ANTIBACTERIAL 3-PHOSPHONO PENAMS

摘要

1526149 3-Phosphono penams PFIZER Inc 20 Sept 1976 [6 Oct 1975 26 April 1976] 38950/76 Headings C2P and C2C The invention comprises compounds of formula wherein R1 is phenyl, phenoxy, 1,4-cyclohexadienyl, thienyl, hydroxyphenyl, (aminomethyl)phenyl; R2 and R3 are each H or Me; and Q is hydrogen, amino, carboxy or sulpho; with the provisos that: (i) when R1 is phenoxy or (aminomethyl)phenyl, then Q is hydrogen; (ii) when Q is carboxy, then R1 is phenyl or thienyl; and (iii) when Q is sulpho, then R1 is phenyl; and pharmaceutically acceptable salts thereof. Preparation of the above compounds is from their 6-aminopenam analogues (in which R2 is H, Me or trialkylsilyl, and R3 is Me) by reaction with an appropriate acylating agent (in which any amino group is protected, or replaced by azido), followed by removal of any aminoprotecting or trialkylsilyl groups or catalytic hydrogenation of any azido group. Any of the above steps may be preceded or followed by salification and/or by conversion of a dimethyl ester (R2 = R3 = Me) to a monomethyl ester (e.g. with LiI/py); and a final product which is a mono- or dimethyl ester may be demethylated (e.g. with LiI/py/Me 3 SiCl) to give the free acid (R2 = R3 = H) which may then be re-dimethylated (Ex. 38). Procedures for effecting all the foregoing reactions are discussed in extenso. Intermediates obtained in the above processes are 6 - (D - 2 - azido 2 - phenylacetamido) - 2,2- dimethyl - 3 - (O - methylphosphono)penam; 6 - {2 - [2 - (azidomethyl)phenyl]acetamido} - 2,2- dimethyl - 3 - (O - methylphosphono)penam; and their O,O - dimethylphosphono analogues (Exs. 12, 20, 35, 36). α - (Tritylamino) - 5,5 - dimethyl - 3 - thiazoline - 2 - acetic acid (see Specification 1,526,150) + dimethyl phosphite#α - (tritylamino) - 5,5 - dimethyl - 4 - (O,O - dimethylphosphono) - thiazolidine - 2 - acetic acid#6- (tritylamino) - 2,2 - dimethyl - 3 - (O,O - dimethylphosphono)penam (IV)#6 - amino - 2,2 - dimethyl - 3 - (O,O - dimethylphosphono)penam via the p-toluenesulphonate (Va) of the latter (Exs. 5, 6, 26). IV#6 - Tritylamino - 2,2 - dimethyl - 3 - (O- methylphosphono)penam#6 - amino - 2,2 - dimethyl - 3 - (O - methylphosphono)penam (VIII) via the p-toluenesulphonate of the latter (Exs. 7-9). Alternatively VIII is obtained from Va supra (Ex. 31). N - (2 - Methoxycarbonyl - 1 - methylvinyl) - D - 2 - phenylglycine Na salt and its 2 - (3- thienyl) analogue are prepared from D-2-phenyl- or D-2-(3-thienyl)-glycine by reaction with methyl acetoacetate (Exs. 15, 17). D - 4 - (1,4 - Cyclohexadienyl) - 1,3 - oxazolidine-2,5-dione is prepared from D-2-(1,4-cyclohexadienyl)glycine by reaction with COCl 2 (Ex. 18). Compounds I and their salts are credited with antibacterial activity, and may be used as animal feed supplements to promote growth.