EP0000330A1 - Lipopeptides, process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

1. Compounds of the formula see diagramm : EP0000330,P30,F1 wherein R1 and R2 each represent a saturated or unsaturated aliphatic or mixed aliphatic-cycloaliphatic hydrocarbon radical which has 11-21 C atoms and which is also optionally substituted by oxygen functions, R3 represents hydrogen or the radical R1 -CO-O-CH2 -, where R1 has the same meaning, and X represents a natural aliphatic amino acid linked by a peptide bond and having a free, esterified or amidated carboxyl group, or an amino acid sequence of 2-10 natural aliphatic amino acids, the terminal carboxyl group of which is free or in the ester or amide form, with the asymmetric centres denoted by * and ** possessing the absolute R- and S- or R-configurations, respectively ; and, possibly, mixtures of the R- and S-compounds epimeric on the C** atoms, and salts and complexes of all these compounds.

Description

worin R₁ und R₂ je einen gesättigten oder ungesättigten, aliphatischen oder gemischt aliphatisch-cycloaliphatischen, gegebenenfalls auch durch Sauerstoffunktionen substituierten, Kohlenwasserstoffrest mit 11-21 C-Atomen, R₃ Wasserstoff oder den Rest R₁-CO-O-CH ₂ wo R₁ die gleiche Bedeutung hat, und X eine peptidisch gebundene natürliche aliphatische Aminosäure mit freier, ver- esterter oder amidierter Carboxylgruppe, oder eine Aminosäurensequenz von 2-10 natürlichen aliphatischen Aminosäuren, deren terminale Carboxylgruppe in freier, veresterter oder amidierter Form vorliegt, bedeuten, wobei die mit ^* bzw. ^** bezeichneten Asymmetrie-Zentren die absolute S-bzw. S- oder R-Konfiguration besitzen, und gegebenenfalls Gemische der an den C^**-Atomen epimeren. R- und S-Verbindungen, und gegebenenfalls Salze und Komplexe dieser Verbindungen, sowie Verfahren zu ihrer synthetischen Herstellung, und pharmazeutische Präparate enthaltend einen oder mehrere dieser Lipopeptide zusammen mit einem pharmazeutischen Trägermaterial und gegebenenfalls zusammen mit anderen pharmazeutischen Verbindungen.The present invention relates to new lipopeptides and in particular to compounds of the formula

wherein R ₁ and R _{2 are} each a saturated or unsaturated, aliphatic or mixed aliphatic-cycloaliphatic, optionally also substituted by oxygen functions, hydrocarbon radical having 11-21 carbon atoms, R ₃ hydrogen or the radical R ₁ -CO-O-CH _2nd where R _{1 has} the same meaning, and X is a peptide-bound natural aliphatic amino acid with a free, esterified or amidated carboxyl group, or an amino acid sequence of 2-10 natural aliphatic amino acids, the terminal carboxyl group of which is free, esterified ter or amidated form, mean, the asymmetry centers denoted by ^* or ^{** being} the absolute S or. S or R configuration, and optionally mixtures of the epimers on the C ^** atoms. R and S compounds, and optionally salts and complexes of these compounds, as well as processes for their synthetic production, and pharmaceutical preparations containing one or more of these lipopeptides together with a pharmaceutical carrier material and optionally together with other pharmaceutical compounds.

oder entsprechende Formeln mit verkürzter Polypeptid-Kette zukommen dürfte, wobei Y_l, Y_2' Y₃ Acylreste verschiedener höherer gesättigter und ungesättigter Fettsäuren, wie etwa solcher mit 14-19 C-Atomen und anderer, darstellen. Dieselbe Struktur liegt auch dem Murein-Protein als solchem zugrunde (loc.cit.), wobei die absolute Konfiguration an den beiden asymmetrischen Kohlenstoffatomen der obigen Formel nicht untersucht wurde. Sowohl das Murein-Lipoprotein wie seine genannten Abbauprodukte zeigen in vitro eine mitogene Wirkung gegenüber Mäuse-Lymphocyten. [Vgl. auch Z. Immun.-Forschung, Vol. 153, pp. 11-22 (1977)].Lipopeptides have already been described as degradation fragments of lipoproteins. For example, Hantke and Braun (Eur. J. Biochem. 34, 284 - 296 (1973) were able to isolate lipopeptides or lipopeptide mixtures from the murein lipoprotein of the outer cell wall of Escherichia coli by means of enzymatic degradation following structure

or corresponding formulas with a shortened polypeptide chain, Y ₁ , Y _{2 '} Y _{3 are} acyl residues of various higher saturated and unsaturated fatty acids, such as those with 14-19 C atoms and others. The same structure also underlies the Murein protein as such (loc.cit.), Whereby the absolute configuration on the two asymmetric carbon atoms of the above formula has not been investigated. Both the murein lipoprotein and its degradation products show one in vitro mitogenic effect on mouse lymphocytes. [See. also Z. Immun.-Forschung, Vol. 153, pp. 11-22 (1977)].

zugrunde. Als Produkte einer enzymatischen Spaltung von Naturprodukten waren diese Fragmente keine in ihrer Zusammensetzung wohl definierten Produkte und stellten offensichtlich komplizierte Gemische von Kondensationsprodukten aus dem genannten Peptidanteil und sehr verschiedenen Acylderivaten des Glyzerylcysteins dar.As can be seen, the degradation lipopeptides obtained from murein protein contain the "glycerylcysteine"

underlying. As products of an enzymatic cleavage of natural products, these fragments were not products with a well-defined composition and were obviously complicated mixtures of condensation products from the peptide portion mentioned and very different acyl derivatives of glycerylcysteine.

The lipopeptides of the present application now differ from the named degradation products of murein proteins in several respects: they represent lipopeptides of precisely defined, uniform chemical constitution and configuration, which are synthetically accessible and are therefore suitable for therapeutic use; the group they form includes compounds in which the rest of the erythritol takes the place of the glycerol portion in the "glycerylcysteine" and / or those in which an amino acid sequence other than that given above for the known degradation-lipopeptide mixtures in formula (II), or in its place there is also only a single amino acid, and finally also derivatives such as amides and esters of the terminal carboxyl group.

In the acyl radicals R ₁ CO, R ₂ CO in the compounds of the formula I and their derivatives, R ₁ and R _{2 are} saturated or unsaturated, aliphatic or aliphatic-cycloaliphatic, optionally also substituted by oxygen functions, hydrocarbon radicals with 11-21 C atoms, ie the acyl radicals are derived from saturated or unsaturated, aliphatic or cycloaliphatic carboxylic acids with 12-22, preferably with 14-18, carbon atoms, optionally oxygenated in the hydrocarbon radical. The saturated or unsaturated fatty acids, such as lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, arachic acid, oleic acid, elaidic acid, linoleic acid, a- and β-elaostearic acid, stearolic acid, a-linolenic acid, and also among the cycloaliphatic-aliphatic, for example, are to be mentioned as such Dihydrosterkulsäure, Malvalic acid, Hydnocarpussäure and Chaulmoograsäure. Oxygenated acids of this type, which are also suitable for the acyl radicals R ₁ CO and R ₂ CO, are, for example, those resulting from epoxidation of the abovementioned olefinic fatty acids and cycloaliphatic-aliphatic acids, for example α, l-epoxystearic acid, and also derivatives of these Acids mentioned above, which have, for example, one or more hydroxyl groups, such as ricinoleic acid.

In the compounds of the formula (I) or their diastereomer mixtures and their salts or complexes, the groups R ₁ and R ₂ can be identical to one another or different from one another. Preference is given to compounds in which all three or four acyl radicals are identical, and in particular those in which these represent the palmitoyl, stearoyl or oleoyl radical.

The peptide sequence X in the compounds of formula (I) or. their salts consist of a maximum of 10 natural aliphatic amino acids, preferably at least half of which are hydrophilic Group, such as especially hydroxyl, amino, carboxyl, carbamide, guanidino or imidazolyl groups. Of the ionic amino acids in this category, aspartic and glutamic and oxyglutamic acids bearing the acidic groups are to be emphasized, and lysine, ornithine, arginine and histidine are among the basic groups bearing. Amino acids with a neutral character are particularly the amides, such as asparagine, glutamine and hyaroxy groups, primarily serine and threonine.

If X in formula (I) represents the amino acid mentioned, it is also e.g. bearing one of said hydrophilic groups, e.g. especially serine or threonine.

Among the amino acids that can go into the above sequence and that do not carry any hydrophilic groups, the unsubstituted ones should be mentioned in particular, e.g. Glycine, alanine, valine, norvaline, leucine, isoleucine, but also some substituted ones that have a non-hydrophilic character, such as methionine.

The order of the amino acids mentioned in the peptide chain X can be arbitrary, but preference is given to those sequences in which all amino acids with hydrophilic groups are bonded directly to one another, and among these in turn those in which this sequence of the hydrophilic amino acids to the carboxyl group of the cysteine in the Triacyl-Glycerylcystein or Tetraacyl-Erythritylcystein part is bound.

worin R₁, R₂ die gleichen Bedeutungen besitzen und X die für Formel (I) gegebene Bedeutung hat, aber im Falle der Aminosäurensequenz 2-5 Aminosäuren aufweist, in welcher vorzugsweise mindestens die Hälfte eine hydrophile Gruppe tragen, sowie ihre Salze und Komplexe. Unter diesen Lipopeptiden seien jene hervorgehoben, deren Aminosäurensequenz in der Gruppe X derjenigen der obengenannten durch Abbau von Murein-Lipoprotein erhaltenen Lipopeptide, d.h. solcher der Formel (II), oder einer sich davon ableitenden verkürzten Kette entspricht. Es seien insbesondere folgende Lipopeptid-Typen erwähnt. (AcGCT= Acyl-Glyzerylcystein-Teil gemäss Formel IV):

sodann die entsprechenden Typen, in welchen Threonin, Glutamin oder Asparagin das Serin ersetzen; ferner die Verbindungstypen der Art:

und die entsprechenden mit Threonin, Glutamin oder Asparagin als Austauschaminosäuren für Serin, und die Amide und Carbonsäureester mit terminaler Carbamid- bzw. Estergruppe, wobei in erster Linie die Verbindungen in Betracht zu ziehen sind, in denen die Acylreste R_l-CO, R₂-CO im Acyl-Glyzerylcystein-Teil gleich sind und Palmitoyl, Stearoyl oder Oleoyl darstellen, und alle diejenigen, in denen R₁-CO und R₂-CO verschieden sind und z.B. Palmitoyl, Stearoyl oder Oleoyl bedeuten, und diese Reste in beliebiger Kombination und/oder Variation vorkommen, wie die in der folgenden Tabelle angeführten, wobei der Glyzerylcystein-teil entsprechend den N- und 0-Acylsubstituenten als N-Acyl-0-0-di-Acyl-Cys abgekürzt geschrieben ist:

ferner die Verbindungen, die sich aus der Substitution des Serins durch Threonin, Glutaminsäure, Glutamin, Asparaginsäure oder Asparagin, aus der Substitution des Lysins durch Glutaminsäure, und solche, die sich aus der gleichzeitigen Substitution von Lysin durch Glutaminsäure und Asparagin durch Phenylalanin ergeben.An important group [group I] of lipopeptides according to the present invention are those in which the peptide chain X consists of a maximum of 5 amino acids. Among these are in particular those of the formula

wherein R ₁ , R _{2 have} the same meanings and X has the meaning given for formula (I), but in the case of the amino acid sequence has 2-5 amino acids, in which at least half preferably carry a hydrophilic group, and their salts and complexes. Among these lipopeptides, those are to be emphasized whose amino acid sequence in group X corresponds to that of the above-mentioned lipopeptides obtained by degradation of murein lipoprotein, ie those of the formula (II), or a shortened chain derived therefrom. The following types of lipopeptides should be mentioned in particular. (AcGCT = acyl-glycerylcysteine part according to formula IV):

then the corresponding types in which threonine, glutamine or asparagine replace the serine; also the connection types of the type:

and the corresponding ones with threonine, glutamine or asparagine as exchange amino acids for serine, and the amides and carboxylic acid esters with terminal carbamide or ester groups, the compounds primarily being considered hen are in which the acyl radicals R ₁ -CO, R ₂ -CO in the acyl-glycerylcysteine part are the same and represent palmitoyl, stearoyl or oleoyl, and all those in which R ₁ -CO and R ₂ -CO are different and for example palmitoyl, stearoyl or oleoyl, and these residues occur in any combination and / or variation, such as those listed in the following table, the glycerylcysteine part corresponding to the N- and 0-acyl substituents as N-acyl-0-0- di-Acyl-Cys is abbreviated:

furthermore the compounds resulting from the substitution of serine by threonine, glutamic acid, glutamine, aspartic acid or asparagine, from the substitution of lysine by glutamic acid, and those resulting from the simultaneous substitution of lysine by glutamic acid and Asparagine resulted from phenylalanine.

und die sich durch Ersatz von Ser durch Phe oder von Phe durch Ser ergebenden Verbindungen.Among the compounds with different acyl residues on N and 0 atoms in the glyceryl cysteine residue, the following should be emphasized:

and the compounds resulting from replacing Ser with Phe or Phe with Ser.

A second group of compounds [Group II] according to the invention are compounds according to formula IV above, but in which the configuration at the C ** atom is S instead of R, and the mixtures of the R and S diastereomers, as described e.g. may arise in the synthetic representation. Specific types and compounds in this group also correspond to those particularly emphasized above for the "R" group (formula IV).

• Ile-Asp-Glu-OH
• Asp-Glu-OH
• Spezifische Verbindungen sind z.B.
• N-Stearoyl-S-[2(R),3-dipalmitoyloxypropyl]-Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH
• N-Palmitoyl-S-[2(R),3-dipalmitoyloxypropyl]-Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH
• N-Palmitoyl-S-[2(R),3-dipalmitoyloxypropyl]-Cys-Ser-Ser-Asn-Ala-Lys-Ile-Asp-Glu-OH.
• Es können erfindungsgemäss auch entsprechende Verbindungen dieses Typs mit der S-Konfiguration am C^**- Atom hergestellt werden, sowie Diastereomerengemische von S- und R-Verbindungen.

A third group [Group III] of the new lipopeptides comprises the compounds according to formula (IV), in which, however, X represents an amino acid sequence with 6-10 amino acids, the first 5 preferably representing the sequences already highlighted above. Amino acids 6-10, any of the in particular serine, asparagine, alanine, glutamic acid, lysine, phenylalanine, and about in the following S _e above-mentioned natural be - sequences occur:

• Ile-Asp-Glu-OH
• Asp-Glu-OH
• Specific connections are, for example
• N-Stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH
• N-Palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH
• N-Palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Lys-Ile-Asp-Glu-OH.
• Corresponding compounds of this type with the S configuration on the C ^** atom can also be prepared according to the invention, and diastereomer mixtures of S and R compounds.

insbesondere solche mit R-Konfiguration an den C^**-Atomen, worin X die für Formel (IV) angegebene Bedeutung besitzt. Die Acylreste R₁-CO- und R₂-CO- sind vorzugsweise dieselben und vor allem wiederum Palmitoyl, Stearoyl oder Oleoyl; sie können aber wie oben für die anderen Gruppen besprochen, in allen Kombinationen und/oder Variationen vorhanden sein.

• Bevorzugte Typen und Verbindungen dieser Klasse
• sind wiederum solche, in denen X die oben spezifizierten Bedeutungen haben.
• Auch für diese Gruppe ist vorzugsweise X eine
• Aminosäure oder eine Sequenz von 5 Aminosäuren, insbesondere eine der oben für die anderen drei Gruppen von Lipopeptiden als bevorzugt bezeichneten. X kann aber auch eine der für die dritte Gruppe der Lipopeptide der vorliegenden Anmeldung beschriebenen Aminosäurensequenzen mit 6-10 Aminosäuren, insbesondere die für jene Gruppe spezifisch erwähnten, darstellen.
• Spezifische Verbindungen sind z.B. die sich aus der obigen für spezifische Verbindungen der Gruppe I zusammengestellte Tabelle ergebenden, wenn in ihnen N-Acyl-0-0-di-Acyl-Cys nicht wie dort den Glyzerylcysteinanteil, sondern den Erythritylcystein-Rest bedeutet, und die sich durch Substitution des Serins durch Threonin, Glutaminsäure, Glutamin, Asparaginsäure oder Asparagin und von Lysin durch Glutaminsäure und, wenn erwünscht, gleichzeitig von Asn durch Phenylalanin ergebenden Verbindungen.

A fourth group [Group IV] of the lipopeptides according to the invention comprises compounds of the formula (I) in which R ₃ denotes the radical R ₁ -CO-O-CH _2nd in which the configuration on the C ^** atoms is any, in particular also diastereomer mixtures. Subgroups are compounds of the formula

in particular those with an R configuration on the C ^** atoms, in which X has the meaning given for formula (IV). The acyl radicals R ₁ -CO- and R ₂ -CO- are preferably the same and especially again palmitoyl, stearoyl or oleoyl; however, as discussed above for the other groups, they can be present in all combinations and / or variations.

• Preferred types and compounds in this class
• are again those in which X has the meanings specified above.
• For this group too, X is preferably one
• Amino acid or a sequence of 5 amino acids, especially one of those above for the other three groups of Lipopepti the designated as preferred. However, X can also represent one of the amino acid sequences with 6-10 amino acids described for the third group of lipopeptides of the present application, in particular those specifically mentioned for that group.
• Specific compounds are, for example, the table shown in the table above for specific compounds of group I, when in them N-acyl-0-0-di-acyl-Cys does not mean the glycerylcysteine portion, but the erythritylcysteine residue, and that by substitution of the serine with threonine, glutamic acid, glutamine, aspartic acid or asparagine and of lysine with glutamic acid and, if desired, simultaneously with Asn by phenylalanine compounds.

und ihre Amide und Ester, insbesondere die im nachfolgend besonders hervorgehobenen.A fifth group of lipopeptides according to the present invention is formed from those compounds according to formula (I) in which X denotes a peptide chain in which the sequence of the first 5 amino acids of those present in the known murein lipoprotein degradation lipopeptides is different, and in particular those in which R _{3 is} hydrogen, that is to say corresponding to the formula (IV) above, where R ₁ -CO and R ₂ -CO are the acyl radicals in the combinations mentioned which are preferably emphasized above or below, and their salts and complexes. The following types of lipopeptides may be mentioned (AcGCT = acyl-glycerylcysteine part according to formula (IV)

and their amides and esters, especially those highlighted below.

und ihre Amide und Ester, insbesondere die im nachfolgenden hervorgehoben.Another subgroup consists of compounds according to formula (IV), in which X represents the “unnatural” sequence of amino acids compared to the murein-lipoprotein degradation products, and 6-10 Amino acids are present. For example, the first five amino acids have the sequence given above or any other; the following lipopeptides may be mentioned, for example, where AcGCT has the above meaning:

and their amides and esters, particularly those highlighted below.

Compounds of this type are preferably prepared in which the configuration on the C ^** atom of the AcGCT is R, or mixtures of R and S epimers.

In the new lipopeptides according to the present invention discussed above, the terminal carboxyl group may be in amidated form. In addition to the unsubstituted amide, there are also those which are derived from a primary or secondary amine. In particular, amides of lower aliphatic amines with 1-7 C atoms are suitable, such as methylamine, ethylamine, propylamine, butylamine, dimethylamine, diethylamine or propyl- and isopropylamine, furthermore aromatic amines, especially monocyclic, such as aniline or toluidine, araliphatic, such as Benzylamine or heterocyclic amines, such as the aminopyridines. The secondary aliphatic amines can also be ring-closed nitrogen bases, such as pyrrolidine, piperidine or piperazine. Specific amides are, for example, the unsubstituted or the methyl, ethyl, dimethyl or diethyl amides of all the specific lipopeptides according to the present invention mentioned above or such amides of the compounds described in the illustrative examples.

In the esterified terminal carboxyl groups of the new lipopeptides, the alcohol component is preferably derived from lower aliphatic alcohols with 1-7 C atoms, such as methyl, ethyl, n-propyl, isopropyl or the butyl alcohols. The esterifying alcohols can also be polyvalent, such as ethylene glycol or propylene glycol or glycerin. Also araliphatic alcohols, especially monocyclic lower aliphatic with 1-7 C atoms in the aliphatic part, such as Benzyl alcohol, or heterocyclic alcohols, such as tetrahydrofuranol or tetrahydropyranol, can be used for the esterification. Specific esters of this type of lipopeptides according to the invention are e.g. the methyl, ethyl and ethylene glycol or propylene glycol esters of all of the specific lipopeptides listed above or those described in the illustrative examples are mentioned.

The present new lipopeptides are neutral, acidic or basic compounds depending on the nature of their substituents. If excess acidic groups are present, they form salts with bases such as ammonium salts or salts with alkali or alkaline earth metals, e.g. Sodium, potassium, calcium or magnesium; however, if excess basic groups are present, they form acid addition salts.

Acid addition salts are particularly pharmaceutically usable, non-toxic acid addition salts, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, Hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids, for example methanesulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid -2-sulfonic acid, also other acid addition salts which can be used, for example, as intermediates, for example for purifying the free compounds or in the preparation of other salts, and for characterization, such as those with picrin, picrolone, flavian, phosphorus tungsten -, Phosphormolyddän-, chloroplatinic, pure corner or perchloric acid.

Complexes are those with metal salts, e.g. compounds formed with heavy metal salts, such as copper, zinc, iron or cobalt salts. The phosphates, pyrophosphates and polyphosphates of these metal salts are preferably used to form such complexes, optionally in combination with acidic organic substances, e.g. acidic group-containing polysaccharides, such as carboxymethyl cellulose, tannic acid, polyglutamic acid or partially hydrolyzed gelatin, and also alkali metal polyphosphates such as e.g. "Calgon N", "Calgon 322", "Calgon 188" or "Plyron B 12".

The compounds of the present invention according to formula (I) above, their salts and complexes and mixtures have valuable pharmacological properties, in particular a pronounced immunopotentiating effect. Thus, the compounds in the dose range of 0.5-320 pg / ml stimulate the proliferation of B lymphocytes determined in vitro by means of thymidine incorporation 20- to 50-fold compared to non-stimulated control lymphocytes. The extent of the stimulation corresponds to that with the most effective B cell mitogens known [dextran sulfate, E. coli lipopolysaccharide, PPD (purified protein derivative)] is achieved, with the new compounds of the present application even high concentrations having no lymphocytotoxic effect.

The new compounds of the formula (I), their salts and complexes and mixtures are also able to induce the formation of antibody-producing cells in concentrations of 0.3-60 µg / ml in spleen cell cultures of normal mice (increase in the 19S-plaque-forming cells by a factor of 20 to 50 above the control value (in the absence of the stimulating substances): For example, in the presence of the compounds mentioned, specific antibodies against sheep erythrocytes are formed without adding sheep erythrocytes to the cultures for immunization. On the other hand, the substances mentioned in the same concentration range can also increase the immunological reactivity of _T- cell-depleted spleen cell cultures (from congenitally athymic nu / nu mice) compared to a normally thymus-dependent antigen (sheep erythrocytes) (factor 10 to 40 compared to untreated control cultures). However, the compounds mentioned not only directly or indirectly induce proliferation and synthesis performance of B-lymphocytes (ie of potentially antibody-forming cells) in vitro, but also effects on T-lymphocytes (which include regulatory active helper and suppressor cells and cytotoxic effector cells ), conveyed. For example, the compounds mentioned in a concentration range of 10-100 µg / ml can significantly (up to 10 times) potentiate the reactivity of cortisone-resistant thymus cells with allogeneic irradiated stimulator lymphocytes.

The above-mentioned effects are probably caused indirectly by the fact that the lipopeptides are macro Activate phages, which in turn promote the reactivity of T and B lymphocytes. In fact, it can be shown that the compounds mentioned release very large amounts of "colony stimulating activity" (CSA) from mouse macrophages even in extremely low concentrations (0.01-10 pg / ml) (induction of up to 150-200 colonies within 7 Days from 10 ⁵ mouse bone marrow cells, after adding 20% supernatant from macrophage cultures incubated with substance for 24 hours, compared to 0-5 colonies when adding supernatants from untreated macrophage cultures) .C ^SA is a biological mediator which is used for the differentiation of Bone marrow stem cells to macrophages and polymorphonuclear leucocytes is necessary. The compounds mentioned thus bring about an increased replenishment of cells which are of central importance for the non-specific resistance and for the induction, amplification and expression of specific (lymphocyte-mediated) immune reactions.

• NMRI Mäuse werden durch intraperitoneale Injektion von 10_/ug präzipitatfreiem BSA am Tag 0 immunisiert. 9,15 und 29 Tage später werden Serumproben entnommen und auf ihren Gehalt an anti-BSA-Antikörpern mit einer passiven Haemagglutinationstechnik untersucht. In der verwendeten Dosis ist lösliches BSA für die Empfängertiere subimmunogen, d.h. es vermag keine oder nur eine ganz geringfügige Produktion von Antikörpern auszulösen. Zusätzliche Behandlung der Mäuse mit gewissen immunpotenzierenden Stoffen vor oder nach der Antigengabe führt zu einem Anstieg der Antikörpertiter im Serum. Der Effekt der Behandlung wird durch den erreichten Scorewert, d.h. durch die Summe der log₂ Titerdifferenzen an den drei Blutungstagen ausgedrückt.
• In diesem Test sind die Verbindungen der Formel (I), ihre Salze oder Komplexe oder Gemische in der Lage bei intraperitonealer oder subkutaner Applikation von 0,03-3 mg/kg Tier an fünf aufeinander folgenden Tagen vor oder nach Immunisierung mit BSA die Antikörperproduktion gegen BSA signifikant zu steigern.

The immunopotentiating effect of the new compounds of the formula (I), their salts or complexes or mixtures can also be demonstrated in vivo: for example, the injection of a lipopeptide according to the invention leads to a high increase in the CSA concentration in the serum within 3-9 hours (up to 120 colonies per 10 ⁵ mouse bone marrow cells after adding chloroform extracted serum [5% final concentration) compared to 0 - 5 colonies in untreated animals). Accordingly, the administration of the same compounds in vivo significantly increases the antibody-producing ability of mice:

• NMRI mice are immunized by intraperitoneal injection of 10 _/ µg of precipitate-free BSA on day 0. 9.15 and 29 days later, serum samples are taken and their content of anti-BSA antibodies is examined using a passive hemagglutination technique. In the The dose used is soluble BSA for the recipient animals subimmunogenically, ie it can induce no or only a very slight production of antibodies. Additional treatment of the mice with certain immunopotentiating substances before or after the antigen administration leads to an increase in the antibody titer in the serum. The effect of the treatment is expressed by the score achieved, ie the sum of the log ₂ titer differences on the three bleeding days.
• In this test, the compounds of the formula (I), their salts or complexes or mixtures are capable of antibody production against five days in a row after intraperitoneal or subcutaneous administration of 0.03-3 mg / kg animal before or after immunization with BSA To significantly increase BSA.

• Während Sensibilisierung von Meerschweinchen mit BSA in inkomplettem Freund'schen Adjuvans nur zu humoraler Antikörperbildung führt, induziert die Beimischung der Lipopeptide gemäss der vorliegenden Erfindung in einem Dosisbereich von 1-15µg zur wässerigen Phase der Antigen-Oelemulsion Spättyp-Ueberempfindlichkeit gegenüber BSA: 3 Wochen nach Immunisierung führt die intrakutane Injektion von BSA bei diesen Tieren zu einer lokalen Enczündungsreaktion mit Erythem und Verdickung der Haut, die innert 24 bis 48 Stunden ihr Maximum erreicht. Diese Spättyp-Reaktionen entsprechen quantitativ und qualitativ denjenigen, die üblicherweise durch Immunisierung mit BSA in komplettem Freund' schem Adjuvans (d.h. mit Zusatz von Mykobakterien) erhalten werden. Die ED₅₀-Werte (benötigte pg/Tier zur Induktion einer Differenz des Reaktionsvolumens (Erythemfläche x Hautdickenzunahme) bei behandelten und unbehandelten Tieren von 200 ul, 24 Stunden nach Auslösung) betragen 2-3 ug.

Manifestations of cell-mediated immunity can also be potentiated in vivo by the compounds mentioned:

• While sensitization of guinea pigs with BSA in incomplete Freund's adjuvant only leads to humoral antibody formation, the admixture of the lipopeptides according to the present invention induces in a dose range of 1-15 μg to the aqueous phase of the antigen-oil emulsion late-type hypersensitivity to BSA: 3 weeks after Immunization causes the intracutaneous injection of BSA in these animals to cause a local inflammation with erythema and thickening of the skin, which reaches its maximum within 24 to 48 hours. These late-type reactions correspond quantitatively and qualitatively to those which are usually obtained by immunization with BSA in a complete Freund's adjuvant (ie with the addition of mycobacteria). The ED ₅₀ values (needed pg / animal to induce a difference in the reaction volume (Ery themed area x increase in skin thickness) of treated and untreated animals of 200 ul, 24 hours after triggering) are 2-3 ug.

The lipopeptides according to the present invention are also not very toxic: 5 times intraperitoneal application in a dose of 10 mg / kg / day on five consecutive days was apparently tolerated without symptoms by mice. Since the doses required for immunostimulation are very small, the therapeutic breadth of the new compound is very large.

The new lipopeptides according to the present invention can thus significantly increase the cellular and especially the humoral immunity, both in a mixture with the antigen itself (adjuvant effect in the narrower sense) and with a supply that is separate in time and place from the antigen injection (systemic immune potentiation).

The new lipopeptides according to the present invention can thus be used as adjuvants in a mixture with vaccines to improve the vaccination success and to improve the protection against infection mediated by humoral antibodies and / or cellular immunity against bacterial, viral or parasitic pathogens.

Finally, the compounds described, in a mixture with various antigens, are suitable as adjuvants in the experimental and industrial production of antisera for therapy and diagnosis and in the induction of immunologically activated lymphocyte populations for cell transfer processes.

In addition, the new lipopeptides can also be used to promote immune reactions in humans and animals that are already taking place, even without simultaneous antigen supply. The connections are therefore suitable especially for the stimulation of the body's defense, e.g. with chronic and acute infections or with selective (antigen-specific) immunological defects, as well as with congenital, but also with acquired general (ie non-antigen-specific) immunological defect states, such as those in old age, in the course of severe primary diseases and especially after therapy with ionizing radiation or with immunosuppressive hormones. The substances mentioned can thus preferably also be administered in combination with antibiotics, chemotherapeutic agents or other healing methods in order to counteract immunological damage. Finally, the substances described are also suitable for the general prophylaxis of infectious diseases in humans and animals.

The new lipopeptides can be made according to methods known per se or their new methods described here. getting produced.

• a) dass man in einer Verbindung der Formel
  
  worin R_., R₂ und R₃ die für Formel (I) angegebene Bedeutung haben und Y eine X in der Formel (I) entsprechende Aminosäure oder Aminosäurensequenz darstellt, worin jedoch mindestens eine der die Aminosäuren substituierenden hydrophilen Gruppen und/oder die terminale Carboxylgruppe durch eine unter neutralen oder milden sauren Bedingungen abspaltbare Schutzgruppe geschützt ist, oder in einem Salz einer solchen Verbindung, die Schutzgruppe(n) abspaltet, oder
• b) dass man eine Verbindung der Formel
  
  worin R₁, R₂ und R₃ die für Formel (I) angegebene Bedeutung haben und W = OH oder eine Aminosäure oder eine unvollständige Sequenz von Aminosäuren gemäss X in Formel (I) darstellt, mit einer Verbindung der Formel
  
  wo Z₁ eine der Gruppe X in Formel (I) entsprechende Gruppe bzw. eine zur genannten Aminosäure oder unvollständigen Sequenz von Aminosäuren gemäss X komplementären Aminosäuresequenz bzw. Aminosäure bedeutet, in welchen Sequenzen jedoch keine freien Aminogruppen vorhanden sind, oder einem Salz derselben, umsetzt, oder
• c) eine Verbindung der Formel
  
  worin R₂ die für Formel (I) angegebene Bedeutung besitzt und R₃ Wasserstoff oder die Gruppe HO-CH₂ darstellt, und Z₂ eine X in Formel (I) entsprechende Gruppe darstellt, worin jedoch keine freien Hydroxygruppen vorhanden sind, oder ein Salz dieser Verbindung, in an sich bekannter Weise acyliert. uhd, wenn erwünscht, in
  erhaltenen Verbindungen mit freier terminaler Carboxylgruppe dieselbe in eine Amidgruppe oder Estergruppe überführt, und/oder die Verbindungen in ihre Salze oder Komplexe überführt.

In a preferred process, the compounds of the formula (I), their diastereomeric mixtures and their salts and complexes are prepared by

• a) that one in a compound of the formula
  
  wherein _R. , R ₂ and R _{3 have} the meaning given for formula (I) and Y represents an amino acid or amino acid sequence corresponding to X in formula (I), but in which at least one of the hydrophilic groups substituting the amino acids and / or the terminal carboxyl group is replaced by a sub is protected in neutral or mild acidic conditions removable protective group, or in a salt of such a compound that releases protective group (s), or
• b) that you have a compound of formula
  
  wherein R ₁ , R ₂ and R _{3 have} the meaning given for formula (I) and W = OH or an amino acid or an incomplete sequence of amino acids according to X in formula (I), with a compound of the formula
  
  where Z ₁ denotes a group corresponding to group X in formula (I) or an amino acid sequence or amino acid complementary to the amino acid or incomplete sequence of amino acids according to X, but in which sequences no free amino groups are present, or a salt thereof , or
• c) a compound of the formula
  
  wherein R _{2 has} the meaning given for formula (I) and R _{3 represents} hydrogen or the group HO-CH ₂ , and Z _{2 represents} a group corresponding to X in formula (I), but in which no free hydroxyl groups are present, or a salt this compound, acylated in a manner known per se. uhd, if desired, in
  Compounds obtained having a free terminal carboxyl group are converted into an amide group or ester group, and / or the compounds are converted into their salts or complexes.

The protective groups in the process according to variant a) are in particular those known from the synthesis of peptides.

Protective groups for amino groups are, for example, acyl or aralkyl groups such as formyl, trifluoroacetyl, phthaloyl, benzenesulfonyl, p-toluenesulfonyl, o-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl groups (these sulfenyl groups can also be reacted with nucleophilic reagents, e.g. sulfophilic reagents, e.g. , Thiosulfates), optionally substituted, such as by lower alkoxy groups, especially o- or p-methoxy groups Substituted benzyl, or diphenyl or triphenylmethyl groups or groups derived from carbonic acid, such as optionally in the aromatic rings, e.g. by halogen atoms such as chlorine or bromine, nitro groups, lower alkyl or lower alkoxy groups or coloring groups, e.g. azo groups, substituted arylmethyloxycarbonyl groups, in which the Methylene group can be substituted by a further aryl radical and / or one or optionally two lower alkyl radicals, such as benzyl, benzhydryl or 2-phenyl-isopropyloxycarbonyl groups, for example carbobenzoxy, p-bromo or p-chlorocarbobenzoxy, p-nitrocarbobenzoxy or p-methoxycarbobenzoxy , p-Phenylazo-benzyloxycarbonyl and p- (p'-methoxy-phenylazo) -benzyloxycarbonyl, 2-tolyl-isopropyloxycarbonyl and in particular 2- (p-biphenylyl) -isopropyloxycarbonyl, as well as aliphatic oxycarbonyl groups such as adamantyloxycarbonyl, cyclopentyloxycarbonyl, trichloroethyl, trichloroethyl. Amyloxycarbonyl or especially tert-butyloxycarbonyl.

The amino groups can also be formed by formation of enamines obtained by reacting the amino group with 1,3-diketones, e.g. Benzoylacetone, acetylacetone or dimedone.

Carboxyl groups are protected, for example, by amide or hydrazide formation or by esterification. The amide and hydrazide groups can be optionally substituted, the amide group, for example, by the 3,4-dimethoxybenzyl or bis- (p-methoxyphenyl) methyl group, the hydrazide group, for example by the carbobenzoxy group, the trichloroethyloxycarbonyl group, the trifluoroacetyl group, the trityl group, the tert .-Butyloxycarbonyl group or the 2- (p-biphenylyl) isopropyloxycarbonyl group. Suitable for the esterification are, for example, lower, optionally substituted alkanols such as methanol, ethanol, Cyanomethyl alcohol, benzoylmethyl alcohol or in particular tert-butanol, furthermore aralkanols such as aryl-lower alkanols, for example benzyl alcohols optionally substituted by lower alkyl or lower alkoxy groups or halogen atoms or benzhydroles such as benzhydrol, p-nitrobenzyl alcohol, p-methoxybenzyl alcohol, 2,4,6-trimethylbenzyl. alcohol, phenols and thiophenols optionally substituted by electron-withdrawing substituents, such as thiophenol, thiocresol, p-nitrothiophenol, 2,4,5- and 2,4,6-trichlorophenol, pentachlorophenol, p-nitrophenol, 2,4-dinitrophenol, p-cyanophenol or p-methanesulfonylphenol, further for example N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxypiperidine, 8-hydroxyquinoline.

The hydroxyl groups of the serine and threonine residues can e.g. be protected by esterification or etherification.

Suitable acyl residues during the esterification are, in particular, residues derived from carbonic acid, such as benzoyloxycarbonyl or ethyloxycarbonyl. Groups suitable for etherification are e.g. Benzyl, tetrahydropyranyl or tert-butyl radicals. Also suitable for protecting the hydroxyl groups are those described in Ber. 100 (1967), 3838-3849 described 2,2,2-trifluoro-1-tert-butyloxycarbonylamino or -1-benzyloxycarbonylaminoethyl groups (Weygand).

Preferably, the tert-butyl ester group or the benzhydrol group is used to protect the carboxyl group of the side chains and optionally the terminal carboxyl group, the tert-butyloxycarbonyl group to protect the amino groups of the side chains, for the hydroxyl groups of serine or threonine, the tert-butyl ether group, and if desired, the 2,2,2-trifluoro-l-tert-butyloxycarbonylamino-ethyl group to protect the imino group of the histidine.

The process-related removal of the protective groups with acidic agents under mild conditions is carried out e.g. in a manner known from peptide chemistry, e.g. by treatment with trifluoroacetic acid.

worin _R ¹ _{9 R} ² und _R ³ je einen Kohlenwasserstoffrest bedeutet, wobei die Reste untereinander auch durch eine einfache C-C Bindung verknüpft sein können, insbesondere Alkylreste mit 1-5 C Atomen. Schutzgruppen dieses Typs sind z.B. die 2-(Dimethyl-tert.-butylsilyl)-äthyl-, die 2-(Dibutyl-methyl-silyl)-äthyl- und vor allem die 2-(Trimethylsilyl)-äthylgruppe. Obwohl diese Schutzgruppen auch basisch abgespalten werden können, ist besonders ihre Abspaltbarkeit unter neutralen Bedingungen, und zwar durch Einwirkung eines Salzes der Fluorwasserstoffsäure, von Interesse. Die Abspaltung der Schutzgruppe wird vorteilhaft in einem aprotischen organischen Lösungsmittel vorgenommen; vorzugsweise wird dabei die Anwesenheit von solchen Lösungsmitteln vermieden, welche das Fluorid-Anion zu solvatisieren vermögen, wie Wasser oder niederaliphatische Alkohole.A special protective group for carboxyl groups which can be split off under neutral conditions is the group of the general formula described, for example, in German Offenlegungsschrift 27 06 490

wherein _R ¹ _{9 R} ² and _R ³ each represent a hydrocarbon radical, where the radicals can also be linked to one another by a simple CC bond, in particular alkyl radicals having 1-5 C atoms. Protecting groups of this type are, for example, the 2- (dimethyl-tert-butylsilyl) ethyl, the 2- (dibutyl-methyl-silyl) ethyl and especially the 2- (trimethylsilyl) ethyl group. Although these protective groups can also be split off under basic conditions, their ability to split off under neutral conditions, in particular by the action of a salt of hydrofluoric acid, is of interest. The protective group is advantageously removed in an aprotic organic solvent; the presence of solvents which are able to solvate the fluoride anion, such as water or lower aliphatic alcohols, is preferably avoided.

The condensation according to variant b) of the compound of formula (VII) with the compound of formula (VIII) is carried out, for example, by reacting compound (VII) in the form of the activated carboxylic acid with (VIII), or by reacting the Acid (VII) with the compound (VIII), whose amino group is present in activated form. If appropriate, the compounds (VII) or (VIII) are used for the condensation in the form of their salts.

The carboxyl group of the compound (VII) can be converted, for example, into an acid azide, anhydride, imidazolide, isoxazolide or an activated ester, such as cyanomethyl ester, carboxymethyl ester, thiophenyl ester, p-nitrothiophenyl ester, thiocresyl ester, p-methanesulfonylphenyl ester, p-nitro , 4-dinitrophenyl ester, 2,4,5- or 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 8-hydroxyquinoline ester, 2-hydroxy-l, 2-dihydro-1-carbäthoxy- quinoline ester, N-hydroxypiperidine ester or an enol ester obtained with N-ethyl-5-phenyl-isoxazolium-3-sulfonate [Woodward Reagent], or by reaction using a carbodiimide (optionally with the addition of N-hydroxysuccinimide) or an unsubstituted or e.g. by halogen, methyl or methoxy substituted 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydrobenzo [d] -1,2,3-triazine or N, N'-carbonyldiimidazole.

The amino group of the compound (VIII) can be activated, for example, by reaction with a phosphite.

The most common methods of condensation are: the Weygand-WUnsch method (carbodiimide in the presence of N-hydroxysuccinimide), the azide method, the N-carboxyanhydride or N-thiocarboxyanhydride method, the activated ester method and the anhydride method. In particular, these condensations can be carried out using the Merrifield method.

It is also possible to carry out the condensation of the compound (VII) using the methods just mentioned with a compound of the formula (VIII), in which the terminal carboxyl group is blocked by a protective group other than an amide or ester group as defined for X, such as one of the abovementioned, and / or one or more of the hydrophilic groups present are in protected form, as described above. This leads to condensation products which belong to the group of starting materials of the formula (VI) used for variant a) described above, which are likewise the subject of the present invention.

According to variant c) above, the free hydroxyl groups in the glyceryl or erythrityl radical are acylated in compounds of the formula (IX) which may not contain any free hydroxyl groups in part Z ₂ . This acylation can be carried out in a manner known per se, for example by reaction with a reactive functional derivative of the acid corresponding to the radical to be introduced, such as the anhydride or an acid halide, preferably in the presence of a tertiary base such as pyridine or collidine.

This process is particularly suitable for the production of process products according to formula I in which the acyl residues in the glyceryl or erythrityl residue and on the cysteine residue are different.

If this variant is used for compounds of the formula (IX) in which, in part Z _z, the terminal carboxyl group is also protected by other protective groups, other than as an imide or ester radical, as intended for X, and / or one or more of the existing hydrophilic groups in a protected form, as described above, there are also starting compounds for variant a) above.

In the lipopeptides according to formula I obtained by any of the described process variants, in which a free terminal carboxyl group is present in part X, the same can be carried out in a manner known per se, for example according to one of those customary in peptide chemistry Methods in which amide or ester groups are converted.

An N-acyl or N, O, O-triacyl-S- (2,3-dihydroxypropyl) cysteine to be used as starting material according to formula (VII), provided that W = OH and R ₃ = H, can be given in the following Way: are obtained: starting from 1,1,5,6-D-mannitol diacetonide, 2-0,3-0-isopropylidene-D-glycerinaldehyde is obtained by periodate oxidation, the aldehyde group is reduced to the carbinol group and esterified with p-toluenesulfonic acid. The 1-0-tosyl-2 (R) -0.3-0-isopropylidene glycerol thus obtained is condensed with N-acyl- (S) -cysteine in the presence of a basic agent, for example potassium carbonate, and the N- Acyl-S- [2 (R), 3-isopropylenedioxy-propyl] - (S) -cysteine, which is acidified, for example with acetic acid. The N-acyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine obtained in this way can, if desired, be in the 2- and 3-position of the glycerol portion, preferably with temporary protection of the carboxyl group, for example by means of the trimethylsilylethyl group described above, or preferably the benzhydryl ester group, can be further acylated.

The preparation of an N-acyl or N, 0,0,0-tetraacyl-S- (2,3,4-trihydroxybutyl) cysteine used as starting material according to formula (VII) can be carried out analogously to the method of Example 7.

The amino acids or peptides to be used for the production of the new lipopeptides according to the process are known or can be prepared by methods known per se.

The above starting compounds (VII) for variant b) in the event that W = OH, and their diastereomeric mixtures, salts and complexes themselves also have an immunopotentiating effect, these in vitro in the same dose range as for the compounds of the formula I. and their derivatives, occurs. In vivo time If the above-mentioned compounds in the test for potentiating the humoral immunity in intraperitoneal administration described 5 days before the antigen was given, an increase in the antibody titer in the serum in the dose range from 1.0 to 3 mg / kg animal.

These compounds can be obtained by acylating a compound of the formula (IX) in which, however, a hydroxyl group is present instead of Z ₂ , as described above for variant c). The preparation of the starting materials required for this, ie the glyceryl or erithrityl-N-acyl cysteines, is described above. Compounds of the formula (IX) in which Z _{2 has} a meaning corresponding to the group X in formula (I) and but in which no free hydroxyl groups are present can be reacted with a compound by reacting the N-acyl-cysteine derivatives just mentioned of the formula NH ₂ -Z ₂ according to the same principles as specified for variant b) of the general process for the preparation of the lipopeptides according to the invention described above.

The lipopeptides obtained can be converted into their salts in a manner known per se, e.g. by reacting acidic compounds obtained with alkali or alkaline earth metal hydroxides or basic compounds obtained with acids.

As a result of the close relationship between the new compounds in free form and in the form of their salts and complexes, the corresponding salts are to be understood in the preceding and following as appropriate and expediently, if appropriate.

The isomer mixtures obtained can be separated in a known manner on the basis of the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystals station. The more effective of the isomers is advantageously isolated.

The methods described above are e.g. carried out according to methods known per se, in the absence or preferably in the presence of diluents or solvents, if necessary, with cooling or heating, under elevated pressure and / or in an inert gas, such as a nitrogen atmosphere. Taking into account all the substituents in the molecule, if necessary, especially in the presence of easily hydrolyzable 0-acyl radicals, particularly gentle reaction conditions, such as short reaction times, use of mild acidic agents in low concentration, stoichiometric quantitative ratios, selection of suitable catalysts, solvents, temperature and / or printing conditions.

The invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or forms a starting material under the reaction conditions or in the form of a reactive one Derivative or salt used. The starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.

The present invention also relates to pharmaceutical preparations which contain the described new lipopeptides according to the invention, both those corresponding to the formula (I) and those of the formula (VII), their mixtures, salts or complexes. At which he Pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal, as well as parenteral administration to warm-blooded animals, which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material. The dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition, as well as on the mode of administration.

The new pharmaceutical preparations contain from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. Pharmaceutical preparations according to the invention can e.g. in unit dose form, such as coated tablets, tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. produced by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.

Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or if desired. Disintegrants, such as the starches mentioned above, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or poly ethylene glycol. Dragee cores are provided with suitable, optionally gastric juice-resistant coatings, including concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings , Solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used. Dyes or pigments can be added to the tablets or dragee coatings, for example for identification or for labeling different doses of active ingredient.

• Z = Carbobenzoxy
• Bu^t = tert. Butyläther
• 0 Bu^t= tert. Butylester
• BOC = tert. Butoxycarbonyl
• DMF = Dimethylformamid
• ONp = p-Nitrophenylester
• HOBt = N-Hydroxybenzotriazol
• DC = DUnnschichtchromatographie

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius. The abbreviations used mean:

• Z = carbobenzoxy
• Bu ^t = tert. Butyl ether
• 0 Bu ^t = tert. Butyl ester
• BOC = tert. Butoxycarbonyl
• DMF = dimethylformamide
• ONp = p-nitrophenyl ester
• HOBt = N-hydroxybenzotriazole
• DC = thin layer chromatography

• System 3: Essigester-Pyridin-Wasser (65:20:15)
• System 157: Chloroform-Methanol-Wasser-Eisessig (70:42: 10:0.5)
• System 157c: Chloroform-Methanol-Wasser-Eisessig (75:25:5:0.5)

In DC, silica gel is used as the adsorbent and the following systems as the eluent:

• System 3: ethyl acetate-pyridine-water (65:20:15)
• System 157: chloroform-methanol-water-glacial acetic acid (70:42: 10: 0.5)
• System 157c: chloroform-methanol-water-glacial acetic acid (75: 25: 5: 0.5)

Example 1:

1.13 g [N-Palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser- ( _B u ^t ) - _S er (Bu ^t ) -Asn-OBut are dissolved in 5 ml 90 percent. Trifluoroacetic acid was added and the solution was concentrated to about 2 ml after 45 minutes at 20 °. The product is precipitated by adding 75 ml of peroxide-free ether, filtered off and dried over potassium hydroxide. The lipopeptide [N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-OH thus obtained shows the following RF values in a thin layer chromatogram on silica gel: Rf (chloroform-methanol-glacial acetic acid-water 79 : 25: 0.5: 4.5) = 0.25.

0.89 λ ([N-palmitoyl-S-2 (R), 3-dihydroxypropyl] -Cys-Ser (Bu ^t) -Ser (Bu ^t) -Asn-OBu ^t are taken up in 10 ml of pyridine, 0.725 ml of palmitoyl chloride added and the solution kept at 45 ° for 24 hours, then 200 ml of chloroform are added and the solution is extracted with 1N citric acid, 1N sodium bicarbonate and water, the organic phase is dried over sodium sulfate and the solvent is evaporated off, and the residue is chromatographed on silica gel in the system chloroform or chloroform-methanol (98: 2) The thin layer chromatographically uniform lipopeptide [N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser- (Bu ^t ) -Ser (Bu ^t ) -Asn-OBu ^t shows in the system chloroform-methanol (9: 1) on silica gel Rf value of 0.75.

To 0.90 g of [N-palmitoyl-S-2 (R), 3-dihydroxypropyl] cysteine and 0.99 g H-Ser (Bu ^t) -Ser (Bu ^t) -Asn-OBu ^t in 20 ml of dimethylformamide 0.472 g of dicyclohexylcarbodiimide and 0.309, N-hydroxybenzotriazole are added at 0 °. After 2 hours at 0 ° and 15 hours at 20 °, the mixture is filtered off and the filtrate is evaporated. The residue is purified by chromatography on a column of silica gel in the chloroform-methanol system (98-2). The lipopeptide thus obtained shows in a thin layer chromatogram on silica gel derivative [N-palmitoyl-S-2 (R), 3-dihydroxypropyl] -Cys-Ser-Bu ^t ) -Ser (Bu ^t ) -Asn-OBu ^t an Rf value of 0.60 (chloroform-methanol 8: 2).

6.09 g of Z-Ser (Bu ^t ) -Ser (Bu ^t ) -Asn-OBu ^t are dissolved in 60 ml of methanol and, after addition of 0.5 g of Pd-carbon (10%), hydrogenated at room temperature for 3 hours . The catalyst is filtered off and the filtrate is evaporated. The product is a white foam. In the thin layer chromatogram on silica gel, the peptide H-Ser (Bu ^t ) -Ser (Bu ^t ) -Asn-OBu ^{t shows} an Rf value of 0.41 in the chloroform-methanol system (8: 2).

4.134 g Z-Ser (Bu ^t) -OH and 4.64 g H-Ser (Bu ^t) -Asn-OBu ^t was dissolved in 50 ml of dimethylformamide and treated at 0 ° 3.172 g of dicyclohexylcarbodiimide and 1.89 g of N-hydroxybenzotriazole were added . After 2 hours at 0 ° and 15 hours at 20 °, the precipitated dicyclohexylurea is filtered off with suction, the filtrate is evaporated, the residue is taken up in ethyl acetate and the solution is extracted with 1N citric acid, 1N sodium bicarbonate and water, dried over sodium sulfate and evaporated. The residue is recrystallized from ethyl acetate-hexane. The peptide Z-Ser (Bu ^t ) -Ser (Bu ^t ) -Asn-OBu ^{t obtained} has a melting point of 96-98 °. On silica gel: Rf (chloroform-methanol 95: 5) = 0.25.

4.65 g of Z-Ser (Bu ^t ) -Asn-OBu ^t are hydrogenated in 50 ml of methanol in the presence of 0.4 g of Pd carbon (10%). After filtering off the catalyst and evaporating the filtrate, the peptide H-Ser (Bu ^t ) Asn-OBu ^{t is obtained} as a white foam. On silica gel: Rf (chloroform-methanol 7: 3) = 0.48

= + 4° (C = 1,5 in Methanol). Auf Silikagel: Rf (Chloroform-Methanol 9:1) = 0,48.5.9 g of _Z- Ser (Bu ^t ) -OH and 3.76 g of H-Asn-OBu ^t are dissolved in 60 ml of dimethylformamide and at 0 ° with 3.06 g of N-hydroxybenzotriazole and 4.53 g of dicyclohexylcarbodiimide transferred. After 2 hours at 0 ° and 15 hours at 20 °, the mixture is filtered, the filtrate is evaporated and the residue is crystallized from ethyl acetate-petroleum ether. The peptide Z-Ser (Bu ^t ) -Asn-OBu ^{t obtained} melts at 114-115 °.

= + 4 ° (C = 1.5 in methanol). On silica gel: Rf (chloroform-methanol 9: 1) = 0.48.

Example 2:

1.6 g of [N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser (Bu ^t) -Ser (Bu ^t) -Asn-Ala-OBu ^t are in 7.5 ml of 90% -Trifluoroacetic acid dissolved and the solution after 15 minutes at 20 ° concentrated to about 2 ml. The product is precipitated with 100 ml of ether, filtered and dried over sodium hydroxide. The result is a white powder with a melting point of 215-217 ° (decomposition), which is the lipopeptide [N-palmitoyl-S-2 (R) 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-OH. On silica gel: Rf (157) = 0.55.

Example 3:

0.95 g of [N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser (Bu ^t) -Ser (Bu ^t) -OBu ^t are dissolved in 4 ml of 90% strength trifluoroacetic acid. After 15 minutes at 20 °, 100 ml of ether are added, the mixture is filtered off and the residue is dried over sodium hydroxide. The lipopeptide [N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-OH obtained is obtained as a colorless, non-hygroscopic powder. On silica gel: Rf (chloroform-methanol-glacial acetic acid-water 79: 25: 0.5: 4.5) = 0.53.

Example 4:

• 13,9 g N-Palmitoyl-(S)-cystein, 5,5 g Kaliumcarbonat und 15 g l-0-Tosyl-2(R)-0-3-0-isopropyliden-glyzerin erhitzt man 8 Stunden bei 80° in 250 ml Aethanol unter Stickstoff. Man reinigt das nach dem Eindampfen erhaltene Reaktionsgemisch durch Chromatographie an 400 g Kieselgel Merck durch Elution, zuerst mit Chloroform/Aceton (8!2), dann_ mit Chloroform/Methanol (8:2). Man erhält so das Kaliumsalz des N-Palmitoyl-S-[2(R),3-isopropylidendioxypropyl)-(S)-cystein, das durch 4-stündiges Erhitzen auf 80° in 80% wässriger Essigsäure verseift wird. Man dampft zur Trockne, löst den Rückstand in Chloroform und schüttelt mit Wasser aus. Nach Trocknen und Eindampfen der Chloroform-Phase erhält man einen farblosen Rückstand, der aus Cyclohexan umkristallisiert wird und das N-Palmitoyl-S-[2(2R),3-dihydroxypropyl)-(S)-cystein darstellt. Fp. 11₀°,
  
  = -25° (c = 0,9, MeOH).

The N-palmitoyl-S- [2 (R), 3-dihydroxypropyl) - (S) -cysteine used as the starting material in Example 1 can be prepared as follows:

• 13.9 g of N-palmitoyl- (S) -cysteine, 5.5 g of potassium carbonate and 15 g of l-0-tosyl-2 (R) -0-3-0-isopropylidene-glycerol are heated at 80 ° in for 8 hours 250 ml of ethanol under nitrogen. The reaction mixture obtained after evaporation is purified by chromatography on 400 g of Merck silica gel by elution, first with chloroform / acetone (8! 2), then with chloroform / methanol (8: 2). The potassium salt of N-palmitoyl-S- [2 (R), 3-isopropylidenedioxypropyl) - (S) -cysteine is thus obtained, which is saponified by heating in 80% aqueous acetic acid at 80 ° for 4 hours. It is evaporated to dryness, the residue is dissolved in chloroform and shaken out with water. After drying and evaporating the chloroform phase, a colorless residue is obtained which is recrystallized from cyclohexane and which is N-palmitoyl-S- [2 (2R), 3-dihydroxypropyl) - (S) -cysteine. Mp 11 ₀ °,
  
  = -25 ° (c = 0.9, MeOH).

• 45 g (S)-Cystein (0,37 mol) suspendiert man in 350 ml Pyridin und tropft unter gutem Rühren und in einer Stickstoffatmosphäre bei Raumtemperatur eine Lösung von 140 ml (1,67 Aequivalente) Palmitinsäurechlorid in 550 ml Methylenchlorid zu. Nach 20-stündigem Rühren säuert man mit 2N-Salzsäure an und verteilt zwischen Chloroform und Wasser. Nach Trocknen und Eindampfen der Chloroform-Phase erhält man ein Kristallgemisch, bestehend aus etwa einem Drittel Dipalmitoylcystein und etwa zwei Drittel Monopalmitoylcystein. Man extrahiert dreimal mit 1 Liter heissem Aceton, aus dem ein 1 : 1-Gemisch von Di- und Mono-Palmitoylcystein auskristallisiert. Aus der Acetonlösung erhält man durch Eindampfen N-Palmitoylcystein, das aus Benzin umkristallisiert wird. F^p 65 - 67°.
  
  = + 1° (c = 0,8; Methanol).

The N-palmitoyl- (S) -cysteine can be produced as follows:

• 45 g of (S) -cysteine (0.37 mol) are suspended in 350 ml of pyridine and a solution of 140 ml (1.67 equivalents) of palmitic acid chloride in 550 ml of methylene chloride is added dropwise with good stirring and in a nitrogen atmosphere at room temperature. After stirring for 20 hours, acidify with 2N hydrochloric acid and partition between chloroform and water. After drying and evaporating the chloroform phase, a crystal mixture consisting of about a third of dipalmitoylcysteine and about two thirds of monopalmitoylcysteine is obtained. It is extracted three times with 1 liter of hot acetone, from which a 1: 1- Mixture of di- and mono-palmitoylcysteine crystallized. Evaporation gives N-palmitoylcysteine from the acetone solution, which is recrystallized from gasoline. F ^p 65-67 °.
  
  = + 1 ° (c = 0.8; methanol).

The mixtures of di- and mono-palmitoyl-cysteine are dissolved in methanolic solution with the addition of an aqueous solution of 12 g sodium sulfide with 2 ml conc. Sodium hydroxide solution treated for 15 minutes at room temperature. After evaporating off the methanol and acidifying the residue with 2N hydrochloric acid, the remaining N-palmitoyl-cysteine is obtained by chloroform extraction, which is also recrystallized from gasoline.

Example 5:

0.80 g of N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine and 0.67 g of H-Ser (Bu ^t ) -Phe-Ala-Glu (OBu ^t ) ₂ taken up in 10 ml of dimethylformamide and 0.22 g of dicyclohexylcarbodiimide and 0.16 g of N-hydroxybenzotriazole added. By briefly heating to 40 ° a clear solution is obtained which solidifies to a gelatin after about an hour at 20 °. The latter is brought back into solution after 24 hours by heating to 40 ° and from this the N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser (But) -Phe-Ala-Glu (OBut) 2 precipitated with water. The product is purified by chromatography on silica gel in the chloroform or chloroform-methanol 98: 2 system and then has an Rf value of 0.64 in chloroform-methanol-water 95: 5.

540 mg of the compound thus obtained are dissolved in 30 ml of 90% trifluoroacetic acid and the solution is concentrated to about half after 30 minutes at 20 ° and the N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] with petroleum ether. -Cys-Ser-Ser-Phe-Ala-Glu-CH precipitated. The compound is centrifuged off, washed three times with petroleum ether and over Potassium hydroxide dried. It represents a white powder with the Rf value (System 157) = 0.63.

• N-Palmitoyl-S-[2(R,S),3-dipalmitoyloxypropyl]-Cys-Phe-Phe-Asn-Ala-Lys-OH, Rf (System 157 c) = 0,18;
• N-Myristoyl-S-[2(R),3-dipalmitoyloxypropyl]-Cys-Glu-Gln-Asn-Ala-Lys-OH, Rf (System 157 c) = 0,12;
• N-Lauroyl-S-[2(R),3-dipalmitoyloxypropyll-Cys-Ser-Ser-Asn-Ala-Glu-OH, Rf (System 157 c) = 0,20;
• N-Stearoyl-S-[2(R),3-dipalmitoyloxypropyl]-Cys-Ser-Ser-Asn-Ala-Ala-OH, Rf

The following lipopeptides are produced in an analogous manner:

• N-Palmitoyl-S- [2 (R, S), 3-dipalmitoyloxypropyl] -Cys-Phe-Phe-Asn-Ala-Lys-OH, Rf (System 157 c) = 0.18;
• N-myristoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Glu-Gln-Asn-Ala-Lys-OH, Rf (System 157 c) = 0.12;
• N-Lauroyl-S- [2 (R), 3-dipalmitoyloxypropyll-Cys-Ser-Ser-Asn-Ala-Glu-OH, Rf (System 157 c) = 0.20;
• N-stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Ala-OH, Rf

• 17,22 g Z-Ala-ONp, 14,8 g HCl. HGlu(OBu^t)₂ und 6,3 ml N-Ethylmorpholin werden in 40 ml Dimethylformamid über Nachtbei 20° stehen gelassen. Die Lösung wird eingedampft, der Rückstand in Essigester aufgenommen und mit 1-N-Natriumbicarbonat und Wasser extrahiert.

The peptide described above which contains the protective groups mentioned and which is used as a starting material for the condensation with N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine can be prepared as follows:

• 17.22 g Z-Ala-ONp, 14.8 g HCl. HGlu (OBu ^t ) ₂ and 6.3 ml of N-ethylmorpholine are left in 40 ml of dimethylformamide overnight at 20 °. The solution is evaporated, the residue is taken up in ethyl acetate and extracted with 1N sodium bicarbonate and water.

The ethyl acetate solution is evaporated and the Z-Ala-Glu (OBut) 2 with the Rf value 0.60 (in chloroform-methanol 95: 5) remains as foam, which is directly processed further: 8.5 g in 60 ml Dissolved methanol and after adding 0.8 mg of Pd carbon (10%) hydrogenated at 20 ° for 2 hours. The catalyst is filtered off and the filtrate is evaporated. The H-Ala-Glu (OBut) 2 is obtained as a white foam which has the Rf 0.36 in chloroform-methanol 9: 1.

8.68 g of dicyclohexylcarbo are added at 0 ° to 11.46 g of Z-Phe-OH and 12.64 g of H-Ala-Glu (OBu ^t ) ₂ in 50 ml of dimethylformamide diimide and 5.86 g of N-hydroxybenzotriazole. After 15 hours at 4 °, the mixture is filtered off, the filtrate is evaporated and the residue is recrystallized from ethyl acetate-hexane. The Z-Phe-Ala-Glu (OBut) 2 of mp 161-163 ° is obtained. Rf (toluene-acetone 1: 1) = 0.63.

6.4 g of this product are dissolved in 50 ml of methanol and, after addition of 0.5 g of Pd carbon (10%), hydrogenated at 20 ° for 20 minutes. The catalyst is filtered off and the filtrate is evaporated, the H-Phe-Ala-Glu (OBut) 2 being obtained as a white foam. Rf (chloroform-methanol 7: 3) = 0.75.

To 4.43 g of Z-Ser (Bu ^t ) -GH and 3.18 g of HCl.H-Ser (Bu ^t ) -OMe in 30 ml of dimethylformamide are added at 1.89 ml of N-ethylmorpholine, 2.29 g HOBt and 3.4 g dicyclohexylcarbodiimide. After 2 hours at 0 ° and 15 hours at 20 °, the mixture is filtered off, the filtrate is evaporated and taken up in ethyl acetate. After extraction of the solution with sodium bicarbonate, dilute hydrochloric acid and water, the mixture is evaporated to give the Z-Ser (Bu ^t ) Ser (Bu ^t ) -GMe as an oil. Rf (toluene-acetone 1: 1) = 0.70.

7.5 ml of hydrazine hydrate are added to a solution of 6.8 g of this product in 40 ml of methanol and, after 24 hours at 20 °, evaporated to about half the volume. It is taken up in 250 ml of ethyl acetate and extracted with water. The ethyl acetate solution is concentrated and the Z-Ser (Bu ^t ) -Ser (Bu ^t ) -NH-NH ₂ obtained is precipitated with petroleum ether. Rf (toluene-acetone 1: 1) = 0.50.

2.26 g of this product are dissolved in 20 ml of dimethylformamide and tert at -10 ° with 7.022 ml of 1.78 N-HC1 in ethyl acetate and 0.635 ml. Butyl nitrite added. After 10 minutes at -10 °, a solution of 2.38 g of H-Phe-Ala-Glu (OBu ^t ) ₂ and 2.52 ml of N-ethylmorpholine is added dropwise and one hour kept at -10 ° and 15 hours at 0 °.

The solution is then evaporated, the residue taken up in ethyl acetate and washed with sodium bicarbonate, dilute hydrochloric acid and water. The Z-Ser (Bu ^t ) -Ser (Bu ^t ) -Phe-Ala-Glu (OBu ^t ) ₂ obtained after evaporation of the solution is recrystallized from ethyl acetate-hexane. Mp 213-215 °, Rf (toluene-acetone 1: 1) = 0.70.

2.30 g of this product are dissolved in 40 ml of methanol and, after addition of 0.5 g of Pd carbon (10%), hydrogenated at 20 ° for 2 hours. The catalyst is filtered off and the filtrate is evaporated, the H-Ser (Bu ^t ) -Ser (Bu ^t ) -Phe-Ala-Glu (OBu ^t ) _{2 being obtained} as a white foam. Rf (toluene - acetone 1: 1) = 0.23.

• 6,3 g (2.78 mMol) N-Palmitoyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein-benzhydrylester löst man in einer Mischung aus 12 ml Trifluoressigsäure und 48 ml Methylenchlorid. Nach einer Stunde bei Raumtemperatur dampft man die Lösung ein und verreibt den öligen Rückstand mit Wasser. Das auskristallisierte N-Palmitoyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein wird abgesaugt, getrocknet und zur Entfernung des Benzhydrds dreimal mit Benzin verrieben. Man kristallisiert den Rückstand aus Aceton-Wasser und erhält so farblose Kristalle dieses Produkts vom Smp. 71-75° und
  
  = -1° (Dioxan).

The N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine used as starting material and the diastereomeric mixture of this compound with the corresponding 2 (S) compound, which is abbreviated here as 2 (R, S) ⁿ can be produced as follows:

• 6.3 g (2.78 mmol) of N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine-benzhydryl ester are dissolved in a mixture of 12 ml of trifluoroacetic acid and 48 ml of methylene chloride. After one hour at room temperature, the solution is evaporated and the oily residue is triturated with water. The crystallized N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine is suction filtered, dried and triturated three times with gasoline to remove the benzohydride. The residue is crystallized from acetone-water and thus colorless crystals of this product of mp. 71-75 ° and
  
  = -1 ° (dioxane).

• 12 g (20 mMol) N-Palmitoyl-S[2(R),3-dihydroxypropyl]-(S)-cystein-benzhydrylester löst man in einer Mischung aus 60 ml Pyridin und 60 ml Methylenchlorid und tropft bei 0-10° 14,5 ml (13,2 g) Palimitinsäurechlorid zu. Nach 2 Stunden bei Raumtemperatur ist die Reaktion gemäss DUnnschichtchromatogramm beendet. Man gibt zur Suspension (Pyridinhydrochlorid) 10 ml Methanol, rührt 20 Minuten bei 25° und dampft dann das Reaktionsgemisch weitgehend ein. Man nimmt den Rückstand in Chloroform auf, schüttelt je zweimal mit 0,5 N-Salzsäure, l0 % Natriumbicarbonat und Wasser aus, trocknet die Chloroform-Phase mit Natriumsulfat und dampft sie zum Syrup ein. Den reinen Ester erhält man durch Chromatographie dieses Syrups über Kieselgel in Chloroform. Die chromatographisch einheitlichen Fraktionen (DC-Kontrolle auf Kieselgel in Chloroform : Essigester 98:2, Rf = 0,5) werden eingedampft und aus Aceton umkristallisiert. Man erhält farblose Kristalle des N-Palmitoyl-(S)-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein-benzhydrylesters vom Smp. 69-71°.

The above ester is obtained in the following way:

• 12 g (20 mmol) N-palmitoyl-S [2 (R), 3-dihydroxypropyl] - (S) - Cysteine-benzhydryl ester is dissolved in a mixture of 60 ml of pyridine and 60 ml of methylene chloride and 14.5 ml (13.2 g) of palimitic acid chloride are added dropwise at 0-10 °. After 2 hours at room temperature, the reaction according to the thin layer chromatogram is complete. 10 ml of methanol are added to the suspension (pyridine hydrochloride), the mixture is stirred at 25 ° for 20 minutes and then the reaction mixture is largely evaporated. The residue is taken up in chloroform, shaken twice with 0.5 N hydrochloric acid, 10% sodium bicarbonate and water, the chloroform phase is dried with sodium sulfate and evaporated to give syrup. The pure ester is obtained by chromatography of this syrup over silica gel in chloroform. The chromatographically uniform fractions (TLC control on silica gel in chloroform: ethyl acetate 98: 2, Rf = 0.5) are evaporated and recrystallized from acetone. Colorless crystals of N-palmitoyl- (S) - [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine-benzhydryl ester of mp 69-71 ° are obtained.

• 23,4 g (54 mMol) N-Palmitoyl-S-[2(R),3-dihydroxypropyl]-(S)-cystein löst man in 150 ml Chloroform-Aethanol-Gemisch 1:1 und tropft dazu bei Raumtemperatur eine Lösung von 13,6 g (70 mMol) Diphenyldiazomethan in 50 ml Chloroform. Nach 3 Stunden bei Raumtemperatur ist die anfänglich rote Lösung entfärbt und nach DC (Chloroform : Methanol = 9:1, Kieselgel) die Reaktion beendet.

The N-palmitoyl-S [2 (R), 3-dihydroxypropyl] - (S) -cysteine used above can be obtained, for example, in the following way:

• 23.4 g (54 mmol) of N-palmitoyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine are dissolved in 150 ml of chloroform-ethanol mixture 1: 1 and a solution is added dropwise at room temperature of 13.6 g (70 mmol) of diphenyldiazomethane in 50 ml of chloroform. After 3 hours at room temperature, the initially red solution is decolorized and the reaction is ended after TLC (chloroform: methanol = 9: 1, silica gel).

It is evaporated to the dry state in a vacuum and the residue is extracted cold with petroleum ether. The residue is filtered through silica gel with methylene chloride as the solvent. This gives colorless crystals of the benzhydryl ester of mp. 88-91 °.

• 50 g (139 mMol) N-Palmitoyl-cystein, 12,4 g Glycid und 45 g Kaliumcarbonat werden in 375 ml Aethanol unter Stickstoff und gutem Rühren 16 Stunden auf 80° erhitzt. Nach dem Abkühlen auf Raumtemperatur säuert man mit 2 N-Salzsäure auf pH ca. 4 an und versetzt mit Wasser; dabei fällt das Produkt aus. Man saugt ab und wäscht mit Wasser bis das Filtrat frei von Chlorionen ist. Nach dem Trocknen des Nutschgutes im Vakuum kristallisiert man aus Essigester um. Man erhält farblose Kristalle des Diastereomerengemisches des N-Palmitoyl-S-[2(R),3-dihydroxypropyl]-(S)-cysteins und N-Palmitoyl-S-[2(S),3-dihydroxypropyl]-(S)-cysteins vom Smp. 76-155°.

The procedure for the preparation of the N-palmitoyl-2- [2 (R, S), 3-dihydroxypropyl] - (S) -cysteine is as follows:

• 50 g (139 mmol) N-palmitoyl-cysteine, 12.4 g glycid and 45 g potassium carbonate are heated in 375 ml ethanol under nitrogen with good stirring for 16 hours at 80 °. After cooling to room temperature, the mixture is acidified to pH about 4 with 2 N hydrochloric acid and water is added; the product fails. It is suctioned off and washed with water until the filtrate is free of chlorine ions. After drying the suction filter in vacuo, the product is recrystallized from ethyl acetate. Colorless crystals of the mixture of diastereomers of N-palmitoyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine and N-palmitoyl-S- [2 (S), 3-dihydroxypropyl] - (S) are obtained. -cysteins of mp 76-155 °.

By reacting the N-palmitoyl-S- [2 (R, S), 3-dihydroxypropyl] - (S) -cysteine with diphenyldiazomethane, as indicated above for the R compound, the N-palmitoyl-S- [2 ( R, S), 3-dipalmitoyloxypropyl] - (S) -cysteinbenzhydrylester: colorless crystals of mp. 84-85 °.

If this mixture of diastereomers (19.8 g) is chromatographed on a column with 250 g of silica gel (Merck) with methylene chloride as the solvent, the first fraction (1.55 g) gives the R-diastereomer (Rf = 0, 61, methylene chloride: ethyl acetate = 98: 2, thin layer, silica gel), in a second fraction 12.7 g of an R, S-diastereomer mixture and in a third fraction (1.1 g) of the S-diastereomer (Rf = 0.53 in methylene chloride: ethyl acetate = 98 _: 2).

= + 1° (Dioxan).The (S) -diastereoisomer gives N-palmitoyl-S- [2 (S), 3-dipalmitoyloxypropyl] - (S) -cysteine in the manner described above; colorless crystals, mp. 64-65 °

= + 1 ° (dioxane).

The new lipopeptides to be prepared in accordance with the invention for the preparation of the new lipopeptides mentioned in this example, such as N-palmitoyl-S [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Phe-Ala-Glu-OH The starting materials are, for example, N-myristoyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine, colorless crystals with a melting point of 140-150 °, and N-stearoyl-S- [2 (R) , 3-dihydroxypropyl] - (S) -cysteine, colorless crystals of mp 140-150 °; N-Lauroyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine, colorless crystals of mp 140-150 ^?

They can be produced according to the information in example 4.

• N-Myristoyl-S-[2(R),3-dihydroxypropyl]-(S)-cystein-benzhydrylester, farblose Kristalle vom Smp. 90-92°;
• N-Stearoyl-S-[2(R),3-dihydroxypropyl]-(S)-cystein-benzhydrylester, farblose Kristalle vom Smp. 95°-97°;
• N-Lauroyl-S-[2(R),3-dihydroxypropyl]-(S)-cystein-benzhydrylester, farblose Kristalle vom Smp. 95-97°.

The benzhydryl esters to be produced according to the above information have the following data:

• N-myristoyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine-benzhydryl ester, colorless crystals of mp 90-92 °;
• N-stearoyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine-benzhydryl ester, colorless crystals of mp 95 ° -97 °;
• N-Lauroyl-S- [2 (R), 3-dihydroxypropyl] - (S) -cysteine-benzhydryl ester, colorless crystals of mp 95-97 °.

• N-Lauroyl-S-[2(R),3-dipalmitoyioxypropyl]-(S)-cystein- benzhydrylester, Smp. 65-68°;
• N-Myristoyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein- benzhydrylester, Smp. 68-70°;
• N-Stearoyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein- benzhydrylester, Smp. 70-72°.

The following N-acyl-S- [2 (R), 3-diacyloxypropyl] - (S) -cysteine-benzhydryl ester with different acyl groups on the N and on the 0 atoms can be obtained in an analogous manner to that described:

• N-lauroyl-S- [2 (R), 3-dipalmitoyioxypropyl] - (S) -cysteine-benzhydryl ester, mp 65-68 °;
• N-myristoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine-benzhydryl ester, mp 68-70 °;
• N-stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine-benzhydryl ester, mp 70-72 °.

• N-Lauroyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein, farblose Kristalle, Smp. 70-72°;
• N-Myristoyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein, farblose Kristalle, Smp. 71-73°;
• N-Stearoyl-S-[2(R),3-dipalmitoyloxypropyl]-(S)-cystein, farblose Kristalle, Smp. 74-77°.

Other compounds to be used as an intermediate, which can be prepared according to the above information, are:

• N-lauroyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine, colorless crystals, mp 70-72 °;
• N-myristoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine, colorless crystals, mp 71-73 °;
• N-Stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine, colorless crystals, mp 74-77 °.

Example 6:

• N-Palmitoyl-S-[2(R),3-dilauroyloxypropyl]-(S)-cystein-_' benzhydrylester, farbloses Wachs;
• N-Palmitoyl-S-[2(R),3-distearoyloxypropyl]-(S)-cystein- benzhydrylester, farblose Kristalle, Smp. 80-82°;
• N-Palmitoyl-S-[2(R),3-dioleoyloxypropyl]-(S)-cystein- benzhydrylester, farbloses Oel;
• N-Palmitoyl-S-[2(R),3-dibehenoyloxypropyl]-(S)-cystein- benzhydrylester, farblose Kristalle, Smp. 85-88°;
• N-Palmitoyl-S-[2(R),3-di-(dihydrosterkuloyloxypropyl]-(S)-cystein-benzhydrylester, farbloses Wachs.

The following starting materials for the production of lipopeptides according to the application are prepared by means of the reactions described in Example 5:

• N-palmitoyl-S- [2 (R), 3-dilauroyloxypropyl] - (S) -cysteine _' benzhydryl ester, colorless wax;
• N-palmitoyl-S- [2 (R), 3-distearoyloxypropyl] - (S) -cysteine-benzhydryl ester, colorless crystals, mp 80-82 °;
• N-palmitoyl-S- [2 (R), 3-dioleoyloxypropyl] - (S) -cysteine-benzhydryl ester, colorless oil;
• N-palmitoyl-S- [2 (R), 3-dibehenoyloxypropyl] - (S) -cysteine-benzhydryl ester, colorless crystals, mp. 85-88 °;
• N-Palmitoyl-S- [2 (R), 3-di- (dihydrosterkuloyloxypropyl] - (S) -cysteine-benzhydryl ester, colorless wax.

• N-Palmitoyl-S-[2(R),3-dilauroyloxypropyl]-(S)-cystein, farbloses Oel, Rf = 0,27;
• N-Palmitoyl-S-[2(R),3-distearoyloxypropyl]-(S)-cystein, farblose Kristalle, Smp. 82-85°;
• N-Palmitoyl-S-[2(R),3-dioleoyloxypropyl]-(S)-cystein,
• farbloses Oel, Rf in Chloroform:Methanol = 9:1 (DUnnschicht-Kieselgel-Merck) = 0,35;
• N-Palmitoyl-S-[2(R),3-dibehenoyloxypropyl]-(S)-cystein, farblose Kristalle, Smp. 87-90°;
• N-Palmitoyl-S-[2(R),3-di-(dihydrosterkuloyloxypropyl]-(S)-cystein, farbloses Wachs, Rf = 0,38 (gleiche Bedingungen wie oben für das N-Palmitoyl-2,3-dioleoyloxy-Derivat angegeben).

The corresponding non-esterified substituted cysteines have the following data:

• N-palmitoyl-S- [2 (R), 3-dilauroyloxypropyl] - (S) -cysteine, colorless oil, Rf = 0.27;
• N-palmitoyl-S- [2 (R), 3-distearoyloxypropyl] - (S) -cysteine, colorless crystals, mp 82-85 °;
• N-palmitoyl-S- [2 (R), 3-dioleoyloxypropyl] - (S) -cysteine,
• colorless oil, Rf in chloroform: methanol = 9: 1 (thin-layer silica gel-Merck) = 0.35;
• N-palmitoyl-S- [2 (R), 3-dibehenoyloxypropyl] - (S) -cysteine, colorless crystals, mp 87-90 °;
• N-Palmitoyl-S- [2 (R), 3-di- (dihydrosterkuloyloxypropyl] - (S) -cysteine, colorless wax, Rf = 0.38 (same conditions as above for the N-palmitoyl-2,3-dioleoyloxy -Derivative specified).

• H-Phe-Phe-Asn-Ala-Lys-OH
• H-Glu-Gln-Asn-Ala-Lys-OH
• H-Ser-Ser-Asn-Ala-Glu-OH

These cysteine derivatives are condensed with the following peptides as described in Example 5:

• H-Phe-Phe-Asn-Ala-Lys-OH
• H-Glu-Gln-Asn-Ala-Lys-OH
• H-Ser-Ser-Asn-Ala-Glu-OH

The corresponding lipopeptides according to the invention are thus obtained.

Example 7:

= -5° (c = 0,819, Dioxan).0.9 g of N-palmitoyl-S-2 (R), 3 (R), 4-trihydroxy-butyl- (S) -cysteine-benzhydryl ester in a mixture of 3 ml of trifluoroacetic acid and 12 ml of methylene chloride are left for 2 hours at room temperature stand. Then it is evaporated to dryness, the residue is triturated with ice water, suction filtered and the solid is dried. Then it is extracted with gasoline and recrystallized from acetone. Colorless crystals of N-palmitoyl-S-2 (R), 3 (R), 4-trihydroxy-butyl- (S) -cysteine with a melting point of 76-76.5 ° and a specific rotation are obtained

= -5 ° (c = 0.819, dioxane).

• 1 g N-Palmitoyl-S-2(R),3(R),4-trihydroxybutyl-(S)-cystein- benzhydrylester werden in einer Mischung aus 6 ml Pyridin in 5 ml Methylenchlorid mit 1,83 ml Palmitinsaurechlorid acyliert. Nach 18 Stunden bei Raumtemperatur gibt man 1 ml Methanol zu und dampft zur Trockne. Den Rückstand filtriert man über 100 g Kieselgel Merck mit Chloroform als Lösungsmittel. Die nach Dünnschichtchromatographie (CHCl₃:Essigester = 98:2) reinen Fraktionen geben nach Eindampfen farblose Kristalle vom Smp. 60-62°.

The benzhydryl ester used as the starting material is obtained in the following way:

• 1 g of N-palmitoyl-S-2 (R), 3 (R), 4-trihydroxybutyl- (S) -cysteine-benzhydryl ester are mixed in a mixture of 6 ml of pyridine acylated in 5 ml of methylene chloride with 1.83 ml of palmitic acid chloride. After 18 hours at room temperature, 1 ml of methanol is added and the mixture is evaporated to dryness. The residue is filtered through 100 g of silica gel Merck with chloroform as a solvent. The fractions pure after thin layer chromatography (CHCl ₃ : ethyl acetate = 98: 2) give colorless crystals of mp. 60-62 ° after evaporation.

• 2,53 g N-Palmitoyl-S-2(R),3(R),4-trihydroxybutyl-(S)-cystein lässt man in einer Mischung aus 12 ml Aethanol und 32 ml Chloroform mit 1,37 g Diphenyldiazomethan 15 Stunden bei Raumtemperatur reagieren. Man dampft zur Trockne und reinigt den entstandenen Benzhydrylester an 150 g Kieselgel in Chloroform als Lösungsmittel. Rf = 0,3 (CHCI₃:Aceton = 95:5) Kieselgel Merck, Dünnschicht.

The starting material for the above reaction is obtained as follows:

• 2.53 g of N-palmitoyl-S-2 (R), 3 (R), 4-trihydroxybutyl- (S) -cysteine are left in a mixture of 12 ml of ethanol and 32 ml of chloroform with 1.37 g of diphenyldiazomethane for 15 hours react at room temperature. The mixture is evaporated to dryness and the benzhydryl ester formed is purified on 150 g of silica gel in chloroform as solvent. Rf = 0.3 (CHCI ₃ : acetone = 95: 5) silica gel Merck, thin layer.

• 20 g N-Palmitoyl-cystein, 27,6 g l-Toxyl-2,4-äthyliden-D-erythrit und 17 g Pottasche werden unter Stickstoff in 240 ml Aethanol 15 Stunden bei 80° gerührt. Dann filtriert man die Salze ab und dampft das Filtrat zur Trockne. Man nimmt den Rückstand in 200 ml H₂0:Tetrahydrofuran = 1:1 auf und säuert mit 2 N-Salzsäure auf pH = 3 an. Dann schüttelt man dreimal mit Aether aus, stellt mit Pyridin den pH der Aetherphase auf 4,5 ein, schüttelt mit Wasser aus, trocknet die Aetherphase und dampft zur Trockne. Diesen Rückstand reinigt man über 200 g Kieselgel Merck mit Chloroform:Aceton = 8:2 ( 1 1) und dann mit CHCI₃:Me0H = 6:4 (1,2 1) als Elutionsmittel.

N-Palmitoyl-S-2 (R), 3 (R), 4-trihydroxybutyl- (S) -cysteine can be obtained in the following way:

• 20 g of N-palmitoyl-cysteine, 27.6 g of l-toxyl-2,4-ethylidene-D-erythritol and 17 g of potash are stirred under nitrogen in 240 ml of ethanol at 80 ° for 15 hours. Then the salts are filtered off and the filtrate is evaporated to dryness. The residue is taken up in 200 ml of H ₂ 0: tetrahydrofuran = 1: 1 and acidified to pH = 3 with 2 N hydrochloric acid. Then shake out three times with ether, adjust the pH of the ether phase to 4.5 with pyridine, shake out with water, dry the ether phase and evaporate to dryness. This residue is purified over 200 g of silica gel Merck with chloroform: acetone = 8: 2 (1 1) and then with CHCI ₃ : MeOH = 6: 4 (1.2 1) as the eluent.

The pure fractions are evaporated, triturated with hexane and recrystallized from ethyl acetate-petroleum ether.

Colorless crystals of N-palmitoyl-S - [(2,4-ethylidene) erythrityl] - (S) -cysteine of mp 62-65 ° are obtained.

The hydrolysis of this compound is carried out with 3 percent. HBF _{4 carried out} at 80 ° for 4.5 hours.

8.2 g of ethylidene derivative in 100 ml of dimethoxyethane and 100 ml of 3 percent. HBF ₄ treated. Then it is cooled to 0 °, whereby the hydrolysis product fails. After suction and drying, one recrystallizes from ethyl acetate. Mp 160-165 °, sintering from 93 °. Rf = 0.285 (CHCl3: MeOH = 6: 4) thin layer, silica gel, Merck.

Example 8:

• N-Stearoyl-S-[2(R),3-dipalmitoyloxypropyl]-Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH, Rf (157) = 0,32;
• N-Palmitoyl-S-[2(R),3(R),4-tripalmitoyloxybutyl]-Cys-Ser-Ser-Asn-Ala-Lys-OH, Rf (157) = 0,55;
• N-Palmitoyl-S-[2(R),3(R),4-tripalmitoyloxybutyl]-Cys-Ser-Ser-Asn-A1a-Lys-Ile-Asp-Glu-OH, Rf (157) = 0,38.

Analogously to the information in Example 5, N-stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] - (S) -cysteine and N-palmitoyl-S- [2 (R), 3 (R), 4 -tripalmitoyloxypropyl] - (S) -cysteine produced the following lipopeptides:

• N-stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH, Rf (157) = 0.32;
• N-Palmitoyl-S- [2 (R), 3 (R), 4-tripalmitoyloxybutyl] -Cys-Ser-Ser-Asn-Ala-Lys-OH, Rf (157) = 0.55;
• N-Palmitoyl-S- [2 (R), 3 (R), 4-tripalmitoyloxybutyl] -Cys-Ser-Ser-Asn-A1a-Lys-Ile-Asp-Glu-OH, Rf (157) = 0.38 .

Example 9

Analogously to the information in Example 5, the lipopeptides listed below are prepared from N-palmitoyl - 2 (R), 3-dipalmitoyloxypropyl - (S) - cysteine or N-palmitoyl 2 (R, S), 3-dipalmitoyloxypropyl - cysteine, the Residues of the cysteine derivatives just mentioned are referred to as PC (R) or PC (R, S):

Furthermore, the R, S-epimer mixtures of all lipopeptides described in the previous examples are prepared.

Claims (27)

1. Compounds of the formula

wherein R ₁ and R ₂ each represent a saturated or unsaturated, aliphatic or mixed aliphatic-cycloaliphatic, optionally also substituted by oxygen functions, hydrocarbon radical having 11-21 carbon atoms, R ₃ hydrogen or the radical R ₁ -CO-O-CH ₂ - , where R _{1 has} the same meaning, and X is a peptide-bound natural aliphatic amino acid with a free, esterified or amidated carboxyl group, or an amino acid sequence of 2-10 natural aliphatic amino acids, the terminal carboxyl group of which is in a free, esterified state or amidated form, mean, the asymmetry centers designated with ^* or ^** being the absolute S or. S or R configuration, and optionally mixtures of the R and S compounds epimeric at the ^** C atoms, and their salts and complexes. 2. Compounds according to claim 2, wherein the acyl radicals R ₁ CO and R ₂ CO are derived from saturated or unsaturated fatty acids having 14-18 C atoms, and wherein R ₁ and R _{2 may be} identical or different. 3. Compounds according to claim 2, wherein the acyl residues are derived from palmitic, stearic, oil, lauric, myristic, behenic, dihydrosterkulic, malvalic, hydnocarpic or chaulmoograsic acid. 4. Compounds according to any one of claims 1-3, wherein hydrophilic amino acids in X carry the ionic amino acids aspartic, glutamic and / or oxyglutamic acid, or lysine, ornithine, arginine and / or histidine, or asparagine, glutamine, serine and / or are threonine, and are not hydrophilic group-bearing amino acids in X glycine, alanine, valine, norvaline, leucine, isoleucine and / or methionine. 5. Compounds according to any one of claims 1-4, wherein in the peptide chain X the amino acids with a hydrophilic character are directly connected to one another. 6. Compounds according to claim 5, wherein the sequence of the amino acids with a hydrophilic character is directly linked to the carboxyl group of the cysteine in the triacylglyceryl or tetracyl, erithrityl cysteine part. 7. Compounds according to any one of claims 1-6, wherein X in formula 1 represents an amino acid or a peptide chain with 2-5 amino acids. 8. Compounds according to claim 16 of the formula

their salts and complexes, in which in a peptide chain X at least half of the amino acids carry a hydrophilic group. 9. Compounds according to claim 8, in which X represents one of the following peptide sequences -Ser-Ser-Asn-Ala-Lys-OH -Ser-Ser-Asn-Ala-OH -Ser-Ser-Asn-OH -Ser-Ser-OH or sequences of this type in which threonine, glutamine or asparagine replace the serine, or Ser-Ser-Phe-Ala-Glu-OH Ser-Ser-Phe-Ala-OH Ser-Ser-Phe-OH or sequences of this type in which threonine, glutamine or asparagine are present as exchange amino acids for serine. 10. Compounds according to any one of claims 1-6, wherein X in formula I of claim 1 is a peptide chain in which the sequence of the first 5 amino acids is different from that of the murein lipoprotein degradation lipopeptides. 11. Compounds according to those of claims 8 or 9, but in which the configuration at the C ^** atom is S instead of R, and the mixtures of the R and S diastereomers. 12. Compounds according to any one of claims 1-6 of the formula

wherein R ₁ and R _{2 have} the meaning given for formula I, and X represents a peptide chain with 6-10 amino acids, and the first 5 amino acids have one of the meanings given for X in claim 9, as well as those on the C ** atom (S) configuration-containing compounds, and the R- and S-diastereomer mixtures, their salts and complexes. 13. Compounds according to one of claims T-6- of the formula

wherein R ₁ and R _{2 have} the meaning given in one of claims 1-6, and X represents an amino acid or a peptide chain with 2-5 amino acids, and mixtures of the stereoisomeric compounds on the ^** C atoms, and their salts and complexes . 14. The amides and esters of the compounds according to claims 7-13, wherein an ester residue in the terminal esterified carboxyl group of X is derived from a lower aliphatic alcohol having 1-7 C atoms, an ethylene glycol or the glycerol, and a terminal amide group in X is the amide group CONH ₂ or an amide group derived from a lower aliphatic amine with 1-7 C atoms, the pyrrolidine, piperidine or piperazine. 15. A lipopeptide selected from the group: N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyll-Cys-Ser-Ser-Asn-OH, N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-OH, N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Lys-OH, N-palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser- OH, and N-Palmitoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-OH. 16. The lipopeptide N-palmitoyl-S- [2 (R), 3-dipalmityl-oxypropyl] -Cys-Ser-Ser-Phe-Ala-Glu-OH. 17. The N-palmitoyl-S- [2 (R), 3-di- (dihydrosterkuloyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Glu-OH. 18. A lipopeptide selected from the group: N-palmitoyl-S- [2 (R, S), 3-dipalmitoyloxypropyl] -Cys-Phe-Phe-Asn-Ala-Lys-OH, N-myristoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Glu-Gln-Asn-Ala-Lys-OH, N-lauroyl-S- [2 (R), 3-dipalmitoyl-oxypropyl] -Cys-Ser-Ser-Asn-Ala-Glu-OH, N-stearoyl-S- [2 (R), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-Ala-Ala-OH, N-stearoyl-S- [2 (R), 3-dipalmitoyloxypropylJ-Cys-Ser-Ser-Asn-Ala-Glu-Ile-Asp-Glu-OH, N-palmitoyl-S- [2 (R), 3 (R), 4-tripalmitoyloxybutyl] -Cys-Ser-Ser-Asn-Ala-Lys-OH, N-palmitoyl-S- [2 (R), 3 (R), 4-tripalmitoyloxybutyl] -Cys-Ser-Ser-Asn-Ala-Lys-Ile-Asp-Glu-OH, N-palmitoyl-S- [2 (R, S), 3-dipalmitoyloxypropyl] -Cys-Ser-Ser-Asn-OH, N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl-Cys-Phe-Ile-Ile-Phe-Ala-OH, N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl-Cys-Val-Lys-Val-Tyr-Pro-OH, N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl-Cys-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH ₂ , N-palmitoyl-S-2 (R), 3-dipalmitoyloxypropyl-Cys-Ser-Ser-Asn-Ala-Lys-Ile-Asp-Glu-OH, or their epimers with a corresponding S configuration on the 2 C atom of the propyl radical. 19. The compounds of claims 14-16 corresponding lipopeptides in which, instead of the palmitoyl residues in the diacyloxypropyl residue, lauroyl, stearoyl, oiloyl, behenoyl or the dihydrosterkuloyI residues are present. 20. One of the compounds of claims 14-19 with R configuration on the 2-C atom of the propyl radical corresponding epimeric compound with S configuration or a mixture of diastereomers of R and S compound. 21. ammonium salts, alkali or alkaline earth salts of basic compounds, and pharmaceutically applicable, non-toxic acid addition salts of acidic compounds, and copper, zinc, iron or cobalt complex salts of compounds according to any one of claims 1-20. 22. Compounds of the formula

wherein R ₁ , R ₂ and R ₃ each represent a saturated or unsaturated, aliphatic or mixed aliphatic-cycloaliphatic hydrocarbon radical with 11-21 C atoms which is optionally also substituted by oxygen functions means, where the asymmetry centers designated with ^* or ^{** have} the absolute S or R configuration, and mixtures of the stereoisomeric compounds on the C ** atoms, and corresponding compounds or mixtures in which the carboxyl group in the form of a for the Suitable activated derivative peptide synthesis is present. 23. Compounds according to claim 1, wherein, however, in X at least one of the hydrophilic groups substituting the amino acids and / or the terminal carboxyl group in the form of a protective group which can be split off under neutral or mild acidic conditions and / or the carboxyl group optionally in the form of a suitable one for peptide synthesis activated derivative is present, mixtures of diastereomers, and salts and complexes of these compounds. 24. Compounds of the formula

wherein R _{2 has} the meaning given for formula (I) of claim 1 and R _{3 represents} hydrogen or the group OH-CH ₂ , and Z _{2 has} the meaning given for X in formula (I) of claim 1, but in which no free Hydroxy groups are present, or OH, and and salts of these compounds. 25. Pharmaceutical preparations containing a compound according to any one of claims 1-22. 26. A compound according to any one of claims 1-22 for use as an immunistimulating agent, in particular as an adjuvant in the experimental and industrial manufacture of antisera for therapy and diagnosis and in the induction of immunologically activated lymphocyte populations for cell transplantation, or as a prophylactic against infectious diseases in humans and animals. 27. Process for the preparation of compounds of the formula

wherein R ₁ and R ₂ each represent a saturated or unsaturated, aliphatic or mixed aliphatic-cycloaliphatic, optionally also substituted by oxygen functions, hydrocarbon radical having 11-21 carbon atoms, R ₃ hydrogen or the radical R ₁ -CO-O-CH ₂ - where R _{1 has} the same meaning and X is a peptide-bonded natural aliphatic amino acid with a free, esterified or amidated carboxyl group, or an amino acid sequence of 2-10 natural aliphatic amino acids, the terminal carboxyl group of which is in free, esterified or amidated form, mean, the asymmetry centers designated with ^* or ^{** have} the absolute S or S or R configuration, and, if appropriate, mixtures of the R and S compounds which are epimeric at the ^** C atoms, and their salts and complexes , characterized in that one a) in a compound of the formula

wherein R ₁ , R ₂ and R _{3 have} the meaning given for formula (I) and Y represents an amino acid or amino acid sequence corresponding to X in formula I, but wherein at least one of the hydrophilic groups substituting the amino acids and / or the terminal carboxyl group is replaced by a protecting group which can be removed under neutral or mild acidic conditions, or in a salt of such a compound which releases protective group (s), or b) that you have a compound of formula

wherein R ₁ , R ₂ and R _{3 have} the meaning given for formula (I) and W - OH or an amino acid or an incomplete sequence of amino acids according to X in formula (I), with a compound of formula

where Z ₁ denotes a group corresponding to group X in formula (I) or an amino acid sequence or amino acid complementary to the amino acid or incomplete sequence of amino acids according to X, but in which sequences there are no free amino groups, or a salt thereof , or c) a compound of the formula

wherein R _{2 has} the meaning given for formula (I) and R ₃ 'is hydrogen or the group HO-CH _2nd and Z _{2 represents} a group corresponding to X in formula (I), but in which there are no free hydroxyl groups, or a salt of this compound, acylated in a manner known per se, and, if desired, in obtained compounds having a free terminal carboxyl group, it is converted into an amide group or ester group, and / or the compounds are converted into their salts or complexes.