Substituted clavulanic acid
The present invention relates to compounds of formula I and to compounds of formula II wherein the substituents have various meanings. These compounds are useful as beta lactamase inhibitors.
1. A compound of formula I
wherein
X is:
COOH or salts thereof,
COOR 1 , wherein R 1 is C 1-4 alkyl which is optionally substituted,
CONR 2 R 3 , wherein R 2 and R 3 independently represent H or C 1-5 alkyl, or C 5-6 cycloalkyl, which optionally contains one or more hetero atoms selected from O, S and N and/or is optionally substituted, or
CON(R 2 )—CH(R 4 )—R 5 , wherein
R 2 is as defined above,
R 4 is methyl or benzyl, and
R 5 is COOH or a salt thereof; COOR 1 , wherein R 1 is as defined above; or
CONR 2 R 3 , wherein R 2 and R 3 are as defined above,
Y and Y′ are both H or together represent ═O,
Z is O, NR 2 or N—CH(R 4 )—R 5 , wherein R 2 , R 4 and R 5 are as defined above,
n is 1 or 2,
m is a number from 0 to 4, and
R is H, or
a saturated or unsaturated chain containing 1 to 8 carbon atoms, which is optionally substituted by a 5 or 6-membered nonaromatic ring containing one or more hetero atoms selected from O, S and N, or by aryl, alkyl or cycloalkyl, optionally containing one or more hetero atoms selected from O, S and N, and/or is optionally substituted with one or more heteroatoms selected from O, S and N, halogens Cl, Br, I and F and/or azido N 3 .
2. The compound according to claim 1 , in a pharmaceutically acceptable salt form.
3. The compound according to claim 1 , wherein R 1 is methyl.
4. The compound according to claim 1 , wherein R 2 and R 3 are independently substituted C 1-4 alkyl or C 5-6 cycloalkyl.
5. The compound according to claim 1 , wherein R 4 is methyl.
6. The compound according to claim 1 , wherein R is a saturated or unsaturated chain containing 1 to 8 carbon atoms which is optionally substituted by an 5 or 6-membered nonaromatic ring, containing one or more hetero atoms selected from O, S and N, or by aryl, alkyl or cycloalkyl.
7. The compound according to claim 1 , wherein R is a saturated or unsaturated chain containing 1 to 8 carbon atoms which is substituted by one or more heteroatoms selected from O, S, and N, wherein the O and S heteroatoms are protected as esters, carbonates or ethers, and the N heteroatoms are alkylated or protected as amides or carbamates.
8. The compound according to claim 1 , having formula III
9. A pharmaceutical composition comprising a compound according to claim 1 , optionally further comprising a β-lactam antibiotic belonging to the class of penicillins or cephalosporins.
10. The compound according to claim 1 , wherein R 4 is benzyl.
11. A compound of formula I
wherein
X is
COOH or salts thereof,
COOR 1 , wherein R 1 is C 1-4 alkyl which is optionally substituted,
CONR 2 R 3 , wherein R 2 and R 3 ,
independently represent H, or C 1-5 alkyl, or C 5-6 cycloalkyl, which optionally contains one or more hetero atoms selected from O, S and N and/or is optionally substituted, or CON(R 2 )—CH(R 4 )—R 5 , wherein
R 2 is as defined above,
R 4 is methyl or benzyl, and
R 5 is COOH or a salt thereof; COOR 1 , wherein R 1 is as defined above; or
CONR 2 R 3 , wherein R 2 and R 3 are as defined above,
Y and Y′ together represent ═O,
Z is O, NR 2 or N—CH(R 4 )—R 5 , wherein R 2 , R 4 and R 5 are as defined above,
n is 1 or 2,
m is a number from 0 to 4, and
R is H, or
a saturated or unsaturated chain containing 1 to 8 carbon atoms, which is optionally substituted by a 5 or 6-membered nonaromatic ring containing one or more hetero atoms selected from O, S and N, or by aryl, alkyl or cycloalkyl, optionally containing one or more hetero atoms selected from O, S and N, and/or is optionally substituted with one or more heteroatoms selected from O, S and N, halogens Cl, Br, I and F and/or azido N 3 .
12. A compound of formula I
wherein
X is
COOH or salts thereof,
COOR 1 , wherein R 1 is methyl,
CONR 2 R 3 , wherein R 2 and R 3 are independently substituted C 1-4 alkyl or C 5-6 cycloalkyl, or
CON(R 2 )—CH(R 4 )—R 5 , wherein
R 2 is as defined above,
R 4 is methyl or benzyl and
R 5 is COOH or a salt thereof; COOR 1 , wherein R 1 is as defined above; or
CONR 2 R 3 , wherein R 2 and R 3 are as defined above,
Y and Y′ together represent ═O,
Z is O, NR 2 or N—CH(R 4 )—R 5 , wherein R 2 , R 4 and R 5 are as defined above,
n is 1 or 2,
m is a number from 0 to 4, and
R is H, or
a saturated or unsaturated chain containing 1 to 8 carbon atoms, which is optionally substituted by a 5 or 6-membered nonaromatic ring containing one or more hetero atoms selected from O, S and N, or by aryl, alkyl or cycloalkyl, optionally containing one or more hetero atoms selected from O, S and N, and/or is optionally substituted with one or more heteroatoms selected from O, S and N, halogens Cl, Br, I and F and/or azido N 3 .
13. A compound according to claim 1 of formula I
wherein
X is
CON(R 2 )—CH(R 4 )—R 5 , wherein
R 2 is substituted C 1-4 alkyl or C 5-6 cycloalkyl,
R 4 is methyl or benzyl, and
R 5 is
COOH or a salt thereof; COOR 1 , wherein R 1 is methyl; or CONR 2 R 3 , wherein R 2 and R 3 independently are substituted C 1-4 alkyl or C 5-6 cycloalkyl,
Y and Y′ are both H or together represent ═O,
Z is O, NR 2 or N—CH(R 4 )—R 5 , wherein R 2 , R 4 and R 5 are as defined above,
n is 1 or 2,
m is a number from 0 to 4, and
R is H, or
a saturated or unsaturated chain containing 1 to 8 carbon atoms, which is optionally substituted by a 5 or 6-membered nonaromatic ring containing one or more hetero atoms selected from O, S and N, or by aryl, alkyl or cycloalkyl, optionally containing one or more hetero atoms selected from O, S and N, and/or is optionally substituted with one or more heteroatoms selected from O, S and N, halogens Cl, Br, I and F and/or azido N 3 .
14. The compound according to claim 13 , wherein R 4 is benzyl.
15. The compound according to claim 13 , wherein R 4 is methyl.
16. The compound according to claim 5 in a pharmaceutically acceptable salt form.
17. The compound according to claim 11 in a pharmaceutically acceptable salt form.
18. The compound according to claim 12 in a pharmaceutically acceptable salt form.
19. The compound according to claim 13 in a pharmaceutically acceptable salt form.
20. The compound according to claim 10 in a pharmaceutically acceptable salt form.