoms and R _m a straight-chain or branched alkyl radical with 10-20 C atoms or an alkenyl radical with 8-10 C atoms or a 5- or 6-membered aromatic heterocycle with one or 2 nitrogen atoms Y⊖a monovalent anion

is.  

Compounds of this general formula are for Part in the Tensid-Taschenbuch, published by Dr. H. Stache, Carl Hauser Verlag, Munich Vienna, 1981, Page 8/9.

Parts of this connection are also the subject of a European patent application, application no. 8 38 10 338.0 dated July 24, 1983, these surfactants being used for Production of unilamellar liposomes in aqueous Dispersion phase can be applied.

It should be noted that these are known N⊕ surfactants of the general formula I both micellar as well as vesicular structures in aqueous and non-polar solvents (see e.g. J. Fendler, Acc. Chem. Res. 1976, 9, 153; H. H. Paradies, J. Phys. Chem. 1986, 90, 5956; H. H. Paradise, 1982, Angew. Chem 10, 737; Appl. chem. Int. Ed. Engl., 1982, 21, 765, Supplement 1982, 1670-1681) and also defined here, depending on Task, certain chemical and biophysical Reactions, catalyze micellar.

In contrast, cationic surfactants with a quaternary nitrogen within a π excess or π - deficient aromatics, substituted or unsubstituted, are less well known. There are descriptions, e.g. B. for hexadecyl-pyridinium halide (cetylpyridinium halide), see, inter alia, Merck Index 9, quinoline, (see K. Lindner, in Tenside-Textile Aid Wash Raw Materials (1964, Vol. 1, 987) and for benzothiazolium salts (Demande de Brevet Europeen 8 54 00 876.0 dated May 6, 1987 and BE 660 802 dated March 8, 1965) with different alkyl chain lengths and counterions with applications in photography and electron transfer through suitable formation of charge transfer However, these are 2-methyl or 2-substituted benzothiazolium compounds with a variable hydrophobic alkyl chain length of 12-30 carbon atoms on the heterocycle of the fused benzene ring.

Furthermore, according to the prior art, the 2- substituted imidazolium salts and 2-thiazolium Compounds described (see Tensid-Taschenbuch, H. Stache, 2nd edition, 1981, page 8/9), without however, KMK and other micellar properties specify. The same is true for the imidazolium connections have been described, see e.g. B. Surfactant-Textile Aid-Washing Raw Materials- K. Lindner, 1964, 993; scientific publishing company, Stuttgart.

For vesicular connections with a pyridine ring only 4- or 3.5 alkyl or Alkoxy compounds have been described, which on quaternary nitrogen contain a methyl group (see e.g. Sudhölter et al. 1982, J. Amer. Chem. Soc. 104, 1069, Sudhölter et al. 1979, J. Amer. Chem. Soc. 102, 2467).

An object of the present invention is N-alkylated quaternary nitrogen-containing heterocycles to accomplish.

This problem is solved by N-alkylated namely quaternary nitrogen-containing heterocycles 2,5,6 substituted N₁-alkyl-pyrimidinium compounds of the formula  

R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = F

in which

n 8-20, in particular 15 and Z⊖chloride, bromide, iodide, maleate, formate, acetate, propionate, hydrogen sulfate, malate, fumarate, salicylate, alginate, gukonate, glucoronate, galactoronate, ethyl sulfate or hydrogen phosphate H₂PO₄ ^-

mean.

A preferred embodiment of the invention consists in the 2,5,6 substituted N₁-hexadecyl pyrimidinium compounds of the formula  

R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = F

in which

Z⊖Chlorid, bromide, iodide, maleate, formate, acetate, propionate, hydrogen sulfate, malate, fumarate, salicylate, alginate, gluconate, gluconate, galactoronate, ethyl sulfate or hydrogen phosphate H₂PO₄ ^-

mean.

Preparation of the n-alkylated according to the invention quaternary nitrogen-containing heterocycles: a.) General about the production:

These cationic surfactants are characterized in that they have a very small micelle formation constant (KMK) of approximately 1.0 × 10 ^-6 -1.5 × 10 ^-7 mol / liter, are very strongly antimicrobial and antifungal, no polydispersity in the presence of inorganic anions or potentiation mixtures, and z. T. themselves are microbial metabolites (antimetabolites) that are not toxic to the host cell.

The formation of the salt-like structure of this class of cationic surfactants of the form (HET≡N⊕- (CH₂) _x -CH₃) Y⊖ is based, inter alia, in the electron density distribution of the heteroaromatic nuclei or in their basicity, including the influence of the substituents . A necessary condition, which leads to the formation of quaternary salts of this five- and six-membered heteroaromatic class, is that the electron density of nitrogen, which is quaternized, according to MO-SCF calculations an amount of -0.08 (e.g. Pyrazine-N₄) to -0.159 (e.g. Imidazole-N₁, Purin-N₇) must have. This stability of the individual heterocyclic cationic surfactants described here is also determined by their symmetry and chain length of the alkyl chain on the quaternary nitrogen:

In the case of imidazole, benzimidazole z. B. will through the formation of the salt on the quaternary Nitrogen N₁ and the lone pair of electrons at N₃ and the resulting high symmetry stabilized. The same applies to the H₉ tautomer of Purins and its symmetrically arranged substituents, which the negative charges at N₁ (- 0.124), N₃ (-0.108) and N₉ (0.149) in such a way influence that the Quaternization on N₉ is preferred in that the above-mentioned. line N₁- <N₃- <N₉ reverses. By choosing suitable ones The yields can be increased by solvents. While for pyridine, pyrimidine and imidazole residues symmetrical effects at the core play an essential role play is z. B. in pyrazine the electronic Significant effect in the 2 position, but there is also very strong inductive effects (e.g. 2-amino  Group), less than mesomers. This also applies to the pyrazole.

The length of the alkyl chain on the quaternary nitrogen atom not only determines melting point and hydrophobicity that later formed in aqueous solutions cationic micelles, but also the yields decrease with increasing chain length, while the Response times e.g. B. in nitrobenzene or 2-ethoxyethanol increase.

Stable and easily crystallizable compounds are obtained for C₁₂-C₁₈, the counterion Y⊖ is bromide and chloride without exception. The others Compounds can easily be made from acetone or chloroform be recrystallized. The corresponding Iodine compounds are sensitive to temperature and light.

b) Especially for manufacturing

• 1. Hexadecylpyrimidinium bromide: 0.01 mol of 5-aminopyrimidine (0.95 g) and hexadecyl bromide, 0.01 mol (3.05 g) are in 20 ml of methanol with stirring and nitrogen at 20 ° C for 24 hours in the presence of catalytic amounts (0.5 mg) of sodium amide reacted. The resulting N₁-hexadecyl-5 aminopyrimidinium bromide is dissolved in acetone at 76 ° C, and after cooling to room temperature, the N₁-hexadecyl-5-aminopyrimidinium bromide with melting point 122 ° C crystallizes. Yield 35%.
  0.01 mol of this N₁-hexadecyl-5-aminopyri midinium bromide (3.20 g) are in methanol / water 50/50 (v / v) at 0 ° C in an ice bath with 1 g NaNO₂ and 0.1 ml Concentrated hydrobromic acid stirred under nitrogen for 6 hours. The mixture is then brought to room temperature and then heated at 80 ° C. under reflux for 2 hours with nitrogen and stirring. The resulting hexadecyl pyrimidinium bromide is extracted with 2-ethoxyethanol and brought to crystallize at 10 ° C. Yield 30%, melting point 105 ° C (bromide) 189 ° C (chloride).
  Preparative separation of unreacted products can be achieved either by high pressure liquid chromatography on an RP 18 column or by dialysis against phosphate-buffered aqueous solutions with subsequent DEAE-Sephadex A-50 exchanger. Chromatography of the residue from the dialysis tube.
  In the UV spectrum of these N (1) alkyl-pyrimidinium salts, depending on the substituent in the 2.5 or 6-position, the maximum is generally between λ _max = 252 nm-265 nm.
  In the ¹H-NMR spectrum of these substituted or unsubstituted N (1) alkyl-pyrimidinium halides in CD Cl₃ / Me₄Si, in addition to the characteristic signals of the corresponding pyrimidines, the following characteristics also result: δ 0.93 (3H, t, J≈3, 5 Hz), 1.27 (nH, M); 5.05 (2H, m), 7.6-9.5 (3H, m, unsubstituted pyrimidine).
  In buffered, aqueous solution below pH 7.0 (pH 3.9-5.9) are at a micelle size of less than 600 Å, the typical sharp signals in diameter at δ about 0.85 - 0.89 ppm (-CH₃ ), δ about 1.28-130 ppm (-CH₂-) and about 3.25 ppm (N-CH₂-) for these N diese surfactants in addition to the proton coupling signals of the unsubstituted pyrimidine nucleus.
• 2. Pyrimidinium compounds substituted in the 2,5,6-position are obtained by reaction in 2-ethoxyethanol under pressure in an autoclave at 100 ° C. with a reaction time of 8 hours from the corresponding n-alkyl bromides or iodides and the substituted pyrimidine compounds in yields between 30 and get 40%. The recrystallizations are carried out for all substituted pyrimidinium compounds from chloroform.
  The preparative separation of unreacted products can be achieved by high pressure liquid chromatography as described above. Also by chromatographic separation on a DEAE Sephadex A 25 (1.5 × 30 cm) on a linear gradient of 0.1-0.5 MNaCl in 0.01 M₂HPO₄, pH 6.5, these N⊕- Surfactants of pyrimidines from impurities can be obtained uniformly and cleanly.
• 3. N₁-n-alkyl compounds of pyrimidine can by converting n-alkyl-Mgx (x = Br, Cl) into good ones Yields with pyrimidine or 2,6,5,6-substituted Pyrimidines in the presence of 1,2- Obtained dimethoxyethane and / or n-heptane will. There is no hetarin or addition Elimination or Elimination Addition Mechanism instead.

0.01 mol (1.0 g) 5-fluoropyrimidine are in 1,2-dimethoxymethane (100 ml) with stirring in Three-necked flask and dissolved under nitrogen. From a dropping funnel, 0.08 mol is left (same order of magnitude as above) n-decyl magnesium chloride (or 0.09 mole 29.6 g n-hexa decyl magnesium bromide), dissolved in 20 ml heptane drip slowly at 20 ° C. This solution will brought to 40 ° C, stirred for 12 hours and after the reaction has been completed, a Dropping funnel 20 ml 50% by weight hydrobromic acid added dropwise at constant temperature. After 1 hour, the excess Grignard Reagent implemented. It is cooled to 0 ° C and the possibly still existing surplus of Grignard reagent by adding methanol destroyed and the quaternary N₁-pyrimidinium bases extracted by 2-ethoxyethanol. The first recrystallization is from Chloroform / methanol performed at 0 ° C, the further recrystallizations at room temperature.

Melting point: 5-fluoro-N₁-decylpyrimidinium bromide 199 ° C (dec.)

Melting point: 5-fluoro-hexadecylpyrimidinium bromide 175 ° C (dec.)

Table 1 summarizes the characteristic ones Properties of the N (1) alkylated quaternaries Pyrimidinium salts together, including their critical micelle concentration (KMK). Table 2 shows the determined hydrodynamic Radii of these N⊕ surfactants of pyrimidines depending on the counterions Z⊖.  

Table 1

Characteristic properties of the N-alkylated quaternary, pyrimidinium compounds

Table 2

Hy 02716 00070 552 001000280000000200012000285910260500040 0002003726101 00004 02597drodynamic radii of the N-surfactants depending on Z⊖

Applications

These newly described compounds surprisingly have a very small KMK in the range of 10 ^-5 -10 ^-7 mol / liter, which is largely independent of pH and ionic strength (0.1 M). They also have, since they are e.g. T. themselves are antimetabolites, biochemical or pharmacodynamic effects. They are able to penetrate the cell membranes of neoplastic tissues because of their "monovalent" cationic nature and then to have an inhibitory effect on the transcription and translation by unknown mechanisms after formation of the corresponding nucleosides and phosphorilization. This is particularly important for infectious processes of a bacterial (prophage) or, above all, viral nature.

It is noteworthy for later use of these N⊕ surfactants that the colloidal chemical “aggregates” (micelles) are controlled by the counterions Z⊖, both inorganic and organic. In contrast to many other amphiphiles, which are not water-soluble, these N⊕-surfactants can form "sheet-like" double membrane structures in water or aqueous solutions due to their hydrophobic effect. Mostly they have a cylindrical shape, but this is very dependent on the counter ion: in the presence of primary phosphate (H₂PO₄ ^- ) as well as in the presence of gluconate or galactoronate, highly oriented micellar fiber structures are formed, which are stabilized by these anions. So z. B. gel-like preparations, helical structures based on micellar cylinders.

Claims (117)

1. Pharmaceutical preparation, characterized in that it is composed of a micelle, consisting of a cationic surfactant with a monovalent anion and a hydrophobic pharmaceutical active ingredient, dispersed in a solvent whose pH is less than 7, the critical micelle formation concentration (KMK ) is in the range of 1.0 x 10 ^-7 to 1.5 x 10 ^-4 mol / liter. 2. Pharmaceutical preparation according to claim 1, characterized in that it is composed of a micelle consisting of a cationic surfactant with a monovalent anion in an amount of 0.01 to 0.1% by weight, based on the entire pharmaceutical preparation, and a hydrophobic active pharmaceutical ingredient in an amount of 0.001 to 0.5% by weight, based on the total pharmaceutical preparation, dispersed in a solvent whose pH is 7.0 in an amount of 99.40 to 99.989% by weight. -% based on the total pharmaceutical preparation, the critical micelle formation concentration (KMK) being in the range from 1.0 · 10 ^-7 mol / l to 1.5 · 10 ^-4 mol / l. 3. Pharmaceutical preparation according to claim 1 or 2, characterized in that the cationic surfactant is a compound of the general formula is, wherein R₁ is an alkyl radical with 1-12 C atoms or an aralkyl radical, R₂ is an alkyl radical with 1-12 C atoms or an aralkyl radical, R _{n is} a straight-chain or branched alkyl radical, substituted or unsubstituted, with 1-22 C atoms, preferably 10-20 C atoms or an alkenyl radical with 8-20 C atoms, preferably 8-10 C atoms or a 5- or 6-membered aromatic heterocycle with one or 2 nitrogen atoms, and optionally a sulfur atom or an oxygen atom and R _{m is} a straight-chain one or branched alkyl radical, substituted or unsubstituted, with 1-22 C atoms, preferably 10-20 C atoms or an alkenyl radical with 8-20 C atoms, preferably 8-10 C atoms or a 5- or 6-membered aromatic heterocycle with one or 2 nitrogen atoms, and optionally a sulfur atom or an oxygen atom or a quinolinium radical and y⊖
is a monovalent anion. 4. Pharmaceutical preparation according to one or more of the previous claims, characterized, that R₁ is an alkyl radical with 6 carbon atoms. 5. Pharmaceutical preparation according to one or more of the previous claims, characterized, that R₂ is an alkyl radical with 6 carbon atoms. 6. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} a straight-chain or branched alkyl radical having 12 to 16 carbon atoms. 7. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{m is} a straight-chain or branched alkyl radical having 12 to 16 carbon atoms. 8. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} a straight-chain or branched alkyl radical having 10 carbon atoms. 9. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{m is} a straight-chain or branched alkyl radical having 10 carbon atoms. 10. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} a straight-chain alkenyl radical having 10 carbon atoms. 11. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _n = R₁ = R₂ is a methyl radical. 12. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} the n-hexadecyl (cetyl) radical. 13. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{m is} an n-hexadecyl (cetyl) radical. 14. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} 2- or 4-methyl or 2- or 4-ethylpyridinium. 15. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} 2-methyl or 2-ethylimidazolinium. 16. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{n is} 2-methyl-8-chloroquinolinium. 17. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{m is} 2- or 4-methyl or 2- or 4-ethylpyridinium. 18. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{m is} 2-methyl or 2-ethylimidazolinium. 19. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that R _{m is} 2-methyl-8-chloroquinolinium. 20. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the monovalent anion chloride, bromide, iodide, formate, Acetate, propionate, hydrogen sulfate, malate, fumarate, Is salicylate, alginate, gluconate or ethyl sulfate. 21. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant has the formula [Het≡N⊕- (CH₂) _x -CH₃] y⊖, where Het≡N⊕-is a substituted or unsubstituted pyridinium radical or a substituted or unsubstituted pyrimidinium or
a substituted pyrazine (1,4-diazinium) residue or an imidazolium residue (4,5-d) pyrimidine residue substituted or unsubstituted, or a substituted or unsubstituted imidazolium residue or
a substituted or unsubstituted pyrazolium residue, or
a substituted or unsubstituted thiazolium radical, or
a substituted or unsubstituted benzothiazolium radical, or
a substituted or unsubstituted benzimidazolium radical, x 8 to 20 and y⊖ mean the anions according to claim 20. 22. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is an N-alkyl-pyridinium of the formula is, where y⊖ mean the anions according to claim 20. 23. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a hexadecylpyridinium of the formula is, where y⊖ mean the anions according to claim 20. 24. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is an N-alkyl-4 hydroxypyridinium of the formula is, where y⊖ mean the anions according to claim 20. 25. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a hexadecyl-4-hydroxypyridinium of the formula is, where y⊖ mean the anions according to claim 20. 26. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 2,5,6 substituted N₁-alkylpyrimidinium compounds of the formula R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = R₁ = OH;
R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = Fsind, wherein y⊖ are the anions according to claim 20. 27. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant 2,5,6 substituted N₁-hexadecylpyrimidinium of the formula R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = R₁ = OH;
R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = Fist, where y⊖ mean the anions according to claim 20. 28. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a 4-n-alkyl-pyrazinium-2-carboxamide of the formula is, where y⊖ mean the anions according to claim 20. 29. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a 4-hexadecylpyrazinium-2-carboxamide of the formula is, where y⊖ mean the anions according to claim 20. 30. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a 7-n-alkyl-imidazolium [4,5-d] pyrimidine of the formula R₁ = OH; R₂ = OH
R₁ = H; R₂ = H
R₁ = F; R₂ = NH₂
R₁ = F; R₂ = OH
R₁ = NH₂; R₂ = H
R₁ = NH₂; R₂ = NH₂, where y⊖ are the anions according to claim 20. 31. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a 7-hexadecylimidazolium [4,5-d] pyrimidine of the formula R₁ = OH; R₂ = OH
R₁ = H; R₂ = H
R₁ = F; R₂ = NH₂
R₁ = F; R₂ = OH
R₁ = NH₂; R₂ = H
R₁ = NH₂; R₂ = NH₂, where y⊖ are the anions according to claim 20. 32. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 3-n-alkyl-5,6-substituted benzimidazolium compounds of the formula R₁ = OH, where y⊖ are the anions according to claim 20. 33. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 3-hexadecyl-5,6-substituted benzimidazolium compounds of the formula R₁ = OH, where y⊖ is the anions according to claim 20. 34. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 4-substituted n-alkyl-2-pyrazolium compounds of the formula R = H; CH₃; OHs, where y⊖ are the anions according to claim 20. 35. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants are 4-substituted 2-hexadecyl-pyrazolium compounds of the formula R = H; CH₃; OH possesses, where y⊖ mean the anions according to claim 20. 36. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 1-n-alkyl-4-substituted imidazolium compounds of the formula R = H; CH₃, wherein y⊖ is the anions according to claim 20. 37. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 1-hexadecyl-4-substituted imidazolium compounds of the formula R = H; CH₃, wherein y⊖ is the anions according to claim 20. 38. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 3-n-alkyl-5,6-substituted thiazolium compounds of the formula R₁ = H; 39. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 3-hexadecyl-5,6-substituted thiazolium compounds of the formula R₁ = H;
R₁ = CH₃, where y⊖ is the anions according to claim 20. 40. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 3-n-alkyl-5,6-substituted benzothiazolium compounds of the formula R₁ = R₂ = H
R₁ = CH₃
R₁ = R₂ = OH
R₁ = R₂ = CH₃sind, wherein y⊖ are the anions according to claim 20. 41. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 4- [1,1bis n-alkyl (lower alkyl)] N-hexadecylpyridinium compounds of the formula are, where y⊖ mean the anions according to claim 20. 42. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactants 3,5-bis [(n-alkyloxy) carbonyl] N-hexadecylpyridinium compounds of the formula are, where y⊖ are the anions according to claim 20. 43. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a 4- (17-tritriacontyl) -N-methyl-pyridinium chloride of the formula is. 44. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant is a 3,5-bis [(n-hexadecyloxy) carbonyl)] - N-methyl-pyridinium chloride of the formula is. 45. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the cationic surfactant has the formula has, wobeix₁ein unsubstituted or in the 4-position or in the 3,5-position or in the 1,2,4,5-position substituted phenyl radical, x₂ein unsubstituted or in the 4-position or in the 3,5-position or in the 1,2,4,5-position substituted phenyl radical and y⊖ mean the anions according to claim 20. 46. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that the critical micelle formation concentration (KMK) is in the range from 1.0 to 8.5 · 10 ^-7 mol / l. 47. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the cationic surfactant with a monovalent anion in an amount of 0.05 to 0.1 wt .-% based on the entire pharmaceutical preparation is included. 48. Pharmaceutical preparation according to one or more of the previous claims, characterized,  that the cationic surfactant with a monovalent anion in an amount of 0.08 to 0.1 wt .-% based on the entire pharmaceutical preparation is included. 49. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic active pharmaceutical ingredient in one Amount of 0.06 to 0.5 wt .-% based on the total pharmaceutical preparation is included. 50. Pharmaceutical preparation according to one or more of the preceding claims, characterized, that the hydrophobic active pharmaceutical ingredient in one Quantity from 0.001 to 0.005% by weight based on the total pharmaceutical preparation is included. 51. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the solvent is water. 52. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the solvent is water + glycerin. 53. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the solvent is water + glycerin + ethanol.   54. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the monovalent anion is a monobasic or dibasic Is fatty acid residue. 55. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the monovalent anion acetate, propionate, fumarate, Maleate, succinate, aspartate or glutamate. 56. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the monovalent anion is a sugar residue. 57. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the monovalent anion gluconate, galacturonate or Is alginate. 58. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the monovalent anion chloride, bromide, iodide, or Is hydrogen sulfate. 59. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical agent is an antimicrobial Active ingredient is.   60. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical ingredient is an antifungal Active ingredient is. 61. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic active pharmaceutical ingredient is an antiproliferative agent. 62. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical agent is an antiviral Active ingredient is. 63. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic active pharmaceutical ingredient is an inorganic Connection of the elements zinc or mercury or is tungsten and / or antimony. 64. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the inorganic compound is ZnSO₄. 65. Pharmaceutical preparation according to one or more of the previous claims, characterized,  that the inorganic compound is ZnO. 66. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the inorganic compound is Hg (CN) ₂. 67. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the inorganic compound (NH₄) ₁₈ (NaW₂₁Sb₉O₈₆) ₁₇ is. 68. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the inorganic compound is an alkali or Alkaline earth metal salt of phosphonic acid ROP (O) Me₂. 69. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the inorganic compound is an N-phosphonoacetyl-1-aspartate is. 70. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical agent is an antibiotic is. 71. Pharmaceutical preparation according to one or more of the previous claims, characterized,  that the antibiotic daunomycin and / or adriamycin and / or canamycin and / or gentamycin and / or neomycin and / or polymyxins and / or tobramycin and / or amikacin and / or tetracycline and / or chloramphenicol and / or Erythromycin and / or clindamycin and / or rifampicin and / or bacitrazin and / or Thyrotrozine is. 72. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical agent is an antiviral Active ingredient is. 73. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the antiviral active ingredient idoxuridine and / or 5-ethyl-2'-deoxyuridine and / or trifluorothymidine and / or ribavirin and / or amantadine and / or rimantadine and / or Vidarabine and / or 2,6-di-amino-kuban and / or 1,1'3,3'-bis-cyclobutane and / or dehydrocuban and / or 2,6-diamino of the Cuban. 74. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical agent is an antifungal Active ingredient is. 75. Pharmaceutical preparation according to one or more of the previous claims, characterized,  that the antifungal active ingredient 5-fluorocytosine and / or Clotrimazole and / or econazole and / or miconazole and / or Oxyconazole (Z form) and / or amphotericin B and / or Nystatin and / or ZnO · EDTA and / or Hg₂ (CN) ₄ and / or Is polyoxins. 76. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the hydrophobic pharmaceutical agent is an antineoplastic Active ingredient is. 77. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the antineoplastic agent 5-fluorocytosine and / or Hg (CN) ₂ and / or Hg (CN) · (ascorbate) ₄ or Hg (CN) ₂ · (acetylacetonate) ₄ and / or azauridine and / or Cytarabine and / or azaribine and / or 6-mercaptopurine and / or deoxycoformycin and / or azathioprine and / or Thioguanine and / or vinblastine and / or vincristine and / or Daunorubicin and / or Doxorubicin is. 78. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the solvent is water and / or ethanol and / or Is glycerin. 79. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the solvent is water and / or ethanol and / or Is dimethyl sulfoxide (DMSO).   80. Pharmaceutical preparation according to one or more of the previous claims, characterized, that the pH of the solvent is 5. 81. Process for the preparation of the pharmaceutical preparation according to one of claims 1-80, characterized, that first the solvent in a reaction vessel is submitted, then the cationic surfactant with stirring is added at room temperature, then to the resulting isotropic micellar solution of the hydrophobic pharmaceutical Active ingredient added with stirring at room temperature and is stirred until it is completely dissolved becomes. 82. Cationic surfactants of the general formula [HET ≡ N⊕ - (CH₂) _x - CH₃] y⊖w thoseHet≡N⊕- a substituted or unsubstituted pyridinium residue or a substituted or unsubstituted pyrimidinium residue or
a substituted pyrazine (1,4-diazinium) residue or an imidazolium (4,5-d) pyrimidine residue substituted or unsubstituted, or
a substituted or unsubstituted imidazolium residue or
a substituted or unsubstituted pyrazolium residue, or
a substituted or unsubstituted thiazolium radical, or
a substituted or unsubstituted benzothiazolium radical, or
a substituted or unsubstituted benzimidazolium radical, x 8 to 20 and y⊖chloride, bromide, iodide, formate, acetate, propionate, hydrogen sulfate, malate, fumarate, salicylate, alginate, gluconate or ethyl sulfate. 83. N-alkyl pyridinium of the formula where y⊖ mean the anions according to claim 82. 84. Hexadecyl pyridinium of the formula where y⊖ mean the anions according to claim 82. 85. N-alkyl-4-hydroxypyridinium of the formula where y⊖ mean the anions according to claim 82. 86. Hexadecyl-4-hydroxypyridinium of the formula where y⊖ mean the anions according to claim 82. 87. 2,5,6 substituted N₁-alkyl-pyridinium compounds of the formula R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = R₁ = OH;
R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = Fw wherein y⊖ mean the anions according to claim 82. 88. Hexadecyl pyridinium of the formula R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = R₁ = OH;
R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = Fw wherein y⊖ mean the anions according to claim 82. 89. 4-n-alkyl-pyrazinium-2-carboxamide of the formula where y⊖ mean the anions according to claim 82. 90. 4-Hexadecylpyrazinium-2-carboxamide of the formula where y⊖ mean the anions according to claim 82. 91. 7-n-alkylimidazolium [4,5-d] pyrimidine of the formula R₁ = OH; R₂ = OH
R₁ = H; R₂ = H
R₁ = F; R₂ = NH₂
R₁ = F; R₂ = OH
R₁ = NH₂; R₂ = H
R₁ = NH₂; R₂ = NH₂ where y⊖ mean the anions according to claim 82. 92. 7-Hexadecylimidazolium [4,5-d] pyrimidine of the formula R₁ = OH; R₂ = OH
R₁ = H; R₂ = H
R₁ = F; R₂ = NH₂
R₁ = F; R₂ = OH
R₁ = NH₂; R₂ = H
R₁ = NH₂; R₂ = NH₂ where y⊖ mean the anions according to claim 82. 93. 3-n-Alkyl-5,6-substituted benzimidazolium compounds of the formula R₁ = OH where y⊖ mean the anions according to claim 82. 94. 4-substituted n-alkyl-2-pyrazolium compounds of the formula R = H; CH₃; OH where y⊖ mean the anions according to claim 82. 95. 1-n-alkyl-4-substituted imidazolium compounds R = H; CH₃; where y⊖ are the anions according to claim 82. 96. 1-Hexadecyl-4-substituted imidazolium compounds of the formula R = H; CH₃; where y⊖ are the anions according to claim 82. 97. 3-n-alkyl-5,6-substituted benzothiazolium compounds of the formula R₁ = R₂ = H
R₁ = CH₃
R₁ = R₂ = OH
R₁ = R₂ = CH₃ where y⊖ mean the anions according to claim 82. 98. 4- [1,1bis n-alkyl (lower alkyl)] N-hexadecylpyridinium compounds of the formula where y⊖ mean the anions according to claim 82. 99. 3,5-bis [(n-alkoxy) carbonyl] N-hexadecylpyridinium compounds of the formula where y⊖ mean the anions according to claim 82. 100. 4- (17-Tritriacontyl) -N-methyl-pyridinium chloride of the formula where y⊖ mean the anions according to claim 82. 101. 3,5-bis [(n-hexadecyloxy) carbonyl)] - N-methylpyridinium chloride where y⊖ mean the anions according to claim 82. 102. Cationic surfactants of the general formula wobeix₁ein a phenyl radical which is unsubstituted or substituted in the 4-position or in the 3,5-position or in the 1,2,4,5-position, x₂ein an unsubstituted or in the 4-position or in the 3,5-position or in the 1,2,4,5-substituted phenyl radical and y⊖ mean the anions according to claim 82. 103. Pharmaceutical preparation according to one or more of the preceding claims, characterized in that x in the general formula of the cationic surfactant in claim 21 has the numerical value 14. 104. Cationic surfactants of the general formula [HET≡N⊕- (CH₂) ₁₄-CH₃] y⊖wherein HET≡N⊕- and y⊖ those specified in claim 21 Have meanings.   105. N-alkylated quaternary nitrogen-containing heterocycles, namely 2,5,6 substituted N₁-alkyl-pyrimidinium compounds of the formula R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = Fwher n is 8 to 20, in particular 15 and Z⊖chloride, bromide, iodide, maleate, formate, acetate, propionate, hydrogen sulfate, malate, fumarate, salicylate, alginate, gluconate, glucoronate, galactoronate, ethyl sulfate or hydrogen phosphate mean H₂PO₄⊖. 106. 2,5,6 substituted N₁-hexadecylpyrimidinium compounds according to claim 105 of the formula R₁ = R₂ = R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = NH₂; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = CH₃
R₁ = OH; R₂ = OH; R₃ = H
R₁ = F; R₂ = OH; R₃ = H
R₁ = OH; R₂ = OH; R₃ = Fw whereinZ⊖chloride, bromide, iodide, maleate, formate, acetate, propionate, hydrogen sulfate, malate, fumarate, salicylate, alginate, gluconate, gluconate, galactoronate, ethyl sulfate or hydrogen sulfate mean H₂PO₄⊖. 107. Process for the preparation of the N-alkylated quaternary nitrogen-containing heterocycles one or more of claims 105-106, characterized, that the heterocycle to be alkylated in one suitable solvent is then dissolved with constant stirring, the stoichiometric Amount of n-alkyl halide added is, then with constant stirring on Reflux is heated for some time after which the final product after cooling fails.   108. Method according to one or more of the Claims 105-107, characterized, that the unsubstituted to be alkylated Heterocycle in a suitable solvent is solved, the stoichiometric amount of n-alkyl halide is added, then under pressure at 100 ° C for a reaction time after 8 hours the reaction is completed after which the final product after cooling fails. 109. Method of manufacturing according to one or several of claims 105-108, characterized, that the alkylated compounds of Pyrimidins dissolved in a solvent be the stoichiometric amount of n-alkyl-magnesium halides in a suitable Solvent added dropwise with constant stirring is heated to 40-80 ° C and stirring is continued for 12 hours, and the Reaction by adding 50% by weight Hydrobromic acid is stopped. 110. Method of manufacture according to one or several of claims 105-109, characterized, that the solvent 1,2-dimethoxy-ethane and / or n-heptane. 111. Method of manufacture according to one or several of claims 105-110, characterized, that the compounds to be alkylated 2,5,6 substituted pyrimidines in  be dissolved in a suitable solvent, with simultaneous addition of triethyloxonium borofluoride (Et₃OBF₄) and the corresponding n-alkyl halide, which is also in is dissolved in a suitable solvent, is added dropwise with constant stirring, and the Reaction with constant stirring at 65-80 ° C after 16 hours, after which the Reaction product fails after cooling. 112. Method of manufacturing according to one or several of claims 105-111, characterized, that the solvent according to claim 111 Acetone or di-isobutyl ketone or isobutyl ethyl ketone are. 113. Method of manufacturing according to one or several of claims 105-112, characterized, that either the reaction vessel is a reaction flask with agitator, dropper and Heater is or that With a stainless steel autoclave Pressure and temperature display is. 114. Use of nitrogen-containing heterocycles according to claim 105 or 106 for the production of micellar or vesicular structures in polar or non-polar solvents, especially with extremely low KMK. 115. Use of nitrogen-containing heterocycles according to claim 105 or 106 for receiving hydrophobic active pharmaceutical ingredients pH 6-8 in polar solvents or non-polar solvents.   116. Use of nitrogen-containing heterocycles according to claim 105 or 106 as an independent active pharmaceutical ingredients at pH 6-8 in polar solvents. 117. Use of nitrogen-containing heterocycles according to claim 105 or 106 as a spectroscopic Markers (reporter groups) in immunological and clinical-biochemical analysis methods as well as colloidal chemical measurement methods to determine the KMK.