WO1993000325A1 - Esters of fatty acids with amino alcohols for use in the treatment of illnesses - Google Patents

Esters of fatty acids with amino alcohols for use in the treatment of illnesses Download PDF

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WO1993000325A1
WO1993000325A1 PCT/EP1992/001340 EP9201340W WO9300325A1 WO 1993000325 A1 WO1993000325 A1 WO 1993000325A1 EP 9201340 W EP9201340 W EP 9201340W WO 9300325 A1 WO9300325 A1 WO 9300325A1
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hydrogen atom
esters
methyl group
acid
amino alcohols
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PCT/EP1992/001340
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German (de)
French (fr)
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Bernhard Bockstiegel
Franz Emling
Andreas Kling
Barbara Jessel
Bernd Janssen
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Basf Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton

Definitions

  • Esters of fatty acids with amino alcohols for use in disease control are esters of fatty acids with amino alcohols for use in disease control
  • the invention relates to esters of fatty acids with amino alcohols of the formula I. in which R 1 is the acyl radical of a straight-chain saturated fatty acid having 8 to 24 carbon atoms,
  • R 2 is a hydrogen atom or a methyl group
  • R 3 is a hydrogen atom or a methyl group
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a hydrogen atom or a methyl group
  • R 6 is a hydrogen atom or a C 1-2 alkyl group
  • R 7 is a hydrogen atom or a C 1-2 alkyl group represent, and their salts with physiologically acceptable acids and C 1-2 -trialkylammonium salts for use in combating diseases.
  • R 1 is preferably a C 12 -C 18 acid residue with an even number of carbon atoms
  • R 2 , R 3 , R 4 and R 5 are preferably hydrogen atoms and R 4 and R 5 are preferably methyl groups.
  • the esters of the formula I are particularly suitable for the production of medicaments with anti-inflammatory properties.
  • the compounds are preferably in the form of salts with physiologically tolerable acids.
  • physiologically acceptable acids hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, mucic acid , Glucuronic acid, oxalic acid, ascorbic acid, acetylglycine, orotic acid.
  • Preferred salts are the hydrochlorides and the trialkylammonium chlorides.
  • the esters of the formula I can be prepared by general methods for the synthesis of carboxylic acid esters and, if appropriate, subsequent ammonium salt formation.
  • amine bases e.g. 4-dimethylaminopyridine
  • dehydrating agents e.g. Dicyclohexylcarbodiimide with 4-dimethylaminopyridine as activator, suitable.
  • the ester or amide bonds are formed at temperatures from -10 to 100 ° C., preferably at temperatures from 0 to 40 ° C. in inert solvents such as ethers, alkanes, chlorinated hydrocarbons, preferably in dichloromethane, chloroform or 1.1.1 -Trichloroethane.
  • the ammonium salts are prepared by reacting the carboxylic acid esters containing an amino group with an acid or with alkyl halides.
  • the hydrochlorides are thus obtained at temperatures from -10 to 40 ° C., preferably at 0 to 20 ° C., in inert solvents, preferably in hexane, by introducing gaseous hydrogen chloride.
  • the exhaustively alkylated ammonium compounds are at temperatures from 0 to 100 ° C, preferably at temperatures from 20 to 60 ° C, in inert solvents, preferably in polar solvents such as nitromethane, by reacting the carboxylic acid esters with C 1-2 alkyl halides, preferably with methyl chloride , manufactured.
  • the compounds of formula I are suitable for the treatment of acute and chronic inflammatory processes, rheumatic diseases, thrombosis and infarcts, psoriasis, shock lung and septic shock. They also show a protective effect in graft versus host disease as well as in ARDS and trauma.
  • the compounds according to the invention can be administered intravenously by infusion or bolus injection in the usual way.
  • the dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active ingredient is between about 1 and 100 mg / kg body weight. The duration of the infusion is 1 to 4 hours.
  • the new compounds can be used as solutions in the usual pharmaceutical application forms. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical additives
  • Stimulated granulocytes are characterized by the release of a large number of lytic enzymes and, in particular, large amounts of various oxygen radicals.
  • Chemiluminescence technology is a very sensitive detection system for oxygen radicals.
  • polymorphonuclear neutrophils from heparinized whole blood from healthy donors were obtained by dextran sedimentation (dextran T250, 3%; 1 ⁇ g; 1 h at room temperature) and subsequent separation using a PERCOLL two-step gradient ( 60% / 68% PERCOLL in HBSS without Ca 2+ / Mg 2+ ) at 600 xg over 30 min at 4 ° C.
  • the cell fraction from the 60% / 68% PERCOLL intermediate phase was washed twice and consisted of> 98% neutrophil granulocytes.
  • the chemiluminescence measurements [Meth. Enzyme. 133, 449 (1986)] were carried out in a BIOLUMAT 9505 (from Berthold, Wildbad) at 37 ° C.
  • BIOLUMAT 9505 from Berthold, Wildbad
  • Stimuli such as TNF, PAF, fMLP or PMA
  • inhibitors carboxylic acid esters
  • Table 1 shows that the new compounds have a good inhibitory effect on the activation of human polymorphonuclear neutrophils at 5 min preincubation. Lower inhibitory effects were observed for the reference substance pentoxifylline.
  • mice Effect of the Test Substances in Endotoxin Shock
  • the sensitivity of mice to lipopolysaccharide depends on the strain and age of the animals. Preliminary experiments with Balb / c mice gave a lethal dose of 20 mg / kg IV. in 6-8 week old animals. The effect of the test substances in endotoxin shock was investigated by i.v. were applied.
  • Table 2 shows the protective activity of the new compounds against lethal doses of LPS in the Balb / c mouse.
  • the test compounds are administered as an iv bolus 30 min before LPS administration (20 mg / kg; iv) in various doses.
  • the percentage of surviving animals and the dose range required for this purpose are given as protective effects.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Described is the use, for the treatment of illnesses, of esters of fatty acids with amino alcohols of the formula I, in which R1 to R7 are as defined in the description.

Description

Ester von Fettsäuren mit Aminoalkoholen zur Verwendung bei der Bekämpfung von Krankheiten Esters of fatty acids with amino alcohols for use in disease control
Beschreibung description
Ester von Fettsäuren mit Aminoalkoholen sind bereits bekannt Esters of fatty acids with amino alcohols are already known
[(Collect. Czech. Chem. Commun. 55 (5), 1278 (1990)]. Ein Teil dieser Substanzen soll eine zerebral stimulierende Wirkung besitzen. [(Collect. Czech. Chem. Commun. 55 (5), 1278 (1990)]. Some of these substances are said to have a cerebral stimulating effect.
Es wurde nun gefunden, daß solche Ester interessante antiinflammatorische Wirkungen besitzen. It has now been found that such esters have interesting anti-inflammatory effects.
Gegenstand der Erfindung sind Ester von Fettsäuren mit Aminoalkoholen der Formel I
Figure imgf000003_0001
worin R1 der Acylrest einer geradkettigen gesättigten Fettsäure mit 8 bis 24 C-Atomen, The invention relates to esters of fatty acids with amino alcohols of the formula I.
Figure imgf000003_0001
in which R 1 is the acyl radical of a straight-chain saturated fatty acid having 8 to 24 carbon atoms,
R2 ein Wasserstoffatom oder eine Methylgruppe, R3 ein Wasserstoffatom oder eine Methylgruppe, R 2 is a hydrogen atom or a methyl group, R 3 is a hydrogen atom or a methyl group,
R4 ein Wasserstoffatom oder eine Methylgruppe, R 4 represents a hydrogen atom or a methyl group,
R5 ein Wasserstoffatom oder eine Methylgruppe, R 5 represents a hydrogen atom or a methyl group,
R6 ein Wasserstoffatom oder eine C1-2-Alkylgruppe und R 6 is a hydrogen atom or a C 1-2 alkyl group and
R7 ein Wasserstoffatom oder eine C1-2-Alkylgruppe darstellen, sowie deren Salze mit physiologisch verträglichen Säuren und C1-2-Trialkylammoniumsalze zur Verwendung bei der Bekämpfung von Krankheiten. In der Formel I ist R1 vorzugsweise ein C12- C18-Säurerest mit einer geraden Zahl an C-Atomen, R2, R3, R4 und R5 sind vorzugsweise Wasserstoffatome und R4 und R5 sind vorzugsweise Methylgruppen. Insbesondere eignen sich die Ester der Formel I zur Herstellung von Arzneimitteln mit antiinflammatorischen Eigenschaften. R 7 is a hydrogen atom or a C 1-2 alkyl group represent, and their salts with physiologically acceptable acids and C 1-2 -trialkylammonium salts for use in combating diseases. In formula I, R 1 is preferably a C 12 -C 18 acid residue with an even number of carbon atoms, R 2 , R 3 , R 4 and R 5 are preferably hydrogen atoms and R 4 and R 5 are preferably methyl groups. The esters of the formula I are particularly suitable for the production of medicaments with anti-inflammatory properties.
Vorzugsweise liegen die Verbindungen als Salze mit physiologisch verträglichen Säuren vor. The compounds are preferably in the form of salts with physiologically tolerable acids.
Als physiologisch verträgliche Säuren sind insbesondere zu nennen: Salzsäure, Zitronensäure, Weinsäure, Milchsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Ameisensäure, Maleinsäure, Fumarsäure, Äpfelsäure, Bernsteinsäure, Malonsäure, Schwefelsäure, L-Glutaminsäure, L-Asparaginsäure, Brenztraubensäure, Schleimsäure, Benzoesäure, Glucuronsäure, Oxalsäure, Ascorbinsäure, Acetylglycin, Orotsäure. Bevorzugte Salze sind die Hydrochloride und die Trialkylammoniumchloride. Die Ester der Formel I lassen sich nach allgemeinen Methoden zur Synthese von Carbonsäureestern und gegebenenfalls anschließender Ammoniumsalzbildung herstellen. In particular, the following can be mentioned as physiologically acceptable acids: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, mucic acid , Glucuronic acid, oxalic acid, ascorbic acid, acetylglycine, orotic acid. Preferred salts are the hydrochlorides and the trialkylammonium chlorides. The esters of the formula I can be prepared by general methods for the synthesis of carboxylic acid esters and, if appropriate, subsequent ammonium salt formation.
Zur Synthese der Carbonsäureester sind vorzugsweise die Umsetzung der Carbonsäurechlorϊde mit den entsprechenden Alkoholen inFor the synthesis of the carboxylic acid esters, the reaction of the carboxylic acid chlorides with the corresponding alcohols is preferred
Gegenwart von Aminbasen, z.B. 4-Dimethylaminopyridin, oder die Umsetzung der Carbonsäuren mit den entsprechenden Alkoholen in Gegenwart wasserentziehender Mittel, z.B. Dicyclohexylcarbodiimid mit 4-Dimethylaminopyridin als Aktivator, geeignet. Presence of amine bases, e.g. 4-dimethylaminopyridine, or the reaction of the carboxylic acids with the corresponding alcohols in the presence of dehydrating agents, e.g. Dicyclohexylcarbodiimide with 4-dimethylaminopyridine as activator, suitable.
Die Knüpfung der Ester- bzw. Amidbindungen geschieht bei Temperaturen von -10 bis 100°C, vorzugsweise bei Temperaturen von 0 bis 40°C in inerten Lösungsmitteln wie Ethern, Alkanen, chlorierten Kohlenwasserstoffen, vorzugsweise in Dichlormethan, Chloroform oder 1,1,1-Trichlorethan. Die Ammoniumsalze werden durch Umsetzung der eine Aminogruppe enthaltenden Carbonsäureester mit einer Säure bzw. mit Alkylhalogeniden hergestellt. So erhält man die Hydrochloride bei Temperaturen von -10 bis 40°C, vorzugsweise bei 0 bis 20°C, in inerten Lösungsmitteln, vorzugsweise in Hexan, durch Einleiten von gasförmigem Chlorwasserstoff. Die erschöpfend alkylierten Ammoniumverbindungen werden bei Temperaturen von 0 bis 100°C, vorzugsweise bei Temperaturen von 20 bis 60°C, in inerten Lösungsmitteln, vorzugsweise in polaren Lösungsmitteln wie Nitromethan, durch Umsetzung der Carbonsäureester mit C1-2-Alkylhalogeniden, vorzugsweise mit Methylchlorid, hergestellt. The ester or amide bonds are formed at temperatures from -10 to 100 ° C., preferably at temperatures from 0 to 40 ° C. in inert solvents such as ethers, alkanes, chlorinated hydrocarbons, preferably in dichloromethane, chloroform or 1.1.1 -Trichloroethane. The ammonium salts are prepared by reacting the carboxylic acid esters containing an amino group with an acid or with alkyl halides. The hydrochlorides are thus obtained at temperatures from -10 to 40 ° C., preferably at 0 to 20 ° C., in inert solvents, preferably in hexane, by introducing gaseous hydrogen chloride. The exhaustively alkylated ammonium compounds are at temperatures from 0 to 100 ° C, preferably at temperatures from 20 to 60 ° C, in inert solvents, preferably in polar solvents such as nitromethane, by reacting the carboxylic acid esters with C 1-2 alkyl halides, preferably with methyl chloride , manufactured.
Die Verbindungen der Formel I eignen sich zur Behandlung von akuten und chronischen Entzündungsprozessen, rheumatische Erkrankungen, Thrombose und Infarkten, Psoriasis, Schocklunge und septischem Schock. Weiter zeigen sie eine protektive Wirkung bei Graft versus Host Disease sowie bei ARDS und Trauma. The compounds of formula I are suitable for the treatment of acute and chronic inflammatory processes, rheumatic diseases, thrombosis and infarcts, psoriasis, shock lung and septic shock. They also show a protective effect in graft versus host disease as well as in ARDS and trauma.
Die erfindungsgemäßen Verbindungen können in üblicher Weise intravenös durch Infusion oder Bolusinjektion verabfolgt werden. The compounds according to the invention can be administered intravenously by infusion or bolus injection in the usual way.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die tägliche Wirkstoffdosis zwischen etwa 1 und 100 mg/kg Körpergewicht, Die Infusionsdauer liegt bei 1 bis 4 Stunden. The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active ingredient is between about 1 and 100 mg / kg body weight. The duration of the infusion is 1 to 4 hours.
Die neuen Verbindungen können in den gebräuchlichen galenischen Applikationsformen als Lösungen angewendet werden. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln verarbeitet werden The new compounds can be used as solutions in the usual pharmaceutical application forms. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical additives
[vgl. H. Sucker et al: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978]. Die so erhaltenen Applikationsformen enthalten den Wirstoff normalerweise in einer Menge von 0,1 bis 10 Gew.-%. In folgenden Versuchen wurde die Wirkung der Ester der Formel I gezeigt: Versuch 1: Einfluß auf die Granulozyten-Aktivierung [see. H. Sucker et al: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978]. The application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 10% by weight. The effect of the esters of the formula I was demonstrated in the following experiments: Experiment 1: Influence on granulocyte activation
Granulozyten stellen den dominierenden Zelltyp unter den Leukozyten-Populationen des Menschen dar und sind insbesondere am frühen als auch am späten Organversagen (early/late organ failure) bei Sepsis und Trauma beteiligt. Es sind die Zellen, die sich aktiv als erste in einem Entzündungsherd anreichern und die erste Reihe der antimikrobiellen Abwehr bilden. Die hohe Reaktivität dieses Zelltyps auf alle möglichen inflammatorischen Stimuli trägt stark zur hohen Lethalitat in ARDS (=Adult Respiratory Distress Granulocytes represent the dominant cell type among the leukocyte populations of humans and are particularly involved in early and late organ failure (sepsis and trauma). It is the cells that are the first to accumulate actively in an inflammatory focus and form the first row of the antimicrobial defense. The high reactivity of this cell type to all possible inflammatory stimuli strongly contributes to the high lethality in ARDS (= Adult Respiratory Distress
Syndrome; Schocklunge) und beim septischen Schock bei [Infect. Immun. 50, 527 (1985); Prostaglandins 27, 227 (1987)]. Stimulierte Granulozyten sind charakterisiert durch die Freisetzung einer großen Zahl lytischer Enzyme und insbesondere von großen Mengen an verschiedenen Sauerstoffradikalen.  Syndromes; Shock lung) and septic shock in [Infect. Immune. 50, 527 (1985); Prostaglandins 27, 227 (1987)]. Stimulated granulocytes are characterized by the release of a large number of lytic enzymes and, in particular, large amounts of various oxygen radicals.
Daher wurde zur Beurteilung der Ester der Formel I zunächst die Hemmwirkung auf mit verschiedenen Stimuli aktivierte neutrophile Granulozyten in einem Chemilumineszenz-Assay gemessen. Die Therefore, in order to assess the esters of formula I, the inhibitory effect on neutrophil granulocytes activated with various stimuli was first measured in a chemiluminescence assay. The
Chemilumineszenz-Technik ist ein sehr sensitives Detektionssystem für Sauerstoffradikale.  Chemiluminescence technology is a very sensitive detection system for oxygen radicals.
Zur Isolierung von PMN aus menschlichem Vollblut [J. Clin. For the isolation of PMN from human whole blood [J. Clin.
Invest. 77, 925 (1986)] und Messung der Aktivität wurden polymorphonukleäre Neutrophile aus heparinisiertem Vollblut gesunder Spender durch Dextran-Sedimentation (Dextran T250, 3 %; 1 × g; 1 h bei Raumtemperatur) und anschließende Auftrennung über einem PERCOLL-Zweistufen-Gradienten (60 %/68 % PERCOLL in HBSS ohne Ca2+/Mg2+) mit 600 x g über 30 min bei 4°C, gewonnen. Die Zellfraktion aus der 60 %/68 % PERCOLL Zwischenphase wurden zweimal gewaschen und bestand zu > 98 % aus neutrophilen Granulozyten. Die Chemilumineszenz-Messungen [Meth. Enzym. 133, 449 (1986)] wurden in einem BIOLUMAT 9505 (Fa. Berthold, Wildbad) bei 37°C durchgeführt. Die Proben setzten sich wie folgt zusammen: Invest. 77, 925 (1986)] and activity measurement, polymorphonuclear neutrophils from heparinized whole blood from healthy donors were obtained by dextran sedimentation (dextran T250, 3%; 1 × g; 1 h at room temperature) and subsequent separation using a PERCOLL two-step gradient ( 60% / 68% PERCOLL in HBSS without Ca 2+ / Mg 2+ ) at 600 xg over 30 min at 4 ° C. The cell fraction from the 60% / 68% PERCOLL intermediate phase was washed twice and consisted of> 98% neutrophil granulocytes. The chemiluminescence measurements [Meth. Enzyme. 133, 449 (1986)] were carried out in a BIOLUMAT 9505 (from Berthold, Wildbad) at 37 ° C. The samples are composed as follows:
Lucigenin 10 μM, HBSS mit Ca2+/Mg2+ je 1 mM und 0,2 % HSA in einem Gesamtvolumen von 0,5 ml. Stimuli (wie TNF, PAF, fMLP oder PMA) wie auch Inhibitoren (Carbonsäureester) in verschiedenen Konzentrationen wurden in 20 μl Volumina zugesetzt. Die Ergebnisse wurden als kumulierte Chemilumineszenz-Impulse über eine Periode von 30 min gewonnen, die prozentuale Hemmung bezogen auf den verwendeten Stimulus errechnet und daraus die halbmaximale Hemmkonzentration bestimmt. Tabelle 1 zeigt, daß die neuen Verbindungen bei 5 min Vorinkubation eine gute Hemmwirkung auf die Aktivierung von humanen polymorphonukleären Neutrophilen besitzen. Für die Referenzsubstanz Pentoxifyllin wurden geringere Hemmeffekte beobachtet. Lucigenin 10 μM, HBSS with Ca 2+ / Mg 2+ each 1 mM and 0.2% HSA in a total volume of 0.5 ml. Stimuli (such as TNF, PAF, fMLP or PMA) as well as inhibitors (carboxylic acid esters) in various Concentrations were added in 20 ul volumes. The results were obtained as cumulative chemiluminescence pulses over a period of 30 minutes, the percentage inhibition based on the stimulus used and the half-maximum inhibitory concentration determined therefrom. Table 1 shows that the new compounds have a good inhibitory effect on the activation of human polymorphonuclear neutrophils at 5 min preincubation. Lower inhibitory effects were observed for the reference substance pentoxifylline.
Tabelle 1 Table 1
Substanz IC50 [μM] Substance IC 50 [μM]
C17H35-CO-O-CH2-CH2-N(CH3)2 15.6 C 17 H 35 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 15.6
C15H31-CO-O-CH2-CH2-N(CH3)2 5.9 C 15 H 31 -CO-O-CH2-CH 2 -N (CH 3 ) 2 5.9
C11H23-CO-O-CH2-CH2-N(CH3)2 4.1 C 11 H 23 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 4.1
C7H15-CO-O-CH2-CH2-N(CH3)2 48.0 C 7 H 15 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 48.0
Pentoxifyllin 72  Pentoxifylline 72
Versuch 2: Effekt der Testsubstanzen im Endotoxinschock Die Sensitivitat von Mäusen gegen Lipopolysaccharid ist abhängig von Stamm und Alter der Tiere. Vorversuche mit Balb/c Mäusen ergaben eine lethale Dosis von 20 mg/kg i.v. bei 6-8 Wochen alten Tieren. Der Effekt der Testsubstanzen im Endotoxinschock wurde untersucht, indem die Inhibitoren 30 min vor der LPS-Gabe (20 mg/Kg) i.v. appliziert wurden. Experiment 2: Effect of the Test Substances in Endotoxin Shock The sensitivity of mice to lipopolysaccharide depends on the strain and age of the animals. Preliminary experiments with Balb / c mice gave a lethal dose of 20 mg / kg IV. in 6-8 week old animals. The effect of the test substances in endotoxin shock was investigated by i.v. were applied.
Tabelle 2 zeigt die protektive Wirkung der neuen Verbindungen gegen lethale Dosen von LPS in der Balb/c Maus. Die Testverbindungen werden als i.v. Bolus 30 min vor der LPS-Gabe (20 mg/kg; i.v.) in verschiedenen Dosen appliziert. Als protektiver Effekt ist der Prozentsatz der überlebenden Tiere und der dazu notwendige Dosisbereich angegeben. Table 2 shows the protective activity of the new compounds against lethal doses of LPS in the Balb / c mouse. The test compounds are administered as an iv bolus 30 min before LPS administration (20 mg / kg; iv) in various doses. The percentage of surviving animals and the dose range required for this purpose are given as protective effects.
Tabelle 2: Protektion gegen lethalen LPS-Effekt Table 2: Protection against lethal LPS effect
Protektion protection
Substanz überlebende Tiere Dosisbereich  Substance surviving animals dose range
[%] mg/kg  [%] mg / kg
C17H35-CO-O-CH2-CH2-N(CH3)2 60-80 5-20 C15H31-CO-O-CH2-CH2-N(CH3)2 80-100 20 C 17 H 35 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 60-80 5-20 C 15 H 31 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 80- 100 20
C11H23-CO-O-CH2-CH2-N(CH3)2 50-60 30-50 C 11 H 23 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 50-60 30-50
In diesen Versuchen zeigten insbesondere die Substanzen In these experiments, the substances in particular showed
C15H31-CO-O-CH2-CH2-N(CH3)2 und C17H35-CO-O-CH2-CH2-N(CH3)2 sehr gute Wirkungen. C 15 H 31 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 and C 17 H 35 -CO-O-CH 2 -CH 2 -N (CH 3 ) 2 very good effects.
Die in der Beschreibung verwendeten Abkürzungen haben folgende Bedeutungen: fMLP Formyl-Methionyl-Leucyl-Phenylalanin The abbreviations used in the description have the following meanings: fMLP formyl-methionyl-leucyl-phenylalanine
HBSS Hanks balanced salt solution  HBSS Hanks balanced salt solution
HSA Human-Serumalbumin  HSA human serum albumin
i.v. intravenös i.v. intravenously
LPS Lipopolysaccharid  LPS lipopolysaccharide
PAF Platelet Activating Factor PAF Platelet Activating Factor
PMA Phorbol-12-myristat-13-acetat  PMA phorbol-12-myristate-13-acetate
PMN Polymorphonucleäre neutrophile Leukozyten  PMN polymorphonuclear neutrophil leukocytes
TNF Tumornekrosefaktor  TNF tumor necrosis factor

Claims

Patentansprüche Claims
1. Ester von Fettsäuren mit Aminoalkoholen der Formel I
Figure imgf000009_0001
1. Esters of fatty acids with amino alcohols of the formula I.
Figure imgf000009_0001
worin  wherein
R1 der Acylrest einer geradkettigen gesättigten Fettsäure mit 8 bis 24 C-Atomen, R2 ein Wasserstoffatom oder eine Methylgruppe, R 1 is the acyl radical of a straight-chain saturated fatty acid with 8 to 24 C atoms, R 2 is a hydrogen atom or a methyl group,
R3 ein Wasserstoffatom oder eine Methylgruppe, R 3 represents a hydrogen atom or a methyl group,
R4 ein Wasserstoffatom oder eine Methylgruppe, R 4 represents a hydrogen atom or a methyl group,
R5 ein Wasserstoffatom oder eine Methylgruppe, R 5 represents a hydrogen atom or a methyl group,
R6 ein Wasserstoffatom oder eine C1-2-Alkylgruppe und R7 ein Wasserstoffatom oder eine C1-2-Alkylgruppe darstellen, sowie deren Salze mit physiologisch verträglichen Säuren und C1-2-Trialkylammoniumsalze zur Verwendung bei der Bekämpfung von Krankheiten. R 6 represents a hydrogen atom or a C 1-2 alkyl group and R 7 represents a hydrogen atom or a C 1-2 alkyl group, as well as their salts with physiologically compatible acids and C 1-2 trialkylammonium salts for use in combating diseases.
Verwendung der Ester der Formel I gemäß Anspruch 1 zur Herstellung von Arzneimitteln mit antiinflammatorischen Eigenschaften. Use of the esters of formula I according to claim 1 for the manufacture of medicaments with anti-inflammatory properties.
GEÄNDERTE ANSPRÜCHE CHANGED REQUIREMENTS
[beim Internationalen Büro am 9. Oktober 1992 (09.10.92) eingegangen, ursprüngliche Ansprüche 1 und 2 durch geänderten Anspruch 1 ersetzt (1 Seite  [Received at the International Office on October 9, 1992 (October 9, 1992), original claims 1 and 2 replaced by amended claim 1 (1 page
1. Verwendung von Estern von Fettsäuren mit Aminoalkoholen der Formel
Figure imgf000010_0001
1. Use of esters of fatty acids with amino alcohols of the formula
Figure imgf000010_0001
worin  wherein
R1 der Acylrest einer geradkettigen gesättigten Fettsäure R 1 is the acyl radical of a straight-chain saturated fatty acid
mit 8 bis 24 C-Atomen, R2 ein Wasserstoffatom oder eine Methylgruppe, with 8 to 24 carbon atoms, R 2 is a hydrogen atom or a methyl group,
R3 ein Wasserstoffatom oder eine Methylgruppe, R 3 represents a hydrogen atom or a methyl group,
R4 ein Wasserstoffatom oder eine Methylgruppe, R 4 represents a hydrogen atom or a methyl group,
R5 ein Wasserstoffatom oder eine Methylgruppe, R 5 represents a hydrogen atom or a methyl group,
R6 ein Wasserstoffatom oder eine C1-2-Alkylgruppe und R7 ein Wasserstoffatom oder eine C1-2-Alkylgruppe darstellen, sowie deren Salze mit physiologisch verträglichen Säuren und C1-2-Trialkylammoniumsalze zur Herstellung von Arzneimitteln mit antiinflammatorischen Eigenschaften. R 6 represents a hydrogen atom or a C 1-2 alkyl group and R 7 represents a hydrogen atom or a C 1-2 alkyl group, as well as their salts with physiologically compatible acids and C 1-2 trialkylammonium salts for the production of medicaments with anti-inflammatory properties.
PCT/EP1992/001340 1991-06-25 1992-06-13 Esters of fatty acids with amino alcohols for use in the treatment of illnesses WO1993000325A1 (en)

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DE19914120917 DE4120917A1 (en) 1991-06-25 1991-06-25 ESTERS OF FATTY ACIDS WITH AMINO ALCOHOLS FOR USE IN THE FIGHT AGAINST DISEASES
DEP4120917.6 1991-06-25

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ITMI991898A1 (en) * 1999-09-09 2001-03-09 Carlo Ghisalberti FIBROBLAST STIMULATORS
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GB971700A (en) * 1961-02-02 1964-09-30 Boots Pure Drug Co Ltd Anti-Inflammatory Agents
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US5687546A (en) * 1984-05-22 1997-11-18 Southpac Trust International, Inc. Method for providing a decorative cover about a floral grouping

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