Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-13
2003-03-11
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S302000
Reexamination Certificate
active
06531466
ABSTRACT:
This invention relates to exomethylene derivatives having antibacterial activity, to processes for their preparation, to compositions containing them and to their use in medicine.
European Patent Application publication No. 0416953A2 describes 10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7,2,0,0
3.8
]undec-1-ene-2-carboxylic acid and certain 4 substituted derivatives thereof, which have antibacterial activity.
European Patent Application publication No. 0422596A2 describes compound of the general formula
wherein R
1
is inter alia a 1-hydroxyethyl group, CO
2
R
2
is a carboxy group which may optionally be esterified and ring B is a cyclic group which may be optionally substituted. Ring B may inter alia be a six membered ring containing a single heteroatom selected oxygen, sulphur or nitrogen or a cyclohexane ring. The compounds have antibacterial activity.
The present invention relates to compounds which have a particularly advantageous profile of anti-bacterial activity, including good activity against gram positive micro-organisms such as methicillin resistant Staphylococcus aureus (MRSA) and methicillin resistant Staphylococcus epidermidis (MRSE).
Thus the present invention, provides compounds of general formula (I)
salts and metabolically labile esters thereof,
wherein R represents optionally substituted aryl or heteroaryl group;
A represents a propylene chain or A is a chain of 3 members one of which is selected from an oxygen or sulphur atom or the group NH or a substituted derivative thereof and the other two members are methylene groups.
In addition to the fixed stereochemical arrangement as defined in formula (I) the molecule contains a further asymmetric carbon atom at the bridged carbon atom to which A group is attached.
It will be appreciated that all stereoisomers including mixtures thereof arising from this additional asymmetric centre are within the scope of the compounds of formula (I). Further, in formula(I) the exocycle double bond can exist in trans(E) or cis(Z) configuration and the invention includes all such isomers and mixtures thereof. 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 group R contains a basic nitrogen atom the invention also includes acid addition salts and quaternary ammonium salts thereof. Such salts and quaternary ammonium salts include internal salts formed with the carboxylic acid group in the molecule.
Suitable acid addition salts are those formed with physiologically acceptable inorganic or organic acids. Examples of suitable quaternary ammonium salts are those formed by reaction of an appropriate compound of formula (I) or a protectived derivative thereof with a C
1-4
alkyl halide or carbamoyl C
1-4
alkyl halide or equivalent thereof.
It will be appreciated that the compounds of formula (I) may be produced in vivo by metabolism of a suitable metabolically labile ester. Such prodrugs include for example physiologically acceptable metabolically labile esters of compounds of the general formula (I). These may be formed by esterfication, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with, where appropriate, prior protection of any other reactive groups present in the molecule followed by deprotection if required.The types of esters grouping that may be used as metabolically esters are those widely used in pharmaceutical chemistry and are well known to those skilled in the art.
The compound of formula (I), salts thereof and metabolically labile esters thereof, may form solvates (e.g. hydrates) and the invention includes all such solvates.
The general formula (I) as drawn includes at least two stereoisomers and mixtures thereof may be represented by the formulae(1 a, 1b)
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 for the bridged carbon atom to which A is attached shown in formula (1 a) is hereinafter referred to as &bgr; configuration and in formula (1b) as the &agr; configuration. In the specific compounds named below the assignment of R or S configuration has been made according to the rules of Cahn. Ingold and Prelog,Experientia 1956 12, 81. Thus for example when A is a propylene chain the &bgr; configuration for the carbon at the 8 position corresponds to the S isomer and the &agr; configuration corresponds to the R isomer.
The term optionally substituted aryl as a group or part of a group when used herein refers to an optionally substituted phenyl, a phenyl fused to one 5 or 6 membered saturated or unsatured carbocyclic group to form a fused bicyclic carbocyclic group or a phenyl fused to two phenyl groups to form a fused tricyclic group. The term optionally substituted heteroaryl as a group or part of a group when used herein refers to a monocyclic, fused bicyclic or fused tricyclic heteroaryl group, which is attached to the carbon atom of the exocyclic double bond via a carbon atom member of the heteroaryl ring.
Example of suitable fused bicyclic carbocyclic groups include naphthyl, 1,2,3,4 tetrahydronaphthyl, indenyl or indanyl. The term fused tricyclic carbocyclic group preferably refers to a phenanthrene or antharacene
Suitable monocyclic heteroaryl groups includes a 5 or 6 membered heteroaryl group in which the 5-membered ring contains 1 or 2 heteroatoms selected from oxygen, sulphur or nitrogen and 6-membered ring containing 1 or 2 nitrogen atoms. Examples of such heteroaryl groups include furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyridinium, pyridazinyl, pyrimidinyl .
Suitable fused bicyclic heteroaryl groups contain 9 or 10 ring members having at least one heteroatom selected from oxygen, sulphur and nitrogen. Conveniently the fused bicyclic heteroaryl group contains from 1 to 3 hetero atoms and examples of such groups include quinolinyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, indolyl, benzothiazolyl, furylpyridine or oxazolopyridyl.
Suitable fused tricyclic hetoroaryl groups contain 13 or 14 ring members having at least one heteroatom selected from oxygen, sulphur and nitrogen. Examples of such groups include carbazolyl, &bgr;-carbolinyl, phenanthridinyl, acridinyl. Where the heteroaryl ring as above defined contains a basic nitrogen atom the invention also includes quaternary derivatives thereof such as C
1-4
alkyl, carbamoyl C
1-4
alkyl quaternary derivatives thereof. When A is chain 3 members and wherein one of the members is a group selected from oxygen, sulphur or NH (or a substituted derivative thereof) suitable examples of such chains include:
—OCH
2
CH
2
—, —CH
2
OCH
2
—, —SCH
2
CH
21
, —CH
2
SCH
2
—, CH
2
CH
2
S, NHCH
2
CH
2
, or —CH
2
NH—CH
2
—.
When a member of the chain A is a substituted NH group examples of suitable substitutents include C
1-4
alkyl (e.g methyl),benzyl, acetyl, C
1-4
alkoxycarbonyl, allyloxycarbonyl or an optionally substituted phenyloxycarbonyl group.
When R is a substituted phenyl group or a substituted monocyclic heteroaryl group these groups are substituted by one to 3 substituents which may be the same or different and selected from alkyl, optionally substituted alkenyl, alkynyl, halogen, cyano, nitro, trifluoromethyl, by one or two (CH
2
)
n
R
1
groups wherein n is zero or an integer from 1 to 4 and R
1
is hydroxy, C
1-4
alkoxy, C
1-4
alkanoyl-amino, NR
2
R
3
(wherein R
2
and R
3
independently represent hy
Andreotti Daniele
Biondi Stefano
Feriani Aldo
Finizia Gabriella
Gaviraghi Giovanni
Bacon & Thomas
Berch Mark L
GlaxoSmithKline SpA
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