WO1997005132A1 - Analogues de l'adenylate d'aminoacyle en tant qu'agents antimicrobiens et antiparasites nouveaux - Google Patents

Analogues de l'adenylate d'aminoacyle en tant qu'agents antimicrobiens et antiparasites nouveaux Download PDF

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Publication number
WO1997005132A1
WO1997005132A1 PCT/US1996/011910 US9611910W WO9705132A1 WO 1997005132 A1 WO1997005132 A1 WO 1997005132A1 US 9611910 W US9611910 W US 9611910W WO 9705132 A1 WO9705132 A1 WO 9705132A1
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WIPO (PCT)
Prior art keywords
compound
anhydro
allo
amino
methyl
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PCT/US1996/011910
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English (en)
Inventor
Jason M. Hill
Guixue Yu
Youe-Kong Shue
Thomas M. Zydowsky
Julius Rebek, Jr.
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Cubist Pharmaceuticals, Inc.
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Priority claimed from US08/683,809 external-priority patent/US5726195A/en
Application filed by Cubist Pharmaceuticals, Inc. filed Critical Cubist Pharmaceuticals, Inc.
Priority to AU65006/96A priority Critical patent/AU6500696A/en
Publication of WO1997005132A1 publication Critical patent/WO1997005132A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This invention relates to the field of isoleucyl-transfer ribonucleic acid (tRNA) synthetase inhibitors, their preparation and their use as antimicrobial and antiparasitic agents.
  • tRNA ribonucleic acid
  • Aminoacyl tRNA synthetases are a family of essential enzymes that are found in virtually every biological cell and are one ofthe factors responsible for maintaining the fidelity of protein synthesis. They specifically catalyze the aminoacylation of tRNA in a two step reaction:
  • the enzyme binds adenosine triphosphate (ATP) and its specific amino acid to catalyze formation of an aminoacyl adenylate intermediate (AA-AMP) with concomitant release of pyrophosphate (PPi).
  • AA-AMP aminoacyl adenylate intermediate
  • PPi pyrophosphate
  • the amino acid is transferred to the 2' or 3' terminus of the tRNA yielding "charged" tRNA and adenosine monophosphate (AMP).
  • AMP adenosine monophosphate
  • Pseudomonic acid A an antibacterial agent currently used in human therapy, provides clear evidence ofthe utility of tRNA synthetase inhibitors as useful pharmaceuticals.
  • Pseudomonic acid A binds to isoleucyl-tRNA synthetase, and inhibits isoleucyl adenylate formation in several Gram positive bacterial pathogens such as Staphylococcus aureus, resulting in the inhibition of protein synthesis, followed by growth inhibition.
  • the prior art has focused on designing compounds to elucidate the mechanism and binding sites of tRNA synthetases. Because the aminoacyl adenylate intermediate is not chemically stable, in an effort to study the binding site and the mechanism of tRNA synthetases, investigators have focused on preparing chemically stable aminoacyl adenylate mimics. These compounds resemble the aminoacyl adenylate intermediate; however, structural modifications have been made to the 5' position ofthe ribose ring. Examples of such modifications include compounds in which the amino acid carbonyl is replaced by a methylene group and structures in which the phosphate moiety has been replaced with a phosphonate, phosphonamide or sulfonamide moiety. There have been no disclosures of stable aminoacyl adenylate mimics for mammalian therapy or which exhibit whole cell activity against organisms.
  • Novel synthetic compounds which target tRNA synthetases offer clear advantages as useful therapeutic agents to curb the threat of drug resistance.
  • Drug resistance allows a pathogen to circumvent the biochemical disruption caused by an antimicrobial agent. This resistance can be a result of a mutation that has been selected for and maintained. Pathogens in the environment have had repeated exposure to current therapeutics. This exposure has led to the selection of variant antimicrobial strains resistant to these drugs. Novel synthetic antimicrobial agents, therefore, would be expected to be useful to treat drug resistant pathogens, since the pathogen has never been exposed to the novel antimicrobial agent.
  • the development of compounds or combinations of compounds targeting more than one tRNA synthetase is also advantageous.
  • inhibition of more than one enzyme should reduce the incidence of resistance since multiple mutations in a pathogen would be required and are statistically rare.
  • the present invention relates to aminoacyl adenylate mimics which inhibit isoleucyl- tRNA synthetases and have efficacy, including whole cell activity, against a broad spectrum of bacteria, fungi and parasites. Described herein are thirty one compounds which exhibit isoleucyl- tRNA synthetase inhibition.
  • the present invention comprises, in a first aspect, compounds of Formula I
  • substituent R is selected from amino, alkyl, aryl, cycloalkyl, alkoxy, and aryloxy groups.
  • Each of substituents R 1 and R2 is independently selected from hydrido, alkyl, aryl, carboalkoxy, alkylthiocarbonyl, carboxyamido, and acyl groups.
  • the substituent R3 of Formula I is selected from ethyl and methoxy groups.
  • n of Formula I is the number 1 or 2.
  • R is alkyl, aryl or cycloalkyl, more preferably, aryl, even more preferably phenyl, substituted phenyl, 5-nitrofuryl or 5-nitrothienyl groups, most preferably ⁇ -substituted phenyl.
  • each of R 1 and R 2 is independently hydrido or acyl, most preferably hydrido.
  • R 3 is ethyl and n is 2.
  • any one or more ofthe groups from which the substituents R, Ri, R2, and R3 are selected can be omitted, provided that said lists each include at least one such group.
  • Pharmaceutically- acceptable salts of compounds of Formula I are also covered by this invention.
  • a second aspect ofthe invention comprises using a composition comprising the compound(s) of Formula I to inhibit an isoleucyl-tRNA synthetase and in particular, to modulate the growth of bacterial, fungal or parasitic organisms in mammals.
  • hydroxido denotes a single hydrogen atom.
  • amino denotes a nitrogen atom containing two substituents independently selected from hydrido, alkyl, cycloalkyl, aryl, acyl, carboxyamido or carboalkoxy groups, wherein the substituent can be the same or different.
  • carboalkoxy denotes a carbonyl radical adjacent to an alkoxy or aryloxy group.
  • carboxyamido denotes a carbonyl radical adjacent to an amino group.
  • thio denotes a divalent sulfur atom containing a substituent selected from hydrido, alkyl, cycloalkyl, or aryl group, such as, methylthio and phenylthio.
  • Alkyl groups can be linear or branched, saturated or unsaturated, and have up to about ten carbon atoms. Preferred alkyl groups are "lower alkyl" groups having one to about five carbon atoms. One or more hydrogen atoms can also be replaced by a substitutent group selected from acyl, amino, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxy, nitro, thio, alkyl, aryl, cycloalkyl, alkoxy, aryloxy, sulfoxy, and guanido groups.
  • alkyl groups examples include methyl, tert-butyl, isopropyl, propenyl, butadienyl, propynyl, phenylethynyl, (5-nitro-2-furyl)ethynyl, (5-nitro-2-thienyl)-ethynyl, methoxymethyl and benzyl groups.
  • Prefererred alkyl groups include substituted alkynyl, dibromoethenyl, benzyl, methyl, trifluoromethyl, 3-phenoxypropyl, and phenoxypheny lmethyi.
  • a more preferred class of alkyl groups are alkynyl groups in which a hydrogen atom is replaced by an aryl group.
  • Aryl groups can contain zero to four hetero atoms selected from oxygen, nitrogen and sulfur in a single or fused carbocyclic or heterocyclic ring system, having from five to fifteen ring members.
  • One or more hydrogen atoms may also be replaced by a substituent group selected from acyl, amino, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxy, nitro, thio, alkyl, aryl, cycloalkyl, alkoxy, aryloxy, sulfoxy, and guanido groups.
  • a preferred class of aryl groups includes unsubstituted phenyl groups, phenyl groups in which one or more hydrogen atoms have been replaced with an alkyl, alkoxy or aryloxy group, 5-nitrofuryl and 5-nitrothienyl groups.
  • aryl groups include phenyl, naphthyl, biphenyl, terphenyl, pyridinyl, thiazolyl, thiadiazoyl, isoquinolinyl, pyrazolyl, benzothienyl, [(5-nitro-2-thienyl)ethynyl]phenyl, [(5- nitro-2-furyl)ethynyl]phenyl,(phenylalkynyl)phenyl, phenoxyphenyl, [1 -(4- carboxymethylphenyl)-phenoxy]phenyl, (4-phenoxyphenoxy)phenyl and pyrrolyl groups.
  • Cycloalkyl groups have, preferably, saturated or partially unsaturated ring systems, each containing zero to four hetero atoms selected from oxygen, nitrogen and sulfur in a single or fused carbocyclic or heterocyclic ring system having from three to fifteen ring members.
  • One or more hydrogen atoms may also be replaced by a substituent group selected from acyl, amino, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxy, nitro, oxo, thio, alkyl, aryl, cycloalkyl, alkoxy, aryloxy, and guanido groups or two substituents together may form a fused cycloalkyl ring.
  • Examples of a cycloalkyl group include cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, mo ⁇ holinyl, piperidinyl, and pyrrolidinyl.
  • An alkoxy group denotes an oxygen atom substituted with an acyl, alkyl or cycloalkyl group. Examples include methoxy, tert- butoxy, benzyloxy, and cyclohexyloxy.
  • An aryloxy group denotes an oxygen atom substituted with an aryl group. Examples of aryloxy groups are phenoxy, 4-carbobenzyloxyphenoxy, 4- phenoxy phenoxy.
  • Preferred aryloxy groups are phenoxy and substituted phenoxy groups.
  • Sulfoxy groups comprise a hexavalent sulfur atom bound to two or three substituents selected from the group consisting of oxo, alkyl, aryl and cycloalkyl groups, wherein at least one of said substituents is oxo.
  • the pharmaceutically-acceptable salts ofthe compounds of Formula I include acid addition salts and base addition salts.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature ofthe salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts ofthe compounds of Formula I may be prepared from an inorganic acid or an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, malonic, galactic, and galacturonic acid.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by treating, for example, the compound of Formula I with the appropriate acid or base.
  • the compounds of Formula I have centers of asymmetry as indicated by the wedge- shaped and dashed lines. Bonds that extend above the plane ofthe paper ( ⁇ bonds) are depicted by darkened wedge-shaped lines, whereas, bonds extending below the plane ofthe paper are shown as dashed lines.
  • the absolute configuration of these centers is indicated by the stereochemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem., 45, 11-30, (1976).
  • the compounds of this invention may have chiral centers in addition to those indicated. Unless otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms.
  • the compounds of Formula I are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof.
  • the compounds of Formula I can be utilized in the present invention as a single diastereomer or as a mixture of stereochemical isomeric forms.
  • Diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation.
  • the optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • the mixture of diastereomers can be separated by crystallization followed by liberation ofthe optically active bases from these salts.
  • An alternative process for separation of optical isomers includes the use of a chiral chromatography column optimally chosen to maximize the separation ofthe enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain the enantiomerically pure compound.
  • the optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form ofa free acid, a free base, an ester or a salt.
  • the invention also embraces isolated compounds.
  • An isolated compound refers to a compound which represents at least 10% ofthe compound present in the mixture and exhibits a detectable ( i.e. statistically significant) antimicrobial or antiparasitic activity when tested in conventional biological assays such as those described herein.
  • the compounds are useful for inhibiting the enzymatic activity of an isoleucyl-tRNA synthetase in vivo or in vitro.
  • the compounds are particularly useful as antimicrobial agents and antiparasitic agents, i. e., agents which inhibit the growth of bacteria or fungii and parasites, respectively.
  • a preferred class of compounds of Formula I are compounds in which R is aryl.
  • a further preferred class of compounds of Formula I are compounds in which n is 2 and R is aryl.
  • a more preferred class of compounds of Formula I are compounds in which n is 2, R is aryl; each of R 1 and R2 is hydrido; and R 3 is ethyl.
  • a family of more highly preferred compounds within Formula I consists of compounds of Formula II
  • R4 is selected from alkyl, alkoxy or aryloxy.
  • An even more preferred family of compounds within Formula II consists of compounds wherein R4 is selected from alkynyl, alkoxy or aryloxy groups substituted with at least one aryl substituent.
  • Specific compounds most preferred within Formula II are [S-(R*,R*)]-3,6-anhydro- l,2-dideoxy-l-[5-[4-[(5-nitro-2-furyl)ethynyl] ⁇ henyl]-2H-tetrazol-2-yl]-D-allo-heptitol 7-(2-amino-3-methyl-l-oxopentyl)sulfamate, [S-(R*,R*)]-3,6-anhydro-l,2-dideoxy-l- [5-[4-[(5-nitro-2-thienyl)ethynyl]phenyl]-2H-tetrazol-2-yl]-D-allo-heptitol 7-(2-amino- 3-
  • the compounds ofthe invention are active against a variety of bacterial organisms. They are active against both Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphylococci, for example S. aureus; Enter ococci, for example E.faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.
  • the compounds ofthe present invention are also active against Mycobacteria, for example M. tuberculosis.
  • the compounds ofthe present invention are also active against intercellular microbes, for example Chlamydia and Rickettsiae.
  • the compounds ofthe present invention are also active against Mycoplasma, for example M. pneumoniae.
  • the compounds ofthe present invention are also active against fiingal organisms, including, among other organisms, the species Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidioides, Pneumocystis, Trichophyton, and Trichosporium.
  • the compounds ofthe present invention are also active against parasites, including Protozoa and Helminths.
  • parasitic species include, among others, Entamoeba, Leishmania, Toxoplasma, Trichinosis, and Schistosomiasis.
  • terapéuticaally-effective amount means that amount of a compound of Formula I which prevents the onset of, alleviates the symptoms of, or stops the progression of an infection (e. g. a microbial or parasitic infection) in vivo or in vitro.
  • microbial means bacterial and fungal, for example a “microbial infection” means a bacterial or fungal infection.
  • treating is defined as administering, to a subject, a therapeutically-effective amount ofa compound of Formula I.
  • subject as described herein, is defined as a mammal, a plant or a cell culture.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, preferably a compound in accordance with the first aspect ofthe invention, and a pharmaceutically-acceptable carrier.
  • a method for inhibiting an isoleucyl- tRNA synthetase comprises contacting an isoleucyl-tRNA synthetase with a compound of Formula I under the conditions in which the isoleucyl-tRNA synthetase interacts with it's substrate to form an aminoacyl adenylate intermediate and, preferably to further form a charged tRNA.
  • Such conditions are known to those skilled in the art (see also e. g., the Examples for conditions).
  • This method involves contacting an isoleucyl-tRNA synthetase with an amount of compound of Formula I that is sufficient to result in detectable isoleucyl-tRNA synthetase inhibition.
  • This method can be performed on an isoleucyl-tRNA synthetase that is contained within an organism or outside an organism.
  • the invention provides a method for inhibiting the growth of microorganisms, preferably bacteria or fungi, comprising contacting said organisms with a compound ofthe invention (preferably a compound of Formula I) under conditions which permit entry ofthe compound into said organism. Such conditions are known to one skilled in the art and are examplified in the Examples.
  • This method involves contacting a microbial or parasitic cell with a therapeutically-effective amount ofa compound(s) of Formula I, e.g. to inhibit cellular isoleucyl-tRNA synthetase in vivo or in vitro.
  • This method is used in vivo, for example, for treating microbial or parasitic infections in mammals.
  • the method is used in vitro, for example, to eliminate microbial or parasitic contaminants in a cell culture, or in a plant.
  • the compositions disclosed herein are used for treating a subject afflicted by or susceptible to a microbial or parasitic infection.
  • the method involves administering to the subject a therapeutically-effective amount ofthe compound of Formula I.
  • the novel compositions disclosed herein are placed in a pharmaceutically-acceptable carrier and are delivered to a recipient subject (preferably a human) in accordance with known methods of drug delivery. Exemplary procedures for delivering an antibacterial, antifungal and antimycoplasmal agent are described in U.S. Patent No. 5,041,567, issued to Rogers et al. and in PCT patent application number EP94/02552 (publication no. WO 95/05384).
  • the methods ofthe invention for delivering the compositions of Formula I in vivo utilize art-recognized protocols for delivering the agent with the only substantial procedural modification being the substitution ofthe compounds of Formula I for the drugs in the art-recognized protocols.
  • the methods for using the claimed composition for treating cells in culture for example, to eliminate or reduce the level of bacterial contamination ofa cell culture, utilize art-recognized protocols for treating cell cultures with antibacterial agent(s) with the only substantial procedural modification being the substitution ofthe compounds of Formula I for the agents used in the art-recognized protocols.
  • the pharmaceutical preparations disclosed herein are prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent or eliminate the infection (See, e.
  • compositions of Formula I can be delivered using controlled or sustained release delivery systems (e.g., capsules, bioerodable matrices).
  • sustained release delivery systems e.g., capsules, bioerodable matrices.
  • Exemplary delayed release delivery systems for drug delivery that would be suitable for administration ofthe compositions of Formula I are described in U.S. Patent Nos. 4,452,775 (issued to Kent), 5,039,660 (issued to Leonard), 3,854,480 (issued to Zaffaroni).
  • compositions ofthe present invention comprise one or more compounds of Formula I in association with one or more nontoxic, pharmaceutically- acceptable carriers and/or diluents and/or adjuvants and/or excipients, collectively referred to herein as "carrier" materials, and if desired other active ingredients.
  • the compounds of the present invention may be administered by any route, preferably in the form of a pharmaceutical composition adapted to such a route, and would be dependent on the condition being treated.
  • the compounds and compositions may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
  • the pharmaceutical compositions may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a therapeutically-effective amount ofthe active ingredient. Examples of such dosage units are tablets and capsules.
  • the tablets and capsules which can contain, in addition to the active ingredient, conventional carriers such as binding agents, for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth; fillers, for example calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose; lubricants, for example, magnesium stearate, polyethylene glycol, silica, or talc; disintegrants, for example potato starch, flavoring or coloring agents, or acceptable wetting agents.
  • binding agents for example, acacia gum, gelatin, polyvinylpyrrolidone, sorbitol, or tragacanth
  • fillers for example calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose
  • lubricants for example, magnesium stearate, polyethylene glycol, silica, or talc
  • disintegrants for example potato
  • Oral liquid preparations generally in the form of aqueous or oily solutions, suspensions, emulsions, syrups or elixirs may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents.
  • additives for liquid preparations include acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methyl cellulose, methyl or propyl para- yd ⁇ oxy benzoate, propylene glycol, sorbitol, or sorbic acid.
  • compositions may also be administered via injection.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions may be prepared from sterile powders or granules having one or more ofthe carriers mentioned for use in the formulations for oral admimstration.
  • the compounds may be dissolved in polyethylene glycol, propylene glycol, ethanol, com oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • the compounds ofthe present invention may also be prepared in suitable forms to be applied to the skin, or mucus membranes ofthe nose and throat, and may take the form of creams, ointments, liquid sprays or inhalants, lozenges, or throat paints.
  • suitable forms may take the form of creams, ointments, liquid sprays or inhalants, lozenges, or throat paints.
  • Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration ofthe active ingredient.
  • DMSO dimethylsulfoxide
  • the compounds ofthe present invention may be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.
  • the compounds ofthe present invention may be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.
  • the compounds ofthe present invention may be in powder form for reconstitution at the time of delivery.
  • the dosage regimen for treating an infection with the compound and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition ofthe patient, the severity ofthe infection, the route and frequency of administration and the particular compound employed. In general, dosages are determined in accordance with standard practice for optimizing the correct dosage for treating an infection.
  • the compositions may contain from 0.1% to 99% by weight, preferably 10-60%) by weight, ofthe active ingredient, depending on the method of administration. If the compositions contain dosage units, each dosage unit will preferably contain from 50-500 mg ofthe active material. For adult human treatment, the dosage employed will preferably range from 100 mg to 3 g, per day, depending on the route and frequency of administration.
  • the amount of compound employed may be less than 1% by weight ofthe diet and preferably no more than 0.5% by weight.
  • the diet for animals may be normal foodstuffs to which the compound may be added or it may be added to a premix.
  • each of R 5 and R6 is independently selected from hydrido, alkyl, aryl, or cycloalkyl; wherein R 7 is selected from alkyl, cycloalkyl or aryl; wherein A is an alcohol protecting reagent such as benzyl bromide, chlorotrimethylsilane, tert-butyldimethylsilyl chloride or chloromethyl methyl ether; wherein P 1 is a protecting group selected from alkoxymethyl, aryloxymethyl, thiomethyl, arylmethyl, trialkylsilyl, triarylsilyl, diphenylmethylsilyl, diphenyl-tert-butylsilyl, (phenyldimethylsilyl)methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, or tetrahydropyranyl, for example benzyl, trimethylsilyl, tert-butyldimethylsilyl and methoxymethyl.
  • A is an
  • Compound 2 is converted to compound 3 by treatment with B in an appropriate solvent such as toluene, dichloromethane, tetrahydrofuran, methanol, ethanol, or 2-methoxyethyl ether, at temperatures ranging from -78° C to 100° C.
  • an appropriate solvent such as toluene, dichloromethane, tetrahydrofuran, methanol, ethanol, or 2-methoxyethyl ether
  • R5, R6, R7 and P 1 are as previously described; wherein B is a reducing agent such as lithium aluminum hydride, aluminum hydride, lithium borohydride, or diisobutylaluminum hydride.
  • Compound 3 is converted to compound 4 by treatment with C and a base such as imidazole or potassium carbonate in an appropriate solvent such as tetrahydrofuran, diethyl ether, dimethyl sulfoxide or dimethylformamide at temperatures ranging from 0° C to 75° C.
  • R5, R6 and Pi are as previously described; wherein C is an alcohol protecting reagent such as benzyl bromide, chlorotrimethylsilane, tert-butyldimethylsilyl chloride, chloromethyl methyl ether or benzoyl chloride such that A is not the same as C; wherein P 2 is a protecting group selected from acyl, alkoxymethyl, aryloxymethyl, thiomethyl, arylmethyl, trialkylsilyl, triarylsilyl, diphenylmethylsilyl, diphenyl-tert-butylsilyl, (phenyldimethylsilyl)- methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, or tetrahydropyranyl, for eample, benzyl, trimethylsilyl, tert-butyldimethylsilyl and methoxymethyl; wherein A and C are chosen such that either group Pi or P 2 can be removed without removing the other alcohol
  • Compound 4 is converted to compound 5 by treatment with D in an appropriate solvent such as tetrahydrofuran, dichloromethane or diethyl ether at temperatures ranging from 0° C to 40° C.
  • an appropriate solvent such as tetrahydrofuran, dichloromethane or diethyl ether at temperatures ranging from 0° C to 40° C.
  • R 5 , R 6 , P 1 and P2 are as previously described; wherein D is an alcohol deprotecting reagent capable of removing P 1 without removing P 2 , such as tetrabutylammonium fluoride, HF- pyridine, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, sodium methoxide, lithium hydroxide or hydrogen gas in the presence of a catalyst such as palladium-on-carbon, platinum oxide or palladium chloride.
  • D is an alcohol deprotecting reagent capable of removing P 1 without removing P 2 , such as tetrabutylammonium fluoride, HF- pyridine, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, sodium methoxide, lithium hydroxide or hydrogen gas in the presence of a catalyst such as palladium-on-carbon, platinum oxide or palladium chloride.
  • Compound 5 is converted to compound 7 by treatment with compound 6 and a base such as triethylamine, 4-methylmorpholine or dusopropylethylamine in an appropriate solvent such as dichloromethane or toluene at temperatures ranging from -20° C to 40° C.
  • a base such as triethylamine, 4-methylmorpholine or dusopropylethylamine in an appropriate solvent such as dichloromethane or toluene at temperatures ranging from -20° C to 40° C.
  • R 5 , R 6 and P 2 are as previously defined; wherein R8 is alkyl.
  • Compound 7 is converted to compound 8 by treatment with E and gaseous hydrogen at 1 to 4 atmospheres in an appropriate solvent such as ethyl acetate, methanol or ethanol at temperatures ranging from ambient to 50° C.
  • an appropriate solvent such as ethyl acetate, methanol or ethanol at temperatures ranging from ambient to 50° C.
  • R 5 , R 6 , R 8 , and P 2 are as previously defined; wherein E is a catalyst such as palladium- on-carbon, platinum oxide or palladium chloride.
  • Compound 10 is converted to compound 11 by treatment with J in an appropriate solvent such as methanol, tetrahydrofuran, dichloromethane, or water at temperatures ranging from -25° C to 40° C.
  • an appropriate solvent such as methanol, tetrahydrofuran, dichloromethane, or water at temperatures ranging from -25° C to 40° C.
  • R 1 , R 3 , R5, R6, R9, and P 2 are as previously defined; wherein J is a reagent capable of removing the protecting group P 2 such as sodium hydroxide, sodium methoxide, tetrabutylammonium fluoride, HF-pyridine or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.
  • P 2 a reagent capable of removing the protecting group P 2 such as sodium hydroxide, sodium methoxide, tetrabutylammonium fluoride, HF-pyridine or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.
  • R, R 1 , R 3 , R5, R6, and R 9 are as previously defined; wherein K is a trialkylphosphine, or triarylphosphine such as triphenylphosphine; wherein L is a dialkylazodicarboxylate such as diethylazodicarboxylate or diisopropylazodicarboxylate.
  • Compound 13 is treated with trifluoroacetic acid and water (5:2) at temperatures ranging from 0° C to 70° C or, 2) Compound 13 is treated as described in step 1 above then treated with E (vide supra) and hydrogen gas at 1 to 4 atmospheres in an appropriate solvent such as ethyl acetate, methanol or ethanol at temperatures ranging from ambient to 50° C, or
  • Compound 14 [For preparation see K. Utimoto et al., Tetrahedron Lett. 23(2), 237-8, (1982)] is converted to compound 15 by treatment with a base such as sodium methoxide, lithium hydroxide or sodium ethoxide followed by an acid such as hydrochloric acid, sulfuric acid or Amberlite® IR120(H+) resin (Rohm and Haas Company, Philadelphia, Pennsylvania) in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or toluene at temperatures ranging from 0° C to 75° C.
  • a base such as sodium methoxide, lithium hydroxide or sodium ethoxide
  • an acid such as hydrochloric acid, sulfuric acid or Amberlite® IR120(H+) resin (Rohm and Haas Company, Philadelphia, Pennsylvania)
  • Amberlite® IR120(H+) resin Amberlite® IR120(H+) resin
  • Ri° is alkyl
  • R 5 , R 6 and R ! ⁇ are as previously defined; wherein M is an aldehyde, ketone or their synthetic equivalents such as 2,2-dimethoxypropane or 2-methoxypropene.
  • R5, R6, Rio ; pi and A are as previously defined.
  • R5, R6, Ri ⁇ 5 pi, and B are as previously described.
  • R, R5, R6, pi, K and L are as previously defined.
  • R, R5, R6, Pi and D are as previously defined.
  • R, R 5 , R 6 and R 8 are as previously defined.
  • R, R 5 , R6, R8 and E are as previously defined.
  • R, R 1 , R 3 , R5, R6, R9, Ri ⁇ 5 F and G are as previously defined.
  • Compound 23 may be partially or fully deprotected according to the standard procedures that apply to compound 13 in General Procedure 1.
  • D-allo-heptitol 7- [(pheny lmethoxy)carbonyl] sulfamate (141 g) in ethanol (300 ml) was added Raney Nickel® (50 g, nickel-aluminum alloy, W. R. Grace, Boca Raton, Florida). The mixture was heated to reflux for 1 hour then allowed to cool to room temperature. The cooled mixture was then filtered and evaporated to dryness. The residue was dissolved in methanol (500 ml) and stirred at room temperature under 1 atmosphere of hydrogen with 10% palladium on carbon (4 g) for 1 day.
  • reaction mixture was stirred at room temperature for 12 hours then diluted with ethyl acetate (200 ml), washed with 1 M hydrochloric acid (100 ml), saturated sodium bicarbonate (200 ml), and 1 M hydrochloric acid (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
  • reaction mixture was stirred at room temperature for 12 hours then diluted with ethyl acetate (200 ml) and washed with 1 M hydrochloric acid (100 ml), saturated sodium bicarbonate (200 ml) and 1 M hydrochloric acid (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
  • the extent of aminoacylation of tRNA with isoleucine catalyzed by isoleucyl- tRNA synthetase enzyme was measured by monitoring the inco ⁇ oration of [3H] isoleucine into trichloroacetic acid-precipitable tRNA in the presence of a compound of Formula I, as compared with activity in the absence of inhibitor.
  • the isoleucyl-tRNA synthetase enzymes are well known in the prior art and can be obtained and purified by known methods (for example see: D. Kern et al., Biochimie, 61, 1257-1272 (1979) and J. Gilbart et al, Antimicrobial Agents and Chemotherapy, 31 (1), 32-38 (1993)).
  • Isoleucyl-tRNA synthetase enzyme (0.08-2.0nM, preferably, 0.4 nM) was first pre-incubated at 25 ° C with 0.05 mg/ml bovine serum albumin, 10 mM DTT, 2.5% dimethyl sulfoxide, with or without a compound of Formula I, for 20 minutes.
  • a substrate solution (a solution containing the following: ATP, [3H]isoleucine, tRNA, HEPES, magnesium chloride, and potassium chloride) was added to give a final concentration of 0.0286 mg/ml bovine serum albumin, 5.7 mM DTT, 4 mM ATP, 5-20 ⁇ M [3H]isoleucine (1-15 Ci/mmol), 90 ⁇ M crude tRNA or 2 ⁇ M isoleucine specific tRNA, 1.4% dimethyl sulfoxide, 30mM HEPES (pH 7.5), lOmM magnesium chloride, and 50mM potassium chloride and incubated at 25 ° C. Aliquots were removed at selected times (e. g. 5, 10, 20 minutes) and applied to 3MM filter paper discs (Whatman) and then dropped into 5%
  • Inhibitor activity is reported in Table II as an IC 50 value (inhibitor concentration causing 50% inhibition of enzyme activity) per a known amount of active enzyme. In the case of irreversible inhibitors (1 :1 stoichiometry) these values are 50% ofthe active enzyme concentration.
  • the IC 50 (in nM, E. coli) values of representative compounds of the present invention are listed in the second column of Table II.
  • MIC minimum inhibitory concentration
  • Brown teaches that the removal ofthe adenine portion of tyrosinyl adenylate or replacement ofthe adenine moiety with naphthyl, results in a 1000 fold decrease in activity of these compounds.
  • V l lnM 50 100 25 25 100 500 500
  • the mouse protection test is an industry standard for measuring the efficacy of a test compound in vivo [for examples of this model see J. J. Clement, et al., Antimicrobial Agents and Chemotherapy, 38 (5), 1071-1078, (1994)]. As exemplified below, this test was used to show the in vivo efficacy of the compounds of the present invention against bacteria.
  • the in vivo antibacterial activity of compound X was established by infecting female CD-I mice (Charles River Lab, MA) weighing 20-24 g intraperitoneally with Streptococcus pyogenes inoculum.
  • the inoculum was prepared from Streptococcus pyogenes (ATCC 8668) which was cultured in brain heart infusion broth (Baltimore Biological Laboratories, Maryland) at 37° C for 18 hr, and then 0.1 ml ofthe overnight culture was diluted with the medium to 5.0 ml for reading its OD at 600 nm (0.017).
  • the turbidity of a 0.5 McFarland standard is equivalent to OD 6 oo 0.1, or 108 cfu/ml.
  • 8 x 105 cfu ofthe bacteria (940 ⁇ l of 1 : 1000 overnight culture) was added to 20 ml of phosphate buffered saline (Sigma P-0261 ) containing 5 % hog gastric mucin (Sigma M-2378). All animals were injected with 0.5 ml of the inoculum, equivalent to 2 x IO 4 cfu/mouse which is the dose causing -100% death ofthe animals without treatment.
  • group 1 animals were subcutaneously (sc) injected with 0.05 M Tris-HCl (no antibiotic) and groups 2 to 5 were given compound X sc at 0.8, 4, 20, and 100 mg/kg, respectively.
  • Group 6 animals received erythromycin sc at 10 mg/kg. These injections were repeated once at 4 hours after the inoculation for the respective groups. The injection volume at each time was 10 ml per kilogram of body weight.
  • the results ofthe in vivo efficacy test are summarized in Table III.
  • the 50% protective dose (PD5 0 ) is calculated on the basis ofthe number of mice surviving 7 days after inoculation. TABLE III
  • the in vivo activity of compound X against multidrug resistant bacteria was established by infecting female CD-I mice (Charles River Lab, MA) weighing 20-24 g intraperitoneally with multidrug resistant Streptococcus pyogenes inoculum.
  • the inoculum was prepared from multidrug resistant Streptococcus pyogenes (resistant to erythromycin, tetracycline, and chloramphenicol, #OTTO 209 obtained from Dr.
  • McFarland standard is equivalent to OD 6 oo 0.1, or 108 cfu/ml. Then, 4 x 108 cfu ofthe bacteria (333 ⁇ l) was added to 20 ml of phosphate buffered saline (Sigma P-0261) containing 10 % hog gastric mucin (Sigma M-2378). All animals were injected with 0.5 ml ofthe inoculum, equivalent to 107 cfu/mouse which is the dose causing -100% death ofthe animals without treatment. Compound X (60 mg) was dissolved in 6.0 ml of 0.05 M Tris-HCl (pH 8.8) to give a solution of 10 mg/ml.
  • the 50% protective dose (PD 50 ) is calculated on the basis ofthe number of mice surviving 7 days after inoculation.

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Abstract

On décrit certains nouveaux analogues de l'adénylate d'aminoacyle. A titre d'exemple, un composé de l'invention est un [S-(R*,R*]-3,6-anhydro-1,2-didésoxy-1-[5-[4-[(5-nitro-2-thiényl)éthynyl]phényl]-2H-tétrazol-2yl]-D-allo-heptitol 7-(2-amino-3-méthyl-1-oxopentyl)sulfamate. Ces composés inhibent les isoleucyle-ARNt synthétases et ils sont utiles en tant qu'agents antimicrobiens et antiparasites.
PCT/US1996/011910 1995-07-28 1996-07-18 Analogues de l'adenylate d'aminoacyle en tant qu'agents antimicrobiens et antiparasites nouveaux WO1997005132A1 (fr)

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US08/683,809 US5726195A (en) 1995-07-28 1996-07-16 Aminoacyl adenylate mimics as novel antimicrobial and antiparasitic agents
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WO2000017206A1 (fr) * 1998-09-18 2000-03-30 Cubist Pharmaceuticals, Inc. Heterocycles tetracycliques utilises comme agents antimicrobiens
WO2000018772A1 (fr) * 1998-09-25 2000-04-06 Cubist Pharmaceuticals, Inc. Imidazolidinones condensees utilisees comme inhibiteurs de l'arnt-synthetase
WO2000021949A1 (fr) * 1998-10-12 2000-04-20 Smithkline Beecham Plc Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens
US6333344B1 (en) 1999-05-05 2001-12-25 Merck & Co. Prolines as antimicrobial agents
EP1176958A1 (fr) * 1999-05-05 2002-02-06 Merck & Co., Inc. Nouveaux catechols utilises comme agents antimicrobiens
EP1466603A2 (fr) * 1999-05-05 2004-10-13 Merck & Co., Inc. Nouveaux catechols utilises comme agents antimicrobiens
JP2004300112A (ja) * 2003-04-01 2004-10-28 Yokohama Kokusai Bio Kenkyusho:Kk 糖エステル及びその製造方法
JP2010500353A (ja) * 2006-08-08 2010-01-07 ミレニアム・ファーマシューティカルズ・インコーポレイテッド Ｅ１活性化酵素のインヒビターとして有用なヘテロアリール化合物
US8008307B2 (en) 2006-08-08 2011-08-30 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US8809356B2 (en) 2011-08-24 2014-08-19 Millennium Pharmaceuticals, Inc. Inhibitors of NEDD8-activating enzyme
US9683003B2 (en) 2014-07-01 2017-06-20 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of SUMO activating enzyme
US9695154B2 (en) 2013-07-02 2017-07-04 Millennium Pharmaceuticals, Inc. Heteroaryl inhibitors of sumo activating enzyme

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WO2000017206A1 (fr) * 1998-09-18 2000-03-30 Cubist Pharmaceuticals, Inc. Heterocycles tetracycliques utilises comme agents antimicrobiens
US6153645A (en) * 1998-09-18 2000-11-28 Cubist Pharmaceuticals, Inc. Heterocycles as antimicrobial agents
WO2000018772A1 (fr) * 1998-09-25 2000-04-06 Cubist Pharmaceuticals, Inc. Imidazolidinones condensees utilisees comme inhibiteurs de l'arnt-synthetase
WO2000021949A1 (fr) * 1998-10-12 2000-04-20 Smithkline Beecham Plc Quinolones tenant lieu d'inhibiteurs d'arnt synthetase et d'agents antibacteriens
US6348482B1 (en) 1999-05-05 2002-02-19 Merck & Co., Inc. Catechols as antimicrobial agents
EP1176958A1 (fr) * 1999-05-05 2002-02-06 Merck & Co., Inc. Nouveaux catechols utilises comme agents antimicrobiens
US6333344B1 (en) 1999-05-05 2001-12-25 Merck & Co. Prolines as antimicrobial agents
US6417217B1 (en) 1999-05-05 2002-07-09 Merck & Co., Inc. Prolines as antimicrobial agents
EP1176958A4 (fr) * 1999-05-05 2002-07-17 Merck & Co Inc Nouveaux catechols utilises comme agents antimicrobiens
US6545015B2 (en) 1999-05-05 2003-04-08 Merck & Co., Inc. Catechols as antimicrobial agents
US6579894B2 (en) 1999-05-05 2003-06-17 Merck & Co., Inc. Prolines as antimicrobial agents
EP1466603A2 (fr) * 1999-05-05 2004-10-13 Merck & Co., Inc. Nouveaux catechols utilises comme agents antimicrobiens
EP1466603A3 (fr) * 1999-05-05 2004-10-20 Merck & Co., Inc. Nouveaux catechols utilises comme agents antimicrobiens
JP2004300112A (ja) * 2003-04-01 2004-10-28 Yokohama Kokusai Bio Kenkyusho:Kk 糖エステル及びその製造方法
JP2010500353A (ja) * 2006-08-08 2010-01-07 ミレニアム・ファーマシューティカルズ・インコーポレイテッド Ｅ１活性化酵素のインヒビターとして有用なヘテロアリール化合物
US9458108B2 (en) 2006-08-08 2016-10-04 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US8481550B2 (en) 2006-08-08 2013-07-09 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US9718788B2 (en) 2006-08-08 2017-08-01 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US8901136B2 (en) 2006-08-08 2014-12-02 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
JP2015013904A (ja) * 2006-08-08 2015-01-22 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Ｅ１活性化酵素のインヒビターとして有用なヘテロアリール化合物
US9150525B2 (en) 2006-08-08 2015-10-06 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US8008307B2 (en) 2006-08-08 2011-08-30 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of E1 activating enzymes
US8809356B2 (en) 2011-08-24 2014-08-19 Millennium Pharmaceuticals, Inc. Inhibitors of NEDD8-activating enzyme
US9850214B2 (en) 2011-08-24 2017-12-26 Millennium Pharmaceuticals, Inc. Inhibitors of NEDD8-activating enzyme
US9695154B2 (en) 2013-07-02 2017-07-04 Millennium Pharmaceuticals, Inc. Heteroaryl inhibitors of sumo activating enzyme
US9683003B2 (en) 2014-07-01 2017-06-20 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of SUMO activating enzyme
US9962386B2 (en) 2014-07-01 2018-05-08 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of SUMO activating enzyme
US10335410B2 (en) 2014-07-01 2019-07-02 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of sumo activating enzyme
US10780090B2 (en) 2014-07-01 2020-09-22 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of SUMO activating enzyme

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