Broad spectrum beta-lactamase inhibitors

1. A compound of formula I:

or a pharmacologically acceptable salt thereof, wherein:

R is an acylamino group or an optionally substituted benzyl-NH— group;

R 1 and R 2 are independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group and a —S—C1-C6-alkyl group;

n is an integer ranging from 1-5;

—Z— is present or absent and

represents —O—(CH 2 )x-, —C—(CH 2 )x-, —NR′—(CH 2 )x-, —SO—(CH 2 )x-, or —SO 2 —(CH 2 )x-, where x is 0 or 1 and R′ is hydrogen or a C1-C6 alkyl group,

when —Z— is present, y is 1 and when it is absent, y is 2;

Y is O—C + or OR 3 , where R 3 is hydrogen, or an optionally substituted alkyl or aryl group and C + is a pharmacologically acceptable cation;

R 4 is hydrogen, a C1-C6 alkyl group, or OR′, where R′ is hydrogen or a C1-C6 alkyl group;

R 5 is hydrogen, or a C1-C6 alkyl group; and

M represents a chemical species which is in the cis or trans position with respect to R 1 , and which is selected from the group consisting of P, B, BZ, D, E, and F as follows:

where:

W is O or C(R″) and each R″ for W groups is independently selected from the group consisting of hydrogen, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted; and

R 6 and R 7 are independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, a 6-10-member-ring heterocyclic aromatic group, a —COR″ group, a —COOR″ group, and a —CON(R″) 2 group, wherein each R″ for R 6 and R 7 groups is independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted;

where:

Z 2 is O, NR 11 or S, where R 11 is selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group, wherein each group is optionally substituted;

each R 8 is independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, 6-10-member-ring heterocyclic aromatic group, a C1-C6 alkoxy group, a —S—C1-C6-alkyl group, a —CO—R′ croup, a —CO 2 R′ croup, a —CO—N(R′) 2 group;

a —N(R′) 2 group, a —NR′—CO—R′ group, and a —NR′CO 2 —R′ group, wherein each R′ for R 8 groups is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted; and

each R 9 is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted;

each R 10 is independently selected from the group consisting of a —CH 2 —X group, hydrogen, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, 6-10-member-ring heterocyclic aromatic group, a C1-C6 alkoxy group, a —S—C1-C6-alkyl group, a —CO—R′ group, a —CO 2 R′ group, a —CO—N(R′) 2 group; a —N(R′) 2 group, a —NR′—CO—R′ group, and a —NR′—CO 2 —R′ group, wherein each R′ for R 10 groups is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted;

R 12 is selected from the group consisting of X, hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, a 6-10-member-ring heterocyclic aromatic group, a C1-C6 alkoxy group, a —S—C1-C6-alkyl group, a —CO—R′ group, a —CO 2 R′ group, a —CO—N(R′) 2 group; a —N(R′) 2 group, a —NR′—CO—R′ group, and a —NR′—CO 2 —R′ group, wherein each R′ for R 12 groups is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted;

R 13 and R 14 are independently selected from the group consisting of X, hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, a 6-10-member-ring heterocyclic aromatic group, a C1-C6 alkoxy group, a —S—C1-C6-alkyl group, a —CO—R′ group, a —CO 2 R′ group, a —CO—N(R′) 2 group; a —N(R′) 2 group, a —NR′—CO—R′ group, and a —NR′—CO 2 —R′ group, wherein each R′ for R 13 and R 14 groups is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted;

wherein optional substitution includes substitution with one or more groups selected from a C1-C3 alkyl group, a C6-C12 aryl group, a C1-C3 haloalkyl group, I, Cl, Br, F, —CN, —OH, a C1-C3 alkoxy group, a —O-aryl group, a —O-benzyl group, a -phenoxy group, —SH, a —S—C1-C3-alkyl group, a —S-phenyl group, a —S-benzyl group, —NH 2 , and a —N(R 16 ) 2 group, where each R 16 is a C1-C3 alkyl group, a benzyl group or a phenyl group;

wherein X is a leaving group;

wherein the compound contains one R 2 and one M group; and

wherein in structures B and Bz at least one R 10 is a —CH 2 —X group, in structure E at least one R 10 is a —CH 2 —X group, or R 12 is X and in structure F one of R 13 or R 14 is X.

2. The compound or pharmaceutically acceptable salt of claim claim 1 of formula:

3. The compound or pharmaceutically acceptable salt of claim 2 , wherein:

R 1 and R 2 are independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group and a —S—C1-C6-alkyl group;

R 4 is hydrogen;

Y is —O − C + or —OR 3 , where R 3 is hydrogen, an alkyl group or an aryl group, each of which groups is optionally substituted,

and C + is a pharmacologically acceptable cation; and

M is selected from:

where:

each R 8 is independently selected from hydrogen, halogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted, and X is a leaving group selected from halogen, a pyridinium group, a —SC(O)R′ group, a —OCOR′ group, —SH, a —SR′ group, a phenoxy group, a pentafluorophenoxy group, and a tosyl group, where R′ for the listed groups is selected from optionally substituted alkyl and aryl groups.

4. The compound or pharmaceutically acceptable salt thereof of claim 3 , where both R 5 are hydrogens.

5. The compound or pharmacologically acceptable salt thereof of claim 4 , wherein X is a halogen or a pyridinium group and each R 8 is independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C6-C12 aryl group.

6. The compound or pharmacologically acceptable salt thereof of claim 4 , wherein X is a halogen and each R 8 is independently hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C6-C12 aryl group.

7. The compound or pharmacologically acceptable salt thereof of claim 4 , wherein M is:

8. The compound or pharmacologically acceptable salt thereof of claim 7 , wherein X is a leaving group selected from halogen, a pyridinium group, a phenoxy group, a pentafluorophenoxy group, and a tosyl group.

9. The compound or pharmacologically acceptable salt thereof of claim 7 , wherein X is halogen or a pyridinium group.

10. The compound or pharmacologically acceptable salt thereof of claim 7 , wherein X is Cl or Br.

11. The compound or pharmacologically acceptable salt thereof of claim 2 , wherein the acyl group of the acylamino group of R is selected from:

where in A1-A14, R′ is selected from hydrogen, a C1-C6 alkyl, and a C6-C12 aryl;

R″ is selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group and a 6-10-member-ring heterocyclic aromatic group; and

R′″ is selected from hydrogen, C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, a 6-10-member-ring heterocyclic aromatic group, a —CO—R 15 , a —CO 2 R 15 , a —CO—N(R 15 ) 2 , a —N(R 15 ) 2 , a —NR 15 —CO—R 15 , and a —NR 15 CO 2 —R 15 , wherein each R 15 is independently selected from hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C7-C19 aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7-member-ring heterocyclic group, a C6-C10 aromatic group, and a 6-10-member-ring heterocyclic aromatic group, wherein each of said groups is optionally substituted.

12. The compound or pharmacologically acceptable salt thereof of claim 11 , wherein R 4 and each R 5 are hydrogens and M is:

13. The compound or pharmacologically acceptable salt thereof of claim 12 , wherein X is a leaving group selected from halogen, a pyridinium group, a phenoxy group, a pentafluorophenoxy group, and a tosyl group.

14. The compound or pharmacologically acceptable salt thereof of claim 12 , wherein X is halogen or a pyridinium group.

15. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1 .

16. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 2 .

17. A method of treatment of bacterial infections, which comprises the step of administering a therapeutically effective amount of one or more compounds of claim 1 to an individual in need of treatment.

18. A method of inhibiting the growth of a microorganism which comprises the step of contacting the microorganism with an effective amount of one or more compounds claim 1 .

19. A method for inhibiting a beta-lactamase which comprises the step of contacting the beta-lactamase with an effective amount of a compound of claim 1 .

20. The compound or pharmacologically acceptable salt thereof of claim 2 , wherein:

R 1 , R 2 , R 4 and each R 5 is hydrogen;

n is 1; and

M is selected from:

where:

each R 8 is hydrogen, and X is a leaving group selected from halogen, a pyridinium group, a —SC(O)R′ group, a —OCOR′ group, —SH, a —SR′ group, a phenoxy group, a pentafluorophenoxy group, and a tosyl group, where R′ for the listed groups is selected from optionally substituted alkyl and aryl groups.

21. The compound or pharmacologically acceptable salt thereof of claim 20 , wherein:

X is a leaving group selected from halogen, a pyridinium group, a pentafluorophenoxy group, and a tosyl group.

22. The compound or pharmacologically acceptable salt thereof of claim 20 of formula:

23. A method of treatment of bacterial infections, which comprises the step of administering a therapeutically effective amount of one or more compounds of claim 3 to an individual in need of treatment.

24. A method of inhibiting the growth of a microorganism which comprises the step of contacting the microorganism with an effective amount of one or more compounds claim 3 .

25. A method for inhibiting a beta-lactamase which comprises the step of contacting the beta-lactamase with an effective amount of a compound of claim 3 .