WO2024258613A2 - Tétrachlorovancomycine et dérivés - Google Patents

Tétrachlorovancomycine et dérivés Download PDF

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WO2024258613A2
WO2024258613A2 PCT/US2024/031453 US2024031453W WO2024258613A2 WO 2024258613 A2 WO2024258613 A2 WO 2024258613A2 US 2024031453 W US2024031453 W US 2024031453W WO 2024258613 A2 WO2024258613 A2 WO 2024258613A2
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compound
vancomycin
equiv
pharmaceutically acceptable
tetrachlorovancomycin
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WO2024258613A3 (fr
WO2024258613A9 (fr
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Dale L. Boger
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Scripps Research Institute
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Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • a new class of structurally simplified synthetic glycopeptide antibiotics is disclosed that is now easily accessible by total synthesis and directly addresses this challenge.
  • the class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the potent antimicrobial activity of vancomycin, and achieves this simplification by an unusual addition, not removal, of benign substituents to the core structure.
  • the diastereoselective introduction of the three elements of atropisomerism embedded in the vancomycin structure is the central challenge to its synthesis (Fig. 1).
  • this simplification allows full control of all stereochemical features, results in a technically straightforward total synthesis with reduction in the step count [15 steps in longest linear sequence (LLS), 15% overall yield], improves the CD/DE macrocyclization rates and efficiencies that are now run concurrently, and provides a synthetic glycopeptide antibiotic that maintains the ligand binding and antimicrobial activity of the natural product.
  • the class of compounds (derivatives) retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the potent antimicrobial activity of vancomycin, and achieves this simplification by an unusual addition, not removal, of benign substituents to the core structure.
  • tetrachlrovancomycin aglycon The structural formula for tetrachlrovancomycin aglycon that is produced solely using synthetic organic chemistry is shown below as Formula II.
  • the above two compounds surprisingly exhibit activity against methicillin-resistant S. aureus at about a factor of 10 or less than the activity of vancomycin against vancomycin-sensitive and vancomycin-resistant bacteria.
  • their derivatives substituted similarly to some of the most active vancomycin derivatives show almost the same activities. Being chemically prepared in relatively high yield provides a route to less expensive very active antibiotics.
  • a generic formula that can encompass tetrachlorovancomycin, contemplated derivatives and a pharmaceutically acceptable salt is shown below as Formula III.
  • R 1 is selected from the group consisting of hydrido (hydrogen), (C 1 -C 16 )hydrocarbyl, aryl(C 1 -C 6 )- hydrocarbyldiyl, heteroaryl-(C 1 -C 6 )hydrocarbyldiyl, (C 1 -C 6 )hydrocarbyldiylheteroaryl, halo(C 2 -C 12 )- hydrocarbyldiyl, and (C 1 -C 16 )amido substituents, wherein an aryl or heteroaryl group is itself optionally substituted with up to three substituents independently selected from the group consisting of: (i) hydroxy, (ii) halo, (iii) nitro, ( iv) (C 1 -C 6 )hydrocarbyl, (v) halo(C 1 -C 16 )hydrocarbyl, (vi) (C 1 -C 6 )hydrocarby
  • the compound above when is H (hydrido), and R 2 is OH, the compound above is tetrachloro- vancomycin.
  • R 1 and R 2 are other than H and OH, respectively, a derivative of tetra- chlorovancomycin is being contemplated.
  • the “X” moiety above can be H,H making the carbon to which the two hydrogens are bonded a methylene group.
  • “X” is O (oxygen) double bonded to the depicted carbon atom as the carbonyl group of an amide.
  • X can also be S (sulfur) double-bonded to the depicted carbon, making that carbon a thiocarbonyl moiety and thereby, the thiocarbonyl bonded to the –NH- group form a thioamide linkage.
  • a compound where “X” is “S” is usually used as an intermediate to the preparation of a compound of Formula I, II and III in which “X” is “H,H” forming a methylene group as above, or is “NH”, forming an amidine linkage. T urning to the R 1 substituents other than H, those hydrophobic materials are present and discussed in one of the inventors’ U.S. Patents No.9,879,049, No. 10,577,395, No.
  • T he substituents can be added to the tetrachlorovancosaminyl amino group by NaCNBH 4 reduction of the corresponding aldehyde as is shown in Scheme 5 hereinafter.
  • T he substituents, other than OH contain at least two nitrogen atoms separated by a linker group referred to as Circle A and depicted as , wherein the remaining valence of the nitrogen in the depicted “-HN-“ group bonds to carboxyl group of the tetrachlorovancomycinyl portion of the molecule to form an amido group.
  • the R 3 contains at least a second nitrogen atom bonded directly to the Circle A linker.
  • the second nitrogen of Circle A is the nitrogen of a tertiary amine or a quaternary ammonium group, as noted above.
  • W hen R 3 is a quaternary ammonium group, an optional anion, Y - , that is preferably pharmaceutically acceptable is also present to balance the charge.
  • R 3 is a tertiary amine or guanidinyl group, both of which are typically basic, a compound containing such a group can also be present as a salt with an acid.
  • the acid of such an acid salt is a pharmaceutically acceptable acid, that provides the optional anion, Y - .
  • a pharmaceutical composition containing an anti- bacterially effective amount a before-described tetrachlorovancomycin or derivative, or a pharmaceutically acceptable salt dissolved or dispersed in a pharmaceutically (physiologically) diluent acceptable diluent is also contemplated.
  • Such a composition can be in solid, liquid, gel or other appropriate form.
  • a method of treating a bacterial infection, particularly from Gram positive bacteria, is also contemplated.
  • Fig. 1 shows a comparison of vancomycin and tetrachlorovancomycin that highlights the structural and synthetic simplification and atropisomerism elimination achieved by adding two benign chlorine substituents
  • Fig. 2 is a schematic representation of key elements of a retrosynthetic analysis for tetrachlorovancomycin
  • Fig. 2 is a schematic representation of key elements of a retrosynthetic analysis for tetrachlorovancomycin
  • FIG. 3 illustrates reaction Scheme 4 that illustrates a direct synthetic route from Compound 27 to Compound 29 in 56% yield and five steps followed by the one-pot two-step enzymatic glycosylation of tetrachlorovancomycin aglycon (29) to form tetrachlorovancomycin (Compound 1) that proceeded in high yield (82%) for installation of both sugar residues despite the added 2 e and 6 e aryl chlorides;
  • Fig. 4 outlines a synthetic pathway by which a tetrachlorovancomycin derivative of Formula III where can be prepared;
  • Fig. 5 shows a reaction scheme whereby the 4-thioamide derivative, Compound 41, can be prepared from Compound 38; Fig.
  • FIG. 6 shows two reaction schemes by which Compounds 40 and 39 can be prepared from Compound 38;
  • Fig. 7B in which Compound 44 is used to prepare Compound 47, that in turn is used to prepare Compounds 48 and 49;
  • Fig. 8 in two panels, as Fig.
  • FIG. 9 in two panels as Figs. 9A and 9B, are tables showing minimum inhibitory concentrations (MIC values) for tetrachlorovancomycin analogue Compounds 41, 44, 47, 48 and 49 against bacteria that are vancomycin-sensitive (Fig. 9A) and vancomycin- resistant (Fig. 9B); data for Figs.
  • hydrocarbyl is used herein as a short-hand term for a non-aromatic group that includes straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen.
  • alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl are grouped as an “aryl“ group.
  • aryl“ group is a specific aliphatic hydrocarbyl substituent group.
  • Exemplary hydrocarbyl groups contain a chain of 2 to about77 carbon atoms, and preferably 2 to about 6 carbon atoms.
  • a particularly preferred hydrocarbyl group is an alkyl group.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
  • suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3- propenyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.
  • alkynyl radicals examples include ethynyl, 2-propynyl, 1-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, and 1-methyl-2-propynyl.
  • a substituent that cannot exist such as a C 1 alkenyl group is not intended to be encompassed by the word "hydrocarbyl", although such substituents with two or more carbon atoms are intended.
  • Usual chemical suffix nomenclature is followed when using the word "hydrocarbyl” except that the usual practice of removing the terminal "yl" and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents.
  • hydrocarbyl ether is referred to as a "hydrocarbyloxy" group rather than a "hydrocarboxy” group as may possibly be more proper when following the usual rules of chemical nomenclature.
  • Illustrative hydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy groups.
  • a wavy line as shown for example in the following representation “ X ” is used to indicate that only a portion of a molecule is being shown, and two bonds of the carbon atom doubly bonded to X are severed from the remainder of the molecule.
  • the present invention has several benefits and advantages.
  • One salient benefit of the invention is the relative ease and enhanced yield of synthetically- prepared tetrachlorovancomycin and derivatives as compared to vancomycin itself when synthetically prepared, and also when compared to vancomycin preparation by fermentation using bacteria whose 4-postiion derivatives are very difficult prepare.
  • a salient advantage of the invention is that the antibacterial activity of tetrachloro- vancomycin compared to that of vancomycin itself is almost identical.
  • tetrachlorovancomycin aglycon The structural formula for tetrachlorovancomycin aglycon that is produced solely using synthetic organic chemistry is shown below as Formula II.
  • the above two compounds surprisingly exhibit activity against methicillin-resistant S. aureus and about a factor of 10 or less the activity of vancomycin against vancomycin-sensitive and vancomycin-resistant bacteria.
  • their derivatives substituted similarly to the most active vancomycin derivatives show almost the same activities as those similarly substituted vancomycins. Being chemically prepared in relatively high yield provide a route to less expensive very active antibiotics.
  • a generic formula that can encompass tetrachlorovancomycin, contemplated derivatives and a pharmaceutically acceptable salt is shown below as Formula III.
  • T hus when is H (hydrido), and R 2 is OH, the compound above is tetrachloro- vancomycin.
  • R 1 and R 2 are other than H and OH, respectively, a derivative of tetra- chlorovancomycin is being contemplated.
  • the chemical syntheses of the tetrachloro- vancomycin and tetrachlorovancomycin aglycon are shown and discussed hereinafter. These syntheses require fewer steps and provide higher yields of the desired compounds in part because of the symmetry provided by the two chloro groups on each substituted phenyl ring that flanks the central substituted phenyl ring to which the vancosaminyl group is bonded.
  • the “X” moiety above can be H,H making the carbon to which the two hydrogens are bonded a methylene group.
  • “X” is O (oxygen) double bonded to the depicted carbon atom as the carbonyl group of an amide.
  • X can also be S (sulfur) double-bonded to the depicted carbon, making that carbon a thiocarbonyl moiety and thereby, the thiocarbonyl bonded to the –NH- group form a thioamide linkage.
  • a compound where “X” is S is usually used as an intermediate to the preparation of a compound of Formula I, II and III in which “X” is H,H forming a methylene group as above, or is NH, forming an amidine linkage.
  • “X” is H,H forming a methylene group as above, or is NH, forming an amidine linkage.
  • R 1 substituents that are presently preferred are the benzyl, 4-chlorobenzyl, (biphenyl)methyl, (4-chlorobiphenyl)methyl [CBP], 4- fluorobenzyl, and (4-fluorobiphenyl)methyl substituent groups.
  • benzyl, 4-chlorobenzyl, (biphenyl)methyl, (4-chlorobiphenyl)methyl [CBP], 4- fluorobenzyl, and (4-fluorobiphenyl)methyl substituent groups Each of these four substituents can be added to the vancosaminyl amino group by NaCNBH 4 reduction of the corresponding aldehyde as is shown in Scheme 5 hereinafter.
  • T he substituents, other than H contain at least two nitrogen atoms separated by a divalent linker group referred to as Circle A and depicted as , wherein the remaining valence of the nitrogen in the depicted “HN“ group bonds to carboxyl group of the tetrachlorovancomycinyl portion of the molecule to form an amido group, and R 3 contains at least a second nitrogen atom.
  • the second nitrogen of Circle A is the nitrogen of a tertiary amine or a quaternary ammonium group.
  • the preparation of the compounds in which the second nitrogen of a Circle A group is the nitrogen of a tertiary amine or a quaternary ammonium group can be carried out as discussed in US Patent No. 10,934,326 and in Okano et al., Proc Natl Acad Sci, USA 114(26):E5052-E5061 (Pub. online 05-30-2017) for otherwise similar derivatives of vancomycin.
  • the chain lengths herein are measured along the longest linear atom chain in the radical between the amido nitrogen and the first nitrogen atom of a guanidinyl group or the nitrogen of a tertiary amine or a quaternary ammonium group.
  • Each atom in the chain is presumed to be carbon for ease in calculation.
  • the lengths are thus recited in terms of carbon atoms.
  • Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a staggered chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values.
  • a 1,4-bonded 6-membered aromatic ring group (phenyl) not part of a fused ring system has a length of about a butyl group.
  • a 1,2- or 1,3-bonded 6-ring has a length of a 2- or 3-carbon chain, respectively, as the shortest path around the ring between the two bonding position regardless of formal naming criteria. Where a 5-membered ring is present, length is calculated as the length of a 2-carbon chain. Thus, for single ring systems, length is calculated as the shortest path around the rings between the two bonding positions to the amido and guanidinyl, quaternary ammonium or tertiary amine nitrogen atoms of a compound of Formula III regardless of formal naming criteria.
  • Radical lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths of saturated C-C bonds, that unsaturated bonds have the same lengths as saturated bonds, and that bond angles for unsaturated bonds are the same as those for saturated C-C bonds (108 o ), although the above-mentioned modes of measurement are preferred. Both methods produce similar results within one or two carbon atoms, and thus the use of "about”.
  • a contemplated linker moiety Circle A can also be a hydrocarbyl chain of two to about 12 saturated carbon atoms, or preferably two to about ten saturated carbon atoms.
  • a more preferred linking Circle A group contains a chain of atoms that is equal to or greater than the length of two saturated carbons and is shorter than about a saturated ten carbon (decyl) chain. More preferably still, the hydrocarbyl chain has a chain length of two saturated carbon atoms to about eight saturated carbon (octyl) atoms. In one illustrative instance, when there is a chain of Circle A atoms linking the amido and guanidinyl nitrogen atoms together, the length is simply the length of the longest chain of atoms linking those two nitrogens.
  • hydrocarbyl linker groups can contain a substituent that is pendant from the chain of atoms that link the amido and second nitrogens (e.g., guanidinyl) shown in Formula III.
  • a substituent are selected from amino acid side chain substituents other than those containing a carboxyl group, a sulfhydryl group (-SH) or a substituent that provides a negative charge in an aqueous solution at physiological pH values, e.g., pH 7.2-7.4.
  • Additional pendant substituents include 2-hydroxyethyl and 2-hydroxypropyl, C 1 -C 3 - hydrocarbyl C 0 -C 2 -carboxylate, and C 0 -C 2 - carboxamide whose amido nitrogen is unsubsubstituted (-NH 2 ), monosubstituted (-NHR 4 ) or disubstituted which the substituent (R4 and/or R5) is one or two same or different C 1 -C 4 - hydrocarbyl group, or whose amido nitrogen along with two substituents together form a 5- or 6- membered hydrocarbyl ring, or a heterocyclic ring containing one additional oxygen (O) atom or a N- methyl group in the ring.
  • substituents include 2-hydroxyethyl and 2-hydroxypropyl, C 1 -C 3 - hydrocarbyl C 0 -C 2 -carboxylate, and C 0 -C 2 - carboxamide whose amido nitrogen is
  • Circle A atom chain need not be entirely hydrocarbyl, but can also be contain 1, 2, or 3 oxygens in place of carbon atoms as when a -CH 2 -CH 2 -0-CH 2 -CH 2 -, -CH 2 -CH 2 -0-CH 2 -CH 2 -0-CH 2 -CH 2 -, or -CH 2 -CH 2 -0-CH 2 - CH 2 -0-CH 2 -CH 2 -0-CH 2 -CH 2 - Circle A linker moiety is utilized.
  • a contemplated divalent Circle A linker moiety also can comprise a ring system that can be carbocyclic or heterocyclic as discussed below.
  • a single 5- or 6-membered ring optionally contains one or two ring hetero atoms that can independently be nitrogen, oxygen or sulfur.
  • Individual rings can be aliphatic or aromatic, including heteroaromatic, and also be aralkyl as in a benzyl group.
  • exemplary divalent aromatic carbocyclic ring moieties include phenyl and naphthyl groups.
  • exemplary divalent heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3- triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups.
  • Aliphatic 5- and 6-membered carbocyclic rings are contemplated such as cyclohexyl and cyclopentyl, as well as their mono- and diethylenically unsaturated derivatives, using monovalent names for convenience.
  • divalent aliphatic 5- and 6-membered heterocyclic rings include, piperidinyl, piperazinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, pyranyl, morpholinyl, oxazinyl, isooxazinyl, and oxathiolyl.
  • a further aspect of the invention is a method of treating a mammal infected with a microbial infection such as a bacterial infection, typically either a Gram-positive infection or a Gram-negative bacterium; i.e., an infection caused by Gram-positive or Gram-negative bacteria, and the infected mammal is in need of antimicrobial (antibacterial) treatment.
  • a mammal infected with a microbial infection such as a bacterial infection, typically either a Gram-positive infection or a Gram-negative bacterium; i.e., an infection caused by Gram-positive or Gram-negative bacteria, and the infected mammal is in need of antimicrobial (antibacterial) treatment.
  • Treatment of Gram-positive bacteria are typically more successful that treatment of Gram-negative bacteria.
  • an antibacterial-effective amount of one or more compounds of Formula III or a pharmaceutically acceptable salt of such a compound is administered to an infected mammal in need.
  • the compound can be administered as a solid, as a liquid formulation, as a thickened preparation e.g., as a gel, as for topical use, and is preferably administered via a pharmaceutical composition discussed hereinafter. That administration can also be oral or parenteral, as are also discussed further hereinafter.
  • mammals are infected with bacteria and other microbes.
  • the present invention’s method of treatment is intended for use against infections of pathogenic bacteria that cause illness in the mammal to be treated.
  • Illustrative pathogenic microbes include S.
  • a mammal in need of treatment (a subject) and to which a pharmaceutical composition containing a Compound of Formula III or its pharmaceutically acceptable salt to be administered can be a primate such as a human, an ape such as a chimpanzee or gorilla, a monkey such as a cynomolgus monkey or a macaque, a laboratory animal such as a rat, mouse or rabbit, a companion animal such as a dog, cat, horse, or a food animal such as a cow or steer, sheep, lamb, pig, goat, llama or the like.
  • a contemplated compound is active in in vitro assay studies at less than 1 ⁇ g/mL amounts, which corresponds to a molar concentration of about 1 to about 100 nanomolar (nM), using the molecular weight of G3-CBP-tetrachlorovancomycin (Compound 31).
  • a contemplated compound is typically present in the composition in an amount that is sufficient to provide a concentration of about 0.1 nM to about 1 ⁇ M to contact microbes to be assayed.
  • the amount of a compound of Formula III or a pharmaceutically acceptable salt of such a compound that is administered to a mammal in a before- discussed method or that is present in a pharmaceutical composition discussed below, which can be used for that administration, is an antibiotic (or antibacterial or antimicrobial) effective amount. It is to be understood that that amount is not an amount that is effective to kill all of the pathogenic bacteria or other microbes present in an infected mammal in one administration. Rather, that amount is effective to kill some of the pathogenic organisms present without also killing the mammal to which it is administered, or otherwise harming the recipient mammal as is well known in the art. As a consequence, the compound usually has to be administered a plurality of times, as is discussed in more detail hereinafter.
  • a contemplated pharmaceutical composition contains an effective antibiotic (or antimicrobial) amount of a Compound of Formula III or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically (pharmaceutically) acceptable diluent or carrier.
  • An effective antibiotic amount depends on several factors as is well known in the art. However, based upon the relative potency of a contemplated compound relative to that of vancomycin itself for a susceptible strain of S. aureus shown hereinafter, and the relative potencies of vancomycin and a contemplated compound against the VanA E. faecalis and E. faecium strains, a skilled worker can readily determine an appropriate dosage amount.
  • Exemplary salts useful for a contemplated compound include but are not limited to the following: sulfate, hydrochloride, hydro bromides, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phen
  • a contemplated composition is typically administered repeatedly in vivo to a mammal in need thereof until the infection is diminished to a desired extent, such as cannot be detected.
  • the administration to a mammal in need can occur a plurality of times within one day, daily, weekly, monthly or over a period of several months to several years as directed by the treating physician.
  • a contemplated composition is administered a plurality of times over a course of treatment until a desired effect is achieved, typically until the bacterial infection to be treated has ceased to be evident.
  • a contemplated pharmaceutical composition can be administered orally (perorally) or parenterally, in a formulation containing conventional nontoxic physiologically acceptable carrier or diluent, adjuvant, and vehicle as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975 and Liberman, H.A.
  • a contemplated pharmaceutical composition is preferably adapted for parenteral administration.
  • a pharmaceutical composition is preferably in liquid form when administered, and most preferably, the liquid is an aqueous liquid, although other liquids are contemplated as discussed below, and a presently most preferred composition is an injectable preparation.
  • injectable preparations for example, sterile injectable aqueous or oleaginous solutions or suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a physiologically acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • a physiologically acceptable diluent or solvent for example, as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, isotonic sodium chloride solution, and phosphate-buffered saline.
  • Other liquid pharmaceutical compositions include, for example, solutions suitable for parenteral administration.
  • Sterile water solutions of a Compound of Formula III or its salt or sterile solution of a Compound of Formula III in a solvent comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • a contemplated Compound of Formula III is provided as a dry powder that is to be dissolved in an appropriate liquid medium such as sodium chloride for injection prior to use.
  • an appropriate liquid medium such as sodium chloride for injection prior to use.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of an injectable composition.
  • Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
  • a sterile solution can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules.
  • the amount of a contemplated Compound or salt of Formula III such as Compounds 48 or 49 in a solid dosage form is as discussed previously, an amount sufficient to provide an effective antibiotic (or antimicrobial) amount.
  • a solid dosage form can also be administered a plurality of times during a one-week time period.
  • a compound of this invention is ordinarily admixed as a solution or suspension in one or more diluents appropriate to the indicated route of administration.
  • the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
  • a sample to be assayed such as cells and tissue can be used.
  • compositions typically contain water, sodium or potassium chloride, and one or more buffer salts such as and acetate and phosphate salts, Hepes or the like, a metal ion chelator such as EDTA that are buffered to a desired pH value such as pH 4.0 -8.5, preferably about pH 7.2-7.4, depending on the assay to be performed, as is well known.
  • the pharmaceutical composition is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active compound.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, in vials or ampules.
  • Saponification of the isopropyl ester Compound 10 was surprisingly clean (Me 3 SnOH, 26 ClCH 2 CH 2 Cl, 96%), providing carboxylic acid Compound 11 without detectable epimerization of the ⁇ -stereocenter.
  • use of even carefully controlled aqueous saponification conditions (3 equiv LiOH, 2:1 t-BuOH– H 2 O, 0 ⁇ C, 1 h) led to significant C ⁇ epimerization (4:1 dr).
  • a one-pot Miyaura borylation–Suzuki coupling sequence conducted with an in situ generated (R)-BINAP(O)-Pd 0 catalyst system 6,31 provided Compound 22 exclusively as a single diastereomer (72%, >30:1 dr), setting the AB biaryl atropisomer stereochemistry.
  • Macrolactamization of Compound 24 under simulated high-dilution conditions promoted by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl- morpholinium hexafluorophosphate 34 provided the AB macrocycle Compound 25 in superb yield (83%/2 steps).
  • the cyclization reaction proceeds essentially instantaneously upon dropwise addition of Compound 24 to a solution containing DMTMMH without trace of epimerization (>30:1 dr) and benefits from the modulated nucleophilicity of the reacting amine that precludes its competitive addition to the coupling reagent.
  • Boc deprotection of Compound 25 was accomplished under conditions that may allow reversible deprotection of the slightly acid-labile t-butyl ester 36 (8 equiv H 2 SO 4 , t-BuOAc, 0 to 23 ⁇ C, 2 h), providing Compound 26 (82%) that serves as the common precursor to tetrachlorovancomycin (Compound 1) as well as future the subsequent binding pocket- modified analogues. Strikingly, NOESY studies of the AB macrocycle Compound 26, bearing the free amine, revealed exclusive adoption of the 5,6-cis amide conformation. The final steps to the full tricyclic skeleton of tetrachlorovancomycin proved exceptionally smooth (Scheme 4, Fig. 3).
  • Highlights in this sequence include not only the mild room temperature double S N Ar cyclization of Compound 27 ( ⁇ 4 h, 95%), but also the clean Fe- mediated dual nitro group reduction with avoidance of hydroxylamine byproducts, 7 a highly refined two-fold Sandmeyer substitution reaction with Lewis acid- mediated diazonium salt formation 7 and deuterated solvent suppression 6 of competitive reduction, a remarkably effective TFA-mediated nitrile hydration, 40 and a scalable AlBr 3 /EtSH-mediated global deprotection.
  • Compound 30 displays activity against the VRE strain comparable to that of CBP- vancomycin, which is derived from direct competitive inhibition of transglycosylase (a second independent mechanism of action) that does not require Ac 2 -L-Lys- D-Ala-D-Ala binding. 49,50 This activity of CBP- tetrachloro-vancomycin (Compound 30) is improved about 100-fold against the sensitive strains due to the expression of two independent and synergistic mechanisms of action.
  • This activity is derived from the direct competitive inhibition of transglycosylase and does not rely on D-Ala-D-Ala or D-Ala-D-Lac binding or transpeptidase inhibition.
  • the increase in potency attributable to G3 is derived from a newly added mechanism of action, permeabilization of the cell envelop without membrane disruption or lysis, 58 that is independent of both the CBP-mediated transglycosylase competitive inhibition and pocket-derived ligand binding and transpeptidase inhibition.
  • Compound 47 expresses this activity now through two synergistic and independent mechanisms of action, neither of which require D-Ala- D-Ala or D-Ala-D-Lac binding.
  • the two peripheral modifications (2 > 1 > 0; CBP and G3) incrementally improve potency regardless of whether the organism is resistant or sensitive to vancomycin.
  • This synergistic behavior is unusual and need not have been the case. It arises presumably because the peripheral modifications express their activity by mechanisms of action independent of one another as well as D-Ala-D-Ala/D-Lac binding, and all, including the pocket modifications, impact bacterial cell wall synthesis or its integrity.
  • the synergistic antimicrobial activity observed with the combined peripheral and pocket modifications within tetrachlorovancomycin analogues likely requires their incorporation in a single molecule as we have demonstrated with vancomycin and its pocket-modified analogues.
  • the defining feature of this class is the introduction of an added chlorine substituent on the vancomycin C and E rings, which reduces synthetic complexity.
  • the class retains the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the potent antimicrobial activity of vancomycin, and achieves this simplification by an unusual addition of benign substituents to the core structure.
  • This added two chlorine substituent modification permitted a streamlined total synthesis of the new glycopeptide antibiotic analogue by removing the challenges associated with CD and DE ring system atropisomer stereochemical control and enabled their simultaneous and further activated S N Ar macrocyclizations that establish the tricyclic skeleton of Compound 1.
  • Additional key elements of the approach include a catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), an epimerization free coupling of the E ring tetrapeptide, the room temperature dual CD/DE ring system S N Ar cyclizations, a refined 4-step conversion of the product to the aglycon, and a one-pot enzymatic glycosylation for disaccharide introduction.
  • this includes the preparation of binding pocket-modified analogues 4 of tetrachlorovancomycin to reinstate binding to the altered target D-Ala-D-Lac of vancomycin-resistant bacteria while maintaining binding for the unaltered target D-Ala-D-Ala found in sensitive bacteria as well as extension to their even more potent and durable peripherally-modified derivatives.
  • 4,7 General Experimental All reagents and solvents were used as supplied without further purification unless otherwise noted. CHCl 3 was pre-treated with alumina for at least 24 h (hours) prior to use.
  • Preparative TLC (PTLC) and column chromatography were conducted using Millipore SiO 2 60 F254 PTLC (0.5 mm) and Zeochem ZEOprep® 60 ECO SiO 2 (40–63 ⁇ m), respectively.
  • Analytical TLC was conducted using Millipore SiO 2 60 F254 TLC (0.250 mm) plates.
  • 1H and 13 C ⁇ 1 H ⁇ NMR spectra were obtained on a Bruker Avance IIITM HD 600 MHz spectrometer equipped with either a 5 mm QCI or 5 mm CPDCH probe. Chemical shifts ( ⁇ ) are reported in parts per million (ppm).
  • reaction mixture was poured into aqueous 1 M HCl (12 mL) and stirred for 5 min, then extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were dried with MgSO 4 , concentrated under reduced pressure, and the residue was purified by chromatography (SiO 2 , wet load 50% CH 2 Cl 2 –hexanes, 50–100% CH 2 Cl 2 –hexanes, rapid elution) to provide 4 (872 mg, 65%) as a yellow foam and recycled 2.
  • reaction mixture was cooled to 23 ⁇ C, concentrated under reduced pressure and the residue was purified by chromatography (SiO 2 , 20–60% EtOAc–hexanes + 1% Et 3 N, rapid elution) to provide 7 (3.84 g, 89%) as a moisture-sensitive yellow oil.
  • the workup is ideally performed immediately upon completion of the hydrolysis. Degradation of 9 is observed after prolonged exposure to the reaction conditions. Free base 9 is unstable at 23 ⁇ C and should either be stored cold ( ⁇ –20 ⁇ C), or preferably used immediately in the following step.
  • the combined filtrate was concentrated under reduced pressure and purified by column chromatography (50 g SiO 2 , wet-load CH 2 Cl 2 , washed with 100% CH 2 Cl 2 (1.5 L) to remove trichloroacetamide, then eluted with 0–10% acetone– CH 2 Cl 2 over 500 mL) to provide 23 (1.87 g, 90%) as a tan solid.
  • Trituration of this sample of 25 with Et 2 O (4 mL) afforded analytically pure 25 (217 mg, 83%/2 steps) as a light tan solid.
  • the structure, relative and absolute stereochemistry, and 5,6-cis amide conformation of 25 were confirmed with a single-crystal X-ray structure determination conducted on crystals grown from MeOH.
  • the structure of 25 has been deposited with the Cambridge Crystallographic Data Center (CCDC 2150607 Crystal data and structure refinement for 25.
  • the light yellow-green reaction mixture was stirred at 0 ⁇ C for 30 min, cooled to –35 ⁇ C, and stirred vigorously as a chilled (0 ⁇ C) suspension of CuCl (320 mg, 3.2 mmol, 250 equiv) and CuCl 2 (520 mg, 3.9 mmol, 300 equiv) in 50% CD 3 CN–H 2 O (1.6 mL) was added by syringe.
  • the reaction mixture was slowly warmed to 5 ⁇ C over 2 h, added to saturated aqueous NH 4 Cl (100 mL), adjusted to pH 9 with the addition of concentrated NH 4 OH, and extracted with EtOAc (100 mL).
  • Tetrachlorovancomycin (1) A solution of 29 (7.5 mg, 5.7 ⁇ mol, 1 equiv) in DMSO (250 ⁇ L) was treated sequentially with TCEP•HCl (3.5 mg, 11.4 ⁇ mol, 2 equiv), commercially available UDP-glucose•2Na (7 mg, 11.4 ⁇ mol, 2 equiv), aqueous 750 mM tricine-NaOH (pH 9, 0.6 mL), H 2 O (2 mL), glycerol (300 ⁇ L), GtfE (50 ⁇ M, 1.2 mL, 0.06 ⁇ mol, 1 mol %) 41 and commercially available calf intestinal alkaline phosphatase (CIAP, Promega, 1 U/ ⁇ L, 5 ⁇ L, 5 U).
  • TCEP•HCl 3.5 mg, 11.4 ⁇ mol, 2 equiv
  • UDP-glucose•2Na 7 mg, 11.4 ⁇ mol, 2 e
  • the reaction mixture was warmed to 37 ⁇ C for 17 h, cooled to 23 ⁇ C, and treated with additional TCEP•HCl (10.5 mg, 35 ⁇ mol, 6 equiv), 750 mM tricine-NaOH (pH 9, 1 mL), the azide precursor to UDP-vancosamine 41 (45 ⁇ mol, 8 equiv), and GtfD 41 (65 ⁇ M, 0.92 mL, 1 mol %).
  • the reaction mixture was warmed to 37 ⁇ C for 16 h, cooled to 23 ⁇ C, diluted with 50% MeOH–MeCN (32 mL), and filtered through a 0.22 ⁇ m PES membrane, rinsing with MeOH.
  • CBP-Tetrachlorovancomycin (30) A solution of tetrachlorovancomycin (1, 6.9 mg, 4.0 ⁇ mol, 1 equiv), i-Pr 2 NEt (3.5 ⁇ L, 20 ⁇ mol, 5 equiv), and 4-(4-chlorophenyl)benzaldehyde (1.2 mg, 5.2 ⁇ mol, 1.3 equiv) in DMF (0.69 mL, 100 vol) was warmed to 70 ⁇ C for 2 h, cooled to 50 ⁇ C, and treated with NaCNBH 3 (1 M in THF, 400 ⁇ L, 400 ⁇ mol, 100 equiv).
  • G3,CBP-Tetrachlorovancomycin (31) A solution of 30 (1.1 mg, 0.57 ⁇ mol, 1 equiv), 1-(3-aminopropyl)guanidine 44 (bis-TFA salt, 0.96 mg, 2.8 ⁇ mol, 5 equiv) and NMM (1.9 ⁇ L, 17 ⁇ mol, 30 equiv) in DMF (200 ⁇ L) was cooled to 0 ⁇ C and treated with T3P (50 wt % in EtOAc, 3.5 ⁇ L, 5.7 ⁇ mol, 10 equiv).
  • Amine 36A is unstable, especially in its free base form, and could not be isolated without decomposition.
  • reaction was quenched by transferring the mixture into a saturated solution of EDTA in H 2 O–MeOH (1:1, 10 mL), and the resulting mixture was stirred at 23 ⁇ C for 1 h with the color changing from dark to light blue.
  • reaction mixture was purged with Ar and warmed at 37 ⁇ C.
  • Compound 38 was initially not completely dissolved in the solution, but slowly goes into the solution as the reaction proceeds (occasional swirling the flask is needed to prevent the suspended solids from sticking to the side wall of flask).
  • reaction was quenched by addition of cold H 2 O (0 ⁇ C, 0.07% TFA, 5 mL) and transferred into a saturated EDTA H 2 O–MeOH (1:1, 5 mL), and the resulting mixture was stirred at 23 ⁇ C for 1 h with the color changing from dark to light blue.
  • tetrachlorovancomycin (1) like vancomycin, fails to bind to an appreciable extent the model ligand of the peptidoglycan precursor found in vancomycin-resistant organisms, Ac 2 -L-Lys-D-Ala-D-Lac (Compound 33). 48 Finally, and although not examined herein, it has been shown elsewhere that addition of the peripheral 4- chlorobiphenylmethyl (CBP) group to vancomycin and related structures does not impact (increase) the solution phase binding affinity for model ligands.
  • CBP peripheral 4- chlorobiphenylmethyl
  • UV spectra were recorded after each addition of a solution of N,N’-Ac 2 -Lys-D- Ala-D-Ala (A) or N,N’-Ac 2 -Lys-D-Ala-D-Lac (B) in 20 mM sodium citrate buffer to each cell from 0.1 to up to 60.0 equiv for the weaker binding partners.
  • the absorbance value at the ⁇ max was recorded, measuring the running change in absorbance.
  • the binding constants were calculated from the well-defined binding curves that plot the absorbance readings versus equiv ligand added ([ligand]/[tetrachlorovancomycin analogue]).
  • Control titration runs were conducted by using blank buffer solution against blank buffer solution, each antibiotic, and the two ligands, respectively to show no heat contribution from the individual binding components.
  • the titration data were processed by using OriginLab software (for ITC) and “one set of sites” fitting model for curve fitting.
  • a solution of the tetrachloro- vancomycin derivative (8 ⁇ 10 –5 M in 20 mM sodium citrate buffer) was placed in a quartz UV cuvette (0.1 cm path length) and the UV spectrum recorded versus a reference cell containing 20 mM sodium citrate buffer.
  • UV spectra were recorded after each addition of a solution of N,N’-Ac 2 -Lys-D-Ala-D-Ala (A) or N,N’-Ac 2 -Lys-D-Ala-D-Lac (B) in 20 mM sodium citrate buffer to each cell from 0.1 to up to 60.0 equiv for the weaker binding partners.
  • the absorbance value at the ⁇ max was recorded, measuring the running change in absorbance.
  • This diluted bacterial stock solution was then inoculated in a 96-well U-shaped glass coated microtiter plate, supplemented with serial diluted aliquots of the antibiotic solution in DMSO (4 ⁇ L), to achieve a total assay volume of 0.1 mL.
  • MICs minimal inhibitory concentrations
  • the plate was then incubated at 37 °C for 18 h, after which minimal inhibitory concentrations (MICs) were determined by monitoring the cell growth (observed as a pellet) in the wells.
  • the lowest concentration of antibiotic (in ⁇ g/mL) capable of eliminating cell growth in the wells is the reported MIC value.
  • the reported MIC values for the vancomycin analogues were determined against vancomycin as a standard in the first well.
  • the initial fresh cultures were grown in the presence of vancomycin (1 ⁇ g/mL) for resistant strains and chloramphenicol for sensitive strains (1 ⁇ g/mL). In the instances of protein removal, filtration of the broth through an Amicon MWCO 3000 membrane was used for protein removal.
  • Tetrachlorovancomycin (1) like vancomycin, fails to bind Ac 2 -L-Lys-D-Ala-D-Lac (33) to an appreciable extent (K a ⁇ 470 M -1 ) being 1000- fold less effective than its binding with Ac 2 -L-Lys-D- Ala-D-Ala. 49.

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Abstract

Une synthèse totale d'une nouvelle classe d'analogues de vancomycine de complexité synthétique réduite a été développée. La synthèse, réalisée par l'ajout de deux substituants du chlorure d'aryle pour proposer un aglycone de tétrachlorovancomycine (Composé II), de la tétrachlorovancomycine (Composé I), et leurs dérivés, permet une synthèse totale rationalisée de la nouvelle classe d'antibiotiques glycopeptidiques par élimination de la commande stéréochimique atropisomère et a permis l'activation simultanée et supplémentaire de macrocyclisations SNAr qui établissent le squelette tricyclique du Composé I. En plus de l'évaluation antimicrobienne de la tétrachlorovancomycine (Composé I), la préparation de la poche de liaison clé et les dérivés à modification périphérique, qui surmontent la résistance à la vancomycine et introduisent des mécanismes d'action indépendants et synergiques, ont révélé leur puissance antimicrobienne exceptionnelle et proposent le fondement pour l'utilisation de cette nouvelle classe d'analogues de glycopeptides synthétiques. Sont également divulgués une composition pharmaceutique contenant une quantité bactéricide de tétrachlorovancomycine, un dérivé de celle-ci ou un sel de celui-ci dissous ou dispersé dans un diluant pharmaceutiquement acceptable.
PCT/US2024/031453 2023-06-16 2024-05-29 Tétrachlorovancomycine et dérivés Ceased WO2024258613A2 (fr)

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