Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
New monobactam antibiotics compounds which contain an 3-amino-azetidin-2-one ring and are active against gram-negative bacteria, wherein the compounds include the compound 2-(2-amino-thiazol-4-yl)-2-[(Z)-(1H,4H-1,5-dihydroxy-4-oxo-pyridin-2-yl)methoxyimino]-N-[3(S)-1-oxysulfonyl-2,2-dimethyl-4-oxo-azetidin-3-yl]acetamide.
1. A compound of the following formula Ia:
in which
Rz is SO 3 H
R2 and R3 are alkyl;
R4 is CH 2 Z, with Z having the formula
R5 signifies hydrogen, alkyl, halogenomethyl, dihalogenomethyl, trihalogenomethyl, alkoxy, formylamino or alkylcarbonylamino;
R6 signifies phenyl which may be substituted with 1 to 5 substituents selected from the group consisting of alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 4 substituents selected from the group consisting of alkyl, hydroxyl, alkoxy, amino, alkylamino, carbonylamino and halogen;
or a pharmaceutically acceptable salt or inner salt of said compound.
2. The compound of claim 1 , wherein R6 is an optionally amino-substituted and optionally chloro-substituted 5-6-membered heteroaromatic ring or pharmaceutically acceptable salt or inner salts of said compound.
3. The compound of claim 1 , wherein R5 is hydrogen or a pharmaceutically acceptable salt or inner salt of said compound.
4. The compound of claim 2 , wherein R6 is selected from the group consisting of 2-amino-1,3-thiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, 5-amino-1,2,4-oxadiazol-3-yl, 3-aminoisoxazol-5-yl, 5-amino-1-methylpyrazol-3-yl, 5-aminopyrazol-3-yl, 6-amino-2-pyridyl, 4-aminopyrimidin-2-yl, 2-carbonylamino-1,3-thiazol-4-yl, 2-amino-5-chloro-1,3-thiazol-4-yl and 2-thienyl; or a pharmaceutically acceptable salt or inner thereof of said compound.
5. A pharmaceutical composition comprising a compound claim 1 or a pharmaceutically acceptable salt or inner salt of said compound.
6. A compound of the following formula Ia:
in which
Rz is SO 3 H;
R2 and R3 are methyl;
R4 is CH 2 Z, with Z having the formula
R5 is hydrogen;
R6 is an amino-substituted and optionally chloro-substituted 5-membered heteroaromatic ring;
or a pharmaceutically acceptable salt or inner salt of said compound.
7. The compound of claim 6 wherein R6 is selected from the group consisting of 2-amino-1,3-thiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, 5-amino-1,2,4-oxadiazol-3-yl, 3-aminoisoxazol-5-yl and 2-amino-5-chloro-1,3-thiazol-4-yl;
or a pharmaceutically acceptable salt or inner salt of said compound.
8. The compound of claim 7 wherein R6 is 2-amino-1,3-thiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl or 2-amino-5-chloro-1,3-thiazol-4-yl;
or a pharmaceutically acceptable salt or inner salt of said compound.
9. The compound of claim 7 wherein R6 is 2-amino-1,3-thiazol-4-yl;
or a pharmaceutically acceptable salt or inner salt of said compound.
10. The compound of claim 7 wherein R6 is 2-amino-5-chloro-1,3-thiazol-4-yl;
or a pharmaceutically acceptable salt or inner salt of said compound.
11. The compound of claim 7 wherein R6 is 5-amino-1,2,4-thiadiazol-3-yl;
or a pharmaceutically acceptable salt or inner salt of said compound.
12. A pharmaceutical composition comprising a compound claim 6 or a pharmaceutically acceptable salt or inner salt of said compound.