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WO2025144774A1 - Composés thérapeutiques et procédés - Google Patents

Composés thérapeutiques et procédés Download PDF

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Publication number
WO2025144774A1
WO2025144774A1 PCT/US2024/061654 US2024061654W WO2025144774A1 WO 2025144774 A1 WO2025144774 A1 WO 2025144774A1 US 2024061654 W US2024061654 W US 2024061654W WO 2025144774 A1 WO2025144774 A1 WO 2025144774A1
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Prior art keywords
compound
alkyl
salt
alkoxy
hydroxy
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Richard H. Ebright
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Rutgers State University of New Jersey
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Rutgers State University of New Jersey
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • antibiotics have been a bulwark against bacterial infectious diseases. This bulwark is failing due to the appearance of resistant bacterial strains.
  • strains resistant to at least one current antibiotic have arisen.
  • strains resistant to all current antibiotics have arisen.
  • RNA polymerase Bacterial RNA polymerase (RNAP) is a proven target for antibacterial therapy (Darst, S. (2004) Trends Biochem. Sci. 29, 159-162; Chopra, I. (2007) Curr. Opin. Investig. Drugs 8, 600-607; Villain-Guillot, P., Bastide, L., Gualtieri, M. & Leonetti, J. (2007) Drug Discov. Today 12, 200-208; Ho, M., Hudson, B., Das, K., Arnold, E., Ebright, R. (2009) Curr. Opin. Struct. Biol. 19, 715-723; and Srivastava et al. (2011) Curr. Opin. Microbiol. 14, 532-543).
  • bacterial RNAP is an essential enzyme (permitting efficacy), the fact that bacterial RNAP subunit sequences are highly conserved (permitting broad-spectrum activity), and the fact that bacterial RNAP-subunit sequences are highly conserved in human RNAP I, RNAP II, and RNAP III (permitting therapeutic selectivity).
  • halo means fluoro, chloro, bromo, or iodo.
  • alkoxy used alone or as part of a larger moiety is a group alkyl-O-, wherein alkyl has any of the values defined herein.
  • aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • aryl can be phenyl, indenyl, or naphthyl.
  • heteroaryl encompasses a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (Ci-C4)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms comprising one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X).
  • heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N- oxide).
  • heterocycle or “heterocyclyl” ring as used herein refers to a ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • the ring can be saturated, partially unsaturated, or aromatic.
  • the term includes single (e.g., monocyclic) saturated, partially unsaturated, and aromatic rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the term includes 5-6 membered saturated, partially unsaturated, and aromatic heterocycles that include 1-5 carbon atoms and 1-4 heteroatoms.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents.
  • structures depicted herein are also meant to include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Therefore, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures, of the present compounds are within the scope of the invention. Similarly, E- and Z-isomers, or mixtures thereof, of olefins within the structures also are within the scope of the invention.
  • this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D).
  • a -CH3 group may be substituted with -CD3.
  • the compound is enriched in that isotope above the natural abundance of that isotope.
  • the compound may be enriched by at least 2-times the natural abundance of that isotope.
  • the compound may be enriched by at least 10-times the natural abundance of that isotope.
  • the compound may be enriched by at least 100-times the natural abundance of that isotope.
  • the compound may be enriched by at least 1000-times the natural abundance of that isotope.
  • R 6 is a C 1 -C 5 alkyl that is substituted with one or more deuterium atoms
  • one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) of the hydrogens on the C 1 -C 5 alkyl group has been replaced with a deuterium as described.
  • ком ⁇ онент of this invention may exist in tautomeric forms, such as keto-enol tautomers.
  • the depiction of a single tautomer is understood to represent the compound in all of its tautomeric forms.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable cation includes sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Particularly acceptable cations are the monovalent catins, including sodium, potassium, lithium, and ammonium, and the like.
  • pharmaceutically acceptable cation also includes cations formed by protonation or alkylation of a pharmaceutically acceptable organic nontoxic bases such as primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • the term “pharmaceutically acceptable cation” includes cations formed from unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C 1 -C 6 )-alkylamine), such as N,N-dimethyl-N-(2- hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.
  • the invention provides new compositions of matter that highly potently inhibit bacterial RNA polymerase and inhibit bacterial growth. Certain compounds of this invention exhibit potencies higher than the potencies of the natural products myxopyronin A and B and of other known analogs of myxopyronin A and B.
  • Certain embodiments of the invention also provide methods for preparation of a compound according to general structural formula (I).
  • Certain embodiments of the invention also provide an assay for inhibition of a RNA polymerase comprising contacting a bacterial RNA polymerase with a compound according to general structural formula (I).
  • Certain embodiments of the invention also provide an assay for antibacterial activity comprising contacting a bacterial RNA polymerase with a compound according to general structural formula (I). Certain embodiments of the invention also provide the use of a compound according to general structural formula (I), as an inhibitor of a bacterial RNA polymerase.
  • Certain embodiments of the invention also provide the use of a compound according to general structural formula (I) as an antibacterial agent.
  • Certain embodiments of the invention also provide the use of a compound according to general structural formula (I) as one of a disinfectant, a sterilant, an antispoilant, an antiseptic, or an anti-infective.
  • W, X, Y, and Z are individually carbon, sulfur, oxygen, selenium, or nitrogen, wherein at least two of W, X, Y, and Z are carbon; one of R 1 and R 2 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, or heteroaryl, wherein any C 1 -C 5 alkyl
  • R 3 is absent or is one of H, C 1 -C 2 alkyl, or halogen- substituted C 1 -C 2 alkyl;
  • R 4 is halo
  • R 5 is H or M + , where M + is a pharmaceutically acceptable cation
  • R 6 is H, halogen, or methyl that is optionally substituted with halogen
  • R 9 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein any C 1 -C 10 alkyl or C 2 -C 10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ;
  • R 10 is C 1 -C 5 alkyl that is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) deuterium atoms.
  • W is sulfur, oxygen, or nitrogen; and X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon.
  • the compound of formula (I) is a compound of formula (la): or a salt thereof, wherein:
  • Y is N or C-R a ;
  • R 9 is methyl
  • R 10 is C 1 -C 5 alkyl.
  • R 10 is methyl
  • R 10 is C 1 -C 5 alkyl that is substituted with one or more deuterium atoms.
  • R 10 is -CD3.
  • the compounds of Formul (I) and the pharmaceutically acceptable salts thereof may be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration (i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes).
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound or salt may be incorporated into sustained-release preparations and devices.
  • the active compound and salts may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salt can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound or salt in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds or salts may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds or salts can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds or salts to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds or salts can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound or salt, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the compound or salt is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound or salt of the invention formulated in such a unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • a formulation comprising from about 0.25 mg/ml to about 10 mg/ml of said compound or salt, about 0% to about 10% dimethylacetamide, and about 0% to about 10% Cremophor EL; b) A formulation comprising from about 0.25 mg/ml to about 10 mg/ml of said compound or salt, about 2% to about 5% dimethylacetamide, and about 0% to about 5% Cremophor EL; c) A formulation comprising from about 0.25 mg/ml to about 10 mg/ml of a pharmaceutically acceptable salt of said compound or salt and about 5% dextrose in about 10 mM sodium phosphate at about pH 7.4; and d) A formulation comprising from about 0.25 mg/ml to about 10 mg/ml of a pharmaceutically acceptable salt of said compound or salt in phosphate-buffered saline at about
  • the compound of Example 3 was prepared as follows:
  • Example 4 The compound of Example 4 was prepared as described in a-f below. a.
  • the reaction was quenched by adding ice-water (7.00 mL).
  • the pH of the mixture was adjusted to ⁇ 5 by adding hydrochloric acid (1 M).
  • Organics were extracted with ethyl acetate (2 x 70.0 mL), and the combined extracts were washed with brine (70.0 mL), dried over anhydrous sodium sulfate, and evaporated to an oil.
  • the yellow oil was purified by prep-HPLC (column: Phenomenex Luna C18 150 mm x 25 mm x 10 ⁇ m; mobile phase: [water(FA)-ACN]; gradient: 63%-93% B over 10 min) and was lyophilized to give methyl-d3-((E)-5-(3-((E)-3-(3-chloro-5-(3,4-difluorophenoxy)- thiophen-2-yl)-2-methylacryloyl)-4-hydroxy-2-oxo-2H-pyran-6-yl)pent-l-en-l-yl)carbamate (230 mg, 404 ⁇ mol, 30.3% yield) as a yellow solid.
  • the compound of Example 5 was prepared as follows:
  • Example 6 The compound of Example 6 was prepared as described in a-f below.
  • the pH of the reaction mixture was adjusted to ⁇ 3 by adding hydrochloric acid (1 M).
  • the mixture was poured into water (100 mL) and was extracted with ethyl acetate (3 x 100 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil.
  • the yellow oil was purified by reversed-phase HPLC (0.1% FA condition) and extracted with ethyl acetate (3 x 100 mL).
  • the compound of Example 7 was prepared as follows:
  • Example 8 The compound of Example 8 was prepared as described in a-f below. a.
  • Example 10 The compound of Example 10 was prepared as described in a-g below. a.
  • the pH of mixture was adjusted to ⁇ 3 by adding hydrochloric acid (1 M).
  • the mixture was poured into water (200 mL) and was extracted with ethyl acetate (3 x 200 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil.
  • the yellow oil was purified by reversed-phase HPLC (0.1% FA condition) and extracted with ethyl acetate (3 x 200 mL).
  • the compound of Example 11 was prepared as follows:
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil.
  • the yellow oil was purified by prep-HPLC (column: CD02-Waters Xbidge BEH Cl 8 150 mm x 25 mm x 10 ⁇ m; mobile phase: [Water-MeOH]; gradient: 26%-56% B over 10 min) and was lyophilized to give a yellow solid, and trace water was removed by azeotropic evaporation of added ethanol azeotrope (3 x 10.0 mL) to give a yellow solid with residual ethanol.
  • Example 12 The compound of Example 12 was prepared as described in a-g below. a.
  • the yellow solid was purified by prep-HPLC (column: Welch Ultimate XB-CN 250 mm x 50 mm x 10 ⁇ m; mobile phase: [Hexane-EtOH]; B%: 1.5%, isocratic elution mode) and was concentrated under vacuum to give 3-bromo-5-(3,4-difluorophenoxy)thiophene-2- carbaldehyde (1.20 g, 3.76 mmol, 29.0% yield) as a yellow solid.
  • the compound of Example 13 was prepared as follows:
  • Example 14 The compound of Example 14 was prepared as described in a-g below. a.
  • the reaction was quenched with ice water (50.0 mL), and the pH was adjusted to 4-5 with hydrochloric acid (1 M).
  • the reaction mixture was poured into water (400 mL), extracted with ethyl acetate (3 x 300 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil.
  • the yellow oil was purified by re -HPLC (column: Phenomenex Luna C18 (250 mm x 70 mm, 10 ⁇ m); mobile phase: [water (FA)- ACN]; gradient: 44%-74% B over 30 min) and extracted with ethyl acetate (3 /300 mL).
  • the pH of mixture was adjusted to ⁇ 3 by adding hydrochloric acid (1 M).
  • the mixture was poured into water (300 mL) and was extracted with ethyl acetate (3 x 300 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil.
  • the yellow oil was purified by prep-HPLC (column: YMC-Triart Prep C18 250 mm x 50 mm x 10 ⁇ m; mobile phase: [water (FA)-ACN]; gradient: 50%-80% B over 20 min) and was extracted with ethyl acetate (3 x 300 mL).
  • Example 14e in acetone (14.0 mL), was added diisopropylethylamine (1.74 g, 13.5 mmol, 2.35 mL, 5.00 eq and isobutyl carb onochlori date (735 mg, 5.39 mmol, 704 pL, 2.00 eq) at 0°C under qa nitrogen atmosphere, and the mixture was stirred at 0°C for 1.5 h.
  • Sodium azide (1.40 g, 21.5 mmol, 8.00 eq in water (14.0 mL) was added, and the mixture was stirred at 25°C for 40 min under a nitrogen atmosphere. The reaction was quenched by adding ice-water (10 mL).
  • the pH of the mixture was adjusted to ⁇ 5 by adding hydrochloric acid (1 M).
  • Organics were extracted with ethyl acetate (2 x 150 mL), and the combined extracts were washed with brine (150 mL), dried over anhydrous sodium sulfate, and evaporated to an oil.
  • the compound of Example 15 was prepared as follows:
  • Example 16 The compound of Example 16 was prepared as described in a-g below. a.
  • the reaction was quenched with ice water (50.0 mL), and the pH was adjusted to 4-5 with hydrochloric acid (1 M).
  • the reaction mixture was poured into water (400 mL), extracted with ethyl acetate (3 x 300 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil.
  • the yellow oil was purified by prep-HPLC (column: Phenomenex Luna Cl 8 (250 mm x 70 mm x 10 ⁇ m); mobile phase: [water (FA)-ACN]; gradient: 55%-85% B over 30 min) and was extracted with ethyl acetate (3 x 300 mL).
  • the pH of the mixture was adjusted to ⁇ 3 by adding hydrochloric acid (1 M).
  • the mixture was poured into water (300 mL) and was extracted with ethyl acetate (3 x 300 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil.
  • the yellow oil was purified by prep-HPLC (column: YMC-Triart Prep C18 250 mm x 50 mm x 10 ⁇ m; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B over 20 min) and was extracted with ethyl acetate (3 x 300 mL).
  • the compound of Example 17 was prepared as follows:
  • Example 23 Preparation of:
  • Example 50 Example 50.
  • Example 65 Example 65.
  • the compounds of Examples 63-66 were prepared by supercritical fluid chromatography (column: SFC-AD-30-DAICEL CHIRALPAK AD (250 mm x 30 mm x 10 ⁇ m; mobile phase: [50% CO 2 -MeOH; 50% (0.1% NH3 in H2O)]) of the compound of Example 48 (yielding the compounds of Examples 63 and 65; retention times 1.956 min and 2.831 min), followed by conversion to sodium salts essentially as described in Example 3 (yielding the compounds of Examples 64, 66, 66, and 68). Examples 67-70.
  • the compounds of Examples 67-70 were prepared by supercritical fluid chromatography (column: SFC-AD-30-DAICEL CHIRALPAK AD (250 mm x 30 mm x 10 ⁇ m; mobile phase: [50% CO 2 -MeOH; 50% (0.1% NH3 in H2O)]) of the compound of Example 50 (yielding the compounds of Examples 67 and 69; retention times 2.419 min and 2.934 min), followed by conversion to sodium salts essentially as described in Example 3 (yielding the compounds of Examples 68 and 70).
  • the compounds of Examples 71, 73, and 75 were prepared essentially as described in Examples 2f-2o, but using reaction with methanol at 25°C for 1 hour in place of reaction with methanol-d4 at 70°C for 3 hours in the step corresponding to Example 2o (yielding the compounds of Examples 71, 73, and 75), followed by conversion to sodium salts essentially as described in Example 3 (yielding the compounds of Examples 72, 74, and 76).
  • Example 77 Assay of inhibition of bacterial RNA polymerase.
  • RNA polymerase assays with E. coli RNA polymerase were performed by a modification of the procedure of Kuhlman et al., 2004 [Kuhlman, P., Duff, H. & Galant, A. (2004) A fluorescence-based assay for multisubunit DNA-dependent RNA polymerases. Anal. Biochem. 324, 183-190], Reaction mixtures contained (20 pl): 0-100 nM test salt, 75 nM E.
  • coli RNA polymerase ⁇ 70 holoenzyme 20 nM 384 bp DNA fragment containing the bacteriophage T4 N25 promoter, 100 pM ATP, 100 pM GTP, 100 pM UTP, 100 pM CTP, 50 mM Tris-HCl, pH 8.0, 100 mM KC1, 10 mM MgCh, 1 mM DTT, 10 pg/ml bovine serum albumin, and 5.5% glycerol. Reaction components other than DNA and NTPs were pre-incubated for 10 min at 37°C.
  • Reactions were carried out by addition of DNA and incubation for 5 min at 37°C, followed by addition of NTPs and incubation for 60 min at 37°C.
  • DNA was removed by addition of 1 pl 5 mM CaCh and 2 U DNasel (Ambion, Inc.), followed by incubation for 90 min at 37°C.
  • IC 50 is defined as the concentration of inhibitor resulting in 50% inhibition of RNA polymerase activity.
  • RNA polymerase assays with Staphylococcus aureus RNA polymerase were performed analogously, using reaction mixtures containing (20 pl): 0-100 nM test salt, 75 nM Staphylococcus aureus RNA polymerase core enzyme, 300 nM S. aureus 20 nM 384 bp DNA fragment containing the bacteriophage T4 N25 promoter, 100 pM ATP, 100 pM GTP, 100 pM UTP, 100 pM CTP, 40 mM Tris-HCl, pH 8.0, 80 mM NaCl, 5 mM MgCh, 2.5 mM DTT, and 12.7% glycerol.
  • Example 78 Assay of inhibition of bacterial growth in culture: MICs.
  • MICs Minimum inhibitory concentrations for Staphylococcus aureus, Staphylococcus epidermidis. Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Acinetobacter baumannii, Burkholderia cepacia, Burkholderia dolosa, Burkholderia mutivorans, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, and Legionella pneumophila were quantified using broth microdilution assays and a starting cell density of 5xl0 5 cfu/ml [Clinical and Laboratory Standards Institute (CLIS/NCCLS) (2012) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;
  • CLIS Document M07-A9 CLIS, Wayne PA
  • CLIS/NCCLS Clinical and Laboratory Standards Institute
  • MICs for Staphylococcus spp., Enterococcus spp., Acinetobacter spp., Burkholderia spp., and Escherichia coli were determined using cation-adjusted Mueller- Hinton II broth (MHII; BD Biosciences, Inc.), an air atmosphere, and incubation for 16 h at 37°C with shaking at 180 r ⁇ m).
  • MHII Mueller- Hinton II broth
  • MICs for Streptococcus spp. were determined using Todd- Hewitt broth (THB; BD Biosciences, Inc.), a 5% CO2 / 95% air atmosphere, and incubation for 16 h at 37°C without shaking.
  • MICs for Haemophilus influenzae were determined using Haemophilus Test Medium broth (HTM; BD Biosciences, Inc), an air atmosphere, and incubation for 20 h at 37°C with shaking at 180 r ⁇ m.
  • MICs for Legionella pneumophilia were determined using buff ered-y east-extract broth (prepared by mixing 10 g yeast extract, 10 g ACES buffer, and 1 g ⁇ -ketoglutarate in 980 ml water; autoclaving; aseptically adding 0.4 g L-cysteine HC1 in 10 ml water and 0.25 g iron (III) nitrate nonahydrate in 10 ml water; and then aseptically adjusting pH to 6.9), an air atmosphere, and incubation for 48 h at 37°C with shaking at 180 r ⁇ m.
  • MICs for Mycoplasma pneumoniae were quantified in colorimetric broth microdilution assays as follows: Cultures of Mycoplasma pneumoniae ATCC 15531 grown in SP4 glucose broth (Thermo Fisher, Inc.) at the stage in which cultures start to turn yellow were diluted 100-fold with fresh SP4 glucose broth, were dispensed into wells of 96-well plates, were supplemented with serial dilutions of test compounds, and were incubated 10 days at 37°C. Untreated control cultures started to turn yellow between day 5 and day 7. The MIC was defined as the lowest concentration of test compound that prevented color change by day 10. SP4 glucose broth contains 10% fetal bovine serum.
  • the raw MIC for each test compound was divided by the serum MIC shift for the test compound (defined as the ratio of brothmicrodilution MICs against Escherichia coli D21f2tolC with and without 10% serum).
  • MICs for Chlamydia pneumoniae were quantified in intracellular infection microdilution assays essentially as in [Bao, X., Gylfe, A., Sturdevant, G., Gong, Z., Xu, S., Caldwell, H., Elofsson, M., Fan, H. (2014) Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner.
  • MICs for Chlamydia trachomatis were quantified in intracellular infection microdilution assays essentially as in [Lu, B., Qiao, Q., Park, E., Wang, Y., Gilleran, J., Pan, M., Pilch, D., Wu, X., Roberge, J., Fan, H. (2023) Acylpyrazoline-based third-generation selective antichlamydial compounds with enhanced potency.
  • Chlamydia trachomatis ATCC VR-902B/mKate was described in [Lu, B., Qiao, Q., Park, E., Wang, Y., Gilleran, J., Pan, M., Pilch, D., Wu, X., Roberge, J., Fan, H. (2023) Acylpyrazoline-based third-generation selective antichlamydial compounds with enhanced potency. ACS Omega 8:6597-6607] and was provided by Dr. H. Fan of Rutgers University. Other bacterial strains were obtained from the American Type Culture Collection (ATCC) and the CDC & FDA Antibiotic Resistance Isolate Bank (AR Isolate Bank).
  • ATCC American Type Culture Collection
  • AR Isolate Bank Antibiotic Resistance Isolate Bank
  • Example 79 Assay of inhibition of bacterial growth in culture: panel MIC50s and panel MIC90s.
  • panels of Enterococcus spp panels of Staphylococcus spp.
  • Vancomycin-resistant strains were cultured in agar and broth containing 4 ug/ml vancomycin, prior to dilution in the absence of vancomycin and addition to assay plates.
  • Daptomycin-resistant isolates of Staphylococcus aureus were described in [Friedman, L., Alder, J., Silverman, J. (2006) Genetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus. Antimicrob Agents Chemother. 50:2137-2145; Song, Y., Rubio, A., Jayaswal, R., Silverman, J., Wilkinson, B. (2013) Additional routes to Staphylococcus aureus daptomycin resistance as revealed by comparative genome sequencing, transcriptional profiling, and phenotypic studies. PLoS One. 8:e58469] and were provided by Dr. J. Silverman of Cubist Pharmaceuticals.
  • Example 80 Assay of pharmacokinetics in mice.
  • Example 81 Assay of antibacterial efficacy in mouse model of Staphylococcus aureus lung infection ("neutropenic lung infection model").
  • mice (0.18-0.20 kg) were rendered immunosuppressed by intraperitoneal injection of 150 mg/kg cyclophosphamide on day -4 and 100 mg/kg cyclophosphamide on day -1 and then were infected by intranasal administration of 1 x 10 7 colony forming units of methicillin-resistant Staphylococcus aureus (MRSA) strain BAA- 1556.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Test compounds in vehicle were administered by intravenous injection into a tail vein (200 pl) 1 h post-infection to provide single intravenous doses of 6.25, 12.5, 25, 50, 100, and/or 200 mg/kg or by oral gavage (200 pl) 1 h post-infection to provide oral doses of 6.25, 12.5, 25, 50, 100, and/or 200 mg/kg.
  • Mice were euthanized and lungs were harvested and homogenized 26 h post-infection; and viable bacteria were quantified.
  • the effective dose was defined as the minimum test-compound dose resulting in P ⁇ 0.05 reduction in bacterial burden.
  • Data for the compound of Example 1 and for representative compounds of this invention are shown in Table 10 (for intravenous dosing) and Table 11 (for oral dosing).
  • Bold data indicate improvement over the compound of Example 1.
  • mice were infected by injection of 1 x 10 5 colony forming units of methicillin-resistant Staphylococcus aureus (MRSA) strain BAA-1556 or BAA-1707 (USA-400, MW2) into thighs, thighs were harvested and homogenized 24 h post-infection; and viable bacteria were quantified.
  • MRSA methicillin-resistant Staphylococcus aureus
  • a broth-microdilution assays b intracellular infection microdilution assays.
  • Table 8 in vivo pharmacokinetics, intravenous a LC/MS-detected mouse iv PK; CD-I mice.
  • b CD-I mice; A aureus MRSA BAA-1556 or MRSA BAA-1707; n 10/arm; P ⁇ 0.05.
  • b CD-I mice; A aureus MRSA BAA-1556 or MRSA BAA-1707; n 10/arm; P ⁇ 0.05.
  • Table 1 show that certain compounds according to general structural formula (I) are at least approximately 4 times more potent in inhibiting Gram-positive and Gram-negative bacterial RNA polymerases than the compound of Example 1, the most potent arylmyxopyronin for which data previously were disclosed.
  • Tables 2-7 show that certain compounds according to general structural formula (I) provide coverage of Gram-positive, fastidious Gram-negative, and non-fastidious Gram-negative pathogens relevant to lower respiratory tract infections, skin/wound infections, and bloodstream infections—including drug-resistant, multi-drug-resistance, and current clinical isolates.
  • mice MRSA methicillin-resistant Staphylococcus aureus
  • Table 10 show that certain compounds according to general structural formula (I) are at least approximately 2 to 4 times more efficacious in clinically relevant mouse methicillin-resistant Staphylococcus aureus (MRSA) infection assays—including both a mouse MRSA lung infection assay with intravenous dosing and a mouse MRSA thigh infection assay with intravenous dosing— than the compound of Example 1, the most potent arylmyxopyronin for which data previously were disclosed.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Examples 2-76 define a new genus of arylmyxopyronins, with potency and properties suggesting that it can be developed to provide a novel, first-in-class, orally available drug for treatment of lower respiratory tract infections, skin/wound infections, and bloodstream infections caused by, at minimum, Staphylococcus spp. (MSSA, MRSA, VRSA, and MDR), Streptococcus spp. (SPN, GAS, GBS, and MDR), Enterococcus spp.
  • VSE VSE, VRE, and MDR
  • fastidious Gram negatives Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae
  • certain non-fastidious Gram negatives Acinetobacteria spp. and Burkholderia spp.

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Abstract

L'invention concerne un composé de formule (I) : ou un sel de celui-ci, formule dans laquelle R'-R10, W, X, Y et Z ont l'une quelconque des valeurs décrites dans la description, ainsi que des compositions comprenant de tels composés ou sels, des procédés de fabrication de tels composés et sels, et des procédés d'utilisation de tels composés et sels, par exemple, en tant qu'inhibiteurs de l'ARN polymérase bactérienne et en tant qu'agents antibactériens.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160263083A1 (en) * 2012-06-19 2016-09-15 Rutgers, The State University Of New Jersey Antibacterial agents: aryl myxopyronin derivatives
US11685723B2 (en) * 2018-02-13 2023-06-27 Rutgers, The State University Of New Jersey Antibacterial agents: O-alkyl-deuterated pyronins

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160263083A1 (en) * 2012-06-19 2016-09-15 Rutgers, The State University Of New Jersey Antibacterial agents: aryl myxopyronin derivatives
US11685723B2 (en) * 2018-02-13 2023-06-27 Rutgers, The State University Of New Jersey Antibacterial agents: O-alkyl-deuterated pyronins

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Title
KORP JULIANE, VELA GUROVIC MARíA S, NETT MARKUS: "Antibiotics from predatory bacteria", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 12, 1 January 2016 (2016-01-01), GB , pages 594 - 607, XP093333124, ISSN: 1860-5397, DOI: 10.3762/bjoc.12.58 *
PARK B K; KITTERINGHAM N R; O'NEILL P M: "Metabolism of fluorine-containing drugs.", ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, vol. 41, 1 January 2001 (2001-01-01), US , pages 443 - 470, XP009114978, ISSN: 0362-1642, DOI: 10.1146/annurev.pharmtox.41.1.443 *
SCHÄBERLE TILL F., MIR MOHSENI MAHSA, LOHR FRIEDERIKE, SCHMITZ ALEXANDER, KÖNIG GABRIELE M.: "Function of the Loading Module in CorI and of the O -Methyltransferase CorH in Vinyl Carbamate Biosynthesis of the Antibiotic Corallopyronin A", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 58, no. 2, 1 February 2014 (2014-02-01), US , pages 950 - 956, XP093333129, ISSN: 0066-4804, DOI: 10.1128/AAC.01894-13 *

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