BETA-LACTAMASE INHIBITORS

• US 20100120715A1
• Filed: 05/12/2009
• Published: 05/13/2010
• Est. Priority Date: 11/13/2007
• Status: Abandoned Application

• Current Assignee: Novartis Institutes for BioMedical Research, Inc. (Novartis Ag), Novartis International Pharmaceutical Limited (Novartis Ag)
• Original Assignee: Novartis International Pharmaceutical Limited (Novartis Ag)
• Inventors: Jackson, Randy W., Goswami, Rajesh, Burns, Christopher J., Xu, Hongyu
• Application Number:
  US12/464,609
• Publication Number:
  US 20100120715A1
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

Disclosed herein are α-aminoboronic acids and their derivatives which act as inhibitors of beta-lactamases. Also disclosed herein are pharmaceutical compositions comprising α-aminoboronic acids and methods of use thereof.

Claims

1. A compound of the formula:

2. The compound of claim 1, wherein R₁ is —

C(O)R₄;

R₂ is hydrogen;

R₃ is an aryl or heteroaryl group substituted with from 2 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2-position relative to the group containing Y₁ and Y₂, and a second substituent is a carboxylic acid group and wherein the remaining substituents are selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;

R₄ is selected from the group consisting of;

(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, oxo, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,

(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, oxo, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,

(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,

(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and

(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, oxo, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;

X₁ and X₂ are hydroxyl, or when taken together X₁ and X₂ form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or X₁ and R₁ together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X₂ is hydroxyl, or X₁ and R₃ together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S and X₂ is hydroxyl;

Y₁ and Y₂ are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido;

or a salt thereof;

provided that, when R₃ is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y₁ and Y₂, X₁ and X₂ are hydroxyl or X₁ is hydroxyl and X₂ is replaced by the ortho-hydroxyl oxygen of R₃ such that a 6-membered ring is formed, and Y₁ and Y₂ are hydrogen, R₄ is not unsubstituted C1 alkyl.

3. The compound of claim 2, wherein R₁ is —

C(O)R₄;

R₂ is hydrogen;

R₃ is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y₁ and Y₂;

R₄ is C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, oxo, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido;

X₁ and X₂ are hydroxyl, or X₁ is hydroxyl and X₂ is replaced by the ortho-hydroxyl oxygen of R₃ such that a 6-membered ring is formed; and

Y₁ and Y₂ are hydrogen;

or a salt thereof;

provided that, when R₃ is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y₁ and Y₂, and X₁ and X₂ are hydroxyl or X₁ is hydroxyl and X₂ is replaced by the ortho-hydroxyl oxygen of R₃ such that a 6-membered ring is formed, R₄ is not unsubstituted C1 alkyl.

4. The compound of claim 2, wherein R₁ is —

C(O)R₄;

R₂ is hydrogen;

R₃ is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y₁ and Y₂;

R₄ is C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, oxo, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;

X₁ and X₂ are hydroxyl, or X₁ is hydroxyl and X₂ is replaced by the ortho-hydroxyl oxygen of R₃ such that a 6-membered ring is formed; and

Y₁ and Y₂ are hydrogen;

or a salt thereof.

5. The compound of claim 2, wherein R₁ is —

C(O)R₄;

R₂ is hydrogen;

R₃ is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y₁ and Y₂;

R₄ is aryl or heteroaryl substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;

X₁ and X₂ are hydroxyl, or X₁ is hydroxyl and X₂ is replaced by the ortho-hydroxyl oxygen of R₃ such that a 6-membered ring is formed; and

Y₁ and Y₂ are hydrogen;

or a salt thereof.

6. The compound of claim 2, wherein R₁ is —

C(O)R₄;

R₂ is hydrogen;

R₃ is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y₁ and Y₂;

R₄ is a heterocycle substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, oxo, thiol, sulfonic acid, sulfate, optionally substituted;

alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;

X₁ and X₂ are hydroxyl, or X₁ is hydroxyl and X₂ is replaced by the ortho-hydroxyl oxygen of R₃ such that a 6-membered ring is formed; and

Y₁ and Y₂ are hydrogen;

or a salt thereof.

7. The compound of claim 2, wherein the compound is

8. A pharmaceutical composition comprising:

(a) one or more compounds of claim 1;

(b) one or more β

-lactam antibiotics; and

(c) one or more pharmaceutically acceptable carriers.

9. The pharmaceutical composition of claim 8, wherein the β

-lactam antibiotic is a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or combination thereof.

10. The pharmaceutical composition of claim 9, wherein the penicillin is benzathine penicillin, benzylpenicillin, phenoxymethylpenicillin, procaine penicillin, oxacillin, methicillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, apalcillin, hetacillin, bacampicillin, sulbenicillin, mecicilam, pevmecillinam, ciclacillin, talapicillin, aspoxicillin, cloxacillin, nafcillin, pivampicillin, or a combination thereof.

11. The pharmaceutical composition of claim 9, wherein the cephalosporin is cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefinenoxime, cefinetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, FR264205, or a combination thereof.

12. The pharmaceutical composition of claim 9, wherein the cephalosporin is an anti-MRSA cephalosporin.

13. The pharmaceutical composition of claim 12, wherein the anti-MRSA cephalosporin is ceftobiprole, ceftaroline, or a combination thereof.

14. The pharmaceutical composition of claim 9, wherein the carbapenem is imipenem, meropenem, ertapenem, faropenem, doripenem, biapenem, panipenem, or a combination thereof.

15. The pharmaceutical composition of claim 9, wherein the carbapenem is an anti-MRSA carbapenem.

16. The pharmaceutical composition of claim 15, wherein the anti-MRSA carbapenem is PZ-601 or ME1036.

17. The pharmaceutical composition of claim 9, wherein the monobactam is aztreonam, carumonam, BAL30072, or a combination thereof.

18. The pharmaceutical composition of claim 8 comprising more than one beta-lactam antibiotic.

19. A pharmaceutical composition comprising:

(a) one or more compounds of claim 1; and

(b) one or more pharmaceutically acceptable carriers.

20. The pharmaceutical composition of claim 19 comprising more than one beta-lactam antibiotic.

21. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof:

(i) an effective amount of a compound having the formula;

22. The method of claim 21, wherein the mammal is a human.

23. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound having the formula:

24. A method of reducing bacterial resistance to a β

-lactam antibiotic comprising contacting a bacterial cell having resistance to a β

-lactam antibiotic with an effective amount of a beta-lactamase inhibitor with broad-spectrum functionality having the formula;

25. The method of claim 24, further comprising contacting the bacterial cell with an effective amount of a β

-lactam antibiotic.

26. The method of claim 24, wherein the contacting of the bacterial cell takes place in vivo.

27. The method of claim 24, wherein the contacting of the bacterial cell takes place in vitro.

28. The method of claim 24, wherein said method is employed as a diagnostic to determine the inhibitory effectiveness of said beta-lactamase inhibitor.

29. The method of claim 24, wherein said method is employed as a diagnostic to aid in determining the presence and/or type of beta-lactamase.