Substituted nitroimidazoles

  • Inventors:
  • Assignees: Merck & Co Inc
  • Publication Date: May 09, 1973
  • Publication Number: GB-1316221-A

Abstract

1316221 Nitroimidazoles MERCK & CO Inc 6 Jan 1971 [7 Jan 1970] 667/71 Heading C2C The invention comprises compounds I (in which R 1 =H, alkyl or CH 2 CH 2 OH and R = a ring of Formula II, III or IV in which Y = alkyl or benzyl, each of R 2 and R 3 = H, alkyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, phenyl, alkylamino or dialkylamino, provided that if R 3 =H, R 2 also = H, or R 2 and R 3 together form a bivalent ring-forming radical of formula -(CH 2 ) n -, where n=3 to 10, -(CH 2 ) q -O-, where q= 2 or 3, where r= 1 to 4, where Z=H or benzoyl or a group of Formula V where m s 1, 2 or 3 and p s 1 or 2, and each of R 4 and R 5 = H, alkyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, phenyl, alkylamino or phenylamino, provided that if R 5 =H, R 4 also=H, or R 4 and R 5 together form a bivalent ring-forming radical of formula -(CH 2 ) n - where n= 3 to 10). The compounds I in which R = a ring of Formula II (i.e. the isoxazoline derivatives) are prepared by reacting an olefin of formula R<SP>1</SP> 2 CH = CHR<SP>1</SP> 3 , in which R<SP>1</SP> 2 and R<SP>1</SP> 3 are as defined above for R 2 and R 3 except that neither of them is amino, alkylamino or dialkylamino, with a hydroxamoyl chloride of Formula VI (in which R<SP>1</SP> is H, alkyl or #-acetoxyethyl) followed by the further steps set forth below when R 1 is to be CH 2 CH 2 OH and/or R 4 and/or R 5 is to be amino, alkylamino or dialkylamino. The compounds I in which R = a ring of Formula IV (i.e. the isoxazole derivatives) are prepared by reacting an acetylene of formula R<SP>1</SP> 4 -C#C-R<SP>1</SP> 5 in which each of R<SP>1</SP> 4 and R<SP>1</SP> 5 is H, alkyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or phenyl with a compound of Formula VI. Followed by the further steps set forth below when R 1 is to be #-hydroxyethyl and/or R 4 and/or R 5 is to be amino, alkylamino or dialkylamino. When R 4 and R 5 in the product are together to be -(CH 2 ) n -, the actylene is replaced by a 1- morpholino-substituted olefin of Formula VII and the resulting product of Formula VIII is then subjected to acid hydrolysis. The compounds I in which R=a ring of Formula III (i.e. the oxazolidine derivatives) are prepared by reacting an olefin of formula R<SP>1</SP> 2 CH = CHR<SP>1</SP> 3 with a nitrone of Formula IX followed by the further steps set forth below when R 1 is to be CH 2 CH 2 OH and/or R 4 and/or R 5 is to be amino, alkylamino or dialkylamino. When a compound in which R 1 is CH 2 CH 2 OH a starting material in which R<SP>1</SP> is #-acetoxyethyl is used and the #-acetoxyethyl group in the product is hydrolysed to the CH 2 CH 2 OH group. When a compound in which one or two of R 2 , R 3 , R 4 and R 5 is desired, a starting material in which one or two of R<SP>1</SP> 2 , R<SP>1</SP> 3 , R<SP>1</SP> 4 and R<SP>1</SP> 5 is alkoxycarbonyl or carbamoyl is used and this group is converted to the free NH 2 group via the groups COOH, COCl, CON 3 , NCO groups. The free amino group can then be alkylated if desired. Compounds of Formulae VI and IX are prepared by reacting a 1-R<SP>1</SP>-5-nitro-imidazole with paraformaldehyde to form a 1-R<SP>1</SP>-2-hydroxymethyl - 5 - nitro - imidazole, oxidizing this to form a 1 - R<SP>1</SP> - 2 - formyl - 5 - nitro - imidazole and reacting this with (a) a substituted hydroxylamine of formula Y-NHOH to give a nitrone of Formula IX, or (b) hydroxylamine itself to give a hydroxylimine and reacting this with NOCl to give a hydroxamoyl chloride of Formula VI. 1 - Alkyl - 5 - nitro - imidazoles are prepared by alkylation of 5-nitro-imidazole. 1 - (2 - Acetoxyethyl) - 5 - nitro - imidazole is prepared by reacting 5-nitro-imidazole with 2- ethoxyethyl tosylate to form 1-(2-ethoxyethyl)- 5-nitro-imidazole, hydrolysing this to form 1-(2- hydroxyethyl) - 5 - nitro - imidazole and esterifying this with acetic anhydride. Antibacterial and antiprotozoal compositions, for oral, topical or parenteral administration, comprise a compound I together with a pharmaceutical carrier.

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