Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-09-21
1995-06-20
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540302, A01N 4300, A61K 31395
Patent
active
054261040
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/00458, filed Mar. 2, 1992.
This invention relates to heterocyclic derivatives having antibacterial activity, to processes for their preparation, to compositions containing them, and to their use in medicine.
Thus the present invention provides compounds of the general formula (I) ##STR2## in which R.sub.1 represents a hydrogen atom or a hydroxyl protecting group; derived from an inorganic base or an organic base; represents a hydrogen atom and R.sub.5 represents a C.sub.1-4 alkyl group or R.sub.4 represents a C.sub.1-4 alkyl group and R.sub.5 represents a hydrogen atom;
Salts of compounds of formula (I) include acid addition salts of such compounds and internal salts formed with the carboxylic acid grouping (R.sub.2 =H).
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).
The compounds of formula (I) are antibacterial agents and/or of use as intermediates for the preparation of other active compounds within the general formula (I). Compounds wherein R.sub.1 represents a hydroxyl protecting group and/or wherein R.sub.2 represents a carboxyl protecting group are in general intermediates for the preparation of other compounds of formula (I).
Suitable hydroxyl protecting groups R.sub.1 and carboxyl protecting groups R.sub.2 include those which may be removed by hydrolysis under buffered conditions or under non-aqueous conditions.
When the group OR.sub.1 is a protected hydroxyl group this is conveniently an ether or an acyloxy group. Examples of particularly suitable ethers include those in which R.sub.1 is a hydrocarbylsilyl group such as trialkylsilyl, e.g. trimethylsilyl or t-butyldimethylsilyl. When the group OR.sub.1 represents an acyloxy group then examples of suitable groups R.sub.1 includes alkanoyl e.g. acetyl, pivaloyl; alkenoyl e.g. allylcarbonyl; aroyl e.g. p-nitrobenzoyl; alkoxycarbonyl e.g. t-butoxycarbonyl; haloalkoxycarbonyl e.g. 2,2,2-trichloroethoxycarbonyl, or 1,1,1-trichloro-2-methyl-2-propoxycarbonyl; aralkyloxycarbonyl e.g. benzyloxycarbonyl or P-nitrobenzyloxycarbonyl; or alkenyloxycarbonyl e.g. allyloxycarbonyl.
A particularly convenient protecting group R.sub.1 is t-butyldimethylsilyl.
Examples of suitable carboxyl protecting groups include arylmethyl groups such as benzyl, p-nitrobenzyl or trityl, or alkenyl groups such as allyl or substituted allyl, t-butyl, haloalkyl e.g. trichloroethyl or trialkylsilylalkyl e.g. trimethylsilylethyl. Preferred protecting groups R.sub.2 include arylmethyl e.g. benzyl or allyl.
Particularly useful compounds of formula (I) for use in medicine as antibacterial agents are those in which the group R.sub.1 represents a hydrogen atom and R.sub.2 represents a hydrogen atom or a physiologically acceptable cation, or an internal salt thereof; or acid addition salts of compounds wherein R.sub.2 represents a hydrogen atom. These compounds exhibit antibacterial activity against a wide range of gram positive and gram negative, aerobic and anaerobic pathogenic microorganisms.
Where R.sub.2 is 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).
Where R.sub.2 is a cation that is not physiologically acceptable then such compounds may be useful as intermediates for the preparation and/or isolation of other compounds of the invention.
Suitable acid addition salts of compounds of formula (I) include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, and phosphoric acid, organic acids such as acetic acid, maleic acid, fuma
REFERENCES:
patent: 4374848 (1983-02-01), Christensen
patent: 5068232 (1991-11-01), Ziegler, Jr. et al.
CA 62:7675e.
Green et al, Protective Groups in Organic Synthesis, 2nd edition, pp. 224-231.
Donati Daniele
Perboni Alcide
Tarzia Giorgio
Cook Rebecca
Glaxo SpA
Richter Johann
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