CH457454A - Process for the preparation of new diazacycloalkane compounds - Google Patents

Process for the preparation of new diazacycloalkane compounds

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Publication number
CH457454A
CH457454A CH1153464A CH1153464A CH457454A CH 457454 A CH457454 A CH 457454A CH 1153464 A CH1153464 A CH 1153464A CH 1153464 A CH1153464 A CH 1153464A CH 457454 A CH457454 A CH 457454A
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CH
Switzerland
Prior art keywords
radical
preparation
nitrothiazolyl
oxo
formula
Prior art date
Application number
CH1153464A
Other languages
German (de)
Inventor
Paul Dr Schmidt
Max Dr Wilhelm
Kurt Dr Eichenberger
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Ciba Geigy
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Publication date
Priority to NL293361D priority Critical patent/NL293361A/xx
Priority to DENDAT1245971D priority patent/DE1245971B/en
Priority to BE632989D priority patent/BE632989A/xx
Priority to NL123747D priority patent/NL123747C/xx
Priority to CH660462A priority patent/CH400171A/en
Priority to GB20497/63A priority patent/GB986562A/en
Priority to FR935808A priority patent/FR1360047A/en
Priority to BR149499/63A priority patent/BR6349499D0/en
Priority to CH1426567A priority patent/CH470413A/en
Priority to CH1426667A priority patent/CH459234A/en
Priority to BR162227/64A priority patent/BR6462227D0/en
Priority to FR985806A priority patent/FR1426946A/en
Priority to GB34566/64A priority patent/GB1065988A/en
Priority to DE1445632A priority patent/DE1445632C3/en
Priority to DE19641670441 priority patent/DE1670441C3/en
Priority to NL6410031A priority patent/NL6410031A/xx
Priority to BE652414A priority patent/BE652414A/xx
Priority to SE10366/64A priority patent/SE311905B/xx
Application filed by Ciba Geigy filed Critical Ciba Geigy
Priority to CH1153464A priority patent/CH457454A/en
Priority to FR995580A priority patent/FR3818M/en
Priority to FR995581A priority patent/FR3836M/en
Priority to GB42874/66A priority patent/GB1078314A/en
Priority to FR13751A priority patent/FR1463820A/en
Priority to GB16556/65A priority patent/GB1078312A/en
Priority to DE1545666A priority patent/DE1545666C3/en
Priority to NL6505225A priority patent/NL6505225A/xx
Priority to BR169146/65A priority patent/BR6569146D0/en
Priority to FR24837A priority patent/FR4613M/fr
Priority to FR24838A priority patent/FR4671M/fr
Priority to GB33845/65A priority patent/GB1075199A/en
Priority to IL24140A priority patent/IL24140A/en
Priority to GB35043/65A priority patent/GB1078313A/en
Priority to FR28478A priority patent/FR1459885A/en
Priority to DE1545693A priority patent/DE1545693C3/en
Priority to BR172735/65A priority patent/BR6572735D0/en
Priority to SE11467/65A priority patent/SE321232B/xx
Priority to ES0317062A priority patent/ES317062A1/en
Priority to NO159579A priority patent/NO120936B/no
Priority to AT1112465A priority patent/AT253502B/en
Priority to AT805365A priority patent/AT253501B/en
Priority to BE669083A priority patent/BE669083A/xx
Priority to NL656511486A priority patent/NL145552B/en
Priority to OA52175A priority patent/OA01812A/en
Priority to US485927A priority patent/US3299069A/en
Priority to FR36149A priority patent/FR89321E/en
Priority to BE671753A priority patent/BE671753A/xx
Priority to CY32865A priority patent/CY328A/en
Priority to FR38524A priority patent/FR4982M/fr
Priority to FR38523A priority patent/FR4981M/fr
Priority to NL6604864A priority patent/NL6604864A/xx
Priority to US564536A priority patent/US3298914A/en
Priority to US594403A priority patent/US3503989A/en
Priority to MY19662A priority patent/MY6600002A/en
Priority to SE518/67A priority patent/SE311910B/xx
Priority to SE519/67A priority patent/SE311911B/xx
Publication of CH457454A publication Critical patent/CH457454A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/58—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

  

  
 



  Verfahren zur Herstellung neuer   Diazacyeloalkanverbindungen   
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von   2-Oxo- 1,3 -diazacycloalkanaverbindun-    gen der allgemeinen Formel
EMI1.1     
 worin T einen gegebenenfalls substituierten   5-Nitro-    thiazolyl-2-rest, Z einen niederen Alkylenrest, der die beiden Stickstoffatome durch 2 bis 5, insbesondere durch 2 Kohlenstoffatome trennt und der durch einen oder mehrere gegebenenfalls substituierte Kohlenwasserstoffreste substituiert sein kann, und R einen Acylrest bedeutet.



   Als Kohlenwasserstoffreste sind insbesondere niedere Alkylreste, Phenylreste und Phenylniederalkylreste, wie Benzyl- oder Phenyläthylreste zu nennen. Als Substituenten der Phenyl- oder Phenylniederalkylreste kommen vor allem niedere Alkylreste, niedere Alkoxygruppen, wie Methoxy-,    thoxy-,    Propoxy- oder Butoxygruppen, Halogenatome, wie Chlor oder Brom, Tri  fluoromethylgruppenoder    Nitrogruppen in Betracht.



   Niedere Alkylreste sind oben und nachfolgend vorzugsweise solche mit höchstens 5 Kohlenstoffatomen, wie Methyl-,   Äthyl-,    Propyl-, Isopropyl-, Butyl-, Isobutyl- oder Pentylreste.



   Die neuen Verbindungen können auch in 4-Stellung des Thiazolringes substituiert sein, z. B. durch niedere Kohlenwasserstoffreste aliphatischen Charakters oder auch durch Arylreste, wobei die Arylreste ihrerseits z. B. wie angegeben substituiert sein können.



  Als niedere Kohlenwasserstoffreste aliphatischen Charakters kommen vor allem niedere Alkylreste in Frage, wie Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl- oder Pentylreste, ferner auch niedere   Alkenyfre-    ste, wie Allyl- oder Methallylreste. Die Arylreste sind vor allem Phenylreste.



   Der Rest Z ist z. B. ein Propylen-(1,3)-, Butylen  (1,4)-,    Pentylen-(1,5)- oder vor allem ein Äthylen  (1,2)-rest.    Diese Reste können wie angegeben substituiert sein, vor allem durch niedere Alkylreste. Z ist vorzugsweise der   Athylen-(1, 2)-rest.   



   Als Acylreste sind in erster Linie diejenigen von Carbonsäuren zu verstehen. In erster Linie kommen in Betracht die Acylreste aliphatischer Carbonsäuren, wie niederer Fettsäuren, z. B. Propionsäure, Buttersäure, Trimethylessigsäure, Valeriansäure, vor allem der Essigsäure, oder substituierter Fettsäuren, wie Halogen-fettsäuren, z. B. Mono- oder Dichloressigsäure oder Trifluoressigsäure. Als weitere Acylreste sind in Betracht zu ziehen die Reste aromatischer oder araliphatischer Carbonsäuren, wie von Benzoesäuren oder   Phenylalkan- oder -alkensäuren,    z. B. Phenylessigsäuren, Phenylpropionsäuren, oder Zimtsäuren, ferner die Acylreste heterocyclischer Carbonsäuren, z. B. von Pyridin-, Furan- oder Thiophen-carbonsäuren. Dabei können die aromatischen oder heterocyclischen Ringe dieser Carbonsäuren noch substituiert sein, z.

   B. durch Halogen, Niederalkoxy, Niederalkyl, Trifluormethyl, Nitro oder Amino.



   Die neuen Verbindungen besitzen wertvolle pharmakologische, insbesondere antiparasitäre und antibakterielle Eigenschaften. Sie zeigen vor allem eine Wirkung gegen Protozoen und Würmer und sind, z. B. am infizierten Tier, beispielsweise an Mäusen, gegen gramnegative Bakterien, z. B. Salmonella typhi oder Coli Bazillen, wie Esch. coli, wirksam. Insbesondere wirken die neuen Verbindungen, wie sich z. B. bei Versuchen an Hamstern zeigt, gegen Trichomonaden und Amoeben sowie, z. B. an Mäusen und Schafen, gegen Schistosomen. Ferner besitzen sie eine Wirkung gegen Coccidien. Die neuen Verbindungen sind entsprechend als antiparasitäre und antibakterielle Mittel nützlich. Insbesondere eignen sie sich zur Behandlung der durch die genannten Erreger verursachten Erkrankungen. Die  neuen Verbindungen sind aber auch wertvolle Zwischenprodukte für die Herstellung anderer nützlicher
Stoffe.



   Besonders hervorzuheben sind die Verbindungen der Formel
EMI2.1     
 worin   Rt    einen niederen Alkylrest, einen gegebenenfalls, z. B. wie oben angegeben, substituierten Phenylrest oder insbesondere ein Wasserstoffatom, R2 einen niederen Fettsäure- oder niederen Halogen-fettsäurerest, vor allem einen Fettsäurerest mit 2-5 Kohlenstoffatomen, in erster Linie den   Acetylrest    darstellt und   Zt    einen durch niedere Alkylreste substituierten oder insbesondere unsubstituierten   Propylen-(1,3)-      Butylen(1,4)-,    Pentylen-(1,5)- oder vor allem Äthylen  (1,2)rest    darstellt.



   Besonders wertvoll bezüglich ihrer biologischen Eigenschaften sind das   1- [5-Nitrothiazolyl-(2)]-2-oxo-      3 - acetyl-hexahydropyrimidin,    das   1- [5 -Nitrothiazolyl-      (2)] -2-oxo-3-acetyl- 1,3    -diazacycloheptan, vor allem aber das   l-[5-Nitrothiazolyl-(2)]-2-oxo-3-acetyl-tetra-    hydroimidazol.



   Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel
EMI2.2     
 worin T und Z die eingangs gegebenen Bedeutungen haben, N-acyliert. Hierzu kann man die 3-unsubstituierten Verbindungen in üblicher Weise mit Säuren oder ihren reaktionsfähigen Derivaten, vor allem den Halogeniden, wie Chloriden oder Bromiden, oder auch Anhydriden, ferner auch aktivierten Estern und Amiden umsetzen. Aktivierte Ester sind z. B. Ester mit Elektronen-anziehenden Strukturen, wie Ester von Phenol, Thiophenol, p-Nitrophenol, Cyanmethylalkohol und ähnlichen. Aktivierte Amide sind z. B. die N-Acylderivate von Pyrazolen, wie 3,5-Dimethyl-pyrazol oder Imidazolen, wie Imidazol selbst. Je nach der Natur der Acylierungskomponente kann die Verwendung eines Kondensationsmittels zweckmässig sein.

   So begünstigen disubstituierte Carbodiimide die Reaktion der Säuren, Basen, wie Pyridin oder Acylationen die Reaktion der Säureanhydride, und Basen, wie Pyridin oder Alkali, z. B. Soda, die Reaktion der Säurehalogenide.



   Die als Ausgangsstoffe verwendbaren Verbindungen der Formel
EMI2.3     
 sind bekannt oder können z. B. hergestellt werden, indem man eine Verbindung der allgemeinen Formel
EMI2.4     
 worin T die angegebene Bedeutung hat, Z einen niederen Alkylenrest, der X vom Stickstoffatom durch 2 bis 5 Kohlenstoff atome trennt und der durch einen oder mehrere gegebenenfalls substituierte Kohlenwasserstoffreste substituiert sein kann, und X eine reaktionsfähig veresterte Hydroxylgruppe, z. B. ein Halogenatom, wie Chlor, bedeutet, unter Abspaltung von Säure, intramolekular kondensiert.



   Zweckmässig verwendet man solche Ausgangsstoffe, die zu den eingangs als besonders wertvoll geschilderten Endstoffen führen.



   Die neuen Verbindungen können als Heilmittel, z. B. in Form pharmazeutischer Präparate, Verwendung finden, welche sie in Mischung mit einem für die enterale, parenterale oder topicale Applikation geeigneten pharmazeutischen organischen oder anorganischen, festen oder flüssigen Trägermaterial enthalten.



   Die eingangs genannten Verbindungen können aber auch zusammen mit gebräuchlichen   Futter- bzw.    Trägerstoffen in Form von   Veterinärpräparaten    oder als   Futter- bzw.    Futterzusatzmittel bei der Aufzucht von Tieren Verwendung finden.



   In den nachfolgenden Beispielen sind die Temperaturen in Celsiusgraden angegeben.



   Beispiel 1
10 g   1 - [5-Nitrothiazolyl-(2)]-2-oxo-tetrahydroiml-    dazol werden mit 50   ml    Acetanhydrid während 4 Stunden gekocht. Nach dem Abkühlen auf Zimmertemperatur filtriert man den ausgefallenen Niederschlag ab und kristallisiert ihn aus   Dimethylformamid-Äthanol    um. Man erhält so das   1-[5-Nitrothiazolyl-(2)]-2-oxo-    3-acetyl-tetrahydro-imidazol der Formel
EMI2.5     
 in gelben Kristallen vom F.   163-166 .   



   Beispiel 2
20,0 g   1- [5- Nitro - thiazolyl -      (2)]- 2-oxo-tetrahydro    imidazol und 80,0 g Chloressigsäureanhydrid werden zusammen während 4 Stunden auf   1200    erhitzt. Nach dem Abkühlen wird das Reaktionsgemisch mit 200   ml    Alkohol versetzt und filtriert. Den Rückstand kristallisiert man aus Dimethylformamid-Wasser um. Man erhält so das   l-[5-Nitro-thiazolyl-(2)]-2-oxo-3-(chlor-    acetyl)-tetrahydro-imidazol der Formel
EMI2.6     
 in Kristallen vom F.   170-173 .     



   Beispiel 3    10,0 0 g 1-[5-Nitro-thiazolyl-(2)]-2-oxo-tetrahydro-    imidazol werden mit 20,0 g   Benzoesäureanhydrid    während 4 Stunden unter gutem Rühren auf   1500    erhitzt.



  Das Reaktionsgemisch kristallisiert man dann aus Dimethylformamid um. Man erhält so das   1^15-Nitro-      thiazolyl-(2)1 -2-oxo-3 -benzoyl-tetrahydro-imidazol    der Formel
EMI3.1     
 in gelben Kristallen vom F.   2730.   



   Beispiel 4    10,0 g 1- [4-M e 4-Methyl-5-nitrothiazolyl-(2)] -2oxo-    tetrahydro-imidazol werden mit 50 ml Essigsäureanhydrid während 4 Stunden zum Kochen erhitzt. Nach dem Abkühlen fällt ein Niederschlag aus, den man aus Dioxan umkristallisiert. Man erhält so das 1-[4  Methyl-5-nitrothiazolyl-(2)] -2-oxo-3 -acetyl-tetrahy-    dro-imidazol der Formel
EMI3.2     
 das bei   213-2150    schmilzt.



   Beispiel 5
10,0 g   1 - [4-(p-Nitrophenyl)-5-nitro-thiazolyl-    (2)]-2-oxo-tetrahydro-imidazol und 50 ml Essigsäureanhydrid werden unter Rühren während 4 Stunden auf 1200 erwärmt. Nach dem Abkühlen wird der ausgefallene Niederschlag filtriert und aus Dimethylformamid Wasser umkristallisiert. Man erhält so das 1-[4-(p Nitrophenyl)-5-nitro-thiazolyl-(2)]-2-oxo-3-acetyl-tetrahydro-imidazol der Formel
EMI3.3     
 in gelben Kristallen vom F.   245-247 .   



   Beispiel 6    2, g 1 - [5-Nitrothiazolyl-(2)] -2-oxo-hexahydropyri-    midin werden in 5,0   ml    Dimethylformamid mit 5,0 ml Essigsäureanhydrid während 2 Stunden auf   1300    erhitzt. Nach dem Abkühlen gibt man 50   ml    Wasser zu und extrahiert mit 50   ml    Methylenchlorid. Die Methylenchlorid-Schicht wird abgetrennt und im Vakuum eingedampft. Es verbleibt ein kristalliner Rückstand von   1 - [5-Nitrothiazolyl- (2)] -2-oxo-3 -acetyl-hexahydro-    pyrimidin der Formel
EMI3.4     
 das nach Umkristallisation aus Methylenchlorid-Petrol äther bei   220-2230    schmilzt.



   Beispiel 7
10,0 g   1 - [5-Nitrothiazolyl- (2)]-oxo-tetrahydroimi-    dazol werden mit 50,0 g Buttersäureanhydrid während 4 Stunden auf 1500 erhitzt. Nach dem Abkühlen wird mit Äthanol versetzt und filtriert. Das Filtrat dampft man ein und kristallisiert den Rückstand aus Äthanol Wasser um. Man erhält das l-[5-Nitrothiazolyl  (2)] -2-oxo-3 -butyryl-tetrahydroimidazol    der Formel
EMI3.5     
 in gelben Kristallen vom F.   143-1450.      



  
 



  Process for the preparation of new diazacyeloalkane compounds
The invention relates to a process for the preparation of 2-oxo-1,3-diazacycloalkanaverbindun- compounds of the general formula
EMI1.1
 wherein T is an optionally substituted 5-nitrothiazolyl-2 radical, Z is a lower alkylene radical which separates the two nitrogen atoms by 2 to 5, in particular by 2 carbon atoms and which can be substituted by one or more optionally substituted hydrocarbon radicals, and R is a Means acyl radical.



   Hydrocarbon radicals that may be mentioned are, in particular, lower alkyl radicals, phenyl radicals and phenyl-lower alkyl radicals, such as benzyl or phenylethyl radicals. Particularly suitable substituents on the phenyl or phenyl lower alkyl radicals are lower alkyl radicals, lower alkoxy groups such as methoxy, thoxy, propoxy or butoxy groups, halogen atoms such as chlorine or bromine, trifluoromethyl groups or nitro groups.



   Lower alkyl radicals above and below are preferably those with a maximum of 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl radicals.



   The new compounds can also be substituted in the 4-position of the thiazole ring, e.g. B. by lower hydrocarbon radicals of aliphatic character or by aryl radicals, the aryl radicals in turn z. B. can be substituted as indicated.



  Lower alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl radicals, and also lower alkenyl radicals, such as allyl or methallyl radicals, are particularly suitable as lower hydrocarbon radicals of aliphatic character. The aryl radicals are primarily phenyl radicals.



   The remainder Z is e.g. B. a propylene (1,3) -, butylene (1,4) -, pentylene (1,5) - or especially an ethylene (1,2) radical. These radicals can be substituted as indicated, especially by lower alkyl radicals. Z is preferably the ethylene (1, 2) radical.



   Acyl radicals are primarily to be understood as meaning those of carboxylic acids. The acyl radicals of aliphatic carboxylic acids, such as lower fatty acids, e.g. B. propionic acid, butyric acid, trimethyl acetic acid, valeric acid, especially acetic acid, or substituted fatty acids such as halogen fatty acids, e.g. B. mono- or dichloroacetic acid or trifluoroacetic acid. Other acyl radicals to be considered are the radicals of aromatic or araliphatic carboxylic acids, such as benzoic acids or phenylalkanoic or alkenoic acids, e.g. B. phenylacetic acids, phenylpropionic acids, or cinnamic acids, also the acyl radicals of heterocyclic carboxylic acids, eg. B. of pyridine, furan or thiophene carboxylic acids. The aromatic or heterocyclic rings of these carboxylic acids can also be substituted, e.g.

   B. by halogen, lower alkoxy, lower alkyl, trifluoromethyl, nitro or amino.



   The new compounds have valuable pharmacological, in particular anti-parasitic and antibacterial properties. Above all, they show an effect against protozoa and worms and are, for. B. on the infected animal, such as mice, against gram-negative bacteria, e.g. B. Salmonella typhi or Coli bacilli such as Esch. coli, effective. In particular, the new compounds act as z. B. in experiments on hamsters shows against trichomonads and amoebas and, for. B. on mice and sheep, against schistosomes. They also have an effect against coccidia. The new compounds are accordingly useful as antiparasitic and antibacterial agents. In particular, they are suitable for treating the diseases caused by the pathogens mentioned. However, the new compounds are also valuable intermediates for the preparation of other useful ones
Fabrics.



   Particularly noteworthy are the compounds of the formula
EMI2.1
 wherein Rt is a lower alkyl radical, an optionally, z. B. as stated above, substituted phenyl radical or in particular a hydrogen atom, R2 is a lower fatty acid or lower halogen fatty acid radical, especially a fatty acid radical with 2-5 carbon atoms, primarily the acetyl radical and Zt is a substituted by lower alkyl radicals or, in particular, unsubstituted Propylene (1,3) - butylene (1,4) -, pentylene (1,5) - or especially ethylene (1,2) radical.



   Particularly valuable in terms of their biological properties are 1- [5-nitrothiazolyl- (2)] - 2-oxo-3-acetyl-hexahydropyrimidine, 1- [5-nitrothiazolyl- (2)] -2-oxo-3-acetyl - 1,3-diazacycloheptane, but especially l- [5-nitrothiazolyl- (2)] - 2-oxo-3-acetyl-tetrahydroimidazole.



   The inventive method for the preparation of the new compounds is characterized in that a compound of the general formula
EMI2.2
 where T and Z have the meanings given at the beginning, N-acylated. For this purpose, the 3-unsubstituted compounds can be reacted in the usual way with acids or their reactive derivatives, especially the halides, such as chlorides or bromides, or else anhydrides, and also activated esters and amides. Activated esters are e.g. B. Esters with electron-attracting structures such as esters of phenol, thiophenol, p-nitrophenol, cyanomethyl alcohol and the like. Activated amides are e.g. B. the N-acyl derivatives of pyrazoles, such as 3,5-dimethylpyrazole or imidazoles, such as imidazole itself. Depending on the nature of the acylation component, the use of a condensing agent may be appropriate.

   For example, disubstituted carbodiimides favor the reaction of the acids, bases such as pyridine or acylate ions favor the reaction of the acid anhydrides, and bases such as pyridine or alkali, e.g. B. Soda, the reaction of the acid halides.



   The compounds of the formula which can be used as starting materials
EMI2.3
 are known or can be e.g. B. be prepared by adding a compound of the general formula
EMI2.4
 wherein T has the meaning given, Z is a lower alkylene radical which separates X from the nitrogen atom by 2 to 5 carbon atoms and which may be substituted by one or more optionally substituted hydrocarbon radicals, and X is a reactive esterified hydroxyl group, e.g. B. a halogen atom, such as chlorine, means intramolecularly condensed with elimination of acid.



   It is expedient to use those starting materials which lead to the end materials described at the beginning as being particularly valuable.



   The new compounds can be used as remedies, e.g. B. in the form of pharmaceutical preparations, which contain them mixed with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral, parenteral or topical application.



   The compounds mentioned at the outset can, however, also be used together with common feed or carrier substances in the form of veterinary preparations or as feed or feed additives in the rearing of animals.



   In the following examples, the temperatures are given in degrees Celsius.



   example 1
10 g of 1 - [5-nitrothiazolyl- (2)] - 2-oxo-tetrahydroiml-dazole are boiled with 50 ml of acetic anhydride for 4 hours. After cooling to room temperature, the precipitate is filtered off and recrystallized from dimethylformamide-ethanol. The 1- [5-nitrothiazolyl- (2)] - 2-oxo-3-acetyl-tetrahydro-imidazole of the formula is obtained in this way
EMI2.5
 in yellow crystals from F. 163-166.



   Example 2
20.0 g of 1- [5-nitro-thiazolyl - (2)] - 2-oxo-tetrahydro-imidazole and 80.0 g of chloroacetic anhydride are heated together to 1200 for 4 hours. After cooling, the reaction mixture is mixed with 200 ml of alcohol and filtered. The residue is recrystallized from dimethylformamide / water. The l- [5-nitro-thiazolyl- (2)] - 2-oxo-3- (chloroacetyl) tetrahydro-imidazole of the formula is obtained in this way
EMI2.6
 in crystals from F. 170-173.



   Example 3 10.0 g of 1- [5-nitro-thiazolyl- (2)] - 2-oxo-tetrahydro-imidazole are heated to 1500 with 20.0 g of benzoic anhydride for 4 hours with thorough stirring.



  The reaction mixture is then recrystallized from dimethylformamide. The 1 ^ 15-nitro-thiazolyl- (2) 1 -2-oxo-3-benzoyl-tetrahydro-imidazole of the formula is obtained in this way
EMI3.1
 in yellow crystals from F. 2730.



   Example 4 10.0 g of 1- [4-M e 4-methyl-5-nitrothiazolyl- (2)] -2oxotetrahydro-imidazole are heated to the boil with 50 ml of acetic anhydride for 4 hours. After cooling, a precipitate separates out and is recrystallized from dioxane. This gives 1- [4 methyl-5-nitrothiazolyl- (2)] -2-oxo-3-acetyl-tetrahydro-imidazole of the formula
EMI3.2
 which melts at 213-2150.



   Example 5
10.0 g of 1 - [4- (p-nitrophenyl) -5-nitro-thiazolyl- (2)] - 2-oxo-tetrahydro-imidazole and 50 ml of acetic anhydride are heated to 1200 with stirring for 4 hours. After cooling, the deposited precipitate is filtered and recrystallized from dimethylformamide water. The 1- [4- (p-nitrophenyl) -5-nitro-thiazolyl- (2)] -2-oxo-3-acetyl-tetrahydro-imidazole of the formula is obtained in this way
EMI3.3
 in yellow crystals from F. 245-247.



   Example 6 2 g of 1 - [5-nitrothiazolyl- (2)] -2-oxo-hexahydropyrimidine are heated to 1300 in 5.0 ml of dimethylformamide with 5.0 ml of acetic anhydride for 2 hours. After cooling, 50 ml of water are added and the mixture is extracted with 50 ml of methylene chloride. The methylene chloride layer is separated and evaporated in vacuo. A crystalline residue of 1 - [5-nitrothiazolyl- (2)] -2-oxo-3-acetyl-hexahydropyrimidine of the formula remains
EMI3.4
 which, after recrystallization from methylene chloride-petroleum ether, melts at 220-2230.



   Example 7
10.0 g of 1 - [5-nitrothiazolyl- (2)] - oxo-tetrahydroimidazole are heated to 1500 with 50.0 g of butyric anhydride for 4 hours. After cooling, it is mixed with ethanol and filtered. The filtrate is evaporated and the residue is recrystallized from ethanol and water. The 1- [5-nitrothiazolyl (2)] -2-oxo-3-butyryl-tetrahydroimidazole of the formula is obtained
EMI3.5
 in yellow crystals from F. 143-1450.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von 2-Oxo-l,3-diazacy- cloalkanverbindungen der Formel EMI3.6 worin T einen gegebenenfalls substituierten 5-Nitrothiazolyl-2-rest, Z einen niederen Alkylenrest, der die beiden Stickstoffatome durch 2 bis 5 Kohlenstoffatome trennt und der durch einen oder mehrere gegebenenfalls substituierte Kohlenwasserstoffreste substituiert sein kann, und R einen Acylrest bedeutet, dadurch gekennzeichnet, dass man eine Verbindung der Formel EMI3.7 worin T und Z die angegebene Bedeutung haben, N-acyliert. PATENT CLAIM Process for the preparation of 2-oxo-1,3-diazacycloalkane compounds of the formula EMI3.6 wherein T is an optionally substituted 5-nitrothiazolyl-2 radical, Z is a lower alkylene radical which separates the two nitrogen atoms by 2 to 5 carbon atoms and which can be substituted by one or more optionally substituted hydrocarbon radicals, and R is an acyl radical, characterized in that that you can get a compound of the formula EMI3.7 where T and Z have the meanings given, N-acylated. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man die N-Acylierung mittels reaktionsfähigen Säurederivaten vornimmt. SUBCLAIMS 1. The method according to claim, characterized in that the N-acylation is carried out by means of reactive acid derivatives. 2. Verfahren nach Pntentanspruch, dadurch gekennzeichnet, dass man die N-Acylierung mittels einem Säurehalogenid vornimmt. 2. The method according to claim, characterized in that the N-acylation is carried out by means of an acid halide. 3. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man die N-Acylierung mittels einem Säureanhydrid vornimmt. 3. The method according to claim, characterized in that the N-acylation is carried out using an acid anhydride. 4. Verfahren nach Patentanspruch oder einem der Unteransprüche 1 bis 3, dadurch gekennzeichnet, dass man zur Herstellung von Verbindungen der Formel EMI4.1 worin RX einen niederen Alkylrest, einen gegebenenfalls substituierten Phenylrest oder Wasserstoff, .R2 einen niederen Fettsäure- oder Halogenfettsäurerest darstellt, und Zt einen durch niedere Alkylreste substituierten oder unsubstituierten Propylen-(1,3)-, Butylen (1, 4)-, Pentylen-(1,5)- oder Äthylen-(1 ;2)-rest darstellt, geeignete Ausgangsstoffe einsetzt. 4. The method according to claim or one of the dependent claims 1 to 3, characterized in that for the preparation of compounds of the formula EMI4.1 where RX is a lower alkyl radical, an optionally substituted phenyl radical or hydrogen, R2 is a lower fatty acid or halogenated fatty acid radical, and Zt is a propylene (1,3), butylene (1,4), pentylene substituted or unsubstituted by lower alkyl radicals - (1,5) - or ethylene (1; 2) radical, uses suitable starting materials. 5. Verfahren nach Patentanspruch oder einem der Unteransprüche 1 bis 3, dadurch gekennzeichnet, dass man zur Herstellung von Verbindungen der Formel EMI4.2 worin R2 einen niederen Fettsäure- oder Halogenfettsäurerest darstellt, und ZE einen durch niedere Alkylreste substituierten oder unsubstituierten Propy len-(1,3)-, Butylen-(1,4)-, Pentylen-(1,5)- oder Äthy len-(1,2)-rest -darstellt, geeignete Ausgangsstoffe einsetzt. 5. The method according to claim or one of the dependent claims 1 to 3, characterized in that for the preparation of compounds of the formula EMI4.2 where R2 is a lower fatty acid or halogenated fatty acid radical, and ZE is a propylene (1,3), butylene (1,4), pentylene (1,5) or ethylene substituted or unsubstituted by lower alkyl radicals (1,2) -rest represents, uses suitable starting materials. 6. Verfahren nach Patentanspruch oder einem der Unteransprüche 1 bis 3, dadurch gekennzeichnet, dass man zur Herstellung des 1-[5-Nitrothiazolyl-(2)]-2-oxo- 3-acetyl-tetrahydro-imidazols geeignete Ausgangsstoffe einsetzt. 6. The method according to claim or one of the dependent claims 1 to 3, characterized in that suitable starting materials are used for the preparation of 1- [5-nitrothiazolyl- (2)] - 2-oxo-3-acetyl-tetrahydro-imidazole. 7. Verfahren nach Patentanspruch oder einem der Unteransprüche 1 bis 3, dadurch gekennzeichnet, dass man zur Herstellung des 1-[5-Nitrothiazolyl-(2)]-2-oxo- 3 -acetyl-hexahydro-pyrimidins geeignete Ausgangsstoffe einsetzt. 7. The method according to claim or one of the dependent claims 1 to 3, characterized in that suitable starting materials are used for the preparation of 1- [5-nitrothiazolyl- (2)] - 2-oxo-3-acetyl-hexahydropyrimidine. 8. Verfahren nach Patentanspruch oder einem der Unteransprüche 1 bis 3, dadurch gekennzeichnet, dass man zur Herstellung des 1 -[5-Nitrothiazolyl-(2)]-2-o-xo 3-(chloracetyl)-tetrahydroimidazols geeignete Ausgangsstoffe einsetzt. 8. The method according to claim or one of the dependent claims 1 to 3, characterized in that suitable starting materials are used for the preparation of 1 - [5-nitrothiazolyl- (2)] - 2-o-xo 3- (chloroacetyl) tetrahydroimidazole.
CH1153464A 1962-05-30 1964-09-03 Process for the preparation of new diazacycloalkane compounds CH457454A (en)

Priority Applications (55)

Application Number Priority Date Filing Date Title
NL293361D NL293361A (en) 1962-05-30
DENDAT1245971D DE1245971B (en) 1962-05-30 Process for the preparation of new tetrahydro-imidazoles
BE632989D BE632989A (en) 1962-05-30
NL123747D NL123747C (en) 1962-05-30
CH660462A CH400171A (en) 1962-05-30 1962-05-30 Process for the preparation of new heterocyclic compounds
GB20497/63A GB986562A (en) 1962-05-30 1963-05-22 New 2-oxo-tetrahydro-imidazole compounds and processes for preparing them
FR935808A FR1360047A (en) 1962-05-30 1963-05-24 Process for the preparation of novel heterocyclic compounds, inter alia 1- [5-nitro-thiazolyl- (2)] - 2-oxo-tetrahydro-imidazole
BR149499/63A BR6349499D0 (en) 1962-05-30 1963-05-30 PROCESS FOR THE MANUFACTURE OF NEW HETEROCYCLIC COMPOUNDS
CH1426567A CH470413A (en) 1962-05-30 1963-08-30 Process for the production of new imidazoles
CH1426667A CH459234A (en) 1962-05-30 1963-08-30 Process for the production of new imidazoles
BR162227/64A BR6462227D0 (en) 1962-05-30 1964-08-08 PROCESS FOR THE PREPARATION OF NEW IMIDAZALS
FR985806A FR1426946A (en) 1962-05-30 1964-08-21 Novel imidazoles and process for their preparation
GB34566/64A GB1065988A (en) 1962-05-30 1964-08-24 New imidazoles and process for their preparation
DE1445632A DE1445632C3 (en) 1962-05-30 1964-08-25 1-square bracket on 5-nitrothiazolyl- (2) square bracket to-oxotetrahydroimidazole
DE19641670441 DE1670441C3 (en) 1962-05-30 1964-08-25 1 - (5-Nitro-2-thiazolyl) -2-oxotetrahydroimidazoles and processes for their preparation
NL6410031A NL6410031A (en) 1962-05-30 1964-08-28
BE652414A BE652414A (en) 1962-05-30 1964-08-28
SE10366/64A SE311905B (en) 1962-05-30 1964-08-28
CH1153464A CH457454A (en) 1964-09-03 1964-09-03 Process for the preparation of new diazacycloalkane compounds
FR995580A FR3818M (en) 1962-05-30 1964-11-19 New imidazole which can be used in therapy, in particular as an antischistosomal and antiamoebic agent.
FR995581A FR3836M (en) 1962-05-30 1964-11-19 New imidazoles which can be used in therapy, in particular as anti-schistosome and anti-amoebic agents.
GB42874/66A GB1078314A (en) 1962-05-30 1965-04-20 N-(5-nitrothiazolyl)-n'-halogenoalkyl-ureas and process for their manufacture
FR13751A FR1463820A (en) 1962-05-30 1965-04-20 New 2-oxo-1, 3-diaza-cyclo-alkanes and process for their preparation
GB16556/65A GB1078312A (en) 1962-05-30 1965-04-20 5-nitrothiazolyl-oxodiazacycloalkanes and process for their manufacture
DE1545666A DE1545666C3 (en) 1962-05-30 1965-04-21 1-square bracket to 5-nitrothiazolyl- (2) square bracket to -2oxo-hexahydropyrimidine
NL6505225A NL6505225A (en) 1962-05-30 1965-04-23
BR169146/65A BR6569146D0 (en) 1962-05-30 1965-04-23 PROCESS FOR THE MANUFACTURE OF 5-NITROTIAZOLYL-OXODIAZACYCLE-ALCANS
FR24837A FR4613M (en) 1962-05-30 1965-07-16
FR24838A FR4671M (en) 1962-05-30 1965-07-16
GB33845/65A GB1075199A (en) 1962-05-30 1965-08-06 New 2-oxo-tetrahydro-imidazole and processes for its preparation
IL24140A IL24140A (en) 1962-05-30 1965-08-11 5-nitro-thiazolyl-2-oxo-diazacyclo-alkane compounds and process for preparing same
GB35043/65A GB1078313A (en) 1962-05-30 1965-08-16 New diazacycloalkane compounds and process for preparing same
FR28478A FR1459885A (en) 1962-05-30 1965-08-17 Process for the preparation of new diaza-cyclo-alkanes
DE1545693A DE1545693C3 (en) 1962-05-30 1965-08-20 New Nltrothiazole Derivatives and Process for Their Preparation
BR172735/65A BR6572735D0 (en) 1962-05-30 1965-08-31 PROCESS FOR IMPROVING PROPERTIES FOR GROWING FORAGE FOR ANIMALS OR ADDITIVES FOR FORAGE FOR ANIMALS
SE11467/65A SE321232B (en) 1962-05-30 1965-09-02
ES0317062A ES317062A1 (en) 1964-09-03 1965-09-02 Procedure for the obtaining of compounds of 2-oxo-1,3-diazadicloalcanicos. (Machine-translation by Google Translate, not legally binding)
NO159579A NO120936B (en) 1962-05-30 1965-09-02
AT1112465A AT253502B (en) 1964-09-03 1965-09-02 Process for the preparation of new 2-oxo-1,3-diazacycloalkane compounds
AT805365A AT253501B (en) 1964-09-03 1965-09-02 Process for the preparation of new 2-oxo-1,3-diazacycloalkane compounds
BE669083A BE669083A (en) 1962-05-30 1965-09-02
NL656511486A NL145552B (en) 1962-05-30 1965-09-02 PROCESS FOR PREPARING 3- (5-NITRO-2-THIAZOLYL) -2-OXO-1,3-DIAZACYCLOALCANE COMPOUNDS WITH ANTIPARASITARY ACTION, PROCESS FOR PREPARING PHARMACEUTICAL PERPARES AS WELL AS THE PREPARATIONS OBTAINED.
OA52175A OA01812A (en) 1964-09-03 1965-09-03 Process for the preparation of new diaza-cyclo-alkanes.
US485927A US3299069A (en) 1962-05-30 1965-09-08 5-nitrothiazolyl oxo-diazacycloalkanes
FR36149A FR89321E (en) 1962-05-30 1965-10-26 Process for the preparation of novel heterocyclic compounds, inter alia 1- [5-nitro-thiazolyl- (2)] - 2-oxo-tetrahydro-imidazole
BE671753A BE671753A (en) 1962-05-30 1965-11-03
CY32865A CY328A (en) 1962-05-30 1965-11-06 New 2-oxo-tetrahydro-imidazole compounds and processes for preparing them
FR38524A FR4982M (en) 1962-05-30 1965-11-16
FR38523A FR4981M (en) 1962-05-30 1965-11-16
NL6604864A NL6604864A (en) 1962-05-30 1966-04-12
US564536A US3298914A (en) 1962-05-30 1966-07-12 Anti-parasitic 5-nitrothiazolyl oxodiazacycloalkane compositions
US594403A US3503989A (en) 1962-05-30 1966-11-15 N-chloro-aliphatic - n'-(5-nitrothiazolyl)-ureas and cyclized compounds thereof
MY19662A MY6600002A (en) 1962-05-30 1966-12-31 New 2-oxo-tetrahydro-imidazole compounds and processes for preparing them
SE518/67A SE311910B (en) 1962-05-30 1967-01-13
SE519/67A SE311911B (en) 1962-05-30 1967-01-13

Applications Claiming Priority (1)

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