Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-04-28
1997-02-11
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514210, C07D51906, A61K 3143
Patent
active
056022506
DESCRIPTION:
BRIEF SUMMARY
This is the national stage of PCT/EP93/02894, filed Oct. 20, 1993 under 35 U.S.C. .sctn.377.
This invention relates to novel chemical compounds, in particular to 6-(substituted-methylene) penems, and derivatives thereof, having .beta.-lactamase inhibitory and antibacterial properties. The invention also relates to methods for the preparation of such compounds, to pharmaceutical compositions containing them, and to uses thereof.
Compounds of this general type are disclosed in WO87/00525 having the structure (A): ##STR2## wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are various; substituent groups. EP 0154132 A and EP 0210065 A disclose compounds of formula (A) in which one of R.sup.c and R.sup.d is hydrogen and the other is respectively a 5-membered heteroaromatic ring or a non-aromatic heterocyclyl group.
According to the present invention, novel penems of formula (I) are provided: ##STR3##
in which: ##STR4##
wherein R.sup.4 and R.sup.5 are independently hydrogen or one or more substituents replacing hydrogen atoms in the ring system shown; m is 2 or 3; p is zero, 1 or 2; and R.sup.3 is hydrogen, a salt-forming cation or an ester-forming group; and the symbol .dbd./.dbd. indicates that the double bond may be in either the E or Z configuration.
The compound of formula (I), its salts and esters, may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric forms are encompassed within the scope of the present invention.
Moreover, the compounds of formula (I) may exist in two isomeric forms at the methylene group at the 8-position, ie the E- and Z- isomeric forms. The Z-isomer is generally preferred as generally being the more active form.
Consequently preferred forms of the compounds of the present invention have the structure (IA): ##STR5##
In general formula (I), R.sup.1 denotes hydrogen or an organic group, which may suitably be linked through a sulphur or carbon atom. For example, R.sup.1 may represent hydrogen or a group of formula --R.sup.5 or --SR.sup.5, where R.sup.5 denotes an unsubstituted or substituted (C.sub.1-10)hydrocarbon or heterocyclyl group.
Preferably, R.sup.1 represents hydrogen, (C.sub.1-10)alkyl or (C.sub.1-10)alkylthio, or substituted (C.sub.1-10)alkyl or substituted (C.sub.1-10)-alkylthio, wherein the substituent may be hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)alkanoyloxy, halogen, mercapto, (C.sub.1-6)alkylthio, heterocyclylthio, amino, (mono or di)-(C.sub.1-6)alkylamino, (C.sub.1-6)alkanoylamino, carboxy, or (C.sub.1-6)alkoxycarbonyl.
Examples of suitable organic groups R.sup.1 include methyl, ethyl, propyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, (1 or 2)-acetoxyethyl, aminomethyl, 2-aminoethyl, acetamidomethyl, 2-acetamidoethyl, carboxymethyl, 2-hydroxyethylthio, methoxymethylthio, 2-methoxyethylthio, acetoxymethylthio, 2-aminoethylthio, acetamidomethylthio, 2-acetamidoethylthio, carboxymethylthio, 2-carboxyethylthio, aryl (especially phenyl), arylthio (especially phenylthio), pyridyl, pyrimidyl, isoxazolyl, pyrimidylthio, tetrazolylthio, and pyridylthio groups.
In particular, R.sup.1 may be hydrogen.
Suitable groups R.sup.2 include: 2,3-dihydroimidazo[2,1-b]thiazol-6-yl, 2,3-dihydro-1-(R,S)-oxoimidazo[2,1-b]thiazol-6-yl, 2,3-dihydro-1,1-dioxoimidazo[2,1-b]thiazol-6-yl, 6,7-dihydro-5H-imidazo[2,1-b]-thiazin-2-yl and 6,7-dihydro-8,8-dioxo-5H-imidazo[2,1-b][1,3]thiazin-2-yl.
Examples of suitable substituents R.sup.4 and R.sup.5 include(C.sub.1-6)alkanoyl, (C.sub.1-6)alkanoyloxy, heterocyclyl, amino, (C.sub.1-6)alkanoylamino, (mono or di)-(C.sub.1-6)alkylamino, hydroxy, (C.sub.1-6)alkoxy, sulpho, mercapto, (C.sub.1-6)alkylthio, (C.sub.1-6)alkylsulphinyl, (C.sub.1-6)alkyl-sulphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters, arylcarbonyl, and heterocyclylcarbonyl groups, and also unsubstituted or substituted (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.2-6)alkynyl, aryl, and aryl(C.sub.1-6)alkyl
REFERENCES:
patent: 2541924 (1951-02-01), Jones
patent: 4798828 (1989-01-01), Osborne
patent: 5015473 (1991-05-01), Chen
Broom Nigel J. P.
Harrington Frank P.
Dustman Wayne J.
Kinzig Charles M.
Lentz Edward T.
Shah Mukund J.
SmithKline Beecham p.l.c.
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