DE3343804A1 - Substituted propionamides, their preparation and their use as antimicrobial substances - Google Patents

Substituted propionamides, their preparation and their use as antimicrobial substances

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DE3343804A1
DE3343804A1 DE19833343804 DE3343804A DE3343804A1 DE 3343804 A1 DE3343804 A1 DE 3343804A1 DE 19833343804 DE19833343804 DE 19833343804 DE 3343804 A DE3343804 A DE 3343804A DE 3343804 A1 DE3343804 A1 DE 3343804A1
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general formula
morpholinyl
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propionic acid
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Werner Dr Gerhardt
Rudolf Dr Lehmann
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Henkel AG and Co KGaA
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Henkel AG and Co KGaA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/524—Preservatives

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  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
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  • Dentistry (AREA)
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  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
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Abstract

3-(4-Morpholinyl)propionamides of the general formula (I) <IMAGE> in which R<1> represents individual linear alkyl radicals having 10 to 14 C atoms or mixtures thereof, an n-dodecyloxytrimethylene radical, an n-dodecyl- or n-tetradecylaminotrimethylene radical or an N-(n-dodecyl/tetradecyl)-3-(4-morpholinyl)propionamido-N-trimethylene radical, are obtained by reacting primary amines of the general formula R<1>-NH2, in which R<1> has the abovementioned meaning, with equimolar amounts of methyl 3-(4-morpholinyl)propionate in solution at elevated temperature. The compounds of the general formula (I) are used as antimicrobial substances.

Description

Substituierte Propionsäureamide, ihre HerstellungSubstituted propionic acid amides, their production

und ihre Verwendung als antimikrobielle Substanzen Die Erfindung betrifft 3- (4-Morpholinyl) -propionsäureamide der allgemeinen Formel (I) in der R1 für einzelne lineare Alkylreste mit 10 bis 14 C-Atomen oder deren Mischungen, einen n-Dodecyloxytrimethylen-Rest, einen n-Dodecyl- oder n-Tetradecylaminotrimethylen-Rest oder einen 3-(4-Morpholinyl)-propionsäure-N- (n-dodecyl/tetradecyl) -amido-N-trimethylen-Rest steht, sowie ihre Salze mit anorganischen oder organischen Säuren.and their use as antimicrobial substances. The invention relates to 3- (4-morpholinyl) propionic acid amides of the general formula (I) in which R1 stands for individual linear alkyl radicals with 10 to 14 carbon atoms or mixtures thereof, an n-dodecyloxytrimethylene radical, an n-dodecyl or n-tetradecylaminotrimethylene radical or a 3- (4-morpholinyl) propionic acid-N- (n-dodecyl / tetradecyl) -amido-N-trimethylene radical, as well as their salts with inorganic or organic acids.

Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung der 3- (4-Morpholinyl) -propionsäureamide der allgemeinen Formel (I), das dadurch gekennzeichnet ist, daß man primäre Amine der allgemeinen Formel 1 1 R -NH2, in der R die oben angegebene Bedeutung hat, mit äquimolaren Mengen des 3-(4-Morpholinyl)-propionsäuremethylesters in Lösung bei erhöhter Temperatur umsetzt.The invention further relates to a method for producing the 3- (4-Morpholinyl) propionic acid amides of the general formula (I), characterized in that is that one primary amines of the general formula 1 1 R -NH2, in which R is the above has given meaning, with equimolar amounts of 3- (4-morpholinyl) propionic acid methyl ester in solution at elevated temperature.

Die Erfindung betrifft schließlich die Verwendung der Verbindungen der allgemeinen Formel (I) als antimikrobielle Substanzen.Finally, the invention relates to the use of the compounds of the general formula (I) as antimicrobial substances.

Beispiele für die einzelnen linearen Alkylreste, für die R¹ steht, sind n-Decyl, n-Dodecyl oder n-Tetradecyl. R1 kann jedoch auch für eine Mischung linearer Alkylreste mit im wesentlichen 12 bis 14 C-Atomen, sogenanntes "Kokos-Alkyl", stehen.Examples of the individual linear alkyl radicals for which R¹ stands, are n-decyl, n-dodecyl or n-tetradecyl. However, R1 can also be used for a mixture linear alkyl radicals with essentially 12 to 14 carbon atoms, so-called "coconut alkyl", stand.

R1 kann jedoch auch für durch Heteroatome substituierte Alkylreste oder für substituierte Carbonsäureamido-N-trimethylen-Reste stehen. Bevorzugte Beispiele für Heteroatom-substituierte Alkylreste sind der n-Dodecyloxytrimethylenrest oder n-Dodecyl- bzw. n-Tetradecylaminotrimethylenreste. Ein Beispiel für einen Carbonsäureamido-N-trimethylen-Rest, für den R1 stehen kann, ist der 3-(4-Morpholinyl)-propionsäure-N- (n-dodecyl/tetradecyl) -amido-N-trimethylen-Rest.However, R1 can also represent alkyl radicals substituted by heteroatoms or represent substituted carboxamido-N-trimethylene radicals. Preferred examples for heteroatom-substituted alkyl radicals are the n-dodecyloxytrimethylene radical or n-dodecyl or n-tetradecylaminotrimethylene radicals. An example of a carboxamido-N-trimethylene radical, for which R1 can stand is 3- (4-morpholinyl) -propionic acid-N- (n-dodecyl / tetradecyl) -amido-N-trimethylene radical.

Die 3-(4-Morpholinyl)-propionsäureamide werden in einem einstufigen Verfahren hergestellt, welches das nachfolgende Reaktionsschema zeigt. Ausgangsverbindungen sind die langkettigen primären Amine R -NH2 (in), in denen R1 die oben angegebene Bedeutung hat, und der durch Addition von Morpholin an Acrylsäuremethylester herstellbare 3- (4-Morpholinyl) -propionsäuremethylester (III).The 3- (4-morpholinyl) propionic acid amides are in a one-step Process prepared which shows the reaction scheme below. Output connections are the long-chain primary amines R -NH2 (in), in which R1 is the above Has meaning, and which can be prepared by adding morpholine to methyl acrylate 3- (4-Morpholinyl) propionic acid methyl ester (III).

Amin (II) und Ester (III) werden in äquimolaren Mengen in einem Lösungsmittel miteinander zur Reaktion gebracht. Als Lösungsmittel geeignet sind vor allem hoch siedende, substituierte, aromatische Kohlenwasserstoffe, bevorzugt 1,2-Dichlorbenzol oder Xylol. Die Umsetzung wird durchgeführt bei Temperaturen von 1100C und höher, bevorzugt bei 115 bis 1180C. Die Reaktion dauert je nach eingesetzter Aminkomponente 12 bis 72 Stunden.Amine (II) and ester (III) are in equimolar amounts in a solvent reacted with each other. Above all, high solvents are suitable as solvents boiling, substituted, aromatic hydrocarbons, preferably 1,2-dichlorobenzene or xylene. The reaction is carried out at temperatures of 1100C and higher, preferably at 115 to 1180C. The reaction lasts depending on the amine component used 12 to 72 hours.

Die Vollständigkeit der Reaktion kann durch dünnschichtchromatographische Kontrolle festgestellt werden.The completeness of the reaction can be determined by thin layer chromatography Control to be determined.

Die entstandenen 3- (4-Morpholinyl) -propionsäureamide (I) werden nach Abdestillieren des Lösungsmittels im Hochvakuum aus n-Hexan umkristallisiert. Die Ausbeuten liegen bei 65 bis 95%.The resulting 3- (4-morpholinyl) propionic acid amides (I) are after the solvent has been distilled off, recrystallized from n-hexane in a high vacuum. The yields are 65 to 95%.

Zur Darstellung der Verbindung mit der allgemeinen Formel (I), in der RI für den 3-(4-Morpholinyl)-propionsäure-N- (n-dodecyl/tetradecyl) -amido-N-trimethylen-Rest steht, wird der 3-(4-Morpholinyl)-propionsäuremethylester mit n-Dodecyl/Tetradecylpropylendiamin im Molverhältnis 2 : 1 umgesetzt.To represent the compound having the general formula (I) in the RI for the 3- (4-morpholinyl) -propionic acid-N- (n-dodecyl / tetradecyl) -amido-N-trimethylene radical is the 3- (4-morpholinyl) -propionic acid methyl ester with n-dodecyl / tetradecylpropylenediamine implemented in a molar ratio of 2: 1.

Reaktionsschema: Die Wasserlöslichkeit der erfindungsgemäßen 3-(4-Morpholinyl)-propionsäureamide der allgemicnen Formel (I) läßt sich dadurch verbessern, daß man sie mit geeigneten anorganischen oder organischen Säuren in entsprechende, in Wasser gut lösliche Salze überführt.Reaction scheme: The water solubility of the 3- (4-morpholinyl) propionic acid amides of the general formula (I) according to the invention can be improved by converting them with suitable inorganic or organic acids into corresponding salts which are readily soluble in water.

Als Säuren eignen sich hierzu beispielsweise Salze säure, Milchsäure und vor allem Essigsäure. Die Umsetzung wird zweckmäßigerweise in einem Lösungmitmtel vorgenommen, in dem das betreffende Salz schwer- oder unlöslich ist, beispielsweise in Ether oder Ethylacetat.Suitable acids for this purpose are, for example, salts acid and lactic acid and especially acetic acid. The reaction is conveniently carried out in a solvent performed, in which the salt in question is sparingly or insoluble, for example in ether or ethyl acetate.

Beispielsweise ergibt die Umsetzung von 3-(4-Morpholinyl)-propionsäuredodecylamid (I, R1 = C12H25) mit Eisessig in Ether das entsprechende Acetat in einer Ausbeute von 98%.For example, the reaction of 3- (4-morpholinyl) propionic acid dodecylamide results (I, R1 = C12H25) with glacial acetic acid in ether the corresponding acetate in one yield of 98%.

Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) und ihre Salze eignen sich aufgrund ihrer mikrobistatischen und mikrobiziden Wirkung beispielsweise als Konservierungsmittel im nicht-medizinischen und nicht-therapeutischen Bereich. Sie können bevorzugt eingesetzt werden in Kombinationen zur Konservierung von Leim, Klebstoffen u.dgl.The compounds of the general formula (I) and according to the invention their salts are suitable due to their microbistatic and microbicidal effect for example as a preservative in non-medicinal and non-therapeutic Area. They can preferably be used in combinations for preservation of glue, adhesives and the like.

So wurde das Acetat des 3-(4-Morpholinyl)-propionsäuredodecylamids (I, R1 = C12H25) in der Leim- und Kühlschmiermittelkonservierung mit Erfolg eingesetzt.So was the acetate of 3- (4-morpholinyl) propionic acid dodecylamide (I, R1 = C12H25) successfully used in glue and cooling lubricant preservation.

Wirkstoffkonzentrationen von O,l+einer 50%igen wässrigen Polyvinylpropionatdispersion führten zu einer Keimzahlreduzierung (Bakterien und Pilze) um 2 - 3 Zehnerpotenzen.Active ingredient concentrations of 0.1 + of a 50% aqueous polyvinyl propionate dispersion led to a reduction in the number of germs (bacteria and fungi) by 2 - 3 powers of ten.

Ferner sind die erfindungsgemäßen Verbindungen verwendbar in der Konservierung von Kosmetika, wie z.B.The compounds according to the invention can also be used in preservation of cosmetics, e.g.

Cremes, öl-in-Wasser- und Wasser-in-öl-Emulsionen u.dgl.Creams, oil-in-water and water-in-oil emulsions and the like.

Zur Verwendung in antimikrobiellen Mitteln können die erfindungsgemäßen Verbindungen in bekannter Weise in flüssige, pastenförmige oder feste Zubereitungen, die als Lösungen, Suspensionen oder Emulsionen vorliegen, eingearbeitet werden.For use in antimicrobial agents, the inventive Compounds in a known manner in liquid, pasty or solid preparations, which are present as solutions, suspensions or emulsions, are incorporated.

+) in Die 3- (4-Morpholinyl) -propionsäureamide der allgemeinen Formel I und ihre essigsauren Salze können als toxikologisch unbedenklich, gut Haut- und Schleimhautverträglich eingestuft werden. Dies ergaben entsprechende Untersuchungen an 3-(4-Plorpholinyl)-propionsäuredodecylamid (I, R1 = C12H25).+) in The 3- (4-morpholinyl) propionic acid amides of general formula I and its acetic acid salts can be considered toxicologically harmless, be classified as being well tolerated by skin and mucous membranes. This resulted in corresponding Investigations on 3- (4-plorpholinyl) propionic acid dodecylamide (I, R1 = C12H25).

Die Erfindung wird in den folgenden Beispielen näher erläutert.The invention is explained in more detail in the following examples.

Beispiele 1. Synthese der 3-(4-Morpholinyl)-propionsäuremide der allgemeinen Formel (I).Examples 1. Synthesis of the 3- (4-morpholinyl) propionic acid amides of the general Formula (I).

Eine Mischung aus 90,1 g (0,52 Mol) 3-(4-Morpholinyl)-propionsäuremethylester (III), 96,4 g (0,52 Mol) Dodecylamin (II; R1 = C12H25) und 140 ml 1,2-Dichlorbenzol wurde unter Rühren bei einer Badtemperatur von 170 bis 1750C (Innentemperatur 115 bis 1180C) 24 Stunden lang erhitzt. Nachdem das Ende der Reaktion durch dünnschichtchromatographische Kontrolle festgestellt worden war, wurde die klare, gelbe Reaktionslösung im Vakuum eingeengt und das restliche Lösungsmittel im Hochvakuum entfernt. Das Rohprodukt wurde zweimal aus n-Hexan umkristallisiert. Dabei wurden 121,9 g 3-(4-Morpholinyl)-propionsäuredodecylamid (I; R1 = C12H25, Substanz B) in Form einer wachsartigen Festsubstanz vom Fp 500C erhalten. Die Ausbeute betrug 72"j der Theorie.A mixture of 90.1 g (0.52 mol) of methyl 3- (4-morpholinyl) propionate (III), 96.4 g (0.52 mol) of dodecylamine (II; R1 = C12H25) and 140 ml of 1,2-dichlorobenzene was stirred at a bath temperature of 170 to 1750C (internal temperature 115 to 1180C) heated for 24 hours. After the end of the reaction by thin layer chromatography Control was established, the clear, yellow reaction solution was in vacuo concentrated and the remaining solvent removed in a high vacuum. The raw product was recrystallized twice from n-hexane. This gave 121.9 g of 3- (4-morpholinyl) propionic acid dodecylamide (I; R1 = C12H25, substance B) in the form of a waxy solid substance with a melting point of 500C obtain. The yield was 72 "of theory.

C19 H38N2O2 (326r53) Elementaranalyse: berechnet (%): 69,89 C; 11,73 H; 8,58 N.C19 H38N2O2 (326r53) Elemental analysis: calculated (%): 69.89 C; 11.73 H; 8.58 N.

gefunden (e): 70,0 C; 12,1 H; 8,06 N.Found (e): 70.0 C; 12.1 H; 8.06 N.

IR-Spektrum (KBr; cm ) 3295 (m, CONH) , 2959 (m), 2922 (s), 2850 (s) 1640 (m) , 1625 (m) , 1116 (m) 1H-NMR (CDC13) &= 0,70 - 1,70 (m, 23 H); 2,25 - 2,85 (m, 8 H); 3,05 - 3,40 (m, 2 H); 3,60 - 3,85 (m, 4 H, CH2OCH2); 7,9 (breit, CONH).IR spectrum (KBr; cm) 3295 (m, CONH), 2959 (m), 2922 (s), 2850 (s) 1640 (m), 1625 (m), 1116 (m) 1 H-NMR (CDC13) & = 0.70-1.70 (m, 23H); 2.25 - 2.85 (m, 8H); 3.05-3.40 (m, 2H); 3.60-3.85 (m, 4H, CH2OCH2); 7.9 (wide, CONH).

In Analogie zu der vorstehend beschriebenen Herstellung von 3- (4-Mophinyl) -propionsäuredodecylamid wurden die Synthesen der in der nachstehenden Tabelle 1 angeführten Substanzen A und D bis H der Formel (I) durchgeführt. Die Substanz C wurde durch Umsetzung von 3- (4-Morpholinyl) -propionsäuredodecylamid (Substanz B) mit einer äquivalenten Menge Eisessig in Ether hergestellt. Das gut in Wasser lösliche Acetat wurde dabei in einer Ausbeute von 98% der Theorie erhalten.In analogy to the preparation of 3- (4-mophinyl) described above -propionsäuredodecylamid were the syntheses of the table 1 below listed substances A and D to H of the formula (I) carried out. The substance C was obtained by reacting 3- (4-morpholinyl) propionic acid dodecylamide (substance B) made with an equivalent amount of glacial acetic acid in ether. That good in water soluble acetate was obtained in a yield of 98% of theory.

Tabelle 1 Verbindungen der allgemeinen Formel (I) Substanz R1 Fp(OC) Ausbeute (% d.Th.) A C1OH21 35-36 80 B C12H25 73 50 12H25; Acetat 44-47 98 D C14H29 57-58 73 E Kokos* 30-40 65 F C12H25O(CH2)3 30-35 74 G Kokos*-NH(CH2)3 30-35 95 H Kokos*-N(CH2)3 30 93 I U N-CH2-CH -C=O *) auf Kokosfettsäure zurückgehendes Alkylrestegemisch der Zusammensetzung (in Gewichtsprozent): 6 - 7 C8; 5 - 6 C10; 47 - 51 C12; 18 - 20 C14; 8 -10 C16; 9 - 14 C18.Table 1 Compounds of the general formula (I) Substance R1 mp (OC) yield (% of theory) A C1OH21 35-36 80 B C12H25 73 50 12H25; Acetate 44-47 98 D C14H29 57-58 73 E coconut * 30-40 65 F C12H25O (CH2) 3 30-35 74 G coconut * -NH (CH2) 3 30-35 95 H coconut * -N (CH2) 3 30 93 I. U N-CH2-CH -C = O *) Mixture of alkyl radicals based on coconut fatty acid and having the composition (in percent by weight): 6 - 7 C8; 5-6 C10; 47-51 C12; 18-20 C14; 8 -10 C16; 9-14 C18.

2. Antimikrobielle Wirksamkeit der Verbindungen der allgemeinen Formel (I).2. Antimicrobial activity of the compounds of the general formula (I).

Die mikrobistatische Wirksamkeit der Substanzen A bis C und F bis H wurde gegenüber folgenden Testkeimsuspensionen bestimmt: 1. Staphylococcus aureus .2 x 109Keime/ml 2. Candida albicans 2 x 108Keime/ml 3. Aspergillus niger 5 rX 107Keime/ml 4. Penicillium camerunense 5 X 10 7Keime/ml Die IIemmkonzentrationen der zu untersuchenden Verbindungen wurden mit Hilfe des Verdünnungstests nach den Richtlinien für die Prüfung chemischer Desinfektionsmittel der Deutschen Gesellschaft für Hygiene und Mikrobiologie (1972) ermittelt. Die Versuche wurden in sterilen Reagenzröhrchen ausgeführt, die Standard-I-Bouillon (pH 7,5 Merck) oder Würze-Bouillon ( pH 5,5, tNerck) enthielten. Nach Zugabe der Wirkstoffe betrug das Nährlösungsvolumen in den Röhrchen jeweils 5 ml.The microbistatic effectiveness of substances A to C and F to H was determined against the following test germ suspensions: 1. Staphylococcus aureus .2 x 109 germs / ml 2. Candida albicans 2 x 108 germs / ml 3. Aspergillus niger 5 rX 107 germs / ml 4. Penicillium camerunense 5 X 10 7 germs / ml The IIemm concentrations of the compounds to be examined were determined using the dilution test according to the Guidelines for the testing of chemical disinfectants of the German Society for Hygiene and Microbiology (1972). The experiments were in sterile Test tubes run the standard I broth (pH 7.5 Merck) or wort broth (pH 5.5, tNerck) included. After adding the active ingredients, the volume of the nutrient solution was 5 ml in each tube.

Anschließend wurden jeweils 0,1 ml der Testkeimsuspension der angegebenen Konzentration in die Röhrchen gebracht. Die mit Bakterien beimpften Nährlösungsproben wurden 3 Tage lang bei 37"C im Brutschrank aufbewahrt. Die mit Pilzen beimpften Proben wurden 3 bis 4 Tage lang bei 30"C bebrütet. Danach wurde festgestellt, welche dem Nährmedium zugeführte Wirkstoffkonzentration das Wachstum der Keime gerade noch gehemmt hatte.Subsequently, 0.1 ml of the test microbial suspension of the specified Concentration brought into the tubes. The nutrient solution samples inoculated with bacteria were kept in an incubator for 3 days at 37 ° C. The inoculated with mushrooms Samples were incubated for 3 to 4 days at 30 ° C. It was then determined which the concentration of active substance supplied to the nutrient medium just about the growth of the germs had inhibited.

Der auf diese Weise gefundene Wert wurde als Hemmkonzentration bezeichnet. Folgende Wirkstoffkonzentrationen in ppm wurden getestet: 1 000, 500, 250, 100, 50 und 10.The value found in this way was called the inhibitory concentration. The following active ingredient concentrations in ppm were tested: 1,000, 500, 250, 100, 50 and 10.

Für die Verbindungen der Beispiele A - C und F - H wurden die in der nachstehenden Tabelle 2 aufgeführten Hemmkonzentrationen ermittelt: Tabelle 2: Mikrobistatische Wirkung der Verbindungen der allgemeinen Formel (I) in der flüssigen Hemmreihe: Hemmkonzentrationen (ppm).For the compounds of Examples A - C and F - H in the The inhibitory concentrations listed in Table 2 below are determined: Tabel 2: Microbistatic effect of the compounds of the general formula (I) in the liquid Inhibition series: inhibitory concentrations (ppm).

Substanz Testkeime 1 2 3 4 A 50 500 250 250 B 50 100 100 50 C 50 250 100 100 F 50 50 50 50 G A10 250 250 250 H 100 250 500 100 Ergebnis: Die Substanzen B, C, und F weisen gegenüber gram-positiven Bakterien, Hefen und Pilzen minimale Hemmkonzentrationen von 50 bis 250 ppm auf, die sie für Kombinationen von Konservierungsmitteln für die Anwendung im nicht-medizinischen und nicht-therapeutischen Bereich geeignet machen.Substance test germs 1 2 3 4 A 50 500 250 250 B 50 100 100 50 C 50 250 100 100 F 50 50 50 50 G A10 250 250 250 H 100 250 500 100 Result: The substances B, C, and F have minimal levels of gram-positive bacteria, yeast, and fungus Inhibitory concentrations of 50 to 250 ppm are appropriate for combinations of preservatives suitable for use in non-medical and non-therapeutic areas do.

3. Toxikologische Daten.3. Toxicological data.

Von 3- (4-Morpholinyl) -propionsäuredodecylamid (I, R1 = C12H25) wurden in der toxikologischen Grundprüfung folgende Befunde erhalten: Akute Toxizität (Maus, oral): LD50 >3 125 mg 1 kg; leichte, reversible Vergiftungssymptome auch bei 625 mgtkg. Of 3- (4-morpholinyl) propionic acid dodecylamide (I, R1 = C12H25) the following findings were obtained in the basic toxicological test: Acute toxicity (Mouse, oral): LD50> 3 125 mg 1 kg; mild, reversible symptoms of intoxication too at 625 mgtkg.

Hautverträglichkeit (haarlose Maus) : 1- bis 25-ig ohne Befund.Skin tolerance (hairless mouse): 1- to 25-ig without findings.

Schleimhautverträglichkeit (Kaninchenauge, 1%ig, lmal.Mucosal compatibility (rabbit eye, 1%, 1mal.

Applikation, Dauerkontakt): Reaktionen der Bindehäute in % der maximal möglichen Reaktion 2 6 24 48 72 Std. nach der Behandlung 10 10 0 0 0 0Application, permanent contact): reactions of the conjunctiva in% of the maximum possible response 2 6 24 48 72 hours after treatment 10 10 0 0 0 0

Claims (8)

P a t e n t a n s p r ü c h e 1. 3- (4-Morpholinyl) -propionsäureamide der allgemeinen Formel (I) in der R1 für einzelne lineare Alkylreste mit 10 bis 14 C-Atomen oder deren Mischungen, einen n-Dodecyloxytrimethylen-Rest, einen n-Dodecyl- oder n-Tetradecylaminotrimethylenrest oder einen 3-(4-Morpholinyl)-propionsäure-N-(n-dodecyl/tetradecyl)-amido-N-trimethylen-Rest steht, sowie deren Salze mit anorganischen oder organische Säuren.P atent claims 1. 3- (4-Morpholinyl) propionic acid amides of the general formula (I) in which R1 stands for individual linear alkyl radicals with 10 to 14 carbon atoms or mixtures thereof, an n-dodecyloxytrimethylene radical, an n-dodecyl or n-tetradecylaminotrimethylene radical or a 3- (4-morpholinyl) propionic acid-N- (n -dodecyl / tetradecyl) -amido-N-trimethylene radical, and their salts with inorganic or organic acids. 2. Verbindungen der allgemeinen Formel (I) nach Anspruch 1, wobei der lineare Alkylrest R1 bevorzugt ein n-Dodecyl- oder ein n-Dodecyloxytrimethylen-Rest ist.2. Compounds of general formula (I) according to claim 1, wherein the linear alkyl radical R1 is preferably an n-dodecyl or an n-dodecyloxytrimethylene radical is. 3. Verbindungen der Formel (I) nach Ansprch 1 in Form ihrer Acetate.3. Compounds of formula (I) according to claim 1 in the form of their acetates. 4. Verfahren zur Herstellung der 3-(4-Morpholinyl)-propionsäureamide der allgemeinen Formel (I), dadurch gekennzeichnet, daß man primäre Amine der allgemeinen Formel R¹ -NH2, in der R¹ die in Anspruch 1 angegebenen Bedeutungen hat, nach allgemein bekannten Methoden mit äquimolaren Plengen des 3-(4-Morpholinyl) -propionsäuremethylesters in Lösung bei erhöhter Temperatur umsetzt.4. Process for the preparation of the 3- (4-morpholinyl) propionic acid amides of the general formula (I), characterized in that primary amines of the general Formula R¹ -NH2, in which R¹ has the meanings given in claim 1, according to general known methods with equimolar plengen of 3- (4-morpholinyl) propionic acid methyl ester in solution at elevated temperature. 5. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß man als Lösungsmittel hoch siedende, substituierte, aromatische Kohlenwasserstoffe, bevorzugt 1,2-Dichlorbenzol oder Xylol, verwendet.5. The method according to claim 3, characterized in that as Solvent, high-boiling, substituted, aromatic hydrocarbons are preferred 1,2-dichlorobenzene or xylene is used. 6. Verfahren nach Ansprüchen 3 und 4, dadurch gekennzeichnet, daß man die Reaktion bei Temperaturen von oberhalb 1100C, bevorzugt 115 bis 118"C, durchführt.6. The method according to claims 3 and 4, characterized in that the reaction is carried out at temperatures above 110.degree. C., preferably 115 to 118.degree. 7. Antimikrobielle Mittel, enthaltend wenigstens eine der Verbindungen der allgemeinen Formel (I) nach Anspruch 1, zusammen mit üblichen Formulierungsstoffen.7. Antimicrobial agents containing at least one of the compounds of the general formula (I) according to Claim 1, together with customary formulation substances. 8. Verwendung der Verbindungen der allgemeinen Formel (I) nach Anspruch 1 als antimikrobielle Substanzen.8. Use of the compounds of general formula (I) according to claim 1 as antimicrobial substances.
DE19833343804 1983-12-03 1983-12-03 Substituted propionamides, their preparation and their use as antimicrobial substances Withdrawn DE3343804A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010990A (en) * 2020-11-11 2022-09-06 绍兴瑞康生物科技有限公司 Steric-hindrance-adjustable weak-base light stabilizer and preparation method and application thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010990A (en) * 2020-11-11 2022-09-06 绍兴瑞康生物科技有限公司 Steric-hindrance-adjustable weak-base light stabilizer and preparation method and application thereof

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