Cephalosporins useful as antibacterial agents
View Patent ↗The present invention provides novel cephalosporin derivatives of formula I, their analogues, their use for the treatment of infections in mammals, pharmaceutical composition containing these novel compounds, and methods for the preparation of these compounds.
1. A compound of formula I
or a pharmaceutically acceptable salt thereof wherein:
R 1 is —NR 4 R 5 , —SO 2 R 6 , —C(═O)NR 4 R 4 , —SR 4 , —S(C═O)R 4 , —C 1-4 alkyl substituted with —SR 4 , —S(C═O)R 4 , —(═O)NR 4 R 5 , or —SO 2 R 6 ; or R 1 is —OC 1-8 alkyl substituted with —SR 4 , —S(C═OR 4 , —C(═O)NR 4 R 5 , or —SO 2 R 6 ;
R 2 and R 3 are independently —H, —OH, —CN, halo, —NO 2 , —C 1-10 alkyl, —OC 1-10 alkyl, —N(R 4 ) 2 ;
R 4 is —H or —C 1-10 alkyl;
R 5 is —SO 2 R 4 ′, —C(═)C 1-10 alkyl;
R 6 is H, C 1-6 alkyl, or NR 4 R 4 ;
at each occurrence, C 1-10 alkyl is optionally substituted with —OH, —CN, halo, —NO 2 , —OC 1-6 alkyl, —SH, —SC 1-4 alkyl, —S(C═O)C 1-4 alkyl, or —O(C═O)C 1-4 alkyl; and
n is 1, 2, or 3.
2. A compound of claim 1 wherein R 1 is —NR 4 R 5 , —SO 2 R 6 , or —C 1-4 alkyl substituted with —SR 4 , —S(C═O)R 4 , —C(═O)NR 4 R 5 , or —SO 2 R 6 .
3. A compound of claim 1 wherein R 1 is —C 1-4 alkyl substituted with —SR 4 , —S(C═O)R 4 , or —SO 2 R 6 .
4. A compound of claim 1 wherein R 1 is a methyl substituted with —SR 4 , —S(C═O)R 4 , or
—SO 2 R 6 .
5. A compound of claim 1 wherein R 1 is a methyl substituted with —SH, or —S(C═O)CH 3 .
6. A compound of claim 2 wherein R 1 is —NHC 1-6 alkyl substituted with —SH, —SC 1-4 alkyl, or —S(C═O)C 1-4 alkyl.
7. A compound of claim 1 wherein R 2 is H or C 1-4 alkyl.
8. A compound of claim 1 wherein R 2 is C 1-4 alkyl.
9. A compound of claim 1 wherein R 3 is H, OH, or C 1-6 alkyl optionally substituted with OH, CN, halo, NO 2 , OC 1-6 alkyl, SH, SC 1-4 alkyl, S(C═O)C 1-4 alkyl, or —O(C═O)C 1-4 alkyl.
10. A compound of claim 1 wherein R 3 is H or C 1-4 alkyl optionally substituted with OH, OC 1-4 alkyl, SH, or SC 1-4 alkyl.
11. A compound of claim 1 wherein R 1 is —NR 4 R 5 , —SO 2 R 6 , —C(═O)NR 4 R 4 , —SR 4 , —S(C═O)R 4 , —C 1-4 alkyl substituted with —SR 4 , —S(C═O)R 4 , —C(═O)NR 4 R 5 , or —SO 2 R 6 ; or R 1 is —OC 1-8 alkyl substituted with —SR 4 , —S(C═O)R 4 , —C(═O)NR 4 R 5 , or —SO 2 R 6 ; R 2 is H or C 1-4 alkyl; and R 3 is H or C 1-4 alkyl optionally substituted with OH, OC 1-4 alkyl, SH, or SC 1-4 alkyl.
12. A compound of claim 1 wherein R 1 is —NR 4 R 5 , —SO 2 R 6 , or —C 1-4 alkyl substituted with —SR 4 , —S(C═O)R 4 , —C(═O)NR 4 R 5 , or —SO 2 R 6 ; R 2 is H or C 1-4 alkyl; and R 3 is H or C 1-4 alkyl optionally substituted with OH, OC 1-4 alkyl, SH, or SC 1-4 alkyl.
13. A compound of claim 1 wherein R 1 is —C 1-4 alkyl substituted with —SR 4 , —S(C═O)R 4 , or —SO 2 R 6 ; R 2 is H or C 1-4 alkyl; and R 3 is H or C 1-4 alkyl.
14. A compound of claim 1 wherein R 1 is a methyl substituted with —SH, or —S(C═O)CH 3 ; R 2 is H or C 1-4 alkyl; and R 3 is H or C 1-4 alkyl.
15. A compound of claim 1 wherein R 1 is a methyl substituted with —SH, or —S(C═O)CH 3 ; R 2 is H or methyl; and R 3 is H or methyl.
16. A compound of claim 1 which is
1) (6R,7R)-3-{3-[(acetylsulfanyl)methyl]-2-methylbenzyl}-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
2) (6R,7R)-3-{4-[(acetylsulfanyl)methyl]-2-methylbenzyl}-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
3) (6R,7R)-3-{5-[(acetylsulfanyl)methyl]-2-methylbenzyl}-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
4) (6R,7R)-3-{3-[(acetylsulfanyl)methyl]-2,6-dimethylbenzyl}-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
5) (6R,7R)-3-{3-[(acetylsulfanyl)methyl]-5-(hydroxymethyl)-2,6-dimethylbenzyl}-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
6) (6R,7R)-3-{4-[(acetylsulfanyl)methyl]-2,6-dimethylbenzyl}-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7) (6R,7R)-3-(3-{[(acetylsulfanyl)acetyl]amino}-2-methylbenzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
8) (6R,7R)-3-(5-{[(acetylsulfanyl)acetyl]amino}-2-methylbenzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
9) (6R,7R)-3-(4-{[(acetylsulfanyl)acetyl](propyl)amino}benzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
10) (6R,7R)-3-(3-{[(acetylsulfanyl)acetyl](methyl)amino}benzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
11) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-(3-{[(methylsulfanyl)acetyl]amino}benzyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
12) (6R,7R)-3-(3-{[(acetylsulfanyl)acetyl]amino}benzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
13) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-{3-[propan-2-yl(sulfanylacetyl)amino]benzyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
14) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{2,3-dimethyl-5-[(methylsulfonyl)amino]benzyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
15) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{2,4-dimethyl-5-[(methylsulfonyl)amino]benzyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
16) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{3-[methyl(methylsulfonyl)amino]benzyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
17) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{3-[(methylsulfonyl)amino]benzyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
18) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{3-methoxy-5-[(methylsulfonyl)amino]benzyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
19) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{3-methyl-5-[(methylsulfonyl)amino]benzyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
20) (6R,7R)-3-(5-{[2-(acetylsulfanyl)ethyl]sulfamoyl}-2-methylbenzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
21) (6R,7R)-3-(3-{[2-(acetylsulfanyl)ethyl](ethyl)sulfamoyl}benzyl)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
22) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[2-methoxy-5-(methylsulfamoyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
23) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[3-(methylsulfamoyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
24) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[2-methyl-5-(methylsulfamoyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
25) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[3-(dimethylsulfamoyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
26) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[3-methoxy-5-(methylsulfamoyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
27) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[3-methyl-5-(methylsulfamoyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; or
28) (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-[2-methyl-4-(methylsulfonyl)benzyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.