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WO1993000325A1 - Esters d'acides gras avec des amino-alcools utiles pour traiter des maladies - Google Patents

Esters d'acides gras avec des amino-alcools utiles pour traiter des maladies Download PDF

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Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen atom
esters
methyl group
acid
amino alcohols
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1992/001340
Other languages
German (de)
English (en)
Inventor
Bernhard Bockstiegel
Franz Emling
Andreas Kling
Barbara Jessel
Bernd Janssen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
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
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of WO1993000325A1 publication Critical patent/WO1993000325A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07C219/06—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.

Landscapes

  • 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 esters d'acides gras avec des amino-alcools ayant la formule (I), dans laquelle R1-R7 ont la notation donnée dans la description, sont utiles pour traiter des maladies.
PCT/EP1992/001340 1991-06-25 1992-06-13 Esters d'acides gras avec des amino-alcools utiles pour traiter des maladies Ceased WO1993000325A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4120917.6 1991-06-25
DE19914120917 DE4120917A1 (de) 1991-06-25 1991-06-25 Ester von fettsaeuren mit aminoalkoholen zur verwendung bei der bekaempfung von krankheiten

Publications (1)

Publication Number Publication Date
WO1993000325A1 true WO1993000325A1 (fr) 1993-01-07

Family

ID=6434681

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001340 Ceased WO1993000325A1 (fr) 1991-06-25 1992-06-13 Esters d'acides gras avec des amino-alcools utiles pour traiter des maladies

Country Status (3)

Country Link
DE (1) DE4120917A1 (fr)
MX (1) MX9203293A (fr)
WO (1) WO1993000325A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5687546A (en) * 1984-05-22 1997-11-18 Southpac Trust International, Inc. Method for providing a decorative cover about a floral grouping

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI991898A1 (it) * 1999-09-09 2001-03-09 Carlo Ghisalberti Stimolatori di fibroblasti
NO20006008L (no) * 2000-11-28 2002-05-29 Thia Medica As Fettsyreanaloger for behandling av inflammatoriske og autoimmune sykdommer

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR911092A (fr) * 1944-12-29 1946-06-27 Prod Chim De La Montagne Noire Procédé pour la condensation d'acides gras et d'amino-alcools
GB971700A (en) * 1961-02-02 1964-09-30 Boots Pure Drug Co Ltd Anti-Inflammatory Agents
DE2121013A1 (de) * 1971-04-29 1972-11-23 Bayer Ag, 5090 Leverkusen Quaternäre Ammoniumverbindungen
US3890357A (en) * 1973-07-23 1975-06-17 Texaco Inc Process for preparation of aminoesters
US3910971A (en) * 1974-07-12 1975-10-07 Commercial Solvents Corp Bacteriostatic compounds
US4046899A (en) * 1976-06-01 1977-09-06 Internx Research Corporation Labile quaternary ammonium salts useful in binding bile acids in warm-blooded animals

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR911092A (fr) * 1944-12-29 1946-06-27 Prod Chim De La Montagne Noire Procédé pour la condensation d'acides gras et d'amino-alcools
GB971700A (en) * 1961-02-02 1964-09-30 Boots Pure Drug Co Ltd Anti-Inflammatory Agents
DE2121013A1 (de) * 1971-04-29 1972-11-23 Bayer Ag, 5090 Leverkusen Quaternäre Ammoniumverbindungen
US3890357A (en) * 1973-07-23 1975-06-17 Texaco Inc Process for preparation of aminoesters
US3910971A (en) * 1974-07-12 1975-10-07 Commercial Solvents Corp Bacteriostatic compounds
US4046899A (en) * 1976-06-01 1977-09-06 Internx Research Corporation Labile quaternary ammonium salts useful in binding bile acids in warm-blooded animals

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 77, no. 10, 4. September 1972, Columbus, Ohio, US; abstract no. 66103, A.BEVILACQUA: 'Dermatological applications of acyl derivatives of (dimethylamino)ethanol' Seite 285 ;Spalte 1 ; *
COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS. Bd. 55, Nr. 5, Mai 1990, PRAGUE CS Seiten 1278 - 1289; M.PROTIVA ET. AL.: 'Potential Cerebral Stimulants: esters of 2-dimethylaminoethanol with some lipophilic carboxylic acids' in der Anmeldung erw{hnt *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5687546A (en) * 1984-05-22 1997-11-18 Southpac Trust International, Inc. Method for providing a decorative cover about a floral grouping

Also Published As

Publication number Publication date
DE4120917A1 (de) 1993-01-07
MX9203293A (es) 1992-12-01

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