Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-05-24
2003-07-29
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S048000
Reexamination Certificate
active
06600035
ABSTRACT:
This invention elates to novel chemical compounds, in particular to substituted-methylene) penems, and derivatives thereof, having &bgr;-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):
wherein R
a
, R
b
, R
c
and R
d
arm various substituent groups.
According to the present invention, novel penems of formula (I) are provided:
in which:
R
1
is hydrogen or an organic substituent group;
R
2
is a fused bicyclic heterocyclic ring system of general formula:
wherein R
4
and R
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
3
is hydrogen, a salt-forming cation or an ester-forming group; and the symbol ═/═ 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):
In general formula (I), R
1
denotes hydrogen or an organic group, which may suitably be linked through a sulphur or carbon atom. For example, R
1
may represent hydrogen or a group of formula —R
5
or —SR
5
, where R
5
denotes an unsubstituted or substituted (C
1
-C
10
)hydrocarbon or heterocyclyl group.
Preferably, R
1
represents hydrogen, (C
1
-
10
)alkyl or (C
1
-
10
)alkylthio, or substituted (C
1
-
10
)alkyl or substituted (C
1
-
10
)-alkylthio, wherein the substituent may be hydroxy, (C
1
-
6
)alkoxy, (C
1
-
6
)alkanoyloxy, halogen, mercapto, (C
1
-
6
)alkylthio, heterocyclylthio, amino, (mono or di)-(C
1
-
6
)alkylamino, (C
1-
6
)alkanoylamino, carboxy, or (C
1
-
6
)alkoxycarbonyl
Examples of suitable organic groups R
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
1
may be hydrogen.
Suitable groups R
2
include: 2,3-dihydroimidazo[2,1-b]thiazol-6yl, 2,3-dihydro-1-(R,S)-oxoimidazo[2,1-b]thiazolyl-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
4
and R
5
include(C
1
-
6
)alkanoyl, (C
1
-
6
)alkanoyloxy, heterocyclyl, amino, (C
1
-
6
)alkanoylamino, (mono or di)-(C
1
-
6
)alkylamino, hydroxy, (C
1
-
6
)alkoxy, sulpho, mercapto, (C
1
-
6
)alkylthio, (C
1
-
6
)alkylsulphinyl, (C
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
1
-
6
)alkyl, (C
2
-
6
)alkenyl, (C
2
-
6
)alkynyl, aryl, and aryl(C
1
-
6
)alkyl groups.
Examples of suitable optional substituents for the above-mentioned (C
1
-
6
)alkyl, (C
2
-
6
)alkenyl, (C
2
-
6
)alkynyl, aryl and aryl(C
1
-
6
)alkyl substitutents include (C
1
-
6
)alkanoyl, (C
1
-
6
)alkanoyloxy, heterocyclyl, amino, (C
1
-
6
)alkanoylamino, (mono or di)-(C
1
-
6
)alkylamino, hydroxy, (C
1
-
6
)alkylsulphinyl, (C
1
-
6
)alkylsulphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters,arylcarbonyl and heterocyclylcarbonyl groups.
Suitably R
4
and R
5
may both be hydrogen.
Suitable pharmaceutically acceptable salts of the 3-carboxylic acid group of the compound of formula (I) or of other carboxylic acid groups which may be present as optional substituents include those in which R
3
is a metal ion e.g. aluminium salts, alkali metal salts (e.g. sodium, lithium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesiun salts) ammonium salts, and substituted ammonium salts, for example those with lower alkylamines (e.g. triethylamine), hydroxy-lower alkylamines (e.g. 2-hydroxyethylamine), di(2-hydroxyethyl)amine, tri(2-hydroxyethyl)amine), bis-(2-hydroxyethyl)amine, tris-(2-hydroxyethyl)amine, lower-alkylamines (e.g. dicyclohexyl-amine), or with procaine, dibenzylamine,
N,N
-dibenzyl-ethylenediamine, 1-ephenamine,
N
-methylmorpholine,
N
-ethylpiperidine,
N
-benzyl-&bgr;-phenethylamine, dehydroabietylamine, ethylenediamine,
N,N
′-bishydroabietylethylenediamine, bases of the pyridine type (e.g. pyridine, collidine and quinoline), and other amines which have been or can be used to form quaternary ammonium salts with penicillins.
Pharmaceutically acceptable salts may also be acid addition salts of any amino or substituted amino group(s) that may be present as optional substituents on the compound of formula (I), or of any heterocyclic group ring nitrogen atoms. Suitable salts include for example hydrochlorides, sulphates, hydrogen sulphates, acetates, phosphates etc. and other pharmaceutically acceptable salts will be apparent to those skilled in the art. Suitable addition salts are the hydrochlorides and hydrogen sulphate.
Preferred salts are sodium salts.
When R
3
is an ester-forming group it may be a carboxylate protecting group or a pharmaceutically acceptable in-vivo hydrolysable ester.
Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions. Such groups for R
3
include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula —N═CHR
6
where R
6
is aryl or heterocyclyl, or an in vivo hydrolysable ester radical such as defined below.
A carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R
3
group, for example, acid-and base-catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups which R
3
may suitably comprise include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
wherein R
a
is hydrogen, (C
1-6
)alkyl, (C
3-7
)cycloalkyl, methyl, or phenyl, R
b
is (C
1-6
)alkyl, (C
1-6
)alkoxy, phenyl, benzyl, (C
3-7
)cycloalkyl, (C
3-7
) cycloalkyloxy, (C
1-6
)alkyl (C
3-7
)cycloalkyl, 1-amino (C
1-6
)alkyl, or 1-(C
1-6
alkyl)amino (C
1-6
)alkyl; or R
a
and R
b
together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R
c
represents (C
1-6
)alkylene optionally substituted with a methyl or ethyl group and R
d
and R
e
independently represent (C
1-6
)alkyl; R
f
(C
1-6
)alkyl; R
g
represents hydrogen or phenyl optionally substituted by up to three groups selected from
Broom Nigel John Perryman
Harrington Frank Peter
Dustman Wayne J.
Ford John M.
Kinzig Charles M.
SMithKline Beecham p.l.c.
Venetianer Stephen
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