CH520657A - Bis-anilides with basic substituents - having chemotherapeutic activity - Google Patents

Bis-anilides with basic substituents - having chemotherapeutic activity

Info

Publication number
CH520657A
CH520657A CH601565A CH601565A CH520657A CH 520657 A CH520657 A CH 520657A CH 601565 A CH601565 A CH 601565A CH 601565 A CH601565 A CH 601565A CH 520657 A CH520657 A CH 520657A
Authority
CH
Switzerland
Prior art keywords
sep
dihydrochloride
formula
alkyl
acid
Prior art date
Application number
CH601565A
Other languages
German (de)
Inventor
Rudolf Dr Hirt
Rudolf Dr Fischer
Original Assignee
Wander Ag Dr A
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 Wander Ag Dr A filed Critical Wander Ag Dr A
Priority to CH1273969A priority Critical patent/CH525896A/en
Priority to CH601565A priority patent/CH520657A/en
Priority to CH1274069A priority patent/CH525897A/en
Priority to CH423470A priority patent/CH525898A/en
Publication of CH520657A publication Critical patent/CH520657A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Title cpds of formula (I) and their acid addn salts (where n is 0 or 1; R is a gp. -C(=NR1)-NR2R3 in which R1 and R2 are H, alkoxyalkyl or alkyl, (is not>7C) and R3 is H or is not >6C alkyl; A is opt. R4-substd phenylene, phenyleneamino or phenylenediamino or its styrylene; and R4 is halogen, amino, NO2, OH, alkyl, alkoxy, alkylthio, acyl amino or aminocarbonyl), which are of particular use as tuberculostatics, agents against trypanosome diseases and anticancer agents. (esp. against leukaemia) and are also useful as intermediates for other cpds are prepd by reacting cpds of formula (II) with amines of formula HNR2R3.

Description

  

  
 



  Verfahren zur Herstellung mehrbasischer Verbindungen Gegenstand der Erfindung ist ein Verfahren zur Herstellung mehrbasischer Verbindungen der Formel I:
EMI1.1     
 oder von Säure-Additionssalzen davon. In der Formel I bedeutet n 0 oder 1, und die Reste R stellen basische Gruppen der Formel II
EMI1.2     
 dar. Hierbei sind R1 und   R2    gleich oder verschieden und bedeuten Wasserstoffatome, Alkoxyalkylgruppen oder gerade oder verzweigte Alkylgruppen mit höchstens 7 C-Atomen.   Rg    ist Wasserstoff oder eine Alkylgruppe mit höchstens 6 C-Atomen. A bedeutet Phenylen, R4substituiertes Phenylen, Phenylenamino,   R-substituiertes    Phenylenamino, Phenylendiamino, R4 - substituiertes Phenylendiamino oder Styrylen. R4 stellt Halogen, Amino, Nitro, Hydroxy, Alkyl, Alkoxy, Alkylthio, Acylamino oder Aminocarbonyl dar.



   Die Verbindungen gemäss Formel I werden erhalten, wenn man eine Verbindung der Formel:
EMI1.3     
 worin n, A und   R1    die genannte Bedeutung haben, mit einem Amin der Formel:
EMI1.4     
 worin   R.2    und   R3    die genannte Bedeutung haben, umsetzt, wobei man das Reaktionsprodukt in Form der freien Base oder eines Additionssalzes mit einer geeigneten anorganischen oder organischen Säure isoliert.



   Die Verbindungen entsprechend Formel I können als freie Basen oder in Form ihrer Salze mit anorganischen oder organischen Säuren gewonnen werden. Als Salze der Basen gemäss Formel I seien diejenigen der Schwefelsäure, Salzsäure, Bromwasserstoffsäure, Jodwasserstoffsäure, Phosphorsäure, Ameisensäure, Essigsäure, Propionsäure, Buttersäure, Weinsäure, Maleinsäure, Oxalsäure, Citronensäure, Salicylsäure und dergleichen erwähnt. Durch besonders gute Löslichkeit zeichnen sich die Salze von Hydroxycarbonsäuren, Ketocarbonsäuren und Aminocarbonsäuren aus, insbesondere die Salze der Glykolsäure, Milchsäure, Zuckersäure, Schleimsäure, Ascorbinsäure, Heptagluconsäure, Galactosidogluconsäure, Galactosido-heptagluconsäure, Lävulinsäure und der Glutaminsäure.



   Die Herstellung löslicher Salze erfolgt zweckmässig, indem man die mehrbasische Verbindung in Wasser aufschlämmt und die zur Neutralisation erforderliche Menge der gewünschten Säure zusetzt, wobei die Base in Lösung geht. Gewünschtenfalls kann man das Salz durch Eindampfen oder Acetonzusatz in fester Form gewinnen.



  Die erhaltenen löslichen Salze ergeben haltbare, steri  lisierbare Lösungen, die sich für Injektionszwecke eignen. Die Lösungen können auch weitere Substanzen enthalten, doch ist zu beachten, dass diese keine Fällungsmittel sein dürfen. So ist zur Herstellung isotonischer Lösungen Kochsalz nicht verwendbar, wenn das Chlorion die mehrbasische Verbindung ausfällen würde; in solchen Fällen eignet sich für diesen Zweck z.B.



  Glucose.



   Die in der beschriebenen Weise erhaltenen mehrbasischen Verbindungen und ihre Salze sind neue Verbindungen. Sie besitzen pharmakologische Wirkung und eignen sich vor allem als Chemotherapeutika, insbesondere Tuberkulostatika und zur Therapie von Trypanosomenerkrankungen sowie zur Krebsbekämpfung, insbesondere zur Bekämpfung der Leukämie. Ausserdem können sie als Zwischenprodukte zur Herstellung weiterer, insbesondere pharmakologisch wirksamer Verbindungen benutzt werden.



   Die antileukämische Wirkung wird bei der durch Übertragung von Krebszellen künstlich leukämisch gemachten Maus mit Wirkstoffmengen von etwa 1 bis 500 mg/kg/Tag erzielt und äussert sich in einer Verlängerung der Überlebenszeit gegenüber unbehandelten Kontrolltieren. Die Überlebenszeit der Kontrolltiere zu   100%    gesetzt, beträgt die Überlebenszeit bei täglicher Verabreichung von 1 bis 500 mg/kg erfindungsgemäss erhaltener Produkte bis zu 400 % und mehr. Der Wirkstoff wird in gegebenenfalls isotonisch gemachter wässeriger Lösung beziehungsweise Suspension i.v. oder i.p.



  gespritzt.



   Zur Bekämpfung anderer Krebsarten sowie für allgemein chemotherapeutische Zwecke, insbesondere zur   Tuberkulosebekämpfung,    eignen sich auch andere Arzneiformen und Applikationsweisen. Zum Beispiel können Carcinome, Sarcome oder Tuberkuloseherde lokal behandelt werden, wobei eine Depotwirkung auftreten kann. Neben Lösungen beziehungsweise Suspensionen kommen für solche Zwecke auch pulver- oder salbenförmige Präparate in Frage, die ausser dem Wirkstoff die üblichen Hilfsstoffe enthalten.



   Beispiel 1
15 g 4,4'-Bis-iminoäther-terephthalanilid-Dihydrochlorid, welches durch Stägiges Stehenlassen des entsprechenden Dinitrils in gesättigter alkoholischer Salzsäure erhalten wurde, werden mit 30 ml n-Propylamin 8 Stunden   bei -Zimmertemperatur    stehen gelassen und anschliessend 1 Stunde unter Rückfluss erhitzt. Dann saugt man überschüssiges n-Propylamin   ab,    suspendiert den Rückstand in 200 ml Wasser, setzt kalte wässerige 2n Sodalösung im Überschuss zu und nutscht ab. Man löst das noch feuchte Produkt in 100 ml 10 %iger wässeriger Lävulinsäure, filtriert klar und versetzt das Filtrat mit 20 ml konzentrierter - - Salzsäure. Das ausgefallene Salz wird abgenutscht, mit Wasser gewaschen und getrocknet. Man erhält 9,6 g des Hydrochlorids der Base der Formel
EMI2.1     
 vom Schmelzpunkt 3250 C (Zersetzung).



   In gleicher Weise wie in Beispiel 1 erhält man ferner die in der nachfolgenden Tabelle I angegebenen Produkte.



   Tabelle I
Beispiel Produkt Srnp. * unter Zersetzung
EMI2.2     


<tb>  <SEP> HN <SEP> /NH
<tb> 2 <SEP> C¯co-LS-CO-NH- <SEP> NH-COOCo-NHt3 <SEP> C <SEP> 365 C <SEP> *
<tb>  <SEP> H2N <SEP> NH2
<tb>  <SEP> CH3-N <SEP> N-CHs
<tb> 3 <SEP> c <SEP> CtfNH-COO <SEP>   <SEP> Dihydrochlorid
<tb>  <SEP> 3650 <SEP> C
<tb>  <SEP> 112N <SEP> rTH2
<tb>  <SEP> CH3N <SEP> 7N-CH3
<tb> 4 <SEP> CNH-CO--CO-NlJ <SEP> C <SEP> Dihydrochlorid
<tb>  <SEP> C <SEP> H3-NH7 <SEP> \NH-CH3 <SEP> 3800C <SEP> *
<tb>  <SEP> CH8-N <SEP> N-CH3
<tb> 5 <SEP> co-Co-NH-C <SEP> Dihydrochlorid
<tb>  <SEP> C2H5-NH7 <SEP> 'H-C2Hs
<tb>   
Tabelle I (Fortsetzung) Beispiel Produkt Smp.

   * unter Zersetzung
EMI3.1     


<tb>  <SEP> CHz <SEP> -N <SEP> ,N-CHs
<tb>  <SEP> 6 <SEP> C < NH-Co > /9Co-NH < C\ <SEP> 345 C <SEP>  NCHs <SEP> Dihydrochlorid
<tb>  <SEP> CsH?- <SEP> 3450 <SEP> C <SEP> 0
<tb>  <SEP> C3H?NH <SEP> NHC3H7
<tb>  <SEP> 7 <SEP> CH3N <SEP> Co0oy#X-\\ <SEP>  N <SEP> OH3 <SEP> NCH3
<tb>  <SEP> CH3\ <SEP> /CH3 <SEP> 346 C <SEP> *
<tb>  <SEP> CH,:

  CH- <SEP> NHCH
<tb>  <SEP> CH3 <SEP> CH3
<tb>  <SEP> CHs-N <SEP> N-CH3
<tb>  <SEP> 8 <SEP> X <SEP> Dihydrochlorid
<tb>  <SEP> 8 <SEP> C- <SEP> 321tslyodcOC*l <SEP> ona
<tb>  <SEP> ¯¯ <SEP> \ <SEP> \= <SEP> 3250C <SEP> *
<tb>  <SEP> 04H9-NH <SEP> NH-04H9
<tb>  <SEP> CHs\ <SEP> /CH3
<tb>  <SEP> CH3 <SEP> NH-0o <SEP> N <SEP> CH <SEP> Dihydrochlorid
<tb>  <SEP> CH3, <SEP> MM <SEP> L/ <SEP> /CH3 <SEP> 34000 <SEP> *
<tb>  <SEP> CHNH <SEP> NHCH
<tb>  <SEP> CH3/ <SEP> \CH3
<tb>  <SEP> CH8-N <SEP> N-CH8
<tb>  <SEP>   <SEP> Base
<tb>  <SEP> 10 <SEP> C < NH-CO < CO-NH < C <SEP> Base <SEP> 0
<tb> 10 <SEP> NH <SEP> NH <SEP> 2082100 <SEP> 0
<tb>  <SEP> (CH2)3 <SEP> (roh2)3
<tb>  <SEP> 0 <SEP> 0
<tb>  <SEP> CH3 <SEP> CH3
<tb>  <SEP> C1
<tb>  <SEP> HN <SEP> i <SEP> NH
<tb>  <SEP> hin <SEP> | <SEP> NH <SEP> Dihydrochlorid-Hydrat
<tb> 11 <SEP> C;

   <SEP> 3 <SEP> 0NH0O00NH <SEP> ¯¯ <SEP> 0 <SEP> 30000 <SEP> *
<tb>  <SEP> O <SEP> H8-NH <SEP> \NH- <SEP> -CH3
<tb>  <SEP> Cl
<tb>  <SEP> CH3N <SEP> &verbar; <SEP> /NCH3
<tb> 12 <SEP> CONH-Cot3CO-NH <  < C <SEP> Dihydrochlorid
<tb>  <SEP> CH,-NH <SEP> NHCH3
<tb>  <SEP>  <  <SEP> NH-CO <SEP> ()CO-NH < 
<tb> 13 <SEP> HN <SEP> ¯/ <SEP> \4 <SEP> ,NH <SEP> Dihydrochlorid
<tb>  <SEP> cx <SEP> \cv <SEP> 37500 <SEP> *
<tb>  <SEP> HsN <SEP> NH2
<tb> 14 <SEP> 0H3-N <SEP> ¯¯ <SEP> 3 <SEP> -NH-CO- <SEP> CO-NH
<tb> - <SEP> ( <SEP> "-CHs <SEP> Dihydrochlorid
<tb>  <SEP> 0NH2 <SEP> wird <SEP> wird <SEP> bei <SEP> *
<tb>  <SEP> C
<tb>  <SEP> HaN <SEP> NHa
<tb>   
Tabelle I (Fortsetzung) Beispiel Produkt Smp.

   * unter Zersetzung
EMI4.1     


<tb>  <SEP> vNH-Cot3CO-NHaO
<tb> 15 <SEP> 0H3-N <SEP> ¹ <SEP> N-CH3 <SEP> Dihydrochlorid
<tb>  <SEP> C <SEP>   <SEP> 3200 <SEP> C <SEP> *
<tb>  <SEP> 0 <SEP> 0
<tb>  <SEP> O <SEP> H3-NH <SEP> NH-OH3
<tb>  <SEP> NH-C <SEP> Hs
<tb> 16 <SEP> C < NH¯cotLCO-NH <SEP> C,,/C <SEP> 330 C <SEP> *
<tb>  <SEP> p <SEP> ¯¯ <SEP> 3300C <SEP> *
<tb>  <SEP> H2N7 <SEP> NH2
<tb>  <SEP> OH3-N <SEP> zu <SEP> N-OH3
<tb> NH-CO-CO-NH-Dihydrochlond
<tb> 0 <SEP> C- <SEP> 355-3620C <SEP> *
<tb>  <SEP> O <SEP> H3-NH7 <SEP> NHCH3
<tb> 18 <SEP> HN\\ <SEP> X <SEP> C <SEP> Dihydrochlorid
<tb>  <SEP> O <SEP> 0
<tb>  <SEP> H2N  <SEP> NH2
<tb>  <SEP> ¯¯\NH-0o{ <SEP> CO-NH
<tb> 19 <SEP> OH3-N <SEP> 9NH-COtCO-NHaO <SEP> H3 <SEP> Dihydrochlorid
<tb>  <SEP> \ <SEP>   <SEP> C/2200 <SEP> C <SEP> *
<tb>  <SEP> O <SEP> 0
<tb>  <SEP> CH-N:

  H/NH-CH3
<tb>  <SEP> HN <SEP> NH
<tb> 20 <SEP> ¸-OH <SEP> 3NH-0O0O-NH <SEP> 0H2-O  <SEP> Dihydrochlorid
<tb>  <SEP> H2N <SEP> NH2
<tb>  <SEP> HN <SEP> ss <SEP> NH
<tb> 21 <SEP>  NH <SEP> 0o0oNH  <SEP> 0 <SEP>   <SEP> Dihydrochlorid
<tb> 0-OH2- <SEP> NH2 <SEP> 2100 <SEP> C <SEP> *
<tb>  <SEP> H2N <SEP> NH2
<tb>  <SEP> OH3-N <SEP> N-0H3
<tb> 22 <SEP> CCH2 < 3 <SEP> NH-CO < CO-NH < CH2C <SEP> B26aOe C <SEP> * <SEP> H2- <SEP>   <SEP> Base
<tb>  <SEP> H2 <SEP> XNH2
<tb>  <SEP> NH2
<tb>  <SEP> CH3N <SEP> N-OH3
<tb> 23 <SEP> C-H-CO-NH-CO-NH-C <SEP> zu <SEP> H- <SEP> 0  <SEP> Dihydro <SEP> chlorid
<tb>  <SEP> 23 <SEP> C¯NH-Co-NH4L3NH-CO-NHOC <SEP> 30000
<tb>  <SEP> OH3-NH <SEP> NH-OH3
<tb>  <SEP> OH3-N <SEP> N-OH3
<tb> 24 <SEP> C}NH-CO-NH < NH-CO-NHOC <SEP> Dihydrochlorid
<tb> 0 <SEP> -- <SEP> -NH-CO-NH- <SEP> 0 <SEP> 29500 <SEP> *
<tb>  <SEP> 04H3-NH7 <SEP> NHCoH9
<tb>   
Tabelle I 

  (Fortsetzung) Beispiel Produkt Smp. * unter Zersetzung
EMI5.1     


<tb>  <SEP> OH <SEP> OH3
<tb>  <SEP> OH <SEP> N <SEP> /N <SEP> CH
<tb> 25 <SEP> OHK <SEP>  -NH-0O-NH <SEP> )NH-CO-NH9OC <SEP> ,CHH33
<tb>  <SEP> O113\ <SEP> ¯¯
<tb>  <SEP> CH3 <SEP> 0 <SEP> Lorid <SEP> 2450 <SEP> -\m <SEP> \m <SEP> \CH3
<tb>  <SEP> OH-NH
<tb>  <SEP> Dihydrochlorid <SEP> 24500 <SEP> *OH3
<tb>  <SEP> OH3-N <SEP> N-0H3
<tb>  <SEP>  NWCO-NH <SEP> --NH-CO-NH- <SEP>  · <SEP> NH <SEP> oo-NHx\- <SEP> Dihydrochlorid
<tb> 26 <SEP> 0 <SEP> ¯¯¯ <SEP> MM- <SEP> - <SEP> -C <SEP> 22000 <SEP> *
<tb>  <SEP> OH3-NH <SEP> NH-OH3
<tb>  <SEP> CH3N <SEP> N-0ll3
<tb> 27 <SEP> C < NH-Co < Co-NH < /3 <SEP> C <SEP>  > 330  <SEP> C <SEP> Dihydrochlorid
<tb>  <SEP> 0
<tb>  <SEP> CH3NH <SEP> NHCH3
<tb>  <SEP> NO2
<tb>  <SEP> CH3-N <SEP> I <SEP> ,N- <SEP> -CH,

  
<tb>  <SEP>   <SEP> Dihydrochlorid-Hydrat
<tb> 28 <SEP> CvNH-CO < CO-NH < C <SEP> etwa <SEP> 34000
<tb>  <SEP> CH3NH <SEP> v\ <SEP> NH- <SEP> OH3
<tb>  <SEP> OCH3
<tb>  <SEP> CH3N <SEP> ss <SEP> NCH3
<tb> 29 <SEP> C <SEP> 3 <SEP> NH-COl LCO-NH < }C <SEP> Dihydrochlorid-Hydrat
<tb>  <SEP> 0 <SEP> 0\ <SEP> etwa <SEP> 32000
<tb>  <SEP> CH3NH <SEP> NH-0H3
<tb>  <SEP> -N <SEP> N-0H3
<tb> 30 <SEP> CH <SEP> C < 3 <SEP> ¸ <SEP> 7 <SEP> -NH-CO- <SEP> Dihydrochlorid-Hydrat
<tb>  <SEP> / <SEP> ¯¯
<tb> 30 <SEP>  OH3 <SEP> 33500
<tb>  <SEP> N <SEP> N
<tb>  <SEP> CH3 <SEP> CH3
<tb>  <SEP> C1
<tb>  <SEP> OH3-N <SEP> | <SEP> zu <SEP> tCo-NH- <SEP> - <SEP> N-OH3
<tb> 31 <SEP> OH <SEP> CK3¯NH-CO¯ < 3 <SEP> CO-NH < C <SEP> /cd3 <SEP> Dihydrochlorid-Hydrat
<tb>   <SEP> CHq <SEP> C <SEP> /-c <SEP> 33000
<tb>  <SEP> N <SEP> N
<tb>  <SEP> CH3 <SEP> CH3
<tb>  <SEP> NOs
<tb>  <SEP> 0H3-N <SEP> ss <SEP> 

  NCH3
<tb> 32 <SEP> OH <SEP> C < NH-CO4LCO-NH <SEP> cm"\ <SEP> H3 <SEP> Dihydrochlorid-Hydrat
<tb>  <SEP>   <SEP>   <SEP> ¹ <SEP> 2700 <SEP> 0
<tb>  <SEP> ¯¯ <SEP> \ <SEP>   <SEP> 27000
<tb>  <SEP> N <SEP> N
<tb>  <SEP> CH3 <SEP> CH3
<tb>  <SEP> CH3N <SEP> /$ <SEP> NCH3
<tb> 33 <SEP> OH\ <SEP>   <SEP> \m-NWCO0O-NH <SEP> y <SEP> /CH3 <SEP> Dihydrochlorid-Hydrat
<tb>  <SEP> N\0M \ <SEP> MM0\N  <SEP> OH3 <SEP> 32000
<tb>  <SEP> CH3 <SEP> CH3
<tb>   
Tabelle I (Fortsetzung) Beispiel Produkt Smp.

   * unter Zersetzung
EMI6.1     


<tb>  <SEP> OH3-N <SEP> NCH3
<tb>  <SEP> 34 <SEP> ¸/-x\NHCo <SEP> % <SEP> CH= <SEP> CH-CO-NHg <SEP> ¯C
<tb>  <SEP> CH3NH <SEP> MX <SEP> \1hlorid-Hidrat <SEP> ¹ <SEP> · <SEP> NHCH3
<tb>  <SEP> Dihydrochlorid-Hidrat <SEP>  > 300  <SEP> C
<tb>  <SEP> CH3-N <SEP> NCH3 <SEP> Dihydrochlorid
<tb>  <SEP> 01I-0O-NH- 0
<tb>  <SEP> 35 <SEP> 0 <SEP> -NH-0O CH <SEP> = <SEP> Sesquihydrat
<tb>  <SEP>  > 30000
<tb>  <SEP> H2N <SEP> NH2
<tb>  <SEP> 36 <SEP> - <SEP> NH-CO-NH <SEP> HN <SEP> NH <SEP> Dihydrochlorid
<tb>  <SEP> \INH-CHs <SEP> H- <SEP> OH3 <SEP> 31000 <SEP> *
<tb>  <SEP> 37 <SEP> HN <SEP> NH <SEP> Dihydrochlorid
<tb>  <SEP> /\ <SEP> CONH \  <SEP> 30800 <SEP> *
<tb> H3CO-(CH2)sNH <SEP> NH(CH2)

  sOCH3
<tb>  <SEP> 38 <SEP> HN <SEP> -NH-CO-- <SEP> -CO-NH-- <SEP> NH <SEP> Dihydrochlorid
<tb>  <SEP> ·/\-0 <SEP> NH-CO4CO-NH <SEP> 28000 <SEP> *
<tb> H3OO-(OH-NH <SEP> NH-(OH2)3-O <SEP> OH3
<tb>  <SEP> C1
<tb>  <SEP> HsC2N <  <SEP> NH-Cot3CO-NHO <SEP> N-O <SEP> 2H3 <SEP> Dihydrochlorid
<tb>  <SEP> HSC2N <SEP> so2ä· \CONH4\¸o23 <SEP> NHCaH6
<tb>  <SEP> H3CNf <SEP>  <  <SEP>  <  <SEP> NH < 3NHX <SEP> Dihydrochlorid
<tb>  <SEP> 40 <SEP> H <SEP> NH <SEP> N-OH3 <SEP> 3200 <SEP> C <SEP> *
<tb>  <SEP> H3C- <SEP> 32000 <SEP> *
<tb>  <SEP> 41 <SEP> HN¸\N <SEP> ITNW <SEP> 0O <SEP> 0NH--N <SEP> y <SEP> H <SEP> Base
<tb>  <SEP> H2N  <SEP> H2 <SEP>  > 38000
<tb>  <SEP> H3CN <SEP> NCH3 <SEP> Dihydrochlorid
<tb>  <SEP> 42 <SEP> /NO <SEP> H3 <SEP> (NH-CH3 <SEP> 3300 <SEP> C
<tb>  <SEP> -NH-CO <SEP> 0NH <SEP> ¯¯ <SEP> 33000
<tb>  <SEP> H3O-NH <SEP> NH-0H3
<tb>  <SEP> CH3
<tb>  <SEP> H3C-N,

   <SEP> - <SEP> H3C-N <SEP> - <SEP> .N-C &  <SEP> Dihydrochlorid
<tb>  <SEP>  NH-C < ) <SEP> NH-CO <SEP> ;'"" <SEP> CH3 <SEP> 34800
<tb>  <SEP> H30-NH <SEP> ¸; <SEP> NH-OH3
<tb>  <SEP> NO2
<tb>  <SEP> NO2
<tb>  <SEP> 44 <SEP> -N,CO-NH-C <SEP> ,NCH3 <SEP> H3 <SEP> Dihydrochlorid
<tb>  <SEP> H3 <SEP> O-N7 <SEP> zu <SEP> \==/ <SEP> NH-OH3
<tb>  <SEP> I
<tb>  <SEP> C1
<tb>   
Tabelle I (Fortsetzung) Beispiel Produkt Smp. * unter Zersetzung
EMI7.1     


<tb>  <SEP> NO2
<tb>  <SEP> 45 <SEP> H30-N <SEP> NO2 <SEP> ¯¯¯ <SEP> Dihydrochlorid
<tb>  <SEP> x -NH-rny)oo-7 <SEP> \ > Co-NH4 <SEP> cC <SEP> \;

  N0H3 <SEP> 23000
<tb> H30 <SEP> 0- <SEP> (0H2Y3-NH  <SEP> ¯¯ <SEP> \=/ <SEP> NH-(0H2)3-O <SEP> OH3
<tb>  <SEP> H30-N <SEP> N-0H3
<tb>  <SEP> 46 <SEP> CO-NH-=-NH-CO-NH-/c <SEP> m <SEP> CHs <SEP> Dihydrochlorid
<tb>  <SEP> .N-CH3 <SEP> 2950 <SEP> C
<tb>  <SEP> H3C <SEP> CH3
<tb>  <SEP> H30-N <SEP> -NH-CO- <SEP> /- <SEP> ONH-CO
<tb>  <SEP> 47 <SEP> ' <SEP> 3070 <SEP> C
<tb>  <SEP> H30-N <SEP> N-OH3 <SEP> 30700
<tb>  <SEP> H3C <SEP> I <SEP> CH3
<tb>  <SEP> NH2
<tb>  <SEP> C1
<tb>  <SEP> H302-N <SEP> 1
<tb>  <SEP> 48 <SEP> \\ <SEP> / <SEP> \NHCO \OONH \/NOJIs <SEP> Dihydrochlorid
<tb>  <SEP> H3 <SEP> 0 <SEP> 2NH'm\ <SEP> NH-O2H3 <SEP> C
<tb>  <SEP> 49 <SEP> H5O2-N <SEP> N-O <SEP> 2H5 <SEP> Dihydrochlorid
<tb>  <SEP> 49 <SEP> N >  < NH-C04 <SEP> 3 <SEP> \3 <SEP> N\C <SEP> H6
<tb>  <SEP> HsC2 <SEP> O2H3
<tb>  <SEP> C1
<tb>  <SEP> HSCa-N <SEP> NH-COOCO¯NHA3 <SEP> N-02H5 <SEP> 

  DihYdrOCh1Orid
<tb>  <SEP> H30 <SEP> 3/N <SEP> ·o2s <SEP> 313 <SEP> 0
<tb>  <SEP> HsC2 <SEP> 02H5
<tb>  <SEP> 51 <SEP>  & C-N,Co-NH- <SEP> NH-CO-NH <SEP> 3 <SEP> NH-CO-NH < f <SEP> ,N-CH3
<tb>  <SEP> ü;¸ \iiCONHNH <SEP> 0ONHMX- \\ <SEP>  
<tb>  <SEP> H3O <SEP> O-(OH2)3-NH <SEP> H(CH2)3OCH2
<tb>  <SEP> Dihydrochlorid <SEP> 2700 <SEP> C <SEP> *
<tb>  <SEP> HCa-NCO-CO-NH--CaHs <SEP> Dihydrochlorid
<tb>  <SEP> 52 <SEP> H2N0000 <SEP> H2 <SEP> 34000
<tb>  <SEP> R,, <SEP> N-O2H3
<tb>  <SEP> 53 <SEP> H3O2NHYNHY¸NHOONHNHCONHMYN <SEP> HYNHO2H3
<tb>  <SEP> H6C2NH <SEP> HC2H5
<tb>  <SEP> Dihydrochlorid <SEP> 3200 <SEP> C <SEP> *
<tb>  <SEP> 54 <SEP> H30-N <SEP> N-OH3 <SEP> N-CHs <SEP> CH3 <SEP> Dihydrochlorid
<tb>  <SEP> H3ONH ·COM'NHiiCONH·¸/NHOH3 <SEP> 23000 <SEP> *
<tb>   
Tabelle   1    (Fortsetzung) Beispiel Produkt Smp.

   * unter Zersetzung
EMI8.1     


<tb>  <SEP> H302-N <SEP> OONH <SEP>  \/NO2HS <SEP> Dihydrochlorid
<tb> 55 <SEP> y·-NH-0o-NHNH- <SEP> - <SEP> \I/ <SEP> \I/ <SEP> NH-O2H3 <SEP> 2800 <SEP> C <SEP> +
<tb>  <SEP> HSC9N <SEP> ¯¯
<tb>  <SEP> H5C2N\vR <SEP> ONH-CO-NH < NH-CO-NH <SEP> 3 <SEP> NC2H5 <SEP> DihYdrOChIOrid
<tb> 56 <SEP> $ <SEP> CNH2 <SEP> 300  <SEP> N-O <SEP> 2H5 <SEP> C <SEP> +
<tb>  <SEP> H2N <SEP> H2 <SEP> 30000 <SEP> *
<tb>  <SEP> 11302N <SEP> N-02H5 <SEP> H <SEP> Dihydrochlorid
<tb> 57 <SEP> ab <SEP> NilMM/\ <SEP> DihYdrOCh10rid
<tb>  <SEP> H6Ca-N <SEP> 5
<tb>  <SEP> MX <SEP> NH-02H3 <SEP> ab <SEP> 33000 <SEP> *
<tb>  <SEP> H30-N-0
<tb>  <SEP> H3 <SEP> Dihydrochlorid
<tb> 58 <SEP> H3 <SEP> \FNHY3NH-CO <SEP> OF <SEP> 34500 <SEP> DihYdrOCh10rid
<tb>  <SEP> 3450 <SEP> C <SEP> +
<tb>  <SEP> H30-N <SEP> CO-NH--MCO-NH-3;

  0YPCp"
<tb> 59 <SEP> CO-NH-e <SEP> /---CO-NH- <SEP> 33000
<tb>  <SEP> H2N <SEP> MX
<tb>  <SEP> H703-N <SEP> N-03H7 <SEP> Dihydrochlorid
<tb> H2N <SEP> ONH-CO-NH <  <SEP> NH-CO-NH <  <  <SEP> 3 <SEP> 7 <SEP> Dihydrochlorid
<tb>  <SEP> H2N <SEP> H2 <SEP> 30000 <SEP> *
<tb> 61 <SEP> H7O3-N <SEP> N-O <SEP> 3H7 <SEP> Dihydrochlorid
<tb> -NH-0o-0o-NH  <SEP> \rn
<tb>  <SEP> H,N/'H, <SEP> 34000 <SEP> *
<tb> 62 <SEP> -NH-- <SEP> -CO-NH-- <SEP> b-CaH, <SEP> Dihydrochlorid
<tb>  <SEP> ¯¯ <SEP> ¯¯ <SEP> ¯¯ <SEP> 33000 <SEP> *
<tb>  <SEP> H2 <SEP> NH2
<tb>  <SEP> H502-N <SEP> /\/\/\/N02H5
<tb> 63 <SEP> \N <SEP> HNHOONHNHCONHNHYNII <SEP> Dihydrochlorid
<tb>  <SEP> H2N <SEP> 2 <SEP>  > 34000 <SEP> *
<tb>  Chemotherapeutische Wirkung der Produkte
In der folgenden Tabelle II sind Angaben über die tuberkulostatische bzw.

   antileukämische Wirkung erfindungsgemäss erhältlicher Produkte zusammengestellt.



   Die tuberkulostatische Wirkung wurde in vitro bestimmt durch Messung der niedrigsten molaren Konzentration (Molekulargewicht in mg/ml) des Wirkstoffes, welche eben noch das Wachstum von Mycobacterium tuberculosis zu hemmen vermag. Die in der zweiten Kolonne angegebenen Werte entsprechen dem negativen Logarithmus dieser geringsten molaren Hemmungskonzentration.



   Die antileukämische Wirkung wurde an Mäusen bestimmt, in welchen künstlich Leukämie hervorgerufen worden war   (Leukämiel210*).   



   Hierbei wurde die Überlebenszeit der mit einem erfindungsgemäss erhaltenen Produkt behandelten Tiere gegenüber unbehandelten Kontrolltieren bestimmt, wobei die durchschnittliche   Überlebenszeit    der Kontrollen zu 100 % gesetzt wurde. Zum Beispiel bedeutet eine mit der angegebenen Dosis erreichte Überlebenszeit von   200%,    dass die behandelten Leukämie-Tiere doppelt so lang überlebten wie die unbehandelten.



  * Die Angaben beziehen sich auf das beim CCNSC benützte Klassierungssystem  
Tabelle II Produkt Tuberkulo- Antileukämische Wirkung gemäss statische Dosis   i. p.      tJberlebens-    Beispiel Wirkung mg/kg/Tag zeit %
3 6,0 15 200
4 7,0 1 200
5 7,0 3 155
6 7,0 8 175
7 7,3
8 7,0
9 4,8
10 7,4
14 5,8
16 5,0
17 5,6
18 4,8
19 6,1
20 15 160
24 6,5
27 7,2 30 181
28 6,8
29 6,0
30 7,2
31 6,9
32 6,1
33 5,5
34 7,2 3,7 248
35 6,9 60 233 Produkt Tuberkulo- Antileukämische Wirkung gemäss statische Dosis   i. p.      tSberlebens-    Beispiel Wirkung mg/kg/Tag zeit %
36 120 205
37 7,0 6 269
38 6,6 7,5 171
39 7,0 7,5 204
40 7,0 3,2 238
41 7,4
42 5,0
43 6,3
44 6,2
45 6,8
46 6,6
47 5,2
48 6,5
49 7,0
50 6,3
51 6,3
52 7,2
53 6,3
54 5,7
55 6,7
56 6,1 5 148
57 7,0 15 142
58 7,9
59 6,3
60 6,6
61 7,4
62 7,9 8 155
63 6,5 



  
 



  Process for preparing polybasic compounds The invention relates to a process for preparing polybasic compounds of the formula I:
EMI1.1
 or acid addition salts thereof. In formula I, n denotes 0 or 1, and the radicals R represent basic groups of the formula II
EMI1.2
 Here, R1 and R2 are identical or different and denote hydrogen atoms, alkoxyalkyl groups or straight or branched alkyl groups with a maximum of 7 carbon atoms. Rg is hydrogen or an alkyl group with a maximum of 6 carbon atoms. A denotes phenylene, R4-substituted phenylene, phenylenamino, R-substituted phenylenamino, phenylenediamino, R4 - substituted phenylenediamino or styrylene. R4 represents halogen, amino, nitro, hydroxy, alkyl, alkoxy, alkylthio, acylamino or aminocarbonyl.



   The compounds according to formula I are obtained when a compound of the formula:
EMI1.3
 wherein n, A and R1 have the meanings mentioned, with an amine of the formula:
EMI1.4
 in which R.2 and R3 have the meaning mentioned, reacted, the reaction product being isolated in the form of the free base or an addition salt with a suitable inorganic or organic acid.



   The compounds corresponding to formula I can be obtained as free bases or in the form of their salts with inorganic or organic acids. Salts of the bases according to formula I include those of sulfuric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, oxalic acid, citric acid, salicylic acid and the like. The salts of hydroxycarboxylic acids, ketocarboxylic acids and aminocarboxylic acids are distinguished by particularly good solubility, in particular the salts of glycolic acid, lactic acid, saccharic acid, mucic acid, ascorbic acid, heptagluconic acid, galactosidogluconic acid, galactosidoheptagluconic acid, levutamic acid and levutamic acid.



   Soluble salts are conveniently prepared by suspending the polybasic compound in water and adding the amount of the desired acid required for neutralization, the base going into solution. If desired, the salt can be obtained in solid form by evaporation or by adding acetone.



  The soluble salts obtained result in stable, sterilizable solutions which are suitable for injection purposes. The solutions can also contain other substances, but it should be noted that these may not be precipitants. For example, table salt cannot be used to produce isotonic solutions if the chlorine ion would precipitate the polybasic compound; in such cases, e.g.



  Glucose.



   The polybasic compounds and their salts obtained in the manner described are new compounds. They have a pharmacological effect and are particularly suitable as chemotherapeutic agents, in particular tuberculostatics, and for the therapy of trypanosomal diseases and for combating cancer, in particular for combating leukemia. In addition, they can be used as intermediate products for the preparation of other, in particular pharmacologically active compounds.



   The antileukemic effect is achieved in mice artificially rendered leukemic by transferring cancer cells with amounts of active ingredient from about 1 to 500 mg / kg / day and is expressed in an increase in survival time compared to untreated control animals. If the survival time of the control animals is set at 100%, the survival time with daily administration of 1 to 500 mg / kg of products obtained according to the invention is up to 400% and more. The active ingredient is administered i.v. or i.p.



  injected.



   Other drug forms and modes of application are also suitable for combating other types of cancer and for general chemotherapeutic purposes, in particular for combating tuberculosis. For example, carcinomas, sarcomas or tuberculosis lesions can be treated locally, whereby a depot effect can occur. In addition to solutions or suspensions, preparations in powder or ointment form that contain the usual excipients in addition to the active ingredient are also suitable for such purposes.



   example 1
15 g of 4,4'-bis-iminoether-terephthalanilide dihydrochloride, which was obtained by leaving the corresponding dinitrile to stand in saturated alcoholic hydrochloric acid for days, are left to stand with 30 ml of n-propylamine for 8 hours at room temperature and then refluxed for 1 hour . Excess n-propylamine is then filtered off with suction, the residue is suspended in 200 ml of water, an excess of cold aqueous 2N soda solution is added and the residue is filtered off with suction. The product, which is still moist, is dissolved in 100 ml of 10% aqueous levulinic acid, filtered until clear and the filtrate is treated with 20 ml of concentrated hydrochloric acid. The precipitated salt is filtered off with suction, washed with water and dried. 9.6 g of the hydrochloride of the base of the formula are obtained
EMI2.1
 melting point 3250 C (decomposition).



   In the same way as in Example 1, the products given in Table I below are also obtained.



   Table I.
Example product Srnp. * with decomposition
EMI2.2


<tb> <SEP> HN <SEP> / NH
<tb> 2 <SEP> C¯co-LS-CO-NH- <SEP> NH-COOCo-NHt3 <SEP> C <SEP> 365 C <SEP> *
<tb> <SEP> H2N <SEP> NH2
<tb> <SEP> CH3-N <SEP> N-CHs
<tb> 3 <SEP> c <SEP> CtfNH-COO <SEP> <SEP> dihydrochloride
<tb> <SEP> 3650 <SEP> C
<tb> <SEP> 112N <SEP> rTH2
<tb> <SEP> CH3N <SEP> 7N-CH3
<tb> 4 <SEP> CNH-CO - CO-NlJ <SEP> C <SEP> dihydrochloride
<tb> <SEP> C <SEP> H3-NH7 <SEP> \ NH-CH3 <SEP> 3800C <SEP> *
<tb> <SEP> CH8-N <SEP> N-CH3
<tb> 5 <SEP> co-Co-NH-C <SEP> dihydrochloride
<tb> <SEP> C2H5-NH7 <SEP> 'H-C2Hs
<tb>
Table I (continued) Example Product Smp.

   * with decomposition
EMI3.1


<tb> <SEP> CHz <SEP> -N <SEP>, N-CHs
<tb> <SEP> 6 <SEP> C <NH-Co> / 9Co-NH <C \ <SEP> 345 C <SEP> NCHs <SEP> dihydrochloride
<tb> <SEP> CsH? - <SEP> 3450 <SEP> C <SEP> 0
<tb> <SEP> C3H? NH <SEP> NHC3H7
<tb> <SEP> 7 <SEP> CH3N <SEP> Co0oy # X - \\ <SEP> N <SEP> OH3 <SEP> NCH3
<tb> <SEP> CH3 \ <SEP> / CH3 <SEP> 346 C <SEP> *
<tb> <SEP> CH ,:

  CH- <SEP> NHCH
<tb> <SEP> CH3 <SEP> CH3
<tb> <SEP> CHs-N <SEP> N-CH3
<tb> <SEP> 8 <SEP> X <SEP> dihydrochloride
<tb> <SEP> 8 <SEP> C- <SEP> 321tslyodcOC * l <SEP> ona
<tb> <SEP> ¯¯ <SEP> \ <SEP> \ = <SEP> 3250C <SEP> *
<tb> <SEP> 04H9-NH <SEP> NH-04H9
<tb> <SEP> CHs \ <SEP> / CH3
<tb> <SEP> CH3 <SEP> NH-0o <SEP> N <SEP> CH <SEP> dihydrochloride
<tb> <SEP> CH3, <SEP> MM <SEP> L / <SEP> / CH3 <SEP> 34000 <SEP> *
<tb> <SEP> CHNH <SEP> NHCH
<tb> <SEP> CH3 / <SEP> \ CH3
<tb> <SEP> CH8-N <SEP> N-CH8
<tb> <SEP> <SEP> Base
<tb> <SEP> 10 <SEP> C <NH-CO <CO-NH <C <SEP> Base <SEP> 0
<tb> 10 <SEP> NH <SEP> NH <SEP> 2082100 <SEP> 0
<tb> <SEP> (CH2) 3 <SEP> (raw2) 3
<tb> <SEP> 0 <SEP> 0
<tb> <SEP> CH3 <SEP> CH3
<tb> <SEP> C1
<tb> <SEP> HN <SEP> i <SEP> NH
<tb> <SEP> towards <SEP> | <SEP> NH <SEP> dihydrochloride hydrate
<tb> 11 <SEP> C;

   <SEP> 3 <SEP> 0NH0O00NH <SEP> ¯¯ <SEP> 0 <SEP> 30000 <SEP> *
<tb> <SEP> O <SEP> H8-NH <SEP> \ NH- <SEP> -CH3
<tb> <SEP> Cl
<tb> <SEP> CH3N <SEP> &verbar; <SEP> / NCH3
<tb> 12 <SEP> CONH-Cot3CO-NH <<C <SEP> dihydrochloride
<tb> <SEP> CH, -NH <SEP> NHCH3
<tb> <SEP> <<SEP> NH-CO <SEP> () CO-NH <
<tb> 13 <SEP> HN <SEP> ¯ / <SEP> \ 4 <SEP>, NH <SEP> dihydrochloride
<tb> <SEP> cx <SEP> \ cv <SEP> 37500 <SEP> *
<tb> <SEP> HsN <SEP> NH2
<tb> 14 <SEP> 0H3-N <SEP> ¯¯ <SEP> 3 <SEP> -NH-CO- <SEP> CO-NH
<tb> - <SEP> (<SEP> "-CHs <SEP> dihydrochloride
<tb> <SEP> 0NH2 <SEP> becomes <SEP> becomes <SEP> with <SEP> *
<tb> <SEP> C
<tb> <SEP> HaN <SEP> NHa
<tb>
Table I (continued) Example Product Smp.

   * with decomposition
EMI4.1


<tb> <SEP> vNH-Cot3CO-NHaO
<tb> 15 <SEP> 0H3-N <SEP> ¹ <SEP> N-CH3 <SEP> dihydrochloride
<tb> <SEP> C <SEP> <SEP> 3200 <SEP> C <SEP> *
<tb> <SEP> 0 <SEP> 0
<tb> <SEP> O <SEP> H3-NH <SEP> NH-OH3
<tb> <SEP> NH-C <SEP> Hs
<tb> 16 <SEP> C <NH¯cotLCO-NH <SEP> C ,, / C <SEP> 330 C <SEP> *
<tb> <SEP> p <SEP> ¯¯ <SEP> 3300C <SEP> *
<tb> <SEP> H2N7 <SEP> NH2
<tb> <SEP> OH3-N <SEP> to <SEP> N-OH3
<tb> NH-CO-CO-NH-Dihydrochlond
<tb> 0 <SEP> C- <SEP> 355-3620C <SEP> *
<tb> <SEP> O <SEP> H3-NH7 <SEP> NHCH3
<tb> 18 <SEP> HN \\ <SEP> X <SEP> C <SEP> dihydrochloride
<tb> <SEP> O <SEP> 0
<tb> <SEP> H2N <SEP> NH2
<tb> <SEP> ¯¯ \ NH-0o {<SEP> CO-NH
<tb> 19 <SEP> OH3-N <SEP> 9NH-COtCO-NHaO <SEP> H3 <SEP> dihydrochloride
<tb> <SEP> \ <SEP> <SEP> C / 2200 <SEP> C <SEP> *
<tb> <SEP> O <SEP> 0
<tb> <SEP> CH-N:

  H / NH-CH3
<tb> <SEP> HN <SEP> NH
<tb> 20 <SEP> ¸-OH <SEP> 3NH-0O0O-NH <SEP> 0H2-O <SEP> dihydrochloride
<tb> <SEP> H2N <SEP> NH2
<tb> <SEP> HN <SEP> ss <SEP> NH
<tb> 21 <SEP> NH <SEP> 0o0oNH <SEP> 0 <SEP> <SEP> dihydrochloride
<tb> 0-OH2- <SEP> NH2 <SEP> 2100 <SEP> C <SEP> *
<tb> <SEP> H2N <SEP> NH2
<tb> <SEP> OH3-N <SEP> N-0H3
<tb> 22 <SEP> CCH2 <3 <SEP> NH-CO <CO-NH <CH2C <SEP> B26aOe C <SEP> * <SEP> H2- <SEP> <SEP> Base
<tb> <SEP> H2 <SEP> XNH2
<tb> <SEP> NH2
<tb> <SEP> CH3N <SEP> N-OH3
<tb> 23 <SEP> C-H-CO-NH-CO-NH-C <SEP> to <SEP> H- <SEP> 0 <SEP> dihydro <SEP> chloride
<tb> <SEP> 23 <SEP> C¯NH-Co-NH4L3NH-CO-NHOC <SEP> 30000
<tb> <SEP> OH3-NH <SEP> NH-OH3
<tb> <SEP> OH3-N <SEP> N-OH3
<tb> 24 <SEP> C} NH-CO-NH <NH-CO-NHOC <SEP> dihydrochloride
<tb> 0 <SEP> - <SEP> -NH-CO-NH- <SEP> 0 <SEP> 29500 <SEP> *
<tb> <SEP> 04H3-NH7 <SEP> NHCoH9
<tb>
Table I.

  (Continued) Example of product m.p. * with decomposition
EMI5.1


<tb> <SEP> OH <SEP> OH3
<tb> <SEP> OH <SEP> N <SEP> / N <SEP> CH
<tb> 25 <SEP> OHK <SEP> -NH-0O-NH <SEP>) NH-CO-NH9OC <SEP>, CHH33
<tb> <SEP> O113 \ <SEP> ¯¯
<tb> <SEP> CH3 <SEP> 0 <SEP> Lorid <SEP> 2450 <SEP> - \ m <SEP> \ m <SEP> \ CH3
<tb> <SEP> OH-NH
<tb> <SEP> dihydrochloride <SEP> 24500 <SEP> * OH3
<tb> <SEP> OH3-N <SEP> N-0H3
<tb> <SEP> NWCO-NH <SEP> --NH-CO-NH- <SEP> · <SEP> NH <SEP> oo-NHx \ - <SEP> dihydrochloride
<tb> 26 <SEP> 0 <SEP> ¯¯¯ <SEP> MM- <SEP> - <SEP> -C <SEP> 22000 <SEP> *
<tb> <SEP> OH3-NH <SEP> NH-OH3
<tb> <SEP> CH3N <SEP> N-0ll3
<tb> 27 <SEP> C <NH-Co <Co-NH </ 3 <SEP> C <SEP>> 330 <SEP> C <SEP> dihydrochloride
<tb> <SEP> 0
<tb> <SEP> CH3NH <SEP> NHCH3
<tb> <SEP> NO2
<tb> <SEP> CH3-N <SEP> I <SEP>, N- <SEP> -CH,

  
<tb> <SEP> <SEP> dihydrochloride hydrate
<tb> 28 <SEP> CvNH-CO <CO-NH <C <SEP> about <SEP> 34000
<tb> <SEP> CH3NH <SEP> v \ <SEP> NH- <SEP> OH3
<tb> <SEP> OCH3
<tb> <SEP> CH3N <SEP> ss <SEP> NCH3
<tb> 29 <SEP> C <SEP> 3 <SEP> NH-COl LCO-NH <} C <SEP> dihydrochloride hydrate
<tb> <SEP> 0 <SEP> 0 \ <SEP> about <SEP> 32000
<tb> <SEP> CH3NH <SEP> NH-0H3
<tb> <SEP> -N <SEP> N-0H3
<tb> 30 <SEP> CH <SEP> C <3 <SEP> ¸ <SEP> 7 <SEP> -NH-CO- <SEP> dihydrochloride hydrate
<tb> <SEP> / <SEP> ¯¯
<tb> 30 <SEP> OH3 <SEP> 33500
<tb> <SEP> N <SEP> N
<tb> <SEP> CH3 <SEP> CH3
<tb> <SEP> C1
<tb> <SEP> OH3-N <SEP> | <SEP> to <SEP> tCo-NH- <SEP> - <SEP> N-OH3
<tb> 31 <SEP> OH <SEP> CK3¯NH-CO¯ <3 <SEP> CO-NH <C <SEP> / cd3 <SEP> dihydrochloride hydrate
<tb> <SEP> CHq <SEP> C <SEP> / -c <SEP> 33000
<tb> <SEP> N <SEP> N
<tb> <SEP> CH3 <SEP> CH3
<tb> <SEP> NOs
<tb> <SEP> 0H3-N <SEP> ss <SEP>

  NCH3
<tb> 32 <SEP> OH <SEP> C <NH-CO4LCO-NH <SEP> cm "\ <SEP> H3 <SEP> dihydrochloride hydrate
<tb> <SEP> <SEP> <SEP> ¹ <SEP> 2700 <SEP> 0
<tb> <SEP> ¯¯ <SEP> \ <SEP> <SEP> 27000
<tb> <SEP> N <SEP> N
<tb> <SEP> CH3 <SEP> CH3
<tb> <SEP> CH3N <SEP> / $ <SEP> NCH3
<tb> 33 <SEP> OH \ <SEP> <SEP> \ m-NWCO0O-NH <SEP> y <SEP> / CH3 <SEP> dihydrochloride hydrate
<tb> <SEP> N \ 0M \ <SEP> MM0 \ N <SEP> OH3 <SEP> 32000
<tb> <SEP> CH3 <SEP> CH3
<tb>
Table I (continued) Example Product Smp.

   * with decomposition
EMI6.1


<tb> <SEP> OH3-N <SEP> NCH3
<tb> <SEP> 34 <SEP> ¸ / -x \ NHCo <SEP>% <SEP> CH = <SEP> CH-CO-NHg <SEP> ¯C
<tb> <SEP> CH3NH <SEP> MX <SEP> \ 1hlorid-Hidrat <SEP> ¹ <SEP> · <SEP> NHCH3
<tb> <SEP> dihydrochloride hydrate <SEP>> 300 <SEP> C
<tb> <SEP> CH3-N <SEP> NCH3 <SEP> dihydrochloride
<tb> <SEP> 01I-0O-NH- 0
<tb> <SEP> 35 <SEP> 0 <SEP> -NH-0O CH <SEP> = <SEP> sesquihydrate
<tb> <SEP>> 30000
<tb> <SEP> H2N <SEP> NH2
<tb> <SEP> 36 <SEP> - <SEP> NH-CO-NH <SEP> HN <SEP> NH <SEP> dihydrochloride
<tb> <SEP> \ INH-CHs <SEP> H- <SEP> OH3 <SEP> 31000 <SEP> *
<tb> <SEP> 37 <SEP> HN <SEP> NH <SEP> dihydrochloride
<tb> <SEP> / \ <SEP> CONH \ <SEP> 30800 <SEP> *
<tb> H3CO- (CH2) sNH <SEP> NH (CH2)

  sOCH3
<tb> <SEP> 38 <SEP> HN <SEP> -NH-CO-- <SEP> -CO-NH-- <SEP> NH <SEP> dihydrochloride
<tb> <SEP> · / \ - 0 <SEP> NH-CO4CO-NH <SEP> 28000 <SEP> *
<tb> H3OO- (OH-NH <SEP> NH- (OH2) 3-O <SEP> OH3
<tb> <SEP> C1
<tb> <SEP> HsC2N <<SEP> NH-Cot3CO-NHO <SEP> N-O <SEP> 2H3 <SEP> dihydrochloride
<tb> <SEP> HSC2N <SEP> so2ä · \ CONH4 \ ¸o23 <SEP> NHCaH6
<tb> <SEP> H3CNf <SEP> <<SEP> <<SEP> NH <3NHX <SEP> dihydrochloride
<tb> <SEP> 40 <SEP> H <SEP> NH <SEP> N-OH3 <SEP> 3200 <SEP> C <SEP> *
<tb> <SEP> H3C- <SEP> 32000 <SEP> *
<tb> <SEP> 41 <SEP> HN¸ \ N <SEP> ITNW <SEP> 0O <SEP> 0NH - N <SEP> y <SEP> H <SEP> Base
<tb> <SEP> H2N <SEP> H2 <SEP>> 38000
<tb> <SEP> H3CN <SEP> NCH3 <SEP> dihydrochloride
<tb> <SEP> 42 <SEP> / NO <SEP> H3 <SEP> (NH-CH3 <SEP> 3300 <SEP> C
<tb> <SEP> -NH-CO <SEP> 0NH <SEP> ¯¯ <SEP> 33000
<tb> <SEP> H3O-NH <SEP> NH-0H3
<tb> <SEP> CH3
<tb> <SEP> H3C-N,

   <SEP> - <SEP> H3C-N <SEP> - <SEP> .N-C & <SEP> dihydrochloride
<tb> <SEP> NH-C <) <SEP> NH-CO <SEP>; '"" <SEP> CH3 <SEP> 34800
<tb> <SEP> H30-NH <SEP> ¸; <SEP> NH-OH3
<tb> <SEP> NO2
<tb> <SEP> NO2
<tb> <SEP> 44 <SEP> -N, CO-NH-C <SEP>, NCH3 <SEP> H3 <SEP> dihydrochloride
<tb> <SEP> H3 <SEP> O-N7 <SEP> to <SEP> \ == / <SEP> NH-OH3
<tb> <SEP> I
<tb> <SEP> C1
<tb>
Table I (continued) Example Product m.p. * with decomposition
EMI7.1


<tb> <SEP> NO2
<tb> <SEP> 45 <SEP> H30-N <SEP> NO2 <SEP> ¯¯¯ <SEP> dihydrochloride
<tb> <SEP> x -NH-rny) oo-7 <SEP> \> Co-NH4 <SEP> cC <SEP> \;

  N0H3 <SEP> 23000
<tb> H30 <SEP> 0- <SEP> (0H2Y3-NH <SEP> ¯¯ <SEP> \ = / <SEP> NH- (0H2) 3-O <SEP> OH3
<tb> <SEP> H30-N <SEP> N-0H3
<tb> <SEP> 46 <SEP> CO-NH - = - NH-CO-NH- / c <SEP> m <SEP> CHs <SEP> dihydrochloride
<tb> <SEP> .N-CH3 <SEP> 2950 <SEP> C
<tb> <SEP> H3C <SEP> CH3
<tb> <SEP> H30-N <SEP> -NH-CO- <SEP> / - <SEP> ONH-CO
<tb> <SEP> 47 <SEP> '<SEP> 3070 <SEP> C
<tb> <SEP> H30-N <SEP> N-OH3 <SEP> 30700
<tb> <SEP> H3C <SEP> I <SEP> CH3
<tb> <SEP> NH2
<tb> <SEP> C1
<tb> <SEP> H302-N <SEP> 1
<tb> <SEP> 48 <SEP> \\ <SEP> / <SEP> \ NHCO \ OONH \ / NOJIs <SEP> dihydrochloride
<tb> <SEP> H3 <SEP> 0 <SEP> 2NH'm \ <SEP> NH-O2H3 <SEP> C
<tb> <SEP> 49 <SEP> H5O2-N <SEP> N-O <SEP> 2H5 <SEP> dihydrochloride
<tb> <SEP> 49 <SEP> N> <NH-C04 <SEP> 3 <SEP> \ 3 <SEP> N \ C <SEP> H6
<tb> <SEP> HsC2 <SEP> O2H3
<tb> <SEP> C1
<tb> <SEP> HSCa-N <SEP> NH-COOCO¯NHA3 <SEP> N-02H5 <SEP>

  DihYdrOCh1Orid
<tb> <SEP> H30 <SEP> 3 / N <SEP> o2s <SEP> 313 <SEP> 0
<tb> <SEP> HsC2 <SEP> 02H5
<tb> <SEP> 51 <SEP> & C-N, Co-NH- <SEP> NH-CO-NH <SEP> 3 <SEP> NH-CO-NH <f <SEP>, N-CH3
<tb> <SEP> ü; ¸ \ iiCONHNH <SEP> 0ONHMX- \\ <SEP>
<tb> <SEP> H3O <SEP> O- (OH2) 3-NH <SEP> H (CH2) 3OCH2
<tb> <SEP> dihydrochloride <SEP> 2700 <SEP> C <SEP> *
<tb> <SEP> HCa-NCO-CO-NH - CaHs <SEP> dihydrochloride
<tb> <SEP> 52 <SEP> H2N0000 <SEP> H2 <SEP> 34000
<tb> <SEP> R ,, <SEP> N-O2H3
<tb> <SEP> 53 <SEP> H3O2NHYNHY¸NHOONHNHCONHMYN <SEP> HYNHO2H3
<tb> <SEP> H6C2NH <SEP> HC2H5
<tb> <SEP> dihydrochloride <SEP> 3200 <SEP> C <SEP> *
<tb> <SEP> 54 <SEP> H30-N <SEP> N-OH3 <SEP> N-CHs <SEP> CH3 <SEP> dihydrochloride
<tb> <SEP> H3ONH COM'NHiiCONH ¸ / NHOH3 <SEP> 23000 <SEP> *
<tb>
Table 1 (continued) Example Product Smp.

   * with decomposition
EMI8.1


<tb> <SEP> H302-N <SEP> OONH <SEP> \ / NO2HS <SEP> dihydrochloride
<tb> 55 <SEP> y -NH-0o-NHNH- <SEP> - <SEP> \ I / <SEP> \ I / <SEP> NH-O2H3 <SEP> 2800 <SEP> C <SEP> +
<tb> <SEP> HSC9N <SEP> ¯¯
<tb> <SEP> H5C2N \ vR <SEP> ONH-CO-NH <NH-CO-NH <SEP> 3 <SEP> NC2H5 <SEP> DihYdrOChIOrid
<tb> 56 <SEP> $ <SEP> CNH2 <SEP> 300 <SEP> N-O <SEP> 2H5 <SEP> C <SEP> +
<tb> <SEP> H2N <SEP> H2 <SEP> 30000 <SEP> *
<tb> <SEP> 11302N <SEP> N-02H5 <SEP> H <SEP> dihydrochloride
<tb> 57 <SEP> from <SEP> NilMM / \ <SEP> DihYdrOCh10rid
<tb> <SEP> H6Ca-N <SEP> 5
<tb> <SEP> MX <SEP> NH-02H3 <SEP> from <SEP> 33000 <SEP> *
<tb> <SEP> H30-N-0
<tb> <SEP> H3 <SEP> dihydrochloride
<tb> 58 <SEP> H3 <SEP> \ FNHY3NH-CO <SEP> OF <SEP> 34500 <SEP> DihYdrOCh10rid
<tb> <SEP> 3450 <SEP> C <SEP> +
<tb> <SEP> H30-N <SEP> CO-NH - MCO-NH-3;

  0YPCp "
<tb> 59 <SEP> CO-NH-e <SEP> / --- CO-NH- <SEP> 33000
<tb> <SEP> H2N <SEP> MX
<tb> <SEP> H703-N <SEP> N-03H7 <SEP> dihydrochloride
<tb> H2N <SEP> ONH-CO-NH <<SEP> NH-CO-NH <<<SEP> 3 <SEP> 7 <SEP> dihydrochloride
<tb> <SEP> H2N <SEP> H2 <SEP> 30000 <SEP> *
<tb> 61 <SEP> H7O3-N <SEP> N-O <SEP> 3H7 <SEP> dihydrochloride
<tb> -NH-0o-0o-NH <SEP> \ rn
<tb> <SEP> H, N / 'H, <SEP> 34000 <SEP> *
<tb> 62 <SEP> -NH-- <SEP> -CO-NH-- <SEP> b-CaH, <SEP> dihydrochloride
<tb> <SEP> ¯¯ <SEP> ¯¯ <SEP> ¯¯ <SEP> 33000 <SEP> *
<tb> <SEP> H2 <SEP> NH2
<tb> <SEP> H502-N <SEP> / \ / \ / \ / N02H5
<tb> 63 <SEP> \ N <SEP> HNHOONHNHCONHNHYNII <SEP> dihydrochloride
<tb> <SEP> H2N <SEP> 2 <SEP>> 34000 <SEP> *
<tb> Chemotherapeutic effect of the products
The following table II gives information about the tuberculostatic resp.

   antileukemic effect of products available according to the invention.



   The tuberculostatic effect was determined in vitro by measuring the lowest molar concentration (molecular weight in mg / ml) of the active ingredient which is just able to inhibit the growth of Mycobacterium tuberculosis. The values given in the second column correspond to the negative logarithm of this lowest molar inhibition concentration.



   The antileukemic effect was determined on mice in which leukemia had been induced artificially (Leukemia 210 *).



   Here, the survival time of the animals treated with a product obtained according to the invention was determined compared to untreated control animals, the average survival time of the controls being set at 100%. For example, a survival time of 200% achieved with the specified dose means that the treated leukemia animals survived twice as long as the untreated animals.



  * The information relates to the classification system used by the CCNSC
Table II Product tuberculo-antileukemic effect according to static dose i. p. survival example Effect mg / kg / day time%
3 6.0 15 200
4 7.0 1,200
5 7.0 3 155
6 7.0 8 175
7 7.3
8 7.0
9 4.8
10 7.4
14 5.8
16 5.0
17 5.6
18 4.8
19 6.1
20 15 160
24 6.5
27 7.2 30 181
28 6.8
29 6.0
30 7.2
31 6.9
32 6.1
33 5.5
34 7.2 3.7 248
35 6.9 60 233 Product Tuberculo- antileukemic effect according to static dose i. p. tSurvival Example Effect mg / kg / day time%
36 120 205
37 7.0 6 269
38 6.6 7.5 171
39 7.0 7.5 204
40 7.0 3.2 238
41 7.4
42 5.0
43 6.3
44 6.2
45 6.8
46 6.6
47 5.2
48 6.5
49 7.0
50 6.3
51 6.3
52 7.2
53 6.3
54 5.7
55 6.7
56 6.1 5 148
57 7.0 15 142
58 7.9
59 6.3
60 6.6
61 7.4
62 7.9 8 155
63 6.5

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung mehrbasischer Verbindungen der Formel: EMI9.1 oder von Säure-Additionssalzen davon, worin n 0 oder 1 ist und die Reste R basische Gruppen der Formel: EMI9.2 sind, in welcher R1 und R2 gleich oder verschieden sind und Wasserstoffatome, Alkoxyalkylgruppen oder gerade oder verzweigte Alkylgruppen mit höchstens 7 C-Atomen bedeuten und Rss Wasserstoff oder eine Alkylgruppe mit höchstens 6 C-Atomen bedeutet; A Phenylen, R4-substituiertes Phenylen, Phenylenamino, R4-substituiertes Phenylenamino, Phenylendiamino, R4-substituiertes Phenylendiamino oder Styrylen darstellt; PATENT CLAIM Process for the production of polybasic compounds of the formula: EMI9.1 or of acid addition salts thereof, in which n is 0 or 1 and the radicals R are basic groups of the formula: EMI9.2 are, in which R1 and R2 are identical or different and denote hydrogen atoms, alkoxyalkyl groups or straight or branched alkyl groups with at most 7 carbon atoms and Rss denotes hydrogen or an alkyl group with at most 6 carbon atoms; A is phenylene, R4-substituted phenylene, phenylenamino, R4-substituted phenylenamino, phenylenediamino, R4-substituted phenylenediamino or styrylene; R4 Halogen, Amino, Nitro, Hydroxy, Alkyl, Alkoxy, Alkylthio, Acylamino oder Aminocarbonyl bedeutet; dadurch gekennzeichnet, dass man eine Verbindung der Formel: EMI9.3 <tb> <SEP> / <SEP> (NH)n+NHC <SEP> O-A-O <SEP> ONH < 3/(NH)nCv <tb> Alkyl-O0-Alkyl <tb> worin n, A und R1 die genannte Bedeutung haben, mit einem Amin der Formel: EMI10.1 worin R9 und R5 die genannte Bedeutung haben, umsetzt, wobei man das Reaktionsprodukt in Form der freien Base oder eines Additionssalzes mit einer geeigneten anorganischen oder organischen Säure isoliert. R4 signifies halogen, amino, nitro, hydroxy, alkyl, alkoxy, alkylthio, acylamino or aminocarbonyl; characterized in that a compound of the formula: EMI9.3 <tb> <SEP> / <SEP> (NH) n + NHC <SEP> O-A-O <SEP> ONH <3 / (NH) nCv <tb> alkyl-O0-alkyl <tb> where n, A and R1 have the stated meaning, with an amine of the formula: EMI10.1 in which R9 and R5 have the meanings mentioned, reacted, the reaction product being isolated in the form of the free base or an addition salt with a suitable inorganic or organic acid.
CH601565A 1961-09-11 1961-09-11 Bis-anilides with basic substituents - having chemotherapeutic activity CH520657A (en)

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CH1273969A CH525896A (en) 1961-09-11 1961-09-11 Cyclic bis-amidine cpds - esp useful as tuberculostats
CH601565A CH520657A (en) 1961-09-11 1961-09-11 Bis-anilides with basic substituents - having chemotherapeutic activity
CH1274069A CH525897A (en) 1961-09-11 1961-09-11 Cyclic bis-amidine cpds - esp useful as tuberculostats
CH423470A CH525898A (en) 1961-09-11 1965-05-01 Cyclic bis-amidine cpds - esp useful as tuberculostats

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