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WO1993000326A1 - Derives d'acides gras polyinsatures omega 3, leur preparation et leur utilisation - Google Patents

Derives d'acides gras polyinsatures omega 3, leur preparation et leur utilisation Download PDF

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Publication number
WO1993000326A1
WO1993000326A1 PCT/EP1992/001337 EP9201337W WO9300326A1 WO 1993000326 A1 WO1993000326 A1 WO 1993000326A1 EP 9201337 W EP9201337 W EP 9201337W WO 9300326 A1 WO9300326 A1 WO 9300326A1
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WIPO (PCT)
Prior art keywords
acid
mmol
aav
epa
substance
Prior art date
Application number
PCT/EP1992/001337
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German (de)
English (en)
Inventor
Bernhard Bockstiegel
Franz Emling
Barbara Jessel
Peter Lechtken
Ulrich Hoercher
Original Assignee
Basf Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Publication of WO1993000326A1 publication Critical patent/WO1993000326A1/fr

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Classifications

    • 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
    • C07C219/08—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 at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/38—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton

Definitions

  • Omega-3 polyunsaturated fatty acid derivatives their production and use
  • the present invention relates to new omega-3 polyunsaturated fatty acid derivatives, their preparation and their use for the treatment of inflammatory processes and septic shock.
  • EPA Eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • one of the mechanisms of action of these fatty acids is due to the influence on the arachidonic acid cascade.
  • an EPA diet leads to an increased formation of the intermediate product leukotriene B5 with a simultaneous reduction in leukotriene B4. the latter has a significantly higher inflammatory potential than leukotriene B 5 [J. Clin. Invest. j " 4 1922 (1984); J. Biol. Chem. 259, 7615 (1984)]; likewise the endogenous formation of the platelet activating factor is reduced [Biochem. Biophy
  • EPA and DHA A number of other functions are influenced by EPA and DHA.
  • the inhibition of the release of mediators from monocytes (tumor necrosis factor, interleukin 1) was described in animals and human subjects after a sufficiently long diet [N. Engl. J. Med. 320, 265 (1989)]; platelet aggregation is also inhibited by EPA [Nephron 43, 196 (1986)].
  • EPA has a dampening effect on the proliferation of lymphocytes; moreover, it inhibits the release of lytic enzymes, oxygen radicals and the adherence of granulocytes to the endothelium [N. Engl. J. Med. 312, 1217 (1985); Biochem. Biophys. Res. Comm. 137, 10094 (1986)].
  • inhibitory effects can be of therapeutic use in a wide variety of clinical pictures; in particular in acute and chronic inflammatory processes [J. Immunol. 134, 1914 (1985)], rheumatoid diseases [J. Rheumatol. 1_5_, 1471 (1988)], thrombosis and infarction, psoriasis [Lancet Vol.l, 378 (1988)] and septic shock.
  • a protective effect in graft versus host disease is also expected.
  • the fatty acid ester must be administered intravenously in order to achieve a quick protective effect. It has recently been shown that an effective reduction of LTB4 can be achieved as early as 6 hours after iv administration when eicosapentaenoic acid triclyceride is used [Abstract 7th Intern. Conf. on
  • the invention relates to compounds of the formula I.
  • Ri is the acyl residue of 5,8, 11, 14, 17-eicosapentaenoic acid
  • X is an oxygen atom or an NH group
  • Y is a C2-C3 alkylene group
  • R2 and R3 are hydrogen atoms or C ⁇ _2 alkyl groups
  • X is preferably an oxygen atom
  • Y is preferably a C2-alkylene group
  • R2 and R3 are preferably methyl or ethyl radicals, but especially methyl radicals.
  • 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 - acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid,
  • Ascorbic acid acetylglycine, orotic acid.
  • Preferred salts are the hydrochlorides and the trialkylaunonium chlorides.
  • the compounds according to the invention can be prepared by general methods for the synthesis of carboxylic acid esters or carboxylic acid amides and, if appropriate, subsequent ammonium salt formation.
  • the synthesis of the carboxylic acid esters or carboxamides is preferably the reaction of the carboxylic acid chlorides with the corresponding alcohols or amines in the presence of tertiary amine bases, for example 4-dimethylaminopyridine, or the reaction of the carboxylic acids with the corresponding alcohols or amines in the presence of dehydrating agents , for example dicyclohexylcarbodimide with 4-dimethylaminopyridine as an activator.
  • 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.
  • ammonium salts are prepared by reacting the carboxylic acid esters or carboxamides 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 HC1.
  • the compounds according to the invention are preferably stored under an inert atmosphere and in the absence of light at temperatures from -30 to 4 ° C.
  • the new compounds are suitable for the treatment of acute and chronic inflammatory processes, rheumatic diseases, thrombosis and infarcts, psoriasis, shock lung and septic shock. They also have a protective effect in graft versus host disease.
  • the compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally).
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance is between approximately 10 and 1000 mg / kg body weight when administered orally and between approximately 1 and 100 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, dragées, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (cf. H. Sucker et al:
  • the application forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 99% by weight.
  • AAV 1 Production of the carboxylic acid chlorides:
  • AAV 2 Preparation of the carboxylic acid esters and carboxamides:
  • Gaseous HC1 is introduced into a solution of amino compound in hexane (5 to 25 ml / mmol amine) under N2 atmosphere at 20 ° C for 30 min. The solvent is then distilled off under reduced pressure at 40 to 50 ° C.
  • 3.0 mmol eicosapentaenoic acid chloride were prepared from 0.92 g (3.0 mmol) EPA and 1.0 g (7.9 mmol) oxalic acid dichloride in 10 ml chloroform according to AAV 1 and with 0.4 g (4.5 mmol) 2-Dimethylaminoethanol and 0.25 g (2.0 mmol) of 4-dimethylaminopyridine in 10 ml of dichloromethane according to AAV 2 (reaction time 14 h). The product was purified by chromatography (MTB / Hex / EtOH 1: 1: 1). The yield was 0.86 g (76%).
  • 16.6 mmol eicosapentaenoic acid chloride were prepared from 5.0 g (16.6 mmol) EPA and 15.0 g (118.1 mmol) oxalic acid dichloride in 75 ml chloroform according to AAV 1 and 1.94 g (16.6 mmol) 2-diethyl-a inoethanol and 2.03 g (16.6 mmol) 4-dimethylaminopyridine in 70 ml dichloromethane according to AAV 2 (reaction time 18 h). The product was purified by chromatography (MTB / Hex / EtOH 1: 1: 1). The yield was 3.24 g (49%).
  • 16.6 mmol eicosapentaenoic acid chloride were prepared from 5.0 g (16.6 mmol) EPA and 15.0 g (118.1 mmol) oxalic acid dichloride in 75 ml chloroform according to AAV 1 and with 1.71 g (16.6 mmol) of 3-dimethylaminopropanol and 2.03 g (16.6 mmol) of 4-dimethylaminopyridine in 70 ml of dichloromethane according to AAV 2 (reaction time 18 h). The product was purified by chromatography (MTB, MTB / EtOH 1: 1). The yield was 1.99 g (31%).
  • 16.6 mmol of eicosapentaenoic acid chloride were prepared from 5.0 g (16.6 mmol) of EPA and 15.0 g (118.1 mmol) of oxalic acid dichloride in 75 ml of chloroform according to AAV 1 and with 1.54 g (14.9 mmol) of 1-dimethylamino-2-propanol and 2.03 g (16.6 mmol) of 4-dimethylamino-pyridine in 70 ml of dichloromethane according to AAV 2 (reaction time 18 h). The product was purified by chromatography (MTB, MTB / EtOH 1: 1). The yield was 2.44 g (38%).
  • 16.6 mmol eicosapentaenoic acid chloride were prepared from 5.0 g (16.6 mmol) EPA and 15.0 g (118.1 mmol) oxalic acid dichloride in 75 ml chloroform according to AAV 1 and with 1.32 g (14.9 mmol) N, N-dimethylethylenediamine and 2.03 g (16.6 mmol) 4-dimethylaminopyridine in 70 ml dichloromethane according to AAV 2 (reaction time 18 h). The product was purified chromatographically (MTB / Hex / EtOH 1: 1: 1). The yield was 1.31 g (24%).
  • 10.8 mmol of octadecatrienoic acid chloride were prepared from 3.0 g (10.8 mmol) of octadecatrienoic acid and 3.40 g (26.8 mmol) of oxalic acid dichloride in 45 ml of chloroform according to AAV 1 and with 0.97 g (10.8 mmol) 2-Dimethylaminoethanol and 1.33 g (10.8 mmol) 4-dimethylaminopyridine in 30 ml dichloromethane according to AAV 2 (reaction time 18 h). The product was purified by chromatography (MTB / Hex / EtOH 1: 1: 1). The yield was 1.65 g (44%).
  • 16.6 mmol of eicosapentaenoic acid chloride were prepared from 5.0 g (16.6 mmol) of EPA and 15.0 g (118.1 mmol) of oxalic acid dichloride in 75 ml of chloroform according to AAV 1 and with 2.65 g (16.6 mmol) of N-tert-butyloxycarbonyl-2-aminoethanol and 1.5 g (12.3 mmol) of 4-dimethyl-a-inopyridine in 50 ml of dichloromethane according to AAV 2 (reaction time 4 h). The product was purified by chromatography (MTB / Hex / EtOH 1: 1: 2). The yield was 7.04 g (92%).
  • Example 6 0.3 g (0.75 mmol) of the substance of Example 6 were reacted in 20 ml of hexane according to AAV 3 with gaseous HC1. The yield was 0.31 g (95%).
  • Example 7 0.7 g (2.0 mmol) of the substance of Example 7 were reacted in 10 ml of hexane according to AAV 3 with gaseous HC1. The yield was 0.77 g (100%).
  • Stimulated granulocytes are characterized by the release of a large number of lytic enzymes and, in particular, large amounts of various oxygen radicals.
  • the inhibitory effect on neutrophil granulocytes activated with various stimuli was first measured in a chemiluminescence assay.
  • the chemiluminescence technique is a very sensitive detection system for oxygen radicals.
  • polymorphonuclear neutrophils from heparinized whole blood from healthy donors were subjected to dextran sedimentation (Dextran T250, 3%; 1 xg; 1 h at room temperature) and subsequent separation using a Percoll two-stage gradient ( 60% / 68% PERCOLL in HBSS without Ca z + / Mg z + ) 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 chiluminescence measurements [Meth. Enzyme.
  • Table 1 shows that the new substances at 5 min. Pre-incubation has a good inhibitory effect on the activation of human polymorphonuclear neutrophils.
  • Examples 1 and 8 show that the ester form has a significantly better inhibitory effect than the ester components alone or as an equimolar mixture of the acid and the amino alcohol component.
  • the reference substance pentoxifylline also results in lower inhibitory effects.
  • Example 8 shows that the substance of Example 8 has a high potency against other natural stimuli (PAF / fMLP) of PMN activation, but not against the phorbol ester and PKC activator PMA. Table 2
  • Table 3 shows the superiority of Example 8 over the tri-EPA glycerol in terms of rapid development of the inhibitory effect in human PMN.
  • the rapid effect on the radical release is neither due to any radical scavenger properties (control in the cell-free system negative) nor to a cytotoxic effect of the test substance on the effector cells.
  • the viability after 4 h of pre-incubation and 30 min exposure to TNF was always> 90%.
  • Splenocytes from Balb / c mice were used to evaluate the effect of omega-3 fatty acids and their derivatives on lymphoproliferation. Stimulation of the splenocyte culture with LPS leads to the proliferation of the B cell subpopulation, stimulation with Enterotoxin B to the T cell proliferation.
  • the splenocyte cultures were preincubated with different concentrations of the test substances in microtiter plates for 2 hours and then induced with LPS or enterotoxin B for proliferation.
  • the relative growth inhibition, based on the corresponding control without inhibitor, was calculated from the count yield of the incorporated [3H] -thymidine after two days of incubation at 37 ° C. and then a 6-hour 3H-tymidine pulse (1 ⁇ Ci / 200 ⁇ l / well) and then determined the half-maximum inhibitory concentrations (IC50).
  • Table 4 shows for eicosapentaenoic acid and for the esters of Examples 1 and 8 an equally pronounced antiproliferative effect on both the B and T cell subpopulation of mouse splenocytes
  • mice 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.
  • test substances in endotoxin shock was investigated by i.v. the inhibitors 30 min before LPS administration (20 mg / kg). were applied.
  • Table 5 shows the protective effects of the substances in comparison with eicosapentaenoic acid and eicosapentaenoic acid triglyceride.
  • the animals (Balb / c mice, 6-8 weeks old) were treated once with different doses of the sample substances (bolus, iv). 30 min later, an iv application with 20 mg / kg lipopolysaccharide (LPS) from E. coli, serotype 0 111 B4 was carried out. This dose was found to be 100% lethal in the control group.
  • LPS lipopolysaccharide
  • 5-10 animals were tested in at least 2 independent experiments.
  • the table shows the percentage survival rate for the specified dose range.
  • Example 7 80-100 20
  • Example 8 80-100 5-20

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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

Des composés ayant la formule: R?1-X-Y-NR2R3¿, ainsi que leurs sels avec des acides physiologiquement tolérables et leurs sels de trialkylammonium C¿1-2? sont utiles pour traiter des maladies.
PCT/EP1992/001337 1991-06-25 1992-06-13 Derives d'acides gras polyinsatures omega 3, leur preparation et leur utilisation WO1993000326A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4120916.8 1991-06-25
DE19914120916 DE4120916A1 (de) 1991-06-25 1991-06-25 Omega-3 mehrfach ungesaettigte fettsaeurederivate, ihre herstellung und verwendung

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038688A1 (fr) * 1996-04-12 1997-10-23 Peptide Technology Pty. Limited Procedes permettant de traiter des immunopathologies au moyen d'acides gras polyinsatures
WO2006054110A3 (fr) * 2004-11-22 2006-07-20 Stanford Rook Ltd Agent immunotherapeutique
CN104119242A (zh) * 2008-10-09 2014-10-29 泰米拉制药公司 改善的氨基脂质和递送核酸的方法
US9896316B2 (en) 2016-06-30 2018-02-20 The Procter & Gamble Company End effector for a transport device for the movement of parent rolls of convolutely wound web materials

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH107776A (de) * 1923-07-17 1924-11-17 Chem Ind Basel Verfahren zur Darstellung eines einseitig acylierten Derivates des Äthylendiamins.
GB833655A (en) * 1955-05-05 1960-04-27 Joseph Nichols Amides
GB971700A (en) * 1961-02-02 1964-09-30 Boots Pure Drug Co Ltd Anti-Inflammatory Agents
EP0002722A1 (fr) * 1977-12-24 1979-07-11 Bayer Ag Emulgateurs cationiques, leur utilisation pour la préparation d'émulsions d'hydrocarbures ainsi que leur utilisation pour le traitement du textile
FR2442829A1 (fr) * 1978-11-28 1980-06-27 Kuraray Co Esters d'acide farnesylacetique et leur utilisation comme agents anti-ulcereux

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH107776A (de) * 1923-07-17 1924-11-17 Chem Ind Basel Verfahren zur Darstellung eines einseitig acylierten Derivates des Äthylendiamins.
GB833655A (en) * 1955-05-05 1960-04-27 Joseph Nichols Amides
GB971700A (en) * 1961-02-02 1964-09-30 Boots Pure Drug Co Ltd Anti-Inflammatory Agents
EP0002722A1 (fr) * 1977-12-24 1979-07-11 Bayer Ag Emulgateurs cationiques, leur utilisation pour la préparation d'émulsions d'hydrocarbures ainsi que leur utilisation pour le traitement du textile
FR2442829A1 (fr) * 1978-11-28 1980-06-27 Kuraray Co Esters d'acide farnesylacetique et leur utilisation comme agents anti-ulcereux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF IMMUNOLOGY. Bd. 134, Nr. 3, M{rz 1985, BALTIMORE US Seiten 1914 - 1919; V.E.KELLEY ET. AL.: 'A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice' in der Anmeldung erw{hnt *
THE LANCET Bd. 1, 13. Februar 1988, LONDON GB Seiten 378 - 380; S.B. BITTINER ET. AL.: 'A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis' in der Anmeldung erw{hnt *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038688A1 (fr) * 1996-04-12 1997-10-23 Peptide Technology Pty. Limited Procedes permettant de traiter des immunopathologies au moyen d'acides gras polyinsatures
GB2328155A (en) * 1996-04-12 1999-02-17 Peptide Technology Pty Limited Methods of treating immunopathologies using polyunsaturated fattyacids
GB2328155B (en) * 1996-04-12 2000-08-02 Peptide Technology Pty Limited Methods of treating immunopathologies using polyunsaturated fattyacids
US6262119B1 (en) 1996-04-12 2001-07-17 Peptide Technology Limited Methods of treating immunopathologies using polyunsaturated fatty acids
WO2006054110A3 (fr) * 2004-11-22 2006-07-20 Stanford Rook Ltd Agent immunotherapeutique
US7569213B2 (en) 2004-11-22 2009-08-04 Stanford Rook Limited Immunotherapeutic agent
CN104119242A (zh) * 2008-10-09 2014-10-29 泰米拉制药公司 改善的氨基脂质和递送核酸的方法
CN104119242B (zh) * 2008-10-09 2017-07-07 泰米拉制药公司 改善的氨基脂质和递送核酸的方法
US9896316B2 (en) 2016-06-30 2018-02-20 The Procter & Gamble Company End effector for a transport device for the movement of parent rolls of convolutely wound web materials

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MX9203292A (es) 1993-09-01
DE4120916A1 (de) 1993-01-07

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