Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-02-21
1996-11-19
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540302, C07D48708, A61K 3140
Patent
active
055763120
DESCRIPTION:
BRIEF SUMMARY
This invention relates to heterocylic compounds having antibacterial activity, to processes for their preparation, to compositions containing them and to their use in medicine.
In EPA No. 0416953A2 there is described 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0..sup.3.8 ]-undec-2-ene-2-carboxylic acid, and 4 substituted derivatives thereof, and salts and esters thereof, which compounds have antibacterial activity.
In EPA No. 0422596A2 there is described inter alia 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0..sup.3.8 ]-undec-2-ene-2-carboxylic and derivatives thereof and salts and metabolically labile esters thereof as having antibacterial activity.
We have now discovered a novel group of 4-substituted 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0..sup.3.8 ]-undec-2-ene-2-carboxylic acids and salts thereof which have useful antibacterial activity.
According to the present invention, therefore we provide compounds of general formula (I) ##STR2## salts and metabolically labile esters thereof; wherein R is a 5 or 6 membered nitrogen containing heteroaryl group which heteraryl group optionally contains 1 or 2 additional heteroatoms selected from nitrogen, oxygen or sulphur and said heteroaryl group is linked to the alkylene chain (CH.sub.2).sub.n via a nitrogen atom in the heteroaryl group;
In addition to the fixed stereochemical arrangement as defined in formula (I) the molecule contains a further asymmetric carbon atom at the 8-position, and another at the 4-position. It will be appreciated that all stereoisomers including mixtures thereof arising from these additional asymmetric centres, are within the scope of the compounds of formula (I).
Salts of compounds of formula (I) include base addition salts for use in medicine such salts are formed with bases that have a physiologically acceptable cation. Suitable cations include those of alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium), amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, and N-methyl glucosamine).
Salts derived from bases wherein the cation is not physiologically acceptable may be useful as intermediates for the preparation and/or isolation of other compounds of the invention, and these salts also form part of the invention.
When the group R contains a basic centre, acid addition salts of such compounds and internal salts formed with the carboxylic acid grouping are also included in the invention.
It will be appreciated that the compound of formula (I) may be produced in vivo by metabolism of a suitable metabolically labile ester. Examples of suitable metabolically labile esters include acyloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-methoxy-1-methyl-ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymetyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxycarbonyloxyethyl) or 1-(4-tetrahydropyranylcarbonyloxyethyl.
Examples of suitable heteroaryl groups R include triazole e.g. 1,2,3 triazole or 1,2,4 triazole, imidazole, pyrazole, pyridinium, pyrimidine, pyrazine, thiazole, thiazine, thiadiazole or triazine.
Where the heteroaryl ring contains a second nitrogen atom the invention also covers quaternary derivatives thereof such as C.sub.1-4 alkyl quaternary derivatives thereof.
The general formula (I) as drawn includes at least 4 stereoisomers and mixtures thereof and these may be represented by the formulae (1a, 1b, 1c and 1d). ##STR3##
The solid wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper.
The configuration shown for the carbon atom at the 8-position in formulae 1a and 1b is hereinafter referred to as the .beta
REFERENCES:
patent: 4962101 (1990-12-01), DiNinno et al.
patent: 4978659 (1990-12-01), DiNinno et al.
Greene, T. W. Protective Groups in Organic Synthesis (John Wiley, New York), pp. 152, 153, 169, and 170 (1981).
Carlesso Roberto
Holman Stuart
Perboni Alcide
Rossi Tino
Glaxo SpA
Shah Mukund J.
Wong King Lit
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