Esters of {60 -aminobenzylpenicillin

Abstract

Abstract The invention comprises antibiotically active new esters of Alpha -aminobenzylpenicillin of the formula: IN WHICH THE ASTERISK INDICATES AN ASYMMETRIC CARBON ATOM; N IS AN INTEGER FROM 0 TO 5; AND A is an unsubstituted or substituted aliphatic, alicyclic, aromatic, or heterocyclic radical; the salts of said esters with pharmaceutically acceptable acids; and methods of preparing the esters and salts. This invention relates to a group of new esters of Alpha aminobenzylpenicillin, these esters having the formula IN WHICH THE ASTERISK INDICATES AN ASYMMETRIC CARBON ATOM; N IS AN INTEGER FROM 0 TO 5; AND A is an unsubstituted or substituted aliphatic, alicyclic, aromatic, or heterocyclic radical, to salts of these esters with pharmaceutically acceptable acids, and to methods of preparing these new esters. More particularly, A may represent an aliphatic hydrocarbon radical in which the carbon chain can be straight or branched, saturated or unsaturated, having from one to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec. and tert. butyl, pentyl, hexyl, and the like; an alicyclic, carbocyclic radical having from three to 10 carbon atoms as ring members, and in which the ring or rings may be saturated or may contain one or two double bonds depending on the number of carbon atoms, such as cyclopentyl, cyclohexyl, 1-adamantyl, 1-bicyclo(2.2.2)octyl, cyclopentenyl, cyclohexenyl, in which the double bond may be placed in the 2,3- or 3,4-position, and the like; an aromatic radical such as a monocyclic carbocyclic aryl radical, e.g., a phenyl or substituted phenyl radical, a bicyclic carbocyclic aryl radical, e.g. a 1- or 2napthyl or substituted naphthyl radical; a heterocyclic aryl radical, which may contain from five to 10 atoms as ring members, such as pyridyl, pyrazinyl, pyrimidyl, thienyl, furyl, or quinolyl, in which the hetero atom may be in any of the available positions, and which may further have substituents in one or more of the remaining positions. As already mentioned, the radical A may have further substituents, such as lower alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl and the like; lower alkoxy, e.g., methoxy, ethoxy and the like; lower alkylthio, e.g., methylmercapto or ethylmercapto; halo-lower alkyl, e.g., mono-, di- or trifluoromethyl, mono-, dior trichloromethyl or the ethyl homologues and the corresponding bromo derivatives; halogens, e.g., fluorine, bromine or chlorine; or nitro groups. The substituents may be placed in any possible positions. Salts of the new esters may be formed with inorganic acids, e.g., hydrochloric, hydrobromic, hydriodic acid and sulphuric acid and the like; and organic acids such as citric, tartaric, maleic acid and the like. Due to the asymmetric carbon atom in the side chain of the compounds of formula (I), these compounds exist in two epimeric forms, and the invention comprises both of the epimeric forms as well as mixtures thereof. The form, in which the compounds are obtained, depends on which of the epimeric starting materials and which coupling methods are used. The mixtures of the epimeric foRms may be separated by fractional crystallization or other known methods. It is known that the acid-resistant Alpha aminobenzylpenicillin is a broad-spectrum antibiotic with a widespread use. It is a disadcantage, however, that when orally administered, Alpha -aminobenzylpenicillin is insufficiently absorbed in the organism, and it is one object of the present invention to provide new antibiotically active derivatives of Alpha -aminobenzylpenicillin which, with a view to adequate absorption, distribution in the organism, and the like factors, are superior to Alpha -aminobenzylpenicillin. Acyloxymethyl esters of some penicillins are known, for instance from Dutch Pat. application No. 6,405,891, from which it appears that by oral administration such esters are practically not absorbed. An exception is the acetoxymethyl ester of benzylpenicillin, which to some degree is absorbed, giving rise to low but prolonged blood concentrations. It is therefore surprising that the compounds of the invention by oral administration give rise to extremely high concentrations of Alpha -aminobenzylpenicillin in blood and tissues due to an efficient absorption combined with a rapid hydrolysis in the organism. Table I below shows that the concentrations obtained in the blood and various organs, such as liver, lungs, kidneys and spleen, are considerably higher after administration of the pivaloyloxymethyl ester of D(-)- Alpha -aminobenzylpenicillin than after administration of a corresponding dose of D(-)- Alpha -aminobenzylpenicillin.

Inventors

• 👤 Erling Knud Frederiksen
• 👤 Wagn Ole Godtfredsen

Bibliographic Details