DE3728917A1 - Novel lipids containing an asymmetrically substituted disulphide bridge, processes for their preparation, and their use as medicaments - Google Patents

Novel lipids containing an asymmetrically substituted disulphide bridge, processes for their preparation, and their use as medicaments

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Publication number
DE3728917A1
DE3728917A1 DE19873728917 DE3728917A DE3728917A1 DE 3728917 A1 DE3728917 A1 DE 3728917A1 DE 19873728917 DE19873728917 DE 19873728917 DE 3728917 A DE3728917 A DE 3728917A DE 3728917 A1 DE3728917 A1 DE 3728917A1
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Hermann J Prof Dr Roth
Christa E Mueller
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Roth hermann J profdr
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulfur or nitrogen atoms
    • C07D239/56One oxygen atom and one sulfur atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/36Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulfur or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36Sulfur atom
    • C07D473/38Sulfur atom attached in position 6
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

Abstract

The invention relates to novel lipids containing an asymmetrically substituted disulphide bridge of the general formula R1-S-S-R2 and processes for the preparation of the novel compounds, and medicaments prepared therefrom having cystostatic, antiviral, antibacterial and immunotropic action, for the treatment of oncoses, viral disorders, bacterial infections and disorders of the immune system.

Description

Die Erfindung betrifft neue amphiphile Lipide mit Disulfidbrücke, ein Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel, insbesondere als radioprotektiv, hepatoprotektiv, chemotherapeutisch, antineoplastisch und immunmodulatorisch wirksame Mittel. The invention relates to novel amphiphilic lipids with disulfide bond, a process for their preparation and their use as medicaments, in particular as radioprotektiv, hepatoprotektiv, chemotherapy, antineoplastic and immunomodulatory effective means.

Betroffen sind Lipide mit Disulfidbrücke der allgemeinen Formel (I) Affected are lipids with disulfide of the general formula (I)

R₁-SS-R₂ (I) R₁-SS-R₂ (I)

in welcher in which
R₁ für eine verzweigte oder unverzweigte Alkylgruppe der Kettenlänge C₈H₁₇ bis C₂₀H₄₁ steht, R₁ stands for a branched or unbranched alkyl group of chain length C₈H₁₇ up C₂₀H₄₁,
für (II) steht, represents (II),

wobei in which
R₃ eine verzweigte oder unverzweigte Alkylgruppe der Kettenlänge C₈H₁₇ bis C₂₀H₄₁ ist, R₃ is a branched or unbranched alkyl group of chain length C₈H₁₇ up C₂₀H₄₁,
oder für (III) steht, or is (III),

wobei in which
R₄, R₅ gleich oder verschieden sein können und verzweigte oder unverzweigte Alkylgruppen der Kettenlänge C₁ bis C₂₁ sind oder Phenyl-, Cyclohexyl- bzw. Benzyl- bedeuten können; R₄, R₅ may be the same or different and are branched or unbranched alkyl groups of chain length C₁-C₂₁ or are phenyl, cyclohexyl or benzyl may represent;
R₂-S- für einen Cystein-, Glutathion-, Mercaptopurin-, MESNA-, N-acetylcystein-, Methylthiouracil- oder Propylthiouracil-Rest steht, sowie ihre Salze; R₂ represents a cysteine-S-, glutathione, mercaptopurine, mesna, N-acetylcystein-, Methylthiouracil- or propylthiouracil radical, and their salts;
oder für (IV) steht or is (IV)

worin wherein
R₆=H, CF₃ und R₇=H, CH₃ sein können. R₆ = H, CF₃ and R₇ = H, may be CH₃.

Es ist bekannt, daß schwefelhaltige amphiphile Lipide unterschiedlicher Struktur eine gute Wirkung gegen Tumoren aufweisen. It is known that sulfur-containing amphiphilic lipids with different structures have a good action against tumors. Dies wird auf die höhere Lipophilie der Schwefelverbindungen im Vergleich zu den Sauerstoffanalogen zurückgeführt. This is attributed to the higher lipophilicity of the sulfur compounds in comparison to the oxygen analogue. (S. Morris-Natschke et al., J. Med. Chem., 29 (1986), 2114). (S. Morris-Natschke et al., J. Med. Chem., 29 (1986), 2114). Bei den bekannten Verbindungen handelt es sich im wesentlichen um Thioester- oder Thioetherphospholipide. In the known compounds are essentially thioester or Thioetherphospholipide. Die Synthese und Aufarbeitung dieser Verbindung ist sehr aufwendig und die Ausbeuten sind meist unbefriedigend. Synthesis and Processing of this compound is very expensive and the yields are mostly unsatisfactory. Die Synthese gemischter Disulfide über Sulfenimide und Thiosulfinsäureester ist bereits bekannt. The synthesis of mixed disulfides over Sulfenimides and Thiosulfinsäureester is already known. (DN Harpp et al., Tetrahedron Lett. 41 (1970), 3551; U. Weber et al., Hoppe Seyler's Z. Physiol. Chem. 351 (1970), 1384). (. DN Harpp et al, Tetrahedron Lett 41 (1970), 3551;. U. Weber et al, Hoppe Seyler's Z. Physiol Chem 351 (1970), 1384...). Diese Methoden konnten jedoch bisher nicht erfolgreich auf größere Moleküle, wie sie die neuen Lipide darstellen, angewendet werden. However, these methods have not yet been successfully applied to larger molecules as they represent the new lipids.

Der Erfindung liegt die Aufgabe zugrunde, Substanzen darzustellen, bei denen ein Lipidrest über eine Disulfidbrücke mit einem mehr hydrophilen Molekül verknüpft ist, um zu neuen Wirkstoffen mit radioprotektiver, hepatoprotektiver, chemotherapeutischer, antineoplastischer und immunmodulatorischer Wirkung zu gelangen und daraus Arzneimittelzubereitungen zu formulieren. The invention has for its object to present substances in which a lipid moiety is attached via a disulfide bridge with a more hydrophilic molecule to arrive at new drugs with radioprotective, hepatoprotective, chemotherapeutic, antineoplastic and immunomodulatory effects and to formulate it pharmaceutical preparations.

Diese Aufgabe wird erfindungsgemäß dadurch gelöst, daß man Verbindungen der allgemeinen Formel (V) This object is inventively achieved in that compounds of the general formula (V)

oder (VI) or (VI)

in welchen in which
R₁ die oben angeführte Bedeutung hat, mit Verbindungen der Formel (VII) R₁ has the meaning given above, with compounds of formula (VII)

R₂-SH (VII) R₂-SH (VII)

in welcher in which
R₂-S- die oben angeführte Bedeutung hat, in Gegenwart organischer Lösungsmittel oder Mischungen organischer Lösungsmittel mit Wasser unter Eiskühlung, bei Raumtemperatur oder bei erhöhter Temperatur umsetzt. R₂-S has the meaning given above, in the presence of organic solvents or mixtures of organic solvents with water under ice-cooling, reacted at room temperature or at elevated temperature. Die erfindungsgemäßen Verbindungen der Formel (I) können zum Teil in ihre Salze überführt werden. The compounds of the invention of formula (I) can be converted in part into their salts.

Die erfindungsgemäßen Reaktionen werden in Gegenwart von Verdünnungsmitteln durchgeführt, in welchen sich die Reaktionspartner lösen, und die selbst an der Reaktion nicht teilnehmen. The reactions according to the invention are carried out in the presence of diluents in which dissolve the reactants and do not attend the reaction. Im Falle der Ausgangsverbindung (V) hat sich Ethanol oder eine Ethanol-Wasser-Mischung mit bis zu 50% Wasseranteil besonders bewährt. In the case of the starting compound (V) has ethanol or an ethanol-water mixture containing up to 50% water content particularly useful. Die Reaktionstemperatur liegt hier im allgemeinen beim Siedepunkt des Lösungsmittels oder auch tiefer. The reaction temperature is here generally at the boiling point of the solvent or lower.

Wird die Ausgangsverbindung (VI) eingesetzt, so arbeitet man bevorzugt unter Eiskühlung oder auch bei Raumtemperatur in wäßrig-organischen Lösungsmitteln; If the starting compound (VI) is used, is preferably carried out under ice cooling or at room temperature in an aqueous-organic solvents; am besten hat sich eine Dichlormethan/Methanol-Mischung bewährt. best a dichloromethane / methanol mixture has proved.

Man arbeitet jeweils mit äquimolaren Mengen an Ausgangsstoffen bzw. mit einem Überschuß an Thiol von bis zu 20%. each process is carried out with equimolar amounts of starting materials or with an excess of thiol of up to 20%.

Die Aufarbeitung erfolgt mittels Ausfällen der Produkte durch Wasserzugabe. Working up is effected by means of precipitation of the product by addition of water. Teilweise kann aus Ethanol umkristallisiert werden und zum Teil muß säulenchromatographisch gereinigt werden. Partially can be recrystallized from ethanol and partly has to be purified by column chromatography.

Die als Ausgangsverbindungen eingesetzten Verbindungen (V) und (VI) sind überwiegend neu, lassen sich aber nach folgenden Verfahren darstellen. The compounds used as starting compounds (V) and (VI) are mostly new, but can be represented by the following methods.

Die Thiophthalimide (V) erhält man durch Umsetzung der symmetrischen Disulfide (VIII), in welchen R₁ die oben angegebene Bedeutung hat, mit N-Bromphthalimid in Benzol bei Siedetemperatur, gegebenenfalls unter Dibenzoylperoxid-Katalyse. one obtains the thiophthalimides (V) by reacting the symmetrical disulfides of (VIII) in which R₁ has the meaning indicated above, with N-bromophthalimide in benzene at boiling temperature, optionally with the dibenzoyl peroxide catalysis. Die Aufarbeitung erfolgt durch Ausfällen mit n-Hexan und Umkristallisieren aus Ethanol. Working up is effected by precipitation with n-hexane and recrystallization from ethanol. Als Beispiel sei hier folgende Verbindung beschrieben: As an example, the following connection is described here:

1,2-Ditetradecanoyl-3-thiophthalimidopropan-1,2-diol 1,2-Ditetradecanoyl-3-thiophthalimidopropan-1,2-diol

10,66 g (10 mmol) 3,3′-Dithiobis(1,2-ditetradecanoylpropan-1,2-diol werden zusammen mit 4,52 g (20 mmol) N-Bromphthalimid und katalytischen Mengen an Dibenzoylperoxid in 30 ml absol. Benzol 2 h unter Rückfluß erhitzt. Das Produkt wird mit n-Hexan ausgefällt und aus Ethanol umkristallisiert. 10.66 g (10 mmol) of 3,3'-dithiobis be (along with 4.52 g 20 mmol) of N-bromophthalimide and catalytic amounts of dibenzoyl peroxide in 30 ml of absolute (1,2-ditetradecanoylpropan-1,2-diol. benzene 2 h heated to reflux. The product is precipitated with n-hexane and recrystallized from ethanol.

Smp.: 70°C M.p .: 70 ° C
Ausb.: 62% Yield .: 62%
C₃₉H₆₃O₆N₁S₁ M R = 673,99 C₃₉H₆₃O₆N₁S₁ M R = 673.99

Die Thiosulfinsäureester (VI) erhält man durch Oxidation der Disulfide (VII) mit Perbenzoesäure. The Thiosulfinsäureester (VI) is obtained by oxidation of the disulfides (VII) with perbenzoic acid. Die Produkte werden ohne Reinigung im nächsten Reaktionsschritt eingesetzt. The products are used without purification in the next reaction step.

Es wurde nun überraschenderweise gefunden, daß einige der erfindungsgemäßen Verbindungen nach Formel (I) im Tierversuch eine gute antineoplastische Wirkung aufweisen. It has now surprisingly been found that some of the compounds of the invention of formula (I) have good anti-neoplastic effects in animal experiments. Im folgenden seien einige typische Vertreter der neuen Verbindungsklasse aufgeführt, ohne jedoch dadurch den Umfang der Erfindung zu beschränken, da weitere Verbindungen analog hergestellt werden können. The following are some typical representatives of the new class of compounds which may be mentioned, but without thereby limiting the scope of the invention since other compounds can be prepared analogously. Die mit der Erfindung erzielten Vorteile bestehen insbesondere darin, daß auf eine neue rationelle Art Lipide mit unsymmetrisch substituierter Disulfidbrücke direkt hergestellt und die pharmakologisch wirksamen Vertreter dieser neuen Verbindungsklasse in Arzneimittel eingearbeitet werden können. The advantages achieved with the invention consist in particular in that formed directly on a new rational way lipids with unsymmetrically substituted disulfide bridge and the pharmacologically active representatives of this new class of compounds can be incorporated into pharmaceuticals. Besonders hervorzuheben ist die geringe Toxizität der neuen Verbindungen im Vergleich zu den bisher bekannten Zytostatika. Particularly noteworthy is the low toxicity of the new compounds as compared to the previously known cytostatic agents.

Die neuen Lipide mit Disulfidbrücke können z. The new lipids disulfide bridge can for. B. in Präparaten zur Anwendung bei Mensch und Tier verarbeitet werden. B. processed in preparations for use in humans and animals. Die Zubereitung der erfindungsgemäßen Arzneimittel erfolgt durch Vermischen oder Auflösen der Wirkstoffe zusammen mit oder in pharmazeutisch üblichen verträglichen Hilfs-, Zusatz- und/oder Trägerstoffen, wie z. The preparation of the medicaments of the invention is carried out by mixing or dissolving the active ingredients together with or in pharmaceutically conventional compatible auxiliaries, additives and / or excipients, such. B. wäßrigen oder nichtwäßrigen Lösungsmitteln, Stabilisatoren, Emulgatoren, Suspensions-, Dispensions- und Netzmitteln und dgl. sowie geeigneten Additiven und erforderlichenfalls auch Farb- und Aromastoffen. As aqueous or non-aqueous solvents, stabilizers, emulsifiers, suspension, Dispensions- and wetting agents, and the like., As well as appropriate additives and if necessary, coloring and flavoring substances.

Die erfindungsgemäßen Arzneimittel-Zusammensetzungen, welche mindestens einen der erfindungsgemäßen Wirkstoffe enthalten, können in Form von Pulver, Puder, Suspensionen, Lösungen, Emulsionen oder auch als Salben, Gele und Pasten konfektioniert werden und parenteral, z. The pharmaceutical compositions of the invention containing at least one of the active ingredients according to the invention, may be formulated and administered parenterally in the form of powders, suspensions, solutions, emulsions or as ointments, gels and pastes such. B. intravenös, intradermal und intramuskulär injiziert oder infundiert, oral, rektal, intravaginal und intranasal verabreicht oder örtlich (z. B. auf Infektionen an der Haut und Schleimhaut) appliziert werden. , Intravenous, intradermal and intramuscular injection or infusion, orally, rectally, intravaginally and administered intranasally or locally (eg. B. on infections on the skin and mucous membrane) be administered.

Beispiel 1 example 1 S-Octadecylthiocystein S-Octadecylthiocystein

1,76 g L-Cystein-HCl-Monohydrat (10 mmol) und 4,32 g N-Octadecylthiophthalimid (10 mmol) werden in 50 ml Ethanol 99% 4,5 h unter Rückfluß erhitzt. 1.76 g L-cysteine ​​HCl monohydrate (10 mmol) and 4.32 g of N-Octadecylthiophthalimid (10 mmol) are heated under reflux in 50 ml ethanol 99% 4.5. Die Lösung wird mit 200 ml heißem Wasser versetzt. The solution is added with 200 ml of hot water. Das ausgefallene Produkt wird abfiltriert und mit 200 ml heißem Wasser gewaschen. The precipitated product is filtered off and washed with 200 ml of hot water.

Smp.: 173°C (Z) M.p .: 173 ° C (Z)
Ausb.: 72% Yield .: 72%
C₂₁H₄₃N₁O₂S₂ M R = 405,7 C₂₁H₄₃N₁O₂S₂ M = 405.7 R

Beispiel 2 example 2 N-acetyl-S-octadecylthiocystein N-acetyl-S-octadecylthiocystein

Analog Beispiel 1 aus 1,63 g (10 mmol) N-Acetyl-L-Cystein in 5stündiger Reaktionszeit. Analogously to Example 1 from 1.63 g (10 mmol) of N-acetyl-L-cysteine ​​in 5 hours reaction time.

Smp.: 107°C M.p .: 107 ° C
Ausb.: 89,5% Yield .: 89.5%
C₂₃H₄₅O₃N₁S₂ M R = 447,74 C₂₃H₄₅O₃N₁S₂ M R = 447.74

Beispiel 3 example 3 2-(Octadecyldithio)ethansulfonsäure-Natrium 2- (Octadecyldithio) ethane sulfonic acid sodium

Analog Beispiel 1 aus 1,64 g (10 mmol) MESNA. Analogously to Example 1 from 1.64 g (10 mmol) MESNA. Die Reinigung erfolgt säulenchromatographisch über Kieselgel mit Methanol als Eluens. Purification is effected by column chromatography on silica gel with methanol as eluent.

Smp.: 190-220°C M.p .: 190-220 ° C
Ausb.: 89% Yield .: 89%
C₂₀H₄₁O₃S₃Na₁ M R = 448,72 C₂₀H₄₁O₃S₃Na₁ M R = 448.72

Beispiel 4 example 4 S-Octadecylthioglutathion S-Octadecylthioglutathion

Analog Beispiel 1 aus 3,07 g (10 mmol) reduziertem Glutathion in 3stündiger Reaktion. reduced analogously to Example 1 from 3.07 g (10 mmol) of glutathione in 3 hours of reaction.

Smp.: 210°C (Z) M.p .: 210 ° C (Z)
Ausb.: 75% Yield .: 75%
C₂₈H₅₃N₃O₆S₂ M R = 591,87 C₂₈H₅₃N₃O₆S₂ M R = 591.87

Beispiel 5 example 5 2-(Octadecyldithio)-6-methyl-pyrimidin-4-on 2- (Octadecyldithio) -6-methyl-pyrimidin-4-one

Analog Beispiel 1 aus 1,42 g (10 mmol) Methylthiouracil in 2stündiger Reaktion. Analogously to Example 1 from 1.42 g (10 mmol) methylthiouracil in 2 hours of reaction.

Smp.: 80°C M.p .: 80 ° C
Ausb.: 56% Yield .: 56%
C₂₃H₄₂O₁N₂S₂ M R = 426,72 C₂₃H₄₂O₁N₂S₂ M R = 426.72

Beispiel 6 example 6 2-(Octadecyldithio)-6-ethyl-pyrimidin-4-on 2- (Octadecyldithio) -6-ethyl-pyrimidin-4-one

Analog Beispiel 1 aus 1,70 g (10 mmol) Propylthiouracil in 2stündiger Reaktion. Analogously to Example 1 from 1.70 g (10 mmol) in 2-hour reaction propylthiouracil.

Smp.: 62°C M.p .: 62 ° C
Ausb.: 39% Yield .: 39%
C₂₅H₄₆O₁N₂S₂ M R = 454,78 C₂₅H₄₆O₁N₂S₂ M R = 454.78

Beispiel 7 example 7 6-(Octadecyldithio)purin 6- (Octadecyldithio) purine

Analog Beispiel 1 aus 1,70 g (10 mmol) 6-Mercaptopurin in 3stündiger Reaktionszeit. Analogously to Example 1 from 1.70 g (10 mmol) of 6-mercaptopurine in 3 hours of reaction time.

Smp.: 122°C M.p .: 122 ° C
Ausb.: 78% Yield .: 78%
C₂₃H₃₉N₄S₂ M R = 435,71 C₂₃H₃₉N₄S₂ M R = 435.71

Beispiel 8 example 8 S-[1,2-Bis(hexadecyloxycarbonyl)ethylthio]cystein S- [1,2-bis (hexadecyloxycarbonyl) ethylthio] cysteine

Zu einer Lösung von 12,12 g (10 mmol) Thiosulfinsäureester in 20 ml Dichlormethan werden 3,51 g (20 mmol) L-Cystein-HCl-Monohydrat, gelöst in 20 ml Methanol langsam bei Raumtemperatur zugetropft. To a solution of 12.12 g (10 mmol) Thiosulfinsäureester in 20 ml of dichloromethane 3.51 g (20 mmol) of L-cysteine ​​HCl monohydrate, dissolved in 20 ml of methanol are slowly added dropwise at room temperature. Anschließend rührt man 3 h lang bei Raumtemperatur, bringt mit methanolischer Natronlauge auf pH 6,5, gibt 50 ml Methanol zu und filtriert den ausgefallenen Feststoff ab. Mixture is then stirred for 3 hours at room temperature, brings with methanolic sodium hydroxide solution to pH 6.5, 50 ml of methanol and filtered from the precipitated solid. Die Reinigung erfolgt durch Eluierung über eine Kieselgelsäule mit einer Dichlormethan/Methanol-Mischung im Verhältnis 3/1. Purify by eluting through a silica column with a dichloromethane / methanol mixture in the ratio 3/1.

Smp.: 132°C M.p .: 132 ° C
Ausb.: 76% Yield .: 76%
C₃₉H₇₅O₆N₁S₂ M R = 718,15 C₃₉H₇₅O₆N₁S₂ M R = 718.15

Beispiel 9 example 9 S-[1,2-Bis(tetradecanoyl)propyl-3-thio]cystein S- [1,2-bis (tetradecanoyl) propyl-3-thio] cysteine

Analog Beispiel 1 aus 1,76 g (10 mmol) L-Cystein-HCl-Monohydrat und 6,74 g (10 mmol) 1,2-Ditetradecanoyl-3-thiophthalimidopropan-1,2-diol in 5,5stündiger Reaktionszeit. Analogously to Example 1 from 1.76 g (10 mmol) of L-cysteine ​​HCl monohydrate and 6.74 g (10 mmol) of 1,2-Ditetradecanoyl-3-thiophthalimidopropan-1,2-diol in 5,5stündiger reaction time.

Smp.: 176°C M.p .: 176 ° C
Ausb.: 56% Yield .: 56%
C₃₄H₆₅N₁O₆S₂ M R = 648,02 C₃₄H₆₅N₁O₆S₂ M R = 648.02

Claims (6)

1. Lipide mit Disulfidbrücke der allgemeinen Formel (I) R₁-SS-R₂ (I)in welcher 1. lipids with disulfide of the general formula (I) R₁-SS-R₂ (I) in which
R₁ für eine verzweigte oder unverzweigte Alkylgruppe der Kettenlänge C₈H₁₇ bis C₂₀H₄₁ steht, R₁ stands for a branched or unbranched alkyl group of chain length C₈H₁₇ up C₂₀H₄₁,
für (II) steht, wobei represents (II), wherein
R₃ eine verzweigte oder unverzweigte Alkylgruppe der Kettenlänge C₈H₁₇ bis C₂₀H₄₁ ist, R₃ is a branched or unbranched alkyl group of chain length C₈H₁₇ up C₂₀H₄₁,
oder für (III) steht, wobei or is (III), wherein
R₄, R₅ gleich oder verschieden sein können und verzweigte oder unverzweigte Alkylgruppen der Kettenlänge C₁ bis C₂₁ sind oder Phenyl-, Cyclohexyl- bzw. Benzyl- bedeuten können; R₄, R₅ may be the same or different and are branched or unbranched alkyl groups of chain length C₁-C₂₁ or are phenyl, cyclohexyl or benzyl may represent;
R₂-S- für einen Cystein-, Glutathion-, Mercaptopurin-, MESNA-, N-acetylcystein-, Methylthiouracil- oder Propylthiouracil-Rest steht, sowie ihre Salze; R₂ represents a cysteine-S-, glutathione, mercaptopurine, mesna, N-acetylcystein-, Methylthiouracil- or propylthiouracil radical, and their salts;
oder für (IV) steht worin or (IV), wherein
R₆=H, CF₃ und R₇=H, CH₃ sein können. R₆ = H, CF₃ and R₇ = H, may be CH₃.
2. Verfahren zur Herstellung von Verbindungen der Formel (I), dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel (V) oder (VI) in welchen 2. A process for the preparation of compounds of formula (I), characterized in that one (VI) into compounds of general formula (V) or which
R₁ die oben angeführte Bedeutung hat, mit Verbindungen der Formel (VII)R₂-SH (VII)in welcher R₁ has the meaning given above, with compounds of formula (VII) R₂-SH (VII) in which
R₂-S- die oben angeführte Bedeutung hat, in Gegenwart organischer Lösungsmittel oder Mischungen organischer Lösungsmittel mit Wasser unter Eiskühlung, bei Raumtemperatur oder bei erhöhter Temperatur umsetzt. R₂-S has the meaning given above, in the presence of organic solvents or mixtures of organic solvents with water under ice-cooling, reacted at room temperature or at elevated temperature.
3. Arzneimittel, enthaltend amphiphile Lipide mit Disulfidbrücke gemäß Formel (I) in Anspruch 1 in einer zur systemischen oder topischen Applikation geeigneten Formulierung. 3. A medicament containing amphiphilic lipids with disulfide of the formula (I) in claim 1 in a form suitable for systemic or topical application formulation.
4. Verfahren zur Herstellung von Arzneimitteln, dadurch gekennzeichnet, daß man Verbindungen gemäß Anspruch 1 gegebenenfalls unter Zusatz von inerten pharmazeutisch unbedenklichen Hilfs- und Trägerstoffen in eine geeignete Applikationsform überführt. 4. A process for the preparation of medicaments, characterized in that one converts the compounds according to claim 1 optionally with the addition of inert pharmaceutically acceptable auxiliaries and excipients, into a suitable administration form.
5. Verwendung von amphiphilen Disulfiden gemäß Anspruch 1 bei der Bekämpfung von Erkrankungen. 5. Use of amphiphilic disulfides according to claim 1 in the control of diseases.
6. Verwendung von amphiphilen Disulfiden gemäß Anspruch 1 bei der Bekämpfung von bakteriellen oder viralen Infektionen, zur Behandlung von Krebserkrankungen und Erkrankungen des Immunsystems sowie als Radio- und Hepatoprotektiva. 6. Use of amphiphilic disulfides according to claim 1 in the control of bacterial or viral infections, for the treatment of cancers and diseases of the immune system as well as a radio and Hepatoprotektiva.
DE19873728917 1987-08-29 1987-08-29 Novel lipids containing an asymmetrically substituted disulphide bridge, processes for their preparation, and their use as medicaments Withdrawn DE3728917A1 (en)

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