Patent GB-1330151-A (GB)
Title: Substituted quinoxaline-di oxides and process of preparation thereof
IPC: A23K1/16
Filed: 1970-11-03
Abstract: 1330151 Quinoxaline-1,4-dioxides PFIZER Inc 3 Nov 1970 [18 March 1970 (2)] 52312/70 Heading C2C Novel compounds I, II and IIA in which X is a 6- or 7-position substituent and is H, Cl, Br, F, CH 3 , CH 3 O or CF 3 ; R 2  is 1-4 C alkyl, R 4  is 1-3 C alkyl; Z is Cl or Br; Z<SP>1</SP> is OH, OCOR, NH 2 , NHR 1  or NR 3 R 5 ; R is H, 1-3 C alkyl, phenyl, alkoxyphenyl or dialkylaminophenyl; R 1  is 1-4 C alkyl, benzoyl or substituted benzoyl; R 3  and R 5  are 1-2 C alkyl; Y is O, S or NR 6 ; R 6  is H or 1-4 C alkyl; and A is alkylene of 2-5 C which places at least 2 C between N and Y, N and Z or O and Z<SP>1</SP> or A is part of a 3-8 C cycloalkylene (A may be substituted by OH), are prepared (a) by reaction of an appropriate benzofuroxan with a compound III or IV: a compound H 2 N-A-Z(HZ) m  (m=0 or 1) and diketene; a compound R 4 COCH 2 COOAZ<SP>1</SP>; a compound R 4 -CO-CH 2 -CO-O-A-NR 1 - COO t-alkyl followed by hydrolysis; or a compound R 4 -CH 2 -CO-CO 2 -A-Z<SP>1</SP>; or (b) by reaction of a compound IX or XI with HO-A-Z<SP>1</SP>; or (c) by reaction of an X- substituted -2-cyano-3-R 2 -quinoxaline 1,4-dioxide with H 2 N-A-SH or H 2 N-A-NHR 6 - C 7 H 7 -SO 3 H; or (d) by reaction of an X-substituted-2-amido ether HCl-3-R 2 -quinoxaline- 1,4-dioxide with an appropriate alkylene diamine or thioalkylamine; or (e) by cyclizing compounds II to give compounds I. 2 - (Acetyloxy)ethyl - acetoacetate is prepared by reaction of 2-hydroxyethyl acetate and diketene. Other compounds CH 3 COCH 2 CO 2 AZ<SP>1</SP> are similarly prepared. N - (2 - Bromoethyl)acetoacetamide is prepared by reaction of diketene with 2-bromoethylamine HBr. Compounds CH 3 CO.CH 2 CO 2 -A-NR 3 R 5  are prepared by reaction of diketene and R 3 R 5 NA-OH. Compounds XII are prepared by reaction of the appropriate benzofuroxan with Compounds are prepared by reaction of diketene with HOA-NR 1 -COOC(CH 3 ) 3 . Compounds HO-A-Z<SP>1</SP> where Z<SP>1</SP> is -O 2 CR, are prepared by reaction of HO-A-OH with an appropriate amide. Compounds HO-A-Z<SP>1</SP> where Z<SP>1</SP> is substituted amino, are prepared by reaction of HO-A-halogen with an appropriate amine. Compounds NH 2 -A-Cl.HCl are prepared by reaction of NH 2 -A-OH.HCl with SOCl 2 . Compounds R 4 COCH 2 CO 2 -A-Z<SP>1</SP> are prepared by the reaction of Dorsch et al., J. Am. Chem. Soc., 54, 2960 (1932). Compounds XIII are prepared by reaction of the appropriate 2 - methyl - 1,3 - oxazacyclic compound with R 4 COCl in the presence of n-butyl-lithium. Compounds XIV are prepared by reaction of HOANH 2  with acetic acid. Compounds XV are prepared by reaction of H 2 N-A-NHR 1  with acetic acid. Compounds XVI are prepared by reaction of Cl-A-Cl with thioacetamide. Compounds XVII are prepared by reaction of the 2-cyano compounds with ethanol.  Compounds XVIII are prepared by reaction of the 2-methyl compound with R 2 COCl and n-butyl lithium. Compounds XIX are prepared by reaction of R 2 COCH 2 CN with an appropriate benzofuroxan. Pharmaceutical compositions comprise a compound I, II or IIA together with a suitable carrier and are useful as antibacterial agents.