Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-04-12
2003-05-20
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S203000, C540S205000
Reexamination Certificate
active
06566355
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates to bicyclic and tricyclic &bgr;-lactams and their pharmaceutically compatible salts.
SUMMARY OF THE INVENTION
The present invention is concerned with compounds having the formula
in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, the acyl residue of an &agr;- or &bgr;-amino acid or a residue of the formula
Q—X—Y— (a)
wherein Q signifies a 3- to 6-membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a fused ring, X signifies a direct bond or a linear “spacer” with up to 6 atoms consisting of carbon, nitrogen, oxygen and/or sulphur, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, and Y represents one of the groups —CO—, —CS—, —CONH— and (where X contains neither sulphur nor carbonyl as a terminal component) —SO
2
—; and in which R
1
signifies hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula —S—Het, wherein Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and R
2
represents the sulpho group —SO
3
H or R
1
and R
2
together signify a group of the formula,
wherein A represents hydrogen or a residue which is usable in the 3-position of cephalosporin antibiotics, and in which R
3
represents hydrogen or R
1
and R
3
together represent a group of the formula
═CH—R
a
(c)
wherein R
a
signifies one of the groups
—COR
b
(c
1
)
—CH
2
—OCOR
c
(c
2
)
—CH
2
—NR
d
R
e
(c
3
)
—CH
2
—S—Het (C
4
)
in which R
b
represents lower alkoxy or amino, R
c
represents lower alkyl, phenyl or amino, R
d
and R
e
each independently represent hydrogen or lower alkyl or R
d
and R
e
together with the N atom to which they are attached represent a 5- or 6-membered N-heterocycle which optionally contains a further nitrogen, oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen,
and pharmaceutically compatible salts of these compounds.
These compounds are novel and are distinguished by therapeutically valuable properties. In particular, they have pronounced &bgr;-lactamase inhibiting properties and are accordingly useful in combination with &bgr;-lactam antibiotics such as the penicillins and cephalosporins in the control of pathogens which form &bgr;-lactamase.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with compounds having the formula
in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, the acyl residue of an &agr;- or &bgr;-amino acid or a residue of the formula
Q—X—Y— (a)
wherein Q signifies a 3- to 6-membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a fused ring, X signifies a direct bond or a linear “spacer” with up to 6 atoms consisting of carbon, nitrogen, oxygen and/or sulphur, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, and Y represents one of the groups —CO—, —CS—, —CONH— and (where X contains neither sulphur nor carbonyl as a terminal component) —SO
2
—; and in which R
1
signifies hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula —S—Het, wherein Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and R
2
represents the sulpho group —SO
3
H or R
1
and R
2
together signify a group of the formula
wherein A represents hydrogen or a residue which is usable in the 3-position of cephalosporin antibiotics, and in which R
3
represents hydrogen or R
1
and R
3
together represent a group of the formula
═CH—R
a
(c)
wherein R
a
signifies one of the groups
—COR
b
(c
1
)
—CH
2
—COR
c
(c
2
)
—CH
2
—NR
d
R
e
(c
3
)
—CH
2
—S—Het (c
4
)
in which R
b
represents lower alkoxy or amino, R
c
represents lower alkyl, phenyl or amino, R
d
and R
e
each independently represent hydrogen or lower alkyl or R
d
and R
e
together with the N atom to which they are attached represent a 5- or 6-membered N-heterocycle which optionally contains a further nitrogen,
oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and pharmaceutically compatible salts of these compounds.
These compounds are novel and are distinguished by therapeutically valuable properties. In particular, they have pronounced &bgr;-lactamase inhibiting properties and are accordingly useful in combination with &bgr;-lactam antibiotics such as the penicillins and cephalosporins in the control of pathogens which form &bgr;-lactamase. Those of ordinary skill in the art will appreciate that &bgr;-lactamase inhibitors possess the ability to inactivate &bgr;-lactamase by blocking the sites of these enzymes.
The term “lower alkyl” taken alone or in combinations such as “lower alkoxy”, “lower alkylthio”, “lower alkylsulphinyl”, “lower alkylsulphonyl”, “lower alkoxycarbonyl”, “alkanoyloxy” and the like signifies straight-chain or branched saturated hydrocarbon residues with a maximum of 7, preferably a maximum of 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like. “Halogen” signifies all four halogens, viz., bromine, chlorine, fluorine, and iodine, but preferably chlorine or fluorine. “Amino” can also be substituted, for example, by lower alkyl, such as methylamino and dimethylamino. “5- or 6-membered N-heterocycle optionally contains a further nitrogen, oxygen or sulphur atom” can also be N- or C-substituted, for example, by lower alkyl. Examples of saturated heterocycles include pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl and thiomorpholinyl. Examples of aromatic heterocycles include residues which are derived from pyridine and (&agr;, &bgr; or &ggr;)-picoline, whereby a positive charge exists on the nitrogen atom (“zwitterion”). The term “Het” stands for a 5- or 6-membered heteroaromatic group such as for example, tetrazolyl, methyltetrazolyl, methylthiozolyl.
The R groups present in the compounds of formula I have the following significances a), b), c) and d):
a) Lower alkoxycarbonyl such as for example, methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl.
b) Lower alkoxycarbonylamino such as for example, methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino.
c) The acyl residue of an &agr;- or &bgr;-amino acid, which can be not only a natural amino acid, such as, for example, alanine, arginine, asparagine, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine, but also a non-natural amino acid, such as for example, an acyl group derived from &bgr;-alanine, ornithine, cystine, 3-hydroxyproline, 4-hydroxyproline, sarcosine, 2-(2-thienyl)-glycine, 2-(2-amino-4-thiazolyl)-glycine, 2-phenylglycine, p-hydroxyphenylglycine, m-hydroxyphenylglycine, o-fluorophenylglycine, m,p-dihydroxyphenylglycine or &agr;-aminocinnamic acid. The amino group can optionally be substituted, for example, by lower alkyl such as methyl or ethyl, by aryl, especially by phenyl (as in N-phenylglycyl), by acyl, especially by lower alkanoyl such as acetyl or propionyl, by benzoyl, benzyloxycarbonyl, t-butoxycarbonyl or N-heterocyclylcarbonyl such as (4-ethyl-2,3-dioxo-1-piperazinyl)-carbonyl or (4-hydroxy-6-methyl-3-pyridyl)-carbonyl. Of the acyl residues of &agr;- and &bgr;-amino acids those which are derived from an &agr;-amino acid are preferred.
d) A residue of the formula
Q—X—Y— (a)
wherein Q, X and Y are defined above.
Q preferably signifies a 5- or 6-membered (hetero)aromatic ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a further fused ring. Heteroaromatic rings generally contain 1-4 nitrogen atoms and/or 1-2 sulphur or oxygen atoms. Examples of (hetero)aro
Charnas Robert
Gubernator Klaus
Heinze Ingrid
Hubschwerlen Christian
Berch Mark L.
Ebel Eileen M.
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
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