WO2010054102A2 - Inhibiteurs polybasiques de pompe à efflux bactérienne et leurs utilisations thérapeutiques - Google Patents

Inhibiteurs polybasiques de pompe à efflux bactérienne et leurs utilisations thérapeutiques Download PDF

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WO2010054102A2
WO2010054102A2 PCT/US2009/063426 US2009063426W WO2010054102A2 WO 2010054102 A2 WO2010054102 A2 WO 2010054102A2 US 2009063426 W US2009063426 W US 2009063426W WO 2010054102 A2 WO2010054102 A2 WO 2010054102A2
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compound
nhr
equal
alkyl
mmol
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WO2010054102A3 (fr
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Tomasz Glinka
Olga Rodny
Keith A. Bostian
David M. Wallace
Robert Higuchi
Chun Chow
Chi Ching Mak
Gavin Hirst
Brian Eastman
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Mpex Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the field of antimicrobial agents and more specifically it relates to Efflux Pump Inhibitor (EPI) compounds to be co-administered with antimicrobial agents for the treatment of infections caused by drug resistant pathogens.
  • EPI Efflux Pump Inhibitor
  • the invention includes novel compounds useful as efflux pump inhibitors, compositions and devices comprising such efflux pump inhibitors, and therapeutic use of such compounds. Description of the Related Art
  • Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of antibacterial therapy.
  • the increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs.
  • Bacteria have developed several different mechanisms to overcome the action of antibiotics. These mechanisms of resistance can be specific for a molecule or a family of antibiotics, or can be non-specific and be involved in resistance to unrelated antibiotics. Several mechanisms of resistance can exist in a single bacterial strain, and those mechanisms may act independently or they may act synergistically to overcome the action of an antibiotic or a combination of antibiotics. Specific mechanisms include degradation of the drug, inactivation of the drug by enzymatic modification, and alteration of the drug target. There are, however, more general mechanisms of drug resistance, in which access of the antibiotic to the target is prevented or reduced by decreasing the transport of the antibiotic into the cell or by increasing the efflux of the drug from the cell to the outside medium.
  • Both mechanisms can lower the concentration of drug at the target site and allow bacterial survival in the presence of one or more antibiotics that would otherwise inhibit or kill the bacterial cells.
  • Some bacteria utilize both mechanisms, combining a low permeability of the cell wall (including membranes) with an active efflux of antibiotics.
  • Some efflux pumps selectively extrude specific antibiotics.
  • examples of such pumps include the Tet or CmIA transporters, which can extrude tetracycline or chloramphenicol, respectively.
  • Other efflux pumps so-called multi-drug resistance (MDR) pumps, extrude a variety of structurally diverse compounds. In the latter case, a single efflux system may confer resistance to multiple antibiotics with different modes of action.
  • MDR pumps are similar to mammalian MDR transporters.
  • P-glycoprotein the first discovered MDR pump, confers multiple drug resistance on cancer cells and is considered to be one of the major reasons tumor resistance to anti-cancer therapy.
  • MexAB-OprM from Pseudomonas aeruginosa. This pump has been shown to affect the susceptibility of the organism to almost all antibiotic classes which fluoroquinolones, ⁇ -lactams, macrolides, phenicols, tetracyclines, and oxazolidinones.
  • Efflux pumps in gram-positive bacteria excrete their substrates across a single cytoplasmic membrane. This is also the case for some pumps in gram-negative bacteria, and as a result their substrates are effluxed into the periplasmic space.
  • Other efflux pumps from gram-negative bacteria efflux their substrates directly into the external medium, bypassing the periplasm and the outer membrane.
  • These pumps are organized in complex three component structures, which traverse both inner and outer membranes. They consist of a transporter located in the cytoplasmic membrane, an outer membrane channel and a periplasmic 'linker' protein, which brings the other two components into contact. It is clearly advantageous for gram-negative bacteria to efflux drugs by bypassing the periplasm and outer membrane.
  • MDR pumps are encoded by the genes, which are normal constituents of bacterial chromosomes. In this case increased antibiotic resistance is a consequence of over-expression of these genes. Thus bacteria have the potential to develop multi-drug resistance without the acquisition of multiple specific resistance determinants. In some cases, the simultaneous operation of efflux pumps and other resistance mechanisms in the same cell results in synergistic effects.
  • aeruginosa laboratory-derived mutant strain PAMl 626 which does not produce any measurable amounts of efflux pump is 8 to 10 fold more susceptible to levofloxacin and meropenem than the parent strain P. aeruginosa PAMl 020, which produces the basal level of MexAB-OprM efflux pump.
  • the spectrum of activity of many so-called 'gram- positive' antibiotics could be expanded to previously non-susceptible gram-negative species.
  • Some embodiments disclosed herein include bacterial efflux pump inhibitors having polybasic functionality. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.
  • One embodiment disclosed herein includes a compound having the structure of formula I, II or III:
  • each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond
  • each R 1 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 carbocyclyl, heterocyclyl, aryl and heteroaryl, each optionally substituted with up to 3 substituents independently selected from the group consisting of a halide, alkyl, carbocyclyl, heterocycle, -(CH 2 ) n aryl, -OR 2 , -OR 10 , -S(R 2 ) 2 , -SO 2 NHR 10 , -(CH 2 ) n SH, -CF 3 , -OCF 3 , -N(R 2 ) 2 , -NO 2 , -CN, -CO 2 alkyl, -CO 2 aryl and -C(O)aryl; each R 2 is independently selected from H,
  • R 8 is selected from H, alkyl, aryl, SH and OH;
  • R 11 is selected from H, -(CH 2 ) n NHR 2 and -(CH 2 ) n CHR 5 R 6 ;
  • R 12 is selected from H, -(CH 2 ) n NHR 2 and -(CH 2 ) n CHR 5 R 6 , wherein at least one of Rn and R 12 is not H;
  • a 3 is H, -CF 3 , C 1 -C 6 alkyl, a lone electron pair when D 8 is N, or A 3 is -CH 2 - bonded to A 1 , A 2 or R 1 to form a ring; al , a2 and a3 are independently equal to 0 or 1 ;
  • Di is selected from -CH 2 -, -N(NHR 7 )-, -CH(NHR 7 )-, -CH[(CH 2 ) m NHR 7 ]-, - CH(R 2 )-, and -CH(CH 2 SH)-;
  • D 8 is selected from C and N; dl, d2, d3, d4, d5 and d6 are independently equal to O or 1;
  • Qi is selected from -CH 2 -, - N(R 2 )N(R 2 )-, and -N(R 2 )-;
  • Q 2 and Q 3 are independently selected from the group consisting of -CH 2 -, CH 2 CH 2 -, and -N(R 2 )-; with the proviso that no more than one of Q 1 , Q 2 , and Q 3 comprises a nitrogen; ql , q2, and q3 are independently equal to O or 1 ;
  • Another embodiment disclosed herein includes a compound having the structure of formula IV:
  • D 8 is selected from C and N; each E is independently CH or N; F is selected from the group consisting of:
  • X is O or S;
  • R 2 O is H, alkyl, or heteroaryl
  • R 21 is -NH 2 , -OH, alkyl, each t is independently an integer from O to 4; each s is independently an integer from O to 3 ; r is O or 1; v is O or 1 ; and n is an integer from 0 to 4.
  • the compounds according to Formulas I-IV do not include a compound selected from the group consisting of:
  • Another embodiment disclosed herein includes a method of treating or preventing a bacterial infection by co-administering to a subject infected with a bacteria or subject to infection with a bacteria, a compound according to any of the above formulas and another anti-bacterial agent.
  • Another embodiment disclosed herein includes a pharmaceutical composition that has a compound according to any of the above formulas and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions and methods for inhibiting intrinsic drug resistance and/or preventing acquired drug resistance in microbes would be of tremendous benefit. Certain embodiments provide such compositions and methods.
  • Some embodiments relate to a method for treating a microbial infection whose causative microbe employs an efflux pump resistance mechanism, comprising contacting the microbial cell with an efflux pump inhibitor in combination with an antimicrobial agent.
  • the efflux pump inhibitors of preferred embodiments can comprise polybasic structures, as disclosed herein.
  • Some embodiments include a method for prophylactic treatment of a mammal.
  • an efflux pump inhibitor is administered to a mammal at risk of a microbial infection, e.g., a bacterial infection.
  • an antimicrobial agent is administered in combination with or coadministered with the efflux pump inhibitor.
  • compositions are provided that are effective for treatment of an infection of an animal, e.g., a mammal, by a microbe, such as a bacterium or a fungus.
  • the composition includes a pharmaceutically acceptable carrier and an efflux pump inhibitor as described herein.
  • Some embodiments provide antimicrobial formulations that include an antimicrobial agent, an efflux pump inhibitor, and a carrier.
  • the antimicrobial agent is an antibacterial agent.
  • the efflux pump inhibitor is administered to the lungs as an aerosol.
  • a co-adminsitered antimicrobial agent may be administered in conjunction with the efflux pump inhibitor by any known means.
  • alkyl means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, isopropyl, isobutyl, sec-butyl and pentyl.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • Carbocyclyl means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents e.g., halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 6.
  • "lower alkyl” means a subset of alkyl, and thus is a hydrocarbon sub
  • Preferred lower alkyls are of 1 to about 4 carbons, and may be branched or linear. Examples of lower alkyl include butyl, propyl, isopropyl, ethyl, and methyl. Likewise, radicals using the terminology "lower” refer to radicals preferably with 1 to about 4 carbons in the alkyl portion of the radical.
  • amido means a H-CON- or alkyl-CON-, aryl-CON- or heterocyclyl-CON group wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is as herein described.
  • aryl means an aromatic radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with only carbon atoms present in the ring backbone.
  • Aryl groups can either be unsubstituted or substituted with one or more substitutents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
  • a preferred carbocyclic aryl is phenyl.
  • heteroaryl means an aromatic radical having one or more heteroatom(s) (e.g., N, O, or S) in the ring backbone and may include a single ring (e.g., pyridine) or multiple condensed rings (e.g., quinoline). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, nitro, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, halo, and mercapto.
  • substituents e.g., amino, cyano, nitro, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy, aryl, halo, and mercapto.
  • heteroaryl examples include thienyl, pyrridyl, furyl, oxazolyl, oxadiazolyl, pyrollyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl and others.
  • substitution on the aryl and heteroaryl rings is within the scope of certain embodiments.
  • the radical is called substituted aryl or substituted heteroaryl.
  • substituents Preferably one to three and more preferably one or two substituents occur on the aryl ring.
  • preferred substituents include those commonly found in aryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like.
  • ether includes an alkyl group in which one or more carbon atoms in the alkyl backbone have been replaced with an oxygen atom.
  • acyl means an H-CO- or alkyl-CO-, aryl-CO- or heterocyclyl-CO- group wherein the alkyl, cycloalkyl, aryl or heterocyclcyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl, butanoyl and palmitoyl.
  • halo or halide is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. The term “halo” also contemplates terms sometimes referred to as “halogen", or "halide”.
  • haloalkyl means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substiuted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbons in length, More preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length.
  • haloalkylene means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group.
  • heterocyclyl means a cyclic ring system comprising at least one heteroatom in the ring system backbone.
  • Heterocyclyls may include multiple fused rings.
  • Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • Heterocyclyls may be substituted or unsubstiruted, and are attached to other groups via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5 or 6 members.
  • the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered, preferably it has one or two heteroatoms selected from O, N, or S.
  • quaternary ammonium refers to a positively charged nitrogen atom linked to four aliphatic carbon atoms or a positively charged nitrogen of the heteroaryl ring linked to an aliphatic carbon as in N-pridinium, N-thiazolium, _N- imidazolium, N-triazolium and like.
  • substituted amino means an amino radical which is substituted by one or two alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, aryl or heterocyclyl are defined as above.
  • substituted thiol means RS- group wherein R is an alkyl, an aryl, or a heterocyclyl group, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are defined as above.
  • sulfonyl means an alkylSO2, arylSO 2 or heterocyclyl- SO 2 group wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are defined as above.
  • sulfamido means an alkyl-N-S(O) 2 N-, aryl-NS(O) 2 N- or heterocyclyl-NS(O)2N- group wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclcyl group is as herein described.
  • sulfonamido means an alkyl- S (O) 2 N-, aryl-S(O) 2 N- or heterocyclyl- S(O) 2 N- group wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclcyl group is as herein described.
  • ureido means an alkyl -NCON-, aryl -NC ON- or heterocyclyl-NCON- group wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclcyl group is as herein described
  • administering refers to a method of giving a dosage of an antimicrobial pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., intrarespiratory, topical, oral, intravenous, intraperitoneal, or intramuscular.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the potential or actual bacterial infection, the microbe involved, and the severity of an actual microbial infection.
  • a "diagnostic” as used herein is a compound, method, system, or device that assists in the identification and characterization of a health or disease state.
  • the diagnostic can be used in standard assays as is known in the art.
  • efflux pump refers to a protein assembly that exports substrate molecules from the cytoplasm or periplasm of a cell, in an energy dependent fashion.
  • an efflux pump will typically be located in the cytoplasmic membrane of the cell (spanning the cytoplasmic membrane). In Gram-negative bacteria the pump may span the periplasmic space and there may also be portion of the efflux pump, which spans the outer membrane.
  • An "efflux pump inhibitor” (“EPF') is a compound that specifically interferes with the ability of an efflux pump to export its normal substrate, or other compounds such as an antibiotic.
  • the inhibitor may have intrinsic antimicrobial (e.g., antibacterial) activity of its own, but at least a significant portion of the relevant activity is due to the efflux pump inhibiting activity.
  • mamal is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
  • microbial infection refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal.
  • a mammal is "suffering" from a microbial infection when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal.
  • this description applies to a bacterial infection.
  • the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.
  • multidrug resistance pump refers to an efflux pump that is not highly specific to a particular antibiotic.
  • the term thus includes broad substrate pumps (efflux a number of compounds with varying structural characteristics). These pumps are different from pumps, which are highly specific for tetracyclines. Tetracycline efflux pumps are involved in specific resistance to tetracycline in bacteria. However, they do not confer resistance to other antibiotics.
  • the genes for the tetracycline pump components are found in plasmids in Gram-negative as well as in Gram-positive bacteria.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of the preferred embodiments and, which are not biologically or otherwise undesirable.
  • the compounds of the preferred embodiments are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 1 1, 1987 (incorporated by reference herein).
  • Solvate refers to the compound formed by the interaction of a solvent and an EPI, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • the term "susceptibility" refers to the sensitivity of the microbe for the presence of the antimicrobial agent. So, to increase the susceptibility means that the microbe will be inhibited by a lower concentration of the antimicrobial agent in the medium surrounding the microbial cells. This is equivalent to saying that the microbe is more sensitive to the antimicrobial agent. In most cases the minimum inhibitory concentration (MIC) of that antimicrobial agent will have been reduced.
  • MIC minimum inhibitory concentration
  • a therapeutically effective amount or “pharmaceutically effective amount” is meant an amount of an efflux pump inhibitor, or amounts individually of an efflux pump inhibitor and an antimicrobial agent, as disclosed in the preferred embodiments, which have a therapeutic effect, which generally refers to the inhibition to some extent of the normal metabolism of microbial cells causing or contributing to a microbial infection.
  • the doses of efflux pump inhibitor and antimicrobial agent, which are useful in combination as a treatment are therapeutically effective amounts.
  • a therapeutically effective amount means those amounts of efflux pump inhibitor and antimicrobial agent which, when used in combination, produce the desired therapeutic effect as judged by clinical trial results and/or model animal infection studies.
  • the efflux pump inhibitor and antimicrobial agent are combined in pre-determined proportions and thus a therapeutically effective amount would be an amount of the combination.
  • This amount and the amount of the efflux pump inhibitor and antimicrobial agent individually can be routinely determined by one of skill in the art, and will vary, depending on several factors, such as the particular microbial strain involved and the particular efflux pump inhibitor and antimicrobial agent used. This amount can further depend upon the patient's height, weight, sex, age and medical history.
  • a therapeutically effective amount is that amount which would be effective if a microbial infection existed.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of the infection, and includes curing an infection. "Curing” means that the symptoms of active infection are eliminated, including the elimination of excessive members of viable microbe of those involved in the infection. However, certain long-term or permanent effects of the infection may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a patient who is not yet infected, but who is susceptible to, or otherwise at risk of, a particular infection.
  • therapeutic treatment refers to administering treatment to a patient already suffering from an infection.
  • treating is the administration to a mammal (either for therapeutic or prophylactic purposes) of therapeutically effective amounts of an efflux pump inhibitor and an antibacterial (or antimicrobial) agent in combination (either simultaneously or serially).
  • Some embodiments include compounds containing within the Box A fragment at least two basic nitrogen functionalities basic enough to be protonated to an appreciable degree at physilogical pH of 7.4.
  • One embodiment includes a compound having the structure of formula (I):
  • each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond
  • each R 1 is independently selected from C 1 -C 6 alkyl, C3-C7 carbocyclyl, heterocyclyl, aryl and heteroaryl, each optionally substituted with up to 3 substituents independently selected from the group consisting of a halide, alkyl, carbocyclyl, heterocyclyl, -(CH 2 ) n aryl, -OR 2 , -OR 10 , -S(R 2 ) 2 , -SO 2 NHR 10 , -(CH 2 ) n SH, -CF 3 , - OCF 3 , -N(R 2 ) 2 , -NO 2 , -CN, -C0 2 alkyl, -CO 2 aryl and -C(O)aryl; each R 2 is independently selected from
  • R 8 is selected from H, alkyl, aryl, SH and OH;
  • R9 and R 1 o are optionally linked to form a ring;
  • a 3 is H, -CF 3 , C 1 -C 6 alkyl, a lone electron pair when D 8 is N, or A 3 is -CH 2 - bonded to A 1 , A 2 or R 1 to form a ring; al , a2 and a3 are independently equal to 0 or 1 ;
  • D 1 is selected from -CH 2 -, -N(NHR 7 )-, -CH(NHR 7 )-, -CH[(CH 2 ) m NHR 7 ]-, - CH(R 2 )-, and -CH(CH 2 SH)-;
  • D 8 is selected from C and N; dl, d2, d3, d4, d5 and d6 are independently equal to 0 or 1;
  • Z 1 is an aryl, heteroaryl, carbocyclyl, or heterocyclyl; z1 is 0 or 1; if zl is 0 then at least one from the group consisting of dl, d2, d3, d4, d5 and d6 are equal to 1, if zl is 1 then at least one from the group consisting of dl, d2, d3, d4, d5 and d6 is equal to 1 ; each n is independently an integer of 0 to 4; and each m is independently an integer of 1 to 3. [0066] In another embodiment, the compounds have the structure of formula (II)
  • each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond
  • each R 1 is independently selected from C 1 -C 6 alkyl, C3-C 7 carbocyclyl, heterocyclyl, aryl and heteroaryl, each optionally substituted with up to 3 substituents independently selected from the group consisting of a halide, alkyl, carbocyclyl, heterocyclyl, -(CH 2 ) n aryl, -OR 2 , -OR 10 , -S(R 2 ) 2 , -SO 2 NHR 10 , -(CH 2 ) n SH, -CF 3 , - OCF 3 , -N(R 2 ) 2 , -NO 2 , -CN, -C0 2 alkyl, -CO 2 aryl and -C(O)aryl; each R 2
  • R 8 is selected from H, alkyl, aryl, SH and OH;
  • R 9 and R 1 o are optionally linked to form a ring
  • Rn is selected from H, -(CH 2 ) n NHR 2 and -(CH 2 ) m CHR 5 R 6 ;
  • R 12 is selected from H, -(CH 2 ) n NHR 2 and -(CH 2 ) m CHR 5 R 6 , wherein at least one of Rn and R 12 is not H;
  • a 3 is H, -CF 3 , C 1 -C 6 alkyl, a lone electron pair when D 8 is N, or A 3 is -CH 2 - bonded to A 1 , A 2 or R 1 to form a ring; al , a2 and a3 are independently equal to O or 1 ; Di is selected from -CH 2 -, -N(NHR 7 )-, -CH(NHR 7 )-, -CH[(CH 2 ) m NHR 7 ]-, - CH(R 2 )-, and -CH(CH 2 SH)-;
  • D 8 is selected from C and N; dl, d2, d3, d4, d5 and d6 are independently equal to 0 or 1;
  • Qi is selected from -CH 2 -, - N(R 2 )N(R 2 )-, and -N(R 2 )-;
  • Q 2 and Q3 are independently selected from the group consisting of -CH 2 -, - CH 2 CH 2 -, and -N(R 2 )-; with the proviso that no more than one of Qi, Q 2 , and Q3 comprises a nitrogen; ql , q2, and q3 are independently equal to 0 or 1 ;
  • the compounds have the structure of formula (III):
  • each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond
  • each R 1 is independently selected from C 1 -C 6 alkyl, C3-C 7 carbocyclyl, heterocyclyl, aryl and heteroaryl, each optionally substituted with up to 3 substituents independently selected from the group consisting of a hahde, alkyl, carbocyclyl, heterocyclyl, -(CH 2 ) n aryl, -OR 2 , -OR 10 , -S(R 2 ) 2 , -SO 2 NHR 10 , -(CH 2 ) n SH, -CF 3 , -
  • each R 2 is independently selected from H, -OH, and C 1 -C 6 alkyl,
  • R 3 is selected from -(CH 2 ) n CHR 5 R 6 , -(CH 2 ) n NR 5 R 6 , and -
  • each R 4 is independently selected from -NHR 2 , -(CH 2 ) J1 CHR 5 R 6 , -
  • each R 5 is independently selected from H and -(CH 2 ) m NH 2
  • each R 6 is independently selected from -(CH 2 ) n NHR 7 , -
  • R 8 is selected from H, alkyl, aryl, SH and OH;
  • R9 and R 1 o are optionally linked to form a ring;
  • a 3 is H, -CF 3 , C 1 -C 6 alkyl, a lone electron pair when D 8 is N, or A 3 is -CH 2 - bonded to A 1 , A 2 or R 1 to form a ring; al , a2 and a3 are independently equal to O or 1 ;
  • Di is selected from -CH 2 -, -N(NHR 7 )-, -CH(NHR 7 )-, -CH[(CH 2 ) m NHR 7 ]-, - CH(R 2 )-, and -CH(CH 2 SH)-;
  • Ds is selected from C and N; dl, d2, d3, d4, d5 and d6 are independently equal to 0 or 1;
  • the compounds have the structure of formula (IV):
  • D 8 is selected from C and N; each E is independently CH or N; X N.- > A N- !
  • F is selected from the group consisting of: X, W ⁇
  • X is O or S;
  • R 2 O is H, alkyl, or heteroaryl
  • R 21 is -NH 2 , -OH, alkyl, each t is independently an integer from O to 4; each s is independently an integer from O to 3 ; r is O or 1; v is O or 1 ; and n is an integer from 0 to 4.
  • compounds according to Formulas I-IV do not include Compounds 1-210.
  • Compound preparation
  • CDI l,r-carbonyldiimidazole
  • CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine
  • DIBAL diisobutylaluminum hydride
  • DIPEA diisopropylethylamine
  • DMT-MM 4-(4,6-dimethoxy-l ,3,5-triazin-2-yl)-4-methylmorpholinium chloride
  • EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • ESIMS electron spray mass spectrometry
  • EtOAc ethyl acetate
  • EtOH ethyl alcohol
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane- 2,4-disulfide
  • MsCl methanesulfonyl chloride
  • Na 2 EDTA disodium ethylene diamine tetraacetic acid
  • NMR nuclear magnetic resonance
  • Pd/C palladium on activated carbon
  • r.t. room temperature
  • TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • the aqueous phase was washed with DCM (4x) and the combined DCM extracts were washed with brine and dried over MgSO 4 .
  • Disodium EDTA (4.6 g; 12.2 mmol) and di-tert-butyl dicarbonate (1.3 g; 5.86 mmol) were added and the mixture was stirred overnight at r.t. The solids were filtered and washed with methanol. The solvent was evaporated and the remaining aqueous solution was acidified with 2 M HCl to pH ⁇ 6 and extracted with DCM. The combined organic layers were dried over anhydrous MgSO4 and removed under reduced pressure.
  • (2S)-2-amino-N-methyl-4-phenyl-N-(2- ⁇ [4- (trifluoromethyl)phenyl] formamido ⁇ ethyl)butanamide CXXIII (0.56 g, 1.26 mmol) was added and the mixture stirred at r.t. overnight. The mixture was washed with 1 M HCl (5x), 1 M K2CO3 (5x), brine and dried over MgSO 4 .
  • Scheme 20 describes an example for the preparation of a parallel synthesis library of polyamine EPIs.
  • carboxylic acid CXXXII was coupled using standard methods with a variety of CAP amines CXXXIII to give the polyamine EPI CXXXIV.
  • Boc-protected compound CLIX (330 mg, 0.71 mmol) was dissolved in ethyl acetate (5mL) and treated with hydrogen chloride (4.0M solution in ethyl acetate, 5 ml). The reaction mixture was stirred over 45 minutes at r. t. and next ethyl ether was added (about 20 ml). The precipitate was filtered off and washed with ether to give white crystalline solid of CLX (73mg, O.l ⁇ mmol, 24%).
  • Boc-protected compound CLXI (30mg, 0.034 mmol) was dissolved in ethyl acetate (2mL) and treated with hydrogen chloride (4.0M solution in ethyl acetate, 2ml). The reaction mixture was stirred over 20 minutes at r.t. and ethyl ether was added (about 10 ml). The precipitate was filtered off and washed with ether to give 3-( ⁇ N'-[(2S)-2-azaniumyl- 3-[bis(2-azaniumylethyl)carbamoyl]propanoyl]-N- ⁇ [4-
  • Boc-protected compound CLXXXVIII (692mg, 1.53mmol) was dissolved in ethyl acetate (5mL) and treated with hydrogen chloride (4.0M solution in ethyl acetate, 5ml). The reaction mixture was stirred over 30 minutes at r.t. and next ethyl ether was added (about 10ml). The precipitate was filtered off and washed with ethyl ether to give white solid CLXXXIX (505mg, 1.30mmol, 85%).
  • Boc-protected peptide CXCI (450mg, 0.88mmol) was dissolved in ethyl acetate (5mL) and treated with hydrogen chloride (4.0M solution in ethyl acetate, 5ml). The reaction mixture was stirred over 30 minutes at r.t. and next ethyl ether was added (about 10ml). Precipitate was filtered off and washed with ether to give white solid CXCII (283mg, 0.81 mmol, 92%).
  • ESIMS found for C 20 H 22 F 3 N 3 O 3 m/z 410.4 (M+H).
  • Boc-protected derivative CXCIV (560mg, O. ⁇ lmmol) was dissolved in ethyl acetate (5mL) and treated with hydrogen chloride (4.0M solution in ethyl acetate, 5ml). The reaction mixture was stirred over 30 minutes at r.t. and next ethyl ether was added (about 10ml). Precipitate was filtered off and washed with ether to give (lS)-2-[bis(2- azaniumylethyl)carbamoyl]-1-[( ⁇ [(l S)-3-phenyl-1-( ⁇ [4-
  • (2S)-2-[(l S)-I -formamido-2-[(l S)-I -formamidoethane-1,2-bis(aminium)] ethan-1-aminium]-4-phenyl-N-[3-(trifluoromethyl)phenyl]butanamide trichloride 334 is depicted below in scheme 29 and example 29.
  • Boc-hydrazine (1.25g, 9.5mmol), ethyl bromoacetate (0.2ImL, 1.9mmol) and DIPEA (0.33mL, 1.9mmol) were dissolved in CH 3 CN and stirred overnight at r.t. The solvent was removed in vacuo. The residue was distributed between IN HCI/CH2CI2 and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with brine, and dried over MgS ⁇ 4, filtered and concentrated to afford CCVII (0.41 g of crude product), that was used in the next stage without any additional purification.

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Abstract

L'invention porte sur des composés ayant des fonctionnalités polybasiques. Les composés inhibent des inhibiteurs de pompe à efflux bactérienne et sont utilisés en combinaison avec un agent antibactérien pour traiter ou prévenir des infections bactériennes. Ces combinaisons peuvent être efficaces contre les infections bactériennes qui ont développé une résistance à des agents antibactériens à travers un mécanisme de pompe à efflux.
PCT/US2009/063426 2008-11-05 2009-11-05 Inhibiteurs polybasiques de pompe à efflux bactérienne et leurs utilisations thérapeutiques WO2010054102A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011144892A1 (fr) * 2010-05-18 2011-11-24 The University Court Of The University Of Edinburgh Lipides cationiques
WO2013185124A1 (fr) 2012-06-08 2013-12-12 Wisconsin Alumni Research Foundation Composés antimicrobiens, compositions et leurs procédés d'utilisation
US9282738B2 (en) 2011-07-11 2016-03-15 Wisconsin Alumni Research Foundation Antimicrobial compositions and methods of use thereof
US9440920B2 (en) 2014-07-03 2016-09-13 Wisconsin Alumni Research Foundation Antimicrobial compounds, compositions and methods of use thereof
WO2017042099A1 (fr) * 2015-09-09 2017-03-16 Basilea Pharmaceutica Ag Inhibiteurs de pompes à efflux et leurs utilisations thérapeutiques
CN107735101A (zh) * 2015-04-20 2018-02-23 新墨西哥州科技研究基金会 抗生素敏感性恢复剂和光敏剂
CN113214106A (zh) * 2021-06-22 2021-08-06 河南师范大学 一种高效合成伯酰胺、n-甲基仲酰胺类化合物的方法
WO2024091450A1 (fr) * 2022-10-24 2024-05-02 The Regents Of The University Of California Composés et méthodes de traitement du cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008141010A2 (fr) * 2007-05-11 2008-11-20 Mpex Pharmaceuticals, Inc. Inhibiteurs de pompes à efflux bactériennes polybasiques et leurs utilisations thérapeutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008141010A2 (fr) * 2007-05-11 2008-11-20 Mpex Pharmaceuticals, Inc. Inhibiteurs de pompes à efflux bactériennes polybasiques et leurs utilisations thérapeutiques

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130065308A1 (en) * 2010-05-18 2013-03-14 The University Court Of The University Of Edinburgh Cationic lipids
US8759104B2 (en) 2010-05-18 2014-06-24 The University Court Of The University Of Edinburgh Cationic lipids
WO2011144892A1 (fr) * 2010-05-18 2011-11-24 The University Court Of The University Of Edinburgh Lipides cationiques
US9282738B2 (en) 2011-07-11 2016-03-15 Wisconsin Alumni Research Foundation Antimicrobial compositions and methods of use thereof
WO2013185124A1 (fr) 2012-06-08 2013-12-12 Wisconsin Alumni Research Foundation Composés antimicrobiens, compositions et leurs procédés d'utilisation
US9849099B2 (en) 2014-07-03 2017-12-26 Wisconsin Alumni Research Foundation Antimicrobial compounds, compositions and methods of use thereof
US9440920B2 (en) 2014-07-03 2016-09-13 Wisconsin Alumni Research Foundation Antimicrobial compounds, compositions and methods of use thereof
EP3285796A4 (fr) * 2015-04-20 2018-12-12 New Mexico Tech Research Foundation Agents photosensibles et de rétablissement de la sensibilité aux antibiotiques
CN107735101A (zh) * 2015-04-20 2018-02-23 新墨西哥州科技研究基金会 抗生素敏感性恢复剂和光敏剂
CN107735101B (zh) * 2015-04-20 2022-11-04 新墨西哥州科技研究基金会 抗生素敏感性恢复剂和光敏剂
WO2017042099A1 (fr) * 2015-09-09 2017-03-16 Basilea Pharmaceutica Ag Inhibiteurs de pompes à efflux et leurs utilisations thérapeutiques
CN113214106A (zh) * 2021-06-22 2021-08-06 河南师范大学 一种高效合成伯酰胺、n-甲基仲酰胺类化合物的方法
CN113214106B (zh) * 2021-06-22 2023-05-09 河南师范大学 一种高效合成伯酰胺、n-甲基仲酰胺类化合物的方法
WO2024091450A1 (fr) * 2022-10-24 2024-05-02 The Regents Of The University Of California Composés et méthodes de traitement du cancer

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