Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-14
2001-05-15
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S222000
Reexamination Certificate
active
06232306
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to antibacterial compounds.
BACKGROUND OF THE INVENTION
Compounds of formula A
wherein
R
1
is hydrogen, C
1-6
-alkyl, C
1-6
-alkyl substituted by fluoro, or C
3-6
-cycloalkyl;
X is CH or N, and
R
5
is hydrogen,
and pharmaceutically acceptable salts thereof, especially (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, are potent antibacterial agents with activity against methicillin resistant staphylococci, both in vitro and in vivo. However, these compounds have limited solubility, not allowing bolus injections. It is therefore necessary to find derivatives of the compounds A to render these compounds suitable for parenteral and intramuscular application.
From J. Med. Chem. (1996), 39(2), 480-6; U.S. Pat. No. 5,466,81 1; Bioorganic and Medicinal Chem. Left. 1997,7,2909-2912; U.S. Pat. No. 5,610,314 (oxodioxolenyl)methyl carbamates are known to form derivatives of amines e.g. for fibrinogen receptor antagonists, ampicillin, norfloxacin and other pharmaceuticals. Furthermore, 2-(alkyloxycarbonyl)-2-alkylideneethyl esters have been described as prodrugs of carboxylic acids for cephalosporins, J. Antibiot. (1992), 45(8), 1358-64. Both types of derivatives have been used to improve the oral bioavailability of the corresponding drugs.
SUMMARY OF THE INVENTION
The present invention is concerned with new compounds of formula I
wherein
R
1
is hydrogen, C
1-6
-alkyl, C
1-6
-alkyl substituted by fluoro, or C
3-6
-cycloalkyl;
R
2
is hydrogen or a substituent selected from the group consisting of —CH
2
C(═CHR)—COOR, —CH
2
OCOR, —CH(R)OCOR, —CH(R)OCOOR, —CH(OCOR)OCOR, —CH
2
COCH
2
OCOR and
R
3
is hydrogen or a substituent selected from the group consisting of —CH
2
C(═CH
2
)—COOR, —COOCH
2
C(═CHR)—COOR, —COOCH
2
OCOR, —COOCH(R)OCOR, —COOCH(R)OCOOR, —COOCH(OCOR)OCOR, —COOCH
2
COCH
2
OCOR, and
with the proviso that one of R
2
and R
3
is hydrogen and the other is not hydrogen,
R is hydrogen or C
1-6
-alkyl;
R
4
is hydrogen or hydroxy,
R
5
is hydrogen or &ohgr;-hydroxyalkyl; and
X is CH or N,
pharmaceutically acceptable salts of the compounds and hydrates of the compounds of formula I and of their salts.
The present invention provides pharmaceutical preparations of a compound of formula I or the salts of the compounds or hydrates of the compounds or of their salts, and an inert carrier.
The present invention also provides for the use of a compound of formula I or the salts of the compounds or hydrates of the compounds or their salts, in the treatment or prophylaxis of infectious diseases.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that the compounds of formula I exhibit good solubility in water and in buffers at physiological pH. In vitro and in vivo they were readily converted to compounds of formula A. The formula I compounds can therefore be used for parenteral and intramuscular dosage application forms. The invention is thus also concerned with pharmaceutical preparations containing a compound of formula I and a therapeutically inert carrier.
As used herein “pharmaceutically acceptable salts” useful in this invention include salts derived from metals, salts derived from amino acids and salts of mineral or organic acids. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li+), sodium (Na+) and potassium (K+). Especially preferred is sodium. Other salts are derived from amino acids such as, for example, salts with arginine or lysine. Examples of salts of mineral acids are for example chlorides, sulphates or phosphates, and examples of salts of organic acids are mesylates (methylsulfonic acid salts), napsylates (naphthtene-2-sulfonic acid salts), besylates (benzenesulfonic acid salts), maleates, salicylates, tartrates, lactates, citrates, benzoates, succinates, acetates and the like. Especially preferred are chlorides, sulfates, phosphates, lactates and mesylates.
In the formulas represented herein, when substituents are illustrated as joined to the nucleus, a solid line (
) indicates that the substituent is in the &bgr;-orientation, that is, above the plane of the molecule, a broken line (
) indicates that the substituent is in the &agr;-orientation, that is, below the plane of the molecule, whereas the zigzagged line (
) indicates that the bond is either in &agr;- or in &bgr;-orientation.
The terms “C
1-6
-alkyl” and “C
1-6
-alkyl substituted by fluoro” refer to both straight and branched chain saturated hydrocarbon groups having 1 to 6 and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like. For “C
1-6
-alkyl substituted by fluoro”, a C
1-6
group is substituted by one or more fluorine atoms as, e.g., in fluoromethyl or trifluoromethyl.
As used herein, the term “&ohgr;-hydroxyalkyl” refers to both straight and branched chain saturated hydrocarbon groups as defined above bearing a hydroxy group in the terminal position, e.g. hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, preferably hydroxymethyl.
By the term “C
3-6
-cycloalkyl” is meant a 3-6 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular cyclopentyl.
Especially preferred compounds of formula I are the compounds of formula
wherein, R
1
, R
2
, R
3
, and X are as defined above and R
4
and R
5
are hydrogen, as well as pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I-a and of their salts.
Further preferred compounds are epimers and diastereoisomers of formula I-a.
Preferred compounds of formula I and formula I-a are compounds wherein R
1
is hydrogen, X is N and R
2
is hydrogen and R
3
is a group chosen from —CH
2
C(═CH
2
)—COOCH
2
CH
3
, —COO—CH
2
C(═CHCH
2
CH
3
)—COOCH
2
CH(CH
3
)
2
, and particularly
Further preferred compounds of formula I are compounds wherein R
1
and R
3
are hydrogen, X is N and R
2
is a group chosen from —CH
2
C(═CHCH
2
CH
3
)—COOCH
2
CH(CH
3
)
2
, —CH
2
C(═CH
2
)—COOCH
2
CH
3
, —CH
2
OCOC(CH
3
)
3
, —CH(CH
3
)OCOCH
3
, —CH(CH
3
)OCOOCH
2
CH
3
, —CH(OCOCH
3
)OCOCH
3
, —CH
2
COCH
2
OCOCH
3
, and
Especially preferred compounds of formula I and I-a are:
(6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1′-(5-methyl-2-oxo-[1,3]dioxol4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
(6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1′-(5-ethyl-2-oxo-[1,3]dioxol4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1);
(6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1′-(2-oxo-5-propyl -[1,3]dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1: 1);
(6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1′-(5-isopropyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1);
(6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-3-[(E)-(R)-1′-(5-tert-butyl-2-oxo-[1,3]dioxol4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxyl
Hebeisen Paul
Hubschwerlen Christian
Specklin Jean-Luc
Berch Mark L.
Ebel Eileen M.
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
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