IE37096B1 - New penicillin compounds their production and their medicinal use - Google Patents

Abstract

1392850 Penicillins and intermediates therefor BAYER AG 23 Oct 1972 [23 Oct 1971 25 March 1972] 48700/71 Heading C2C Penicillins of the general formula or their salts in which C* is a carbon atom constituting a centre of chirality; A is a radical of one of the general formulµ (in which general formulµ X is Y is Q 1 is or a radical of formula and Q 2 is a radical of formula wherein R is a straight-chain or branched alkyl radical with up to 5 carbon atoms; R 1 is a hydrogen atom or an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical with up to 10 carbon atoms, or a vinyl, arylvinyl, mono-, di- or trihalo C 1-6 alkyl radical, or an H 2 N-, R-NH-, (R) 2 =N-, aryl -NH-, or aryl C 1-6 alkylamino radical or an alkoxy*, or aralkoxy* radical with up to 8 carbon atoms, or a cycloalkoxy* radical with up to 7 carbon atoms, or an aryloxy*, R-O-V-, R-S-V-, (R) 2 =N-CO-V- or a radical of formulµ V is a divalent organic radical with 1 to 3 carbon atoms; n is 0, 1, or 2; R 2 and R 3 which may be the same or different are each a hydrogen atom or an alkyl or alkenyl radical having up to 8 carbon atoms or a vinyl, allyl or propenyl radical, or a cycloalkyl or cycloalkenyl radical having up to 6 carbon atoms, or a mono-, di-, or tri-halogeno C 1-6 alkyl or aryl radical; R 4 , R 5 and R 6 which may be the same or different are each a hydrogen, nitro, nitrile, (R) 2 =N-, (R) 2 = N-CO-, R-CO-NH-, R-O-CO-, R-CO-O-, R, R-O, H 2 N-SO 2 -, chlorine, bromine, iodine, fluorine or trifluoromethyl radical; and G is a hydrogen atom. or a radical R; with the proviso that the meanings marked* are only available if X is not an -SO 2 - radical); Z is a - CO- or -SO- radical; and B is a radical of the general formula in which R 7 , Rs and R 9 are identical or different radicals selected from hydrogen, halogen, R-, R-O-, R-S-, R-SO-, R-SO 2 -, nitro(R 2 )=N-, R-CO-NH-, HO, and radicals and R is as above defined; and in which above general formulµ the arrow in the divalent linkage member ##Q2 means that the linkage of two atoms by the two free valencies of this linking member is not free to take place in either direction but only in the manner indicated by the arrow are prepared by (i) producing a reactive intermediate by reacting a carboxylic acid, a carboxylic acid salt, or a carboxylic acid silyl or hemisilyl ester of the general formulµ in an aqueous or anhydrous organic solvent when a compound of general formula a or b is reacted, or in an anhydrous inert organic solvent free of hydroxyl groups when a compound of general formula c or d is reacted, at - 70‹ to + 30‹ C., with either (a) a compound of one of the following general formulµ or (b) with a reaction product produced by the reaction of a compound of the general formula with about 1 mol. equivalent of thionyl chloride in an inert anhydrous organic solvent in the presence of at least one mol. equivalent of an organic base acting as an acid-acceptor at a temperature within the range - 40‹ to + 25‹ C.; the reaction product being reacted without prior isolation in the presence of a further mol. equivalent of a base, with about 1 mol. equivalent of the acid of formula (a), or in the presence of 0-1 mol. equivalent of a base, with about 1 mol. equivalent of a compound of formula b, c or d, at a temperature of - 40‹ to + 30‹ C., whereby the reactive intermediate produced is of the general formula (c) (only available for carboxylic acids of formula a) with about 1 mol. equivalent of a carbodiimide in a diluent and in the presence of about 1 mol. equivalent of a compound of Formula XIX whereby the reactive intermediate produced is of the general Formula XX the diluent being anhydrous and free of hydroxyl groups if a compound of the general formula is to be used in step (ii); and (ii) reacting the reactive intermediate with 6-aminopenicillanic acid of the general formula or silyl or disilyl-6-aminopenicillanic acid of Formula XXI and XXII in a solvent in the presence of a base when 6-aminopenicillanic acid is used, or in an anhydrous solvent free of hydroxyl groups when a compound of the Formula XXI or XXII is used, at a temperature in the range of - 70‹ to 50‹ C., to produce the desired penicillin compound, wherein Me<SP>n(+)</SP> is a cation of an n-valent alkali metal or alkaline earth metal or an aluminium cation; R 10 , R 11 and R 12 are the same or different C 1-6 alkyl radicals, R 13 can have any of the meanings given for R and can also be a phenyl radical; R 14 is a -(CH 2 ) 4 -, -(CH 2 ) 5 - or -(CH 2 ) 2 -O-(CH 2 ) 2 , radical; the groups U which can be the same or different are -C # N or -CO-O-C 1-6 alkyl radicals; and W is a halogen atom). Penicillins of the above general formula wherein B is as above defined except that it is not cyclohexadienyl and in which R 7 , R 8 and R 9 which may be the same or different, are each a hydrogen, halogen, R-, R-O-, R-S-, R-SO-, R-SO 2 -, nitro, (R) 2 =N, R-CO-NH, HO or R-CO-O- radical, R being as above defined, provided that when two of R 7 , R 8 and R 9 are hydrogen the other cannot be hydroxyl, and that all three of R 7 , R 8 and R 9 cannot at once be hydrogen, are stated to be novel. The carboxylic acids of formula (a) can be obtained from the amino acids of the general formula by reaction with compounds of the general formula A-Z-W(e), (in which A, B, Q 1 , Q 2 , R 1 , R 2 , X, Y, Z, C* and W are as defined above). Compounds of formulµ (e), (f), (g), (h) and (i) are prepared by conventional methods. Pharmaceutical compositions having antibacterial activity useful in human and veterinary medicine comprise the above penicillins and a carrier. The compositions may be administered orally, parenterally, rectally or topically in conventional pharmaceutical forms. The following starting materials are prepared; α[(3 - methyl - sulphonyl - imidazolidin - 2 - on- 1 - yl)carbonylamino] - phenylacetic acid, -4 - chloro - phenyl acetic acid, and -α- thienyl - (2) - acetic acid and 2,6 - dichlorophenyl acetic acids; α[(3-acetyl-imidazolidin- 2 - on - 1 - yl)carbonylamino] - phenyl acetic acid, -4 - chloro - phenylacetic acid, 4 - mothylphenyl acetic acid, -α - thienyl - (2) - acetic acid, 2,6 - dichloro - phenyl acetic acids, α - [(3 - ethylsulphonyl - imidazolidin - 2 - on- 1 - yl) carbonylamino] - phenyl acetic acid and -p - chlorophenyl acetic acid; and α[(3- methoxy carbonyl - imidazolidin - 2 - on - 1- yl) carbonylamino] - 4 - chlorophenylacetic and α-thienyl (2)-acetic acids. [GB1392850A]