Tricyclic carbacephems

Details Tricyclic carbacephems Tricyclic carbacephems

1997-05-16

2001-04-17

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S205000

Reexamination Certificate

active

06218379

ABSTRACT:

The present invention is concerned with compounds of formula I
wherein
R is hydrogen, unsubstituted lower (cyclo)alkyl or lower (cyclo)alkyl substituted by carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, phenylcarbamoyl or hydroxyphenylcarbamoyl; lower alkenylmethyl; lower alkenylmethoxycarbonyl; formyl; unsubstituted lower (cyclo)alkanoyl or lower (cyclo)alkanoyl substituted by halogen, cyano, carbamoyl-lower alkoxy, carbamoyl-lower alkylthio, or carbamoyl-lower alkylamino; unsubstituted lower (cyclo)alkylsulphonyl; or lower (cyclo)alkylsulphonyl substituted by halogen, cyano, carbamoyl-lower alkoxy, carbamoyl-lower alkylthio or carbamoyl-lower alkylamino; unsubstituted carbamoyl or carbamoyl substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl-lower alkyl, carboxy-lower alkyl, hydroxyphenyl or carbamoylphenyl; or a ring structure of the formula
Q—X—CO—  (a1)
or
Q—X—SO
2
—  (a2)
Q is a 5- or 6-membered ring optionally containing nitrogen, sulphur and/or oxygen and which is optionally substituted by lower alkyl, lower alkoxy, lower alkylthio, hydroxy, carbamoyl, carbamoyl methyl, carbamolyamino, hydroxy phenyl-carbamoyl, sulphamoyl, lower alkanoyloxy, sulphonyloxy, halogen, amino, methylamino, dimethylamino, chloroacetylamino, and pyridin-1-yl-acetylamino;
X is a direct bond or a group —CH
2
—, —CH
2
CH
2
—, —CH═CH—, —NH—, —NHCH
2
—, —CH
2
NH—, —CH(NH
2
)—, —CH
2
CH
2
NH—, —C(═NOCH
3
)—, —OCH
2
— or —SCH
2
—; and
A is a group of formula (b1) or (b2)
wherein
R
3
is unsubstituted aryl or aryl substituted by one or two substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl, lower alkoxy, aralkyl, —CONR
5
R
6
, —CH
2
—CONR
5
R
6
, —N(R
6
)COOR
7
, R
6
CO—, R
6
OCO— or R
6
COO— in which R
5
is hydrogen, lower alkyl or lower cycloalkyl; R
6
is hydrogen or lower alkyl; and R
7
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; an unsubstituted heterocyclyl; a heterocyclyl substituted by lower alkyl, lower alkoxy, halogen, halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio, carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted benzyl, lower alkenyl substituted phenyl, —CONR
5
R
6
, —CH
2
—CONR
5
R
6
, —N(R
6
)COOR
7
, R
6
CO—, R
6
OCO— or R
6
COO— in which R
5
is hydrogen, lower alkyl or lower cycloalkyl; R
6
is hydrogen or lower alkyl; and R
7
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; a heterocyclyl having a phenyl ring fused thereto, the heterocyclyl thereof being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, halo substituted alkyl, amino, mercapto, hydroxyl, carbamoyl, carboxyl, oxo, lower alkylthio, carbamoylmethyl, carbamoylamino, hydroxyphenylcarbamoyl, lower alkanoyloxy, methylamino, dimethylamino, chloroacetylamino, unsubstituted benzyl, lower alkoxy substituted benzyl, halo lower alkoxy substituted benzyl, or lower alkenyl substituted phenyl; and
R
4
is, hydrogen, hydroxy, lower (cyclo)alkyl, lower alkoxy, lower (cyclo)alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoyloxy, heterocyclyl or heterocyclylalkyl, with each of lower (cyclo)alkyl, lower alkoxy, lower (cyclo)alkenyl, aralkyl, aryl, aryloxy, aralkoyloxy or heterocyclyl being unsubstituted or substituted by carboxy, amino, nitro, cyano, lower alkyl, benzyl, lower alkoxy, hydroxy, halogen, —CONR
5
R
6
, —CH
2
—CONR
5
R
6
, —N(R
6
)COOR
7
, R
6
CO—, R
6
OCO— or R
6
COO— in which R
5
is hydrogen, lower alkyl or lower cycloalkyl; R
6
is hydrogen or lower alkyl; and R
7
is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group;
and pharmaceutically compatible, readily hydrolyzable esters and salts of these compounds.
European Patent Application EP-A-0 671 401 describes &bgr;-lactams which have &bgr;-lactamase inhibiting and, in part, also antibacterial properties. The compounds in accordance with the invention differ from these known compounds by the substituent A.
It has surprisingly been found that compounds in accordance with the invention have, in addition to their &bgr;-lactamase inhibiting properties, an improved spectrum of activity against gram-positive and gram-negative microorganisms and also against &bgr;-lactamase producing strains.
These compounds are useful in the control of &bgr;-lactamase forming pathogens in combination with &bgr;-lactam antibiotics such as the penicillins, cephalosporins, penems and carbapenems. They also have an antibacterial activity themselves and can accordingly also be used alone against bacterial pathogens.
Objects of the present invention are &bgr;-lactams of formula I above and pharmaceutically compatible salts thereof, the manufacture of these compounds, medicaments containing a compound of formula I or pharmaceutically compatible salt thereof as well as the use of compounds of formula I and of pharmaceutically compatible salts thereof for the production of medicaments for the control or prevention of infectious diseases, especially those which are caused by &bgr;-lactamase forming microorganisms.
The terms in brackets set forth in the definition of formula I, e.g. “lower (cyclo)alkyl”, “lower (cyclo)alkanoyl”, “lower (cyclo)alkyl-sulphonyl” are to be understood as being optional, and accordingly “lower alkyl”, “lower alkanoyl” and “lower alkylsulphonyl” as well as “lower cycloalkyl”, “lower cycloalkanoyl” and “lower cycloalkylsulphonyl” are intended.
The term “lower alkyl”, taken alone or in combinations, such as “lower alkoxy”, “lower alkylamino”, “lower alkylcarbamoyl”, “lower alkoxy carbonyl”, “lower alkanoyl” (=“lower alkylcarbonyl”), “lower alkylsulphonyl”, “lower alkylthio” and the like, is straight-chain or branched saturated hydrocarbon residues with 7, preferably 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and the like.
“Lower cycloalkyl”, taken alone or in corresponding combinations, is cyclic hydrocarbon residues with 3-6 hydrocarbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term “lower alkenyl”, taken alone or in combinations, such as “lower alkenylmethyl” and “lower alkenylmethoxycarbonyl” embraces unsaturated hydrocarbon residues with up to 7, preferably up to 4, carbon atoms, containing a double bond, such as vinyl, allyl and the like.
The term “lower alkynyl” embraces unsaturated hydrocarbon residues with up to 7, preferably up to 4, carbon atoms containing a triple bond, such as ethynyl, propargyl and the like.
“Halogen” is fluorine, chlorine, bromine or iodine, especially fluorine.
The “5- or 6-membered ring optionally containing nitrogen, sulphur and/or oxygen” set forth under R (residue Q) are e.g. phenyl, saturated heterocycles such as pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and tetrahydrofuryl, and aromatic heterocycles such as 2-furyl, 3-furyl, thiazolyl, thiadiazolyl, oxadiazolyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyridinio, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl and pyrimidinyl. The 5- or 6-membered ring optionally containing nitrogen sulfur and/or oxygen can also be substituted, e.g. by lower alkyl, lower alkoxy, lower alkylthio, hydroxy, carbamoyl, carbamoylmethyl, carbamoylamino, hydroxy phenyl carbamoyl, sulphamoyl, lower alkanoyloxy, sulphonyloxy, halogen, amino, methylamino, dimethylamino, chloroacetylamino and pyridin-1-yl-acetylamino as well as those additional substituents found on the heterocyclic ring as discussed below. Additional substituents include unsubstituted aryl or aryl substituted by one or two substituents selected from halogen, hydroxy, cyano, nitro, lower alkyl, lower alkoxy, aralkyl, —CONR
5
R
6
, —CH
2
—CONR
5
R
6
, —N(R
6
)COOR
7
, R
6
CO—, R
6
OCO— or R
6
COO— in which R5 signifies hydrog

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