CH484906A - Process for the preparation of new amides of aliphatic carboxylic acids - Google Patents

Process for the preparation of new amides of aliphatic carboxylic acids

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Publication number
CH484906A
CH484906A CH116869A CH116869A CH484906A CH 484906 A CH484906 A CH 484906A CH 116869 A CH116869 A CH 116869A CH 116869 A CH116869 A CH 116869A CH 484906 A CH484906 A CH 484906A
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CH
Switzerland
Prior art keywords
acid
formula
preparation
aliphatic carboxylic
carboxylic acids
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Application number
CH116869A
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German (de)
Inventor
Alex Dr Meisels
Emilio Dr Schott
Original Assignee
Geigy Ag J R
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Publication date
Application filed by Geigy Ag J R filed Critical Geigy Ag J R
Priority to CH116869A priority Critical patent/CH484906A/en
Publication of CH484906A publication Critical patent/CH484906A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Edible Oils And Fats (AREA)
  • Bakery Products And Manufacturing Methods Therefor (AREA)
  • Saccharide Compounds (AREA)

Description

       

  Verfahren zur     Herstellung    von neuen     Amiden        aliphatischer        Carbonsäuren       Die vorliegende Erfindung     betrifft    Verfahren zur  Herstellung von neuen     Amiden        aliphatischer        Carbon-          säuren.     



       Amide    der Formel I,  
EMI0001.0011     
    in welcher     R,-CO-    den     Acylrest    einer     Alkansäure    oder       Alkensäure    mit 15-22     Kohlenstoffatomen,        R2    eine     Alk-          anoylaminogruppe    und R:3 Wasserstoff oder einen nie  deren     Alkylrest    bedeutet, sind bisher nicht bekanntge  worden.  



  Wie nun überraschenderweise gefunden wurde, be  sitzen derartige Verbindungen und ihre Additionssalze  mit anorganischen und organischen Säuren     wertvolle     pharmakologische Eigenschaften,     insbesondere        anti-          virale    und tumorhemmende Wirksamkeit, wobei auch  das günstige Verhältnis der signifikant wirksamen zu  den maximal tolerierten Dosen     bemerkenswert    ist. Die       antivirale    Wirksamkeit konnte z.

   B. an der Maus bei       subcutaner    und oraler Applikation gegenüber Herpes       simplex-Virus,        Influenza-A-Virus,        Columbia        SK-Virus     und     Louping        ill-Virus        (Schafencephalitis-Virus)    und die  tumorhemmende Wirkung im Tierversuch bei     subcuta-          ner    und oraler Applikation am transplantierten     Ehrlich-          Carcinom,    am induzierten     Methylcholanthren-Sarkom,

            Dimethylbenzanthracen-Hautcarcinom    und an Spontan  tumoren der Maus sowie am transplantierten     Yoshida-          Sarkom    und am induzierten     Dimethylbenzanthracen-          Mammacarcinom    der Ratte festgestellt werden.

   Die  Tierversuche charakterisieren die     Verbindungen    der  Formel 1 als     geeignet    zur Behandlung von Viruskrank  heiten, wie Herpes     simplex,    Herpes     zoster,    Influenza,       Encephalitis    und andern sowie zur Behandlung von     Neo-          plasien.       In den     Verbindungen    der Formel I ist     R,-CO-    z. B.

    der     Acylrest    der     Pentadecansäure,        Palmitinsäure,        Hep-          tadecansäure,        Stearinsäure,        Nonadecansäure,        Eicosan-          säure        (Arachidinsäure),        Heneicosansäure,        Docosansäure          (Behensäure),        2-Methyltetradecansäure,        2-Äthyl-tetra-          decansäure,        2-Methyl-hexadecansäure,

          2-(n-Butyl)-tetra-          decansäure,        2-(n-Pentyl)-tetradecansäure,        2-Äthyl-octa-          decansäure,        2-Methyl-eicosansäure,        Hexadecensäuren,     wie     cis-9-Hexadecensäure        (Palmitoleinsäure),        Heptade-          censäuren,    wie     cis-9-Heptadecensäure,        Octadecensäure,     wie Ölsäure,     Elaidinsäure,        cis-6-,    -8-,

   -10- und     -11-          Octadecensäure,    9     -Nonadecensäure,        Eicosensäuren,          Heneicosensäuren.        Docosensäuren,    wie     cis-13-Docosen-          säure        (Erucasäure)    und     trans-13-Docosensäure        (Brassi-          dinsäure),        2-Allyl-dodecansäure,        2-Allyl-tridecansäure,          2-Allyl-tetradecansäure    und     2-(n-Heptyl)

  -12-tridecen-          säure.     



  Der     Substituent        R._@    ist z. B. die     Formamido-    oder       Acetamidogruppe.     



  Als niedere     Alkylreste        Rs    kommen z. B. die     Me-          thyl-,    Äthyl-,     Propyl-    oder     Butylgruppe    in Betracht.  Unter der Formel 1 sind auch     Harnstoffaddukte    von  Verbindungen der Formel 1 zu verstehen.  



  Als reaktionsfähige funktionelle Derivate beider  Reaktionskomponenten sowie als     Reaktionsbedingungen     für die     Amidbildung    kommen im wesentlichen die oben  für die direkte Herstellung von Verbindungen der allge  meinen Formel I genannten in Frage. Die     Debromierung     erfolgt beispielsweise durch Kochen der Zwischenpro  dukte mit Zink in Äthanol. Dieses zweistufige Verfahren  zur Herstellung von Verbindungen der allgemeinen For  mel I erscheint komplizierter als das erstgenannte, ein  stufige. Es kann jedoch von Vorteil sein, wenn     Amide     von solchen     Alkensäuren    herzustellen sind, die schwer  zu reinigen sind, z. B. von     Isomeren    und; oder Homolo  gen zu trennen sind.

   In solchen Fällen kann gegebenen  falls     eine    Reinigung, z. B. Kristallisation, auf der Stufe  der     Bromadditionsprodukte    der Säuren durchgeführt  werden, oder es lassen sich die mit solchen Brom-           additionsprodukten    erhaltenen substituierten     Pyridyl-          amide    von     Dibromalkansäuren    besser reinigen, z. B.

         umkristallisieren,    als die im     Acylrest    bromfreien     End-          stoffe.    Trifft das letztere zu, so kann man auch im     Sinne     einer Reinigungsoperation an ein nach dem erstgenann  ten Verfahren erhaltenes     Alkenamid    der allgemeinen  Formel 1 Brom addieren, das Additionsprodukt durch  Kristallisation oder ein anderes übliches Verfahren reini  gen und     anschliessend        debromieren.     



       Amide    der Formel 1     "erden    hergestellt, indem man       Amide    der Formel 11,  
EMI0002.0016     
    in welcher     R,-CO-    und     R:;    die unter Formel 1 angege  bene Bedeutung haben, mit einer einen niedern     Alkan-          oylrest    einführenden Verbindung umsetzt.  



  Die     Alkanovlierung,    z. B.     Acetvlierung,    erfolgt nach  an sich bekannten Methoden, beispielsweise durch Um  setzung mit einem niedern     Alkansäurehalogenid    oder       -anhydrid    bei Raumtemperatur oder     mässig    erhöhten  Temperaturen.     Nötigenfalls    wird die Umsetzung in Ge  genwart eines säurebindenden Mittels, wie z.

   B. von       Pyridin    als gleichzeitigem Reaktionsmedium, von einem       Alkalicarbonat    in einem     inerten    organischen Lösungs  mittel oder von Natronlauge in einem     zweiphasigen,     organisch     wässrigen    System vollzogen.  



  Ausgangsstoffe der Formel IV sind beispielsweise  durch Reduktion entsprechender     Nitropyridylamide    er  hältlich. Letztere sind ihrerseits beispielsweise durch       Acylierung    von     Amino-nitropyridinen        herstellbar.    Führt  man in die genannten     Amino-nitro-pyridine    zunächst  eine in der     Peptidsynthese    übliche Schutzgruppe ein,  reduziert dann die Nitrogruppe,     führt    den     Acylrest          R,-CO-    analog dem erstgenannten Herstellungsverfah  ren für Verbindungen der Formel I ein und spaltet an  schliessend die Schutzgruppe ab,

   so erhält man aus den  selben     Amino-nitro-pyridinen    Ausgangsstoffe der For  mel     1I    mit vertauschter Stellung von     Amidgruppe        und          Aminogruppe.     



  Die Umwandlung der Verbindungen der Formel 1  in die bereits erwähnten     Harnstoffaddukte    geschieht  z. B. durch Versetzen einer Verbindung der Formel I  mit einer Lösung von Harnstoff in Methanol und Ab  trennen des ausgefallenen     Adduktes.     



  Die Umwandlung von Verbindungen der     Formel    1  in die weiter oben bereits erwähnten     Säureadditions-          salze    kann in üblicher Weise erfolgen. Als zur Salz  bildung geeignete Säuren seien beispielsweise genannt:       Chlorwasserstoffsä        ure,        Bromwasserstoffsäure,    Schwefel  säure.

   Phosphorsäure,     Methansulfonsäure,        Äthan-          disulfonsäure,        ;i-Hydroxväthansulfonsäure,    Essigsäure,  Milchsäure,     Oxalsäure,    Bernsteinsäure,     Fumarsäure,          Maleinsäure,        Äpfelsäure,    Weinsäure,     Citronensäure,          Benzoesäure,        Salicylsäure,        Phenylessigsäure    und Man  delsäure.  



  Die zur Behandlung von Viruskrankheiten und     Neo-          plasien    geeigneten     tä=lichen    Dosen von     Amiden    ent  sprechend der Formel I oder ihrer     Salze    liegen bei er  wachsenen Menschen von normalem Gewicht zwischen  100 und 3000 mg und innerhalb dieses Bereiches bei       parenteraler    Applikation im allgemeinen niedriger als    bei oraler Applikation.

   Die genannten Tagesdosen wer  den zweckmässig in     Doseneinheitsformen    mit 50 bis  500 mg Wirkstoff verabreicht, doch können auch ent  sprechende Mengen von     nicht-einzeldosierten        Applika-          tionsformen,    wie Sirups, Sprays, Aerosole, Puder und  Salben, angewendet werden.  



       Doseneinheitsformen    für die orale     .Anwendung    ent  halten als Wirkstoffe     vorzussweise    zwischen 10 und       90ö    eines     Amides    der allgemeinen Formel 1 oder eines  pharmazeutisch annehmbaren Salzes desselben. Zu ihrer  Herstellung vermischt man den     Wirkstoff    z.

   B. mit fe  sten, pulverförmigen Trägerstoffen. wie     Lactose,        Saccha-          rose,        Sorbit,        Mannit;    Stärken, wie Kartoffelstärke, Mais  stärke oder     Amylopektin,    ferner     Laminariapulver    oder       Citruspulpenpulver;

          Cellulosederivaten    oder Gelatine,  gegebenenfalls unter Zusatz von Gleitmitteln, wie Ma  gnesium- oder     Calciumstearat    oder     Polväthylenglykolen     von geeigneten     Molekulargewichten,    und presst die Mi  schung zu Tabletten oder zu     Dragee-Kernen.    Letztere  überzieht man beispielsweise mit konzentrierten Zucker  lösungen, welche z. B. noch arabischen Gummi. Talk  und/oder     Titandioxyd    enthalten können, oder mit einem  in leichtflüchtigen organischen Lösungsmitteln oder     Lö-          sungsmittelgemischen    gelösten Lack.

   Diesen Überzügen  können Farbstoffe     zugefügt    werden, z. B. zur Kenn  zeichnung verschiedener     Wirkstoffdosen.     



  Als     Doseneinheitsformen    für die rektale Anwendung  kommen z. B. Suppositorien, welche aus einer Kombi  nation eines     Amides    der Formel 1 oder eines     geeigneter.,          pharmazeutisch        annehmbaren    Salzes derselben mit einer       Neutralfettgrundlage    bestehen, oder auch     Gelatine-Rek-          talkapseln,    welche eine Kombination des Wirkstoffes  oder eines geeigneten Salzes desselben mit     Polväthylen-          glykolen    von geeignetem     Molekulargewicht    enthalten, in  Betracht.  



  Ampullen zur     parenteralen,    insbesondere intravenö  sen, intramuskulären oder     subcutanen    Verabreichung  enthalten ein wasserlösliches,     pharmazeutisch    annehm  bares Salz eines     Amides    der Formel I in einer Konzen  tration von vorzugsweise 0,5-10      ,    gegebenenfalls zu  sammen mit geeigneten Stabilisierungsmitteln und Puf  fersubstanzen, in wässriger Lösung.  



  Als weitere     Applikationsformen    kommen insbeson  dere zur     Behandlung    von Virusinfektionen der Luft  wege Sirups sowie Aerosole und zur lokalen Behand  lung von Viruskrankheiten Salben und Puder in Be  tracht. Alle diese     Applikationsformen    lassen sich unter  Verwendung der     hiezu    üblichen Trägerstoffe, Verdün  nungsmittel und Zusatzstoffe bereiten.  



  Die nachfolgenden Beispiele erläutern die Herstel  lung der neuen Verbindungen der Formel I, sollen je  doch den Umfang der Erfindung in keiner Weise be  schränken. Die Temperaturen sind in Celsiusgraden an  gegeben.  



  <I>Beispiel</I>  3,75 g (0,01     Mol)        N-(6-.Amino-3-pyridyl)-octadecan-          amid    werden in 20 ml     Pvridin    und 10 ml     Acetanhvdrid     bei Raumtemperatur 12 Stunden     stehengelassen.        y    Das  Reaktionsprodukt wird auf 150 g Eis gegossen und die  ausgefallenen Kristalle des     N-(5-Acetamido-2-pyridvl)-          octadecanamids        abgenutscht    und aus Methanol     umkri-          stallisiert,        Smp.        161        =.  



  Process for the preparation of new amides of aliphatic carboxylic acids The present invention relates to processes for the preparation of new amides of aliphatic carboxylic acids.



       Amides of formula I,
EMI0001.0011
    in which R, -CO- denotes the acyl radical of an alkanoic acid or alkenoic acid with 15-22 carbon atoms, R2 denotes an alkanoylamino group and R: 3 denotes hydrogen or an alkyl group thereof, have not yet been disclosed.



  As has now been found, surprisingly, such compounds and their addition salts with inorganic and organic acids have valuable pharmacological properties, in particular antiviral and tumor-inhibiting activity, the favorable ratio of the significantly effective to the maximum tolerated doses is also noteworthy. The antiviral effectiveness could e.g.

   B. on the mouse with subcutaneous and oral application to herpes simplex virus, influenza A virus, Columbia SK virus and Louping ill virus (sheep cephalitis virus) and the tumor-inhibiting effect in animal experiments with subcutaneous and oral application on transplanted Ehrlich's carcinoma, induced methylcholanthrene sarcoma,

            Dimethylbenzanthracene skin carcinoma and spontaneous tumors in mice, as well as transplanted Yoshida sarcoma and induced dimethylbenzanthracene mammary carcinoma in rats.

   The animal experiments characterize the compounds of formula 1 as being suitable for the treatment of viral diseases such as herpes simplex, herpes zoster, influenza, encephalitis and others, and for the treatment of neoplasias. In the compounds of formula I, R, -CO- is z. B.

    the acyl radical of pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid (arachidic acid), heneicosanoic acid, docosanoic acid (behenic acid), 2-methyltetradecanoic acid, 2-ethyl-tetra- decanoic acid, 2-methyl-hexadecanoic acid,

          2- (n-butyl) -tetra- decanoic acid, 2- (n-pentyl) -tetradecanoic acid, 2-ethyl-octadecanoic acid, 2-methyl-eicosanoic acid, hexadecenoic acids such as cis-9-hexadecenoic acid (palmitoleic acid), heptadic cenoic acids, such as cis-9-heptadecenoic acid, octadecenoic acid, such as oleic acid, elaidic acid, cis-6-, -8-,

   -10- and -11- octadecenoic acid, 9 -nonadecenoic acid, eicosenoic acids, heneicosenoic acids. Docosenoic acids, such as cis-13-docosenoic acid (erucic acid) and trans-13-docosenoic acid (brassidic acid), 2-allyl-dodecanoic acid, 2-allyl-tridecanoic acid, 2-allyl-tetradecanoic acid and 2- (n-heptyl)

  -12-tridecenoic acid.



  The substituent R ._ @ is z. B. the formamido or acetamido group.



  As lower alkyl radicals Rs, for. B. the methyl, ethyl, propyl or butyl group into consideration. Formula 1 also includes urea adducts of compounds of formula 1.



  The reactive functional derivatives of both reaction components and the reaction conditions for amide formation are essentially those mentioned above for the direct preparation of compounds of the general formula I. Debromination takes place, for example, by boiling the intermediate products with zinc in ethanol. This two-step process for the preparation of compounds of the general formula I appears more complicated than the first-mentioned, one-step process. However, it can be advantageous if amides are to be prepared from such alkenoic acids which are difficult to purify, e.g. B. of isomers and; or homologues are to be separated.

   In such cases, if necessary, a cleaning, for. B. crystallization, can be carried out at the stage of the bromine addition products of the acids, or the substituted pyridyl amides obtained with such bromine addition products of dibromoalkanoic acids can be better purified, eg. B.

         recrystallize than the end substances free of bromine in the acyl radical. If the latter applies, it is also possible in the sense of a purification operation to add bromine to an alkenamide of the general formula 1 obtained by the first-mentioned process, purify the addition product by crystallization or another conventional process and then debromination.



       Amides of the formula 1 "are produced by adding amides of the formula 11,
EMI0002.0016
    in which R, -CO- and R :; have the meaning given under formula 1, with a compound introducing a lower alkanoyl radical.



  The alkanolation, e.g. B. Acetvlation, is carried out by methods known per se, for example by implementation with a lower alkanoic acid halide or anhydride at room temperature or moderately elevated temperatures. If necessary, the implementation in the presence of an acid-binding agent such.

   B. of pyridine as a simultaneous reaction medium, of an alkali metal carbonate in an inert organic solvent or of sodium hydroxide in a two-phase, organically aqueous system.



  Starting materials of the formula IV are available, for example, by reducing the corresponding nitropyridylamides. The latter can in turn be prepared, for example, by acylation of amino-nitropyridines. If a protective group customary in peptide synthesis is first introduced into the amino-nitro-pyridines mentioned, the nitro group is then reduced, the acyl radical R, -CO- is introduced analogously to the first-mentioned manufacturing process for compounds of the formula I and the protective group is then split off ,

   thus obtained from the same amino-nitro-pyridines starting materials of the formula 1I with the position of amide group and amino group interchanged.



  The conversion of the compounds of formula 1 into the urea adducts already mentioned is done, for. B. by adding a compound of formula I with a solution of urea in methanol and separating from the precipitated adduct.



  The conversion of compounds of the formula 1 into the acid addition salts already mentioned above can be carried out in the customary manner. Examples of acids suitable for salt formation are: hydrochloric acid, hydrobromic acid, sulfuric acid.

   Phosphoric acid, methanesulphonic acid, ethanesulphonic acid,; i-hydroxvethanesulphonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.



  The daily doses of amides suitable for the treatment of viral diseases and neoplasms corresponding to the formula I or their salts are between 100 and 3000 mg for adults of normal weight and, within this range, generally lower for parenteral administration than for oral administration Application.

   The daily doses mentioned are expediently administered in unit dosage forms with 50 to 500 mg of active ingredient, but corresponding amounts of non-single-dose application forms such as syrups, sprays, aerosols, powders and ointments can also be used.



       Unit dosage forms for oral use contain as active ingredients preferably between 10 and 90 ° of an amide of the general formula 1 or a pharmaceutically acceptable salt thereof. To produce them, the active ingredient is mixed, for.

   B. with fe most, powdery carriers. such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder;

          Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethyleneglycols of suitable molecular weights, and the mixture is pressed into tablets or coated tablets. The latter is coated, for example, with concentrated sugar solutions, which z. B. still arabic gum. Can contain talc and / or titanium dioxide, or with a paint dissolved in volatile organic solvents or solvent mixtures.

   Dyes can be added to these coatings, e.g. B. to mark different doses of active ingredient.



  As unit dosage forms for rectal use, for. B. suppositories, which consist of a combination nation of an amide of formula 1 or a suitable., Pharmaceutically acceptable salt thereof with a neutral fat base, or gelatin recalculated capsules, which are a combination of the active ingredient or a suitable salt thereof with polyethyleneglycols of suitable molecular weight.



  Ampoules for parenteral, especially intravenous, intramuscular or subcutaneous administration contain a water-soluble, pharmaceutically acceptable salt of an amide of the formula I in a concentration of preferably 0.5-10, optionally together with suitable stabilizers and buffer substances, in aqueous solution .



  Other forms of application that are particularly suitable for treating viral infections of the airways are syrups and aerosols, and for the local treatment of viral diseases, ointments and powders. All of these application forms can be prepared using the usual carriers, diluents and additives.



  The following examples explain the preparation of the new compounds of the formula I, but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees Celsius.



  <I> Example </I> 3.75 g (0.01 mol) of N- (6-amino-3-pyridyl) octadecanamide are left to stand in 20 ml of pvridine and 10 ml of acetane hydride at room temperature for 12 hours. y The reaction product is poured onto 150 g of ice and the precipitated crystals of N- (5-acetamido-2-pyridvl) octadecanamide are suction filtered and recrystallized from methanol, mp 161 =.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von neuen Amiden ali- phatischer Carbonsäuren entsprechend der Formel I, EMI0003.0001 in welcher R,-CO- den Acylrest einer Alkansäure oder Alkensäure mit 15-22 Kohlenstoffatomen, R= eine nie dere Alkanoylaminogruppe und R3 Wasserstoff oder einen niederen Alkylrest bedeutet, und deren Additions salzen mit anorganischen und organischen Säuren, da durch gekennzeichnet, PATENT CLAIM Process for the production of new amides of aliphatic carboxylic acids according to the formula I, EMI0003.0001 in which R, -CO- denotes the acyl radical of an alkanoic acid or alkenoic acid with 15-22 carbon atoms, R = a lower alkanoylamino group and R3 denotes hydrogen or a lower alkyl radical, and their addition salts with inorganic and organic acids, as characterized by dass man ein Amid der Formel 11, EMI0003.0012 in welcher RICO- und R:; die unter Formel 1 angege bene Bedeutung haben, mit einer einen niederen Alkan- oylrest einführenden Verbindung umsetzt und ge- wünschtenfalls eine erhaltene Verbindung der Formel 1 in ein Additionssalz mit einer anorganischen oder orga nischen Säure überführt. that one is an amide of formula 11, EMI0003.0012 in which RICO and R :; have the meaning given under formula 1, are reacted with a compound introducing a lower alkanoyl radical and, if desired, a compound of formula 1 obtained is converted into an addition salt with an inorganic or organic acid.
CH116869A 1966-01-28 1966-01-28 Process for the preparation of new amides of aliphatic carboxylic acids CH484906A (en)

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CH123666 1966-01-28
CH116869A CH484906A (en) 1966-01-28 1966-01-28 Process for the preparation of new amides of aliphatic carboxylic acids

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AT (2) AT269880B (en)
BE (1) BE693264A (en)
CH (2) CH484906A (en)
DE (1) DE1695007A1 (en)
DK (1) DK115260B (en)
ES (1) ES336149A1 (en)
FR (2) FR1510320A (en)
GB (1) GB1179263A (en)
GR (1) GR35672B (en)
IL (1) IL27338A (en)
NL (1) NL6701360A (en)
NO (1) NO122421B (en)
SE (1) SE329848B (en)

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MX22406A (en) * 1989-09-15 1994-01-31 Pfizer NEW DERIVATIVES OF N-ARIL AND N-HETEROARILAMIDAS AND UREA AS INHIBITORS OF ACIL COENZYME A: ACIL TRANSFERASA DEL COLESTEROL (ACAT).
CN105017096B (en) * 2015-07-03 2017-08-08 厦门大学 A kind of Oleoyl monoethanolamide derivative, its preparation method and application

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DE1695007A1 (en) 1971-02-25
AT269880B (en) 1969-04-10
ES336149A1 (en) 1968-10-16
FR1510320A (en) 1968-01-19
GR35672B (en) 1968-10-17
DK115260B (en) 1969-09-22
CH491112A (en) 1970-05-31
GB1179263A (en) 1970-01-28
AT267526B (en) 1969-01-10
NL6701360A (en) 1967-07-31
BE693264A (en) 1967-07-27
FR6382M (en) 1968-10-14
IL27338A (en) 1971-02-25
NO122421B (en) 1971-06-28
SE329848B (en) 1970-10-26

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