Peptidomimetic efflux pump inhibitors

• US 6,204,279 B1
• Filed: 06/03/1998
• Issued: 03/20/2001
• Est. Priority Date: 06/03/1998
• Status: Expired due to Fees

• Current Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Original Assignee: Essential Therapeutics, Inc. (Trine Pharmaceuticals, Inc.)
• Inventors: Leger, Roger, Lee, Ving J., She, Miles
• Primary Examiner(s): Lee, Howard C.
• Application Number:
  US09/089,734
• Time in Patent Office: 1,021 Days
• Field of Search: 514/212, 514/227.8, 514/228.2, 514/231.5, 514/233.5, 514/235.2, 514/235.8, 514/236.5, 514/236.8, 514/252, 514/253, 514/336, 514/337, 514/339, 514/340-343, 514/365, 514/374, 514/375, 514/383, 514/397, 514/406, 514/414, 514/422, 514/438, 514/443, 514/444, 514/469, 514/471, 540/524, 544/58.4, 544/132-133, 544/137, 544/139-141, 544/146, 544/152-3, 544/369, 544/370, 544/372, 544/373, 544/376, 544/379, 546/269, 546/273-6, 546/278-284, 548/204, 548/231, 548/236, 548/266.2, 548/266.4, 548/266.6, 548/267.6, 548/336, 548/343, 548/344, 548/374, 548/378, 548/468, 548/517-8, 548/525, 548/527, 548/561, 548/215, 548/217, 549/58-60, 549/76, 549/407, 549/496
• US Class Current: 514/375
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06086 with the first amino acid being basic
• CPC Class Codes: C07K 5/06095 Arg-amino acid
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds are described which have efflux pump inhibitor activity. Also described are methods of using such efflux pump inhibitor compounds and pharmaceutical compositions which include such compounds.

Claims

1. A method of enhancing the antimicrobial activity of an antimicrobial agent against a microbe, comprising contacting said microbe with said antimicrobial agent and an efflux pump inhibitor in an amount effective to inhibit an efflux pump in said microbe, wherein said efflux pump inhibitor has the chemical structure:

wherein;

M* is selected from the group consisting of (CH₂)_n, and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, alyl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

2. The method of claim 1, wherein said efflux pump inhibitor has the structure:

wherein;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, monosubstituted aryl, disubstituted aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)-pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, benzyl, cyano, hydroxy, and nitro;

or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxy, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

3. The method of claim 1, wherein said microbe is a bacterium.

4. The method of claim 3, wherein said bacterial infection involves a bacterium selected from the group consisting of Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Yibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saccharolyticus.

5. The method of claim 1, wherein said microbial infection is a bacterial infection and said antimicrobial agent is an antibacterial agent.

6. The method of claim 5, wherein said antibacterial agent is a quinolone.

7. The method of claim 5, wherein said antibacterial agent is a tetracycline.

8. The method of claim 5, wherein said antibacterial agent is a β

-lactam.

9. The method of claim 5, wherein said antibacterial agent is a coumermycin.

10. The method of claim 5, wherein said antibacterial agent is chloranphenicol.

11. The method of claim 5, wherein said antibacterial agent is a glycopeptide.

12. The method of claim 5, wherein said antibacterial agent is an aminoglycoside.

13. The method of claim 5, wherein said antibacterial agent is a macrolide.

14. The method of claim 5, wherein said antibacterial agent is a rifamycin.

15. The method of claim 5, wherein said antibacterial agent is an oxazolidonone.

16. The method of claim 1, wherein said antimicrobial agent is effluxed by a microbe.

17. A pharmaceutical composition effective for treatment of an infection of an animal by a microbe, comprising an efflux pump inhibitor, an antimicrobial agent and a pharmaceutically acceptable carrier, wherein said efflux pump inhibitor has the chemical structure:

wherein;

M* is selected from the group consisting of (CH₂)_n, and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroallyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

18. The pharmaceutical composition of claim 17, wherein said efflux pump inhibitor has the structure:

wherein;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkcyl, aryl, monosubstituted aryl, disubstituted aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)-pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, benzyl, cyano, hydroxy, and nitro;

or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxy, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

19. A method of suppressing growth of a bacterium expressing an efflux pump, comprising contacting said bacterium with an efflux pump inhibitor in the presence of a concentration of antibacterial agent below the MIC of said bacterium, wherein said efflux pump inhibitor has the chemical structure:

wherein;

M* is selected from the group consisting of (CH₂)_n,and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkyltho, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

20. The method of claim 19, wherein said efflux pump inhibitor has the structure:

wherein;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, monosubstituted aryl, disubstituted aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or

     4)-pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a , R^b , and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, benzyl, cyano, hydroxy, and nitro;

or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxy, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

21. An efflux pump inhibitor compound, wherein said compound has the chemical structure:

wherein;

M* is selected from the group consisting of (CH₂)_N, and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.

22. The efflux pump inhibitor compound of claim 21, wherein said compound has the chemical structure:

wherein;

R and R¹ are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, monosubstituted aryl, disubstituted aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or

     4)-pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH₂)_nNR^bR^c, (CH₂)_nNHC═

(NR^a)NR^bR^c, (CH₂)_nSC═

(NR^a)NR^bR^c, (CH₂)_nC═

(NR^a)NR^bR^c, and (CH₂)_nN═

C(H)NR^bR^c, wherein n is 1, 2, 3, or 4;

R^a, R^b, and R^c are independently selected from the group consisting of H, lower alkyl, phenyl, benzyl, cyano, hydroxy, and nitro;

or R^a and R^b or R^b and R^c taken together form a group selected from the group consisting of (CH₂)_2-3 and —

CH═

CH—

;

R³ and R⁴ are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;

W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxy, alkoxy, alkylthio, guanidino, and amidino; and

where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.