IP Library › Granted Patent US 10,239,890

Granted Patent B2

US 10,239,890 · App. 15/991,315 · Granted Mar 26, 2019

Broad spectrum beta-lactamase inhibitors

Inventors: Larry Sutton (Atchison, KS); Sophia Yu (Atchison, KS)

Assignee: Gladius Pharmaceuticals Corporation

C07D501/24 A01N43/90 C07D501/22 C07D501/60

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Quick Facts

Patent No.: US 10,239,890
App. No.: 15/991,315
Granted: Mar 26, 2019
Kind: B2

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Abstract

Broad spectrum beta-lactamase inhibitors. Certain inhibitors also exhibit potent antibiotic activity in addition to beta-lactamase inhibition. Compounds of the invention are designed such that on cleavage of the beta-lactam ring reactive moieties are generated which can inactivate beta-lactamase. Also provided are methods of making beta-lactamase inhibitors and beta-lactam antibiotics exhibiting such inhibition. Additionally provided are pharmaceutical compositions for treatment or prevention of bacterial infections and methods of treatment of such infections.

Claims (56)

1. A compound of Formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R is an acylamino group:

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

n is an integer ranging from 1 to 5;

—Z— is absent or present and, if present, represents —O—(CH 2 ) X —, —S—(CH 2 ) X —, —CH 2 —(CH 2 ) X —, —NR′—(CH 2 ) X —, —SO—(CH 2 ) X —, or —SO 2 —(CH 2 ) X —, where x is 0 or 1;

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

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

M, which is in the cis or trans position with respect to R 1 , is selected from the group consisting of B, E, and F as follows:

where:

each R 8 is independently selected from hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 3-7-member ring heterocyclic group, C6-C10 aromatic group, 6-10-member ring heterocyclic aromatic group, C1-C6 alkoxy group, —S-alkyl where the alkyl group is a C1-C6 alkyl, —CO—R′, —CO 2 R′, —CO—N(R′) 2 , —N(R′) 2 , —NR′—CO—R′, and —NR′CO 2 —R′, wherein each R′ for R 8 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 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 —CH 2 —X, hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 3-7-member ring heterocyclic group, C6-C10 aromatic group, 6-10-member ring heterocyclic aromatic group, C1-C6 alkoxy group, C1 C6 thioalkyl group S-alkyl, where the alkyl group is a C1-C6 alkyl, —CO—R′, —CO 2 -R′, —CO—N(R′) 2 ; —N(R′) 2 , —NR′—CO—R′, and —NR—CO 2 —R′, wherein each R′ for R 10 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 3-7-member ring heterocyclic group, C6-C10 aromatic group, and 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, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 3-7-member ring heterocyclic group, C6-C10 aromatic group, and 6-10-member ring heterocyclic aromatic group, C1-C6 alkoxy group, —S-alkyl group, where the alkyl group is a C1-C6 alkyl group, —CO—R′, —CO 2 R′, —CO—N(R′) 2 ; —N(R′) 2 , —NR′—CO—R′, and —NR—CO 2 —R′, wherein each R′ for R 12 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 3-7-member ring heterocyclic group, C6-C10 aromatic group, and 6-10-member ring heterocyclic aromatic group, wherein each of said groups is optionally substituted; and

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

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

wherein X is a leaving group;

wherein in structure B at least one R 10 is —CH 2 —X, in structure E at least one R 10 is —CH 2 —X, or R 12 is X and in structure F one of R 13 or R 14 is X; and

wherein the compound contains at least one M.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein M is

3. The compound or pharmaceutically acceptable salt of claim 2 , wherein each R 8 is independently selected from hydrogen or halogen and each R 10 is independently selected from hydrogen, halogen or —CH 2 —X and at least one R 10 is —CH 2 —X.

4. The compound or pharmaceutically acceptable salt of claim 2 , wherein each R 8 is hydrogen and each R 10 is independently selected from hydrogen or —CH 2 —X and at least one R 10 is —CH 2 —X.

5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R is selected from:

where:

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

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

7. The compound or pharmaceutically acceptable salt of claim 6 , wherein M is

8. The compound or pharmaceutically acceptable salt of claim 7 , wherein each R 8 is independently selected from hydrogen or halogen and each R 10 is independently selected from hydrogen, halogen or —CH 2 —X and at least one R 10 is —CH 2 —X.

9. The compound or pharmaceutically acceptable salt of claim 7 , wherein each R 8 is hydrogen and each R 10 is independently selected from hydrogen or —CH 2 —X and at least one R 10 is —CH 2 —X.

10. The compound or pharmaceutically acceptable salt of claim 6 , wherein R is selected from:

where:

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

12. The compound or pharmaceutically acceptable salt of claim 11 , wherein R is selected from:

where:

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

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

14. The compound or pharmaceutically acceptable salt of claim 13 , wherein R is selected from:

where:

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

16. The compound or pharmaceutically acceptable salt of claim 15 , wherein R is selected from:

where:

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

18. The compound or pharmaceutically acceptable salt of claim 17 , wherein R is selected from:

where:

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

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

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

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 25, 2018

From: SUTTON, LARRY; YU, SOPHIA

To: SOPHARMIA, INC.

Reel/Frame 046450/0551 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 25, 2018

From: SOPHARMIA, INC.

To: GLADIUS PHARMACEUTICALS CORPORATION

Reel/Frame 046450/0571 →

Continuity (7)

Continuation 15808204 · Nov 9, 2017

Continuation 15247536 · Aug 25, 2016

Division 14491806 · Sep 19, 2014

Continuation 12248760 · Oct 9, 2008

Provisional Application 60997898 · Oct 9, 2007

Provisional Application 60997941 · Oct 9, 2007

Related Publication 20180273549A1 · Sep 27, 2018

Cited By (2)

US 12,195,755 US 12,509,559