WO2007067906A2 - Inhibiteurs de la peptide deformylase - Google Patents

Inhibiteurs de la peptide deformylase Download PDF

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WO2007067906A2
WO2007067906A2 PCT/US2006/061641 US2006061641W WO2007067906A2 WO 2007067906 A2 WO2007067906 A2 WO 2007067906A2 US 2006061641 W US2006061641 W US 2006061641W WO 2007067906 A2 WO2007067906 A2 WO 2007067906A2
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methyl
amino
optionally substituted
hydroxy
cyclopentyl
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PCT/US2006/061641
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WO2007067906A3 (fr
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Jinhwa Lee
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the use of novel antibacterial compounds, and pharmaceutical compositions containing these compounds as peptide deformylase inhibitors.
  • Bacterial initiator methionyl tRNA is modified by methionyl tRNA formyltransferase (FMT) to produce formyl-methionyl tRNA.
  • FMT methionyl tRNA formyltransferase
  • the formyl methionine (f-met) is then incorporated at the N-termini of newly synthesized polypeptides.
  • Polypeptide deformylase PDF or Def
  • PDF deformylates primary translation products to produce N-methionyl polypeptides.
  • Most intracellular proteins are further processed by methionine amino peptidase (MAP) to yield the mature peptide and free methionine, which is recycled.
  • PDF and MAP are both essential for bacterial growth, and PDF is required for MAP activity. This series of reactions is referred to as the methionine cycle.
  • Polypeptide deformylase is found in all eubacteria for which high coverage genomic sequence information is available. Sequence diversity among PDF homologs is high, with as little as 20% identity between distantly related sequences. However, conservation around the active site is very high, with several completely conserved residues, including one cysteine and two histidines which are required to coordinate the active site metal (Meinnel, T. et a!., J. MoI. Biol. 267, 749-761, 1997).
  • PDF inhibitors can potentially serve as broad spectrum antibacterial agents, and has been a subject of several reviews (Aubart and Zalacain, Progress in Medicinal Chemistry, 44, 109-143; Jain et al., Current Medicinal Chemistry, 12, 1607-1621, 2005; Johnson et al., Current Drug Targets: Infectious Disorders, 5, 39-52, 2005; Boularot et al., Current Opinion in Investigational Drugs, 5, 809-822, 2004; Giglione et al., Molecular Microbiology, 36, 1197-1205, 2000.
  • the present invention involves novel antibacterial compounds represented by Formula (I) herein below and their use as PDF inhibitors.
  • R1 is optionally substituted C2-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or (CH2) m -R3,
  • C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one to three substituents each independently selected from the following: C1-C3 alkoxy, halo, and C1-C3 alkylsulfanyl;
  • R2 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl, where said C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 cycloalkyl are optionally substituted with one to three substituents each independently selected from the following: hydroxy, C1-C4 alkoxy, and halo;
  • aryl and heteroaryl are optionally substituted with one to three substituents each independently selected from: cyano, nitro, halo, C1-C3 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, -NR4R4, -C(O)R4, -C(O)NR4R4, -NHC(O)H, -OR4, and
  • heterocycloalkyl optionally substituted by one or two substituents each independently selected from C1-C3 alkyl and hydroxyl;
  • R3 is C3-C6 cycloalkyl optionally substituted with one to three substituents each independently selected from the following: C1-C3 alkoxy, halo, and C1-C3 alkylsulfanyl; or R3 is phenyl, furanyl, benzofuranyl, thiophenyl, benzothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, 1,4-benzodioxanyl or benzo[1,3]dioxolyl, each of which is optionally substituted with one to three substituents each independently selected from the following: halo, C1-C3 alky], C1-C3 haloalkyl, and C1-C2 alkoxy optionally substituted with one to three fluoro groups; each R4 is independently selected from: hydrogen, C1-C6 alkyl, and phenyl.
  • X is O, CH2, or a covalent bond
  • One embodiment of the present invention is a compound according to formula (I) with the following configuration:
  • R1 , R2, X, Y and n are as defined above.
  • One embodiment of the present invention is a compound according to formula (II):
  • R1 , R2 and X are as defined above.
  • One embodiment of the present invention is a compound according to formula (III):
  • R2 is as defined above.
  • Compounds useful in the present invention are selected from the group consisting of:
  • alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms.
  • C1-C6 alkyl refers to an alkyl group having from 1 to 6 member atoms.
  • Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups may be straight or branched.
  • alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • alkenyl refers to an unsaturated hydrocarbon chain having the specified number of member atoms and having one or more carbon-carbon double bonds within the chain.
  • C2-C6 alkenyl refers to an alkenyl group having from 2 to 6 member atoms.
  • alkenyl groups have one carbon-carbon double bond within the chain. In other emodiments, alkenyl groups have more than one carbon- carbon double bond within the chain. Alkenyl groups may be optionally substituted with one or more substituents as defined herein. Alkenyl groups may be straight or branched. Representative branched alkenyl groups have one, two, or three branches. Alkenyl includes ethylenyl, propenyl, butenyl, pentenyl, and hexenyl. As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon chain having the specified number of member atoms and having one or more carbon-carbon triple bonds within the chain.
  • C2-C6 alkynyl refers to an alkynyl group having from 2 to 6 member atoms.
  • alkynyl groups have one carbon-carbon triple bond within the chain.
  • alkynyl groups have more than one carbon- carbon triple bond within the chain.
  • Alkynyl groups may be optionally substituted with one or more substituents as defined herein.
  • Alkynyl groups may be straight or branched. Examples of "alkynyl" as used herein include, but are not limited to, acetylenyl and 1- propynyl.
  • alkoxy refers to -O-alkyl, where alkyl is as described herein including -OCH3 and -OC(CH3)2CH3.
  • alkylsulfanyl' refers to -S-alkyl, where alkyl is as decribed herein.
  • aryl refers to an aromatic hydrocarbon ring.
  • Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl rings refer to napthyl and rings wherein phenyl is fused to a cycloalkyl or cycloalkenyl ring having 5, 6, or 7 member atoms. Aryl groups may be optionally substituted with one or more substituents as defined herein.
  • cycloalkyl refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term “haloalkyl” refers to an alkyl group wherein at least one hydrogen atom attached to a member atom within the alkyl group is replaced with halo. Haloalkyl includes trifluoromethyl.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), and "halo” refers to the halogen radicals fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substitue ⁇ ts as defined herein. Heteroaryl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 11 member atoms.
  • Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system.
  • Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and napthy
  • heterocycloalkyl refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring.
  • heterocycloalkyl rings are not aromatic.
  • Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms.
  • Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Heterocycloalkyl groups are monocyclic ring systems having from 4 to 7 member atoms.
  • heterocycloalkyl is saturated.
  • heterocycloalkyl is unsaturated but not aromatic.
  • Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3- oxathianyl, 1,3-dithianyl, and azetidinyl.
  • member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • the term "optionally substituted” indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted or substituted with one or more substituents as defined herein.
  • “Substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e.
  • a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • Tr retention time
  • RP reverse phase
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • DCM dichloromethane
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • CDI (1,1-carbonyldiimidazole); HOAc (acetic acid);
  • HOSu ⁇ /-hydroxysuccinimide
  • Ac acetyl
  • HOBT 1-hydroxybenzotriazole
  • BOC te/t-butyloxycarbonyl
  • mCPBA metal-chloroperbenzoic acid
  • FMOC 9-fluorenylmethoxycarbonyl
  • DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
  • NMM N-methyl morpholine
  • HOAt 1-hydroxy-7-azabenzotriazole
  • TBAF tetra-n-butylammonium fluoride
  • TMS trimethylsilyl
  • BOP bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • HBTU O-Benzotriazole-1-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • ether refers to diethyl ether; brine refers to a saturated aqueous solution of NaCI.
  • pharmaceutically-acceptable salts of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula (I).
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • compounds according to Formula (I) may contain an acidic functional group. Suitable pharmaceutically-acceptable salts include salts of such acidic functional groups.
  • Representative salts include pharmaceutically-acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically- acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • pharmaceutically-acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts
  • carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc
  • compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically- acceptable inorganic acids and pharmaceutically-acceptable organic acids.
  • Representative pharmaceutically-acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o- acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as acetone, ethanol, n-propanol, isopropanol, n- butanol, te/t-butanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates. The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state.
  • Polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the present invention provides compounds of Formula (1 ) that can be prepared from the common racemic intermediate (8), or common chiral intermediates (17) and (25).
  • intermediate (8) can be prepared by reacting the mono-substituted dialkyl malonate (2) with a base, such as potassium hydroxide, in an appropriate solvent, such as ethanol/water, to afford the mono-acid (3).
  • a base such as potassium hydroxide
  • a coupling reagent such as 1 -[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)
  • EDCI 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide
  • Formylation of the amine group of (7) is achieved using formic acid and acetic anhydride in a solvent, such as dichloromethane, to provide the formylated compound (8).
  • a solvent such as dichloromethane
  • Any racemates can be resolved at the level of any intermediate during the synthesis or at the level of the final product using, for example, a chiral chromatography method, to provide compound (8) in each of two enantiomeric forms.
  • an enantiomer of intermediate (8) such as (17) in Scheme 2 or (25) in Scheme 3, can be prepared by reacting an appropriate acid chloride (9) with a chiral agent, such as Evans' chiral oxazolidinone, in the presence of a base, such as n-butyl lithium, to afford the chiral intermediate (10) in Scheme 2 or (18) in Scheme 3.
  • a chiral agent such as Evans' chiral oxazolidinone
  • the compounds of the invention can be prepared as depicted in Scheme 4 and 5 from commercially available starting materials.
  • 1- ⁇ [(phenylmethyl)oxy]carbonyl ⁇ -l_-proline (26) and glycinamide hydrochloride (27) are coupled using standard coupling reagents such as EDCI in the presence of DMAP.
  • a rearrangement is performed using [bis(trifluororacetoxy)iodo]benzene (PIFA) in acetonitrile and water and the product (29) is isolated as a hydrochloride salt.
  • a carboxylic acid is then attached to this amine using a second set of coupling reagents, such as HOAT with EDCl in the presence of a base such as NMM.
  • Compound (31 ) can then be hydrogenated in the presence of a catalyst to remove the carbonyl benzyloxy protecting group to provide the corresponding pyrrolidine (32).
  • the compounds of the invention are inhibitors of microbial peptide deformylase. These compounds can be useful in the treatment of mammalian, particularly human, bacterial infections including upper and lower respiratory tract infections, skin and soft tissue infections and malaria. Activity of these compounds has been shown specifically against bacteria from the genera Streptococcus, Staphylococcus, Moraxella, Escherichia, and Haemophilus.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
  • Individual embodiments of the invention include methods of treating any one of the above-mentioned disorders by administering a safe and effective amount of a compound according to Formula (I) or a pharmaceutically- acceptable salt thereof to a patient in need thereof.
  • treat in reference to a disorder means: (1 ) to ameliorate or prevent the disorder or one or more of the biological manifestations of the disorder, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the disorder or (b) one or more of the biological manifestations of the disorder, (3) to alleviate one or more of the symptoms or effects associated with the disorder, or (4) to slow the progression of the disorder or one or more of the biological manifestations of the disorder.
  • treatment of a disorder includes prevention of the disorder. The skilled artisan will appreciate that "prevention” is not an absolute term.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular compound chosen (e.g.
  • patient refers to a human or other mammal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.01 mg to 50mg per kg of total body weight; suitably from 1 mg to 100 mg/Kg.
  • Typical daily dosage regimen for parenteral administration is about 0.001 mg/Kg to 40 mg/Kg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • Typical daily dosage regimen for intranasal and inhalation administration is suitably about 10 to about 500 mg/person.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the invention also provides a compound of the invention for use in medical therapy, and particularly in the treatment of bacterial infections.
  • the invention is directed to the use of a compound according to Formula (I) or a pharmaceutically- acceptable salt thereof in the preparation of a medicament for the treatment of bacterial infections.
  • compositions of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules, creams and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example, aqueous gums, celluloses, silicates or oils, and incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example, polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example, polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non- aqueous vehicle, for example, a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • NMR 1 H NMR
  • Mass spectra were run on open access LC-MS systems using electrospray ionization.
  • the LC conditions used were either: 1 ) 4.5% to 90% CH 3 CN (0.02% TFA) in 3.2 min with a 0.4 min hold and 1.4 min re-equilibration; detection by MS, UV at 214 nm and 254 nm, and a light scattering detector (ELS).
  • IR Infrared
  • PIFA (4.85 mmol, 2.09 g) was dissolved in CH 3 CN (15 mL) and diluted with H 2 O (15 ml_). 1- ⁇ [(Phenylmethyl)oxy]carbonyl ⁇ -L-prolylglycinamide (4.8 mmol, 1.48 g) was added to this solution and the reaction mixture was stirred at room temperature overnight. It was then diluted with 1 N HCI (150 mL) and washed twice with diethyl ether. The aqueous layer was concentrated in vacuo to give the desired product in quantitative yield. The resulting white solid was used without further purification.
  • Enzymatic activity of PDF is measured using a FDH-coupled assay (Lazennec and Meinnel (1997) Anal. Biochem. 244, 180-182).
  • FDH-coupled assay Lazennec and Meinnel (1997) Anal. Biochem. 244, 180-182).
  • formate is released from methionine by PDF, it is oxidized by FDH thereby reducing one molecule of NAD to NADH and resulting in an increase in absorbance at 340 nm.
  • Reactions are initiated by adding PDF to microtiter plates containing all other reaction components and continuously monitored for 20 minutes at 25 0 C.
  • the final reaction composition for Staphylococcus aureus PDF is 50 mM potassium phosphate, pH 7.6, 5 units/ml FDH, 7 mM NAD, 5% DMSO, 1 nM SaPDF, and 2.9 mM formyl-Met-Ala-Ser in 50 ⁇ l total volume. Serial dilutions of inhibitors are performed in DMSO. Reagents and assay format are identical for Haemophilus influenzae PDF except that formyl-Met-Ala-Ser is 6 mM final. In the Streptococcus pneumoniae assay, reaction conditions are similar but contain 30 pM enzyme, 2 mM NAD and 4 mM formyl-Met-Ala-Ser.
  • the Examples of the present invention were tested in the PDF Enzymatic Activity Assay.
  • the Examples were shown to have IC50's of 100 nM or less against Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae PDF.
  • This panel consisted of the following laboratory strains: Staphylococcus aureus Oxford, Staphylococcus aureus WCUH29, Enterococcus faecalis I, Enterococcus faecalis 7, Haemophilus influenzae Q1 , Haemophilus influenzae NEMC1, Moraxella catarrhalis 1502, Streptococcus pneumoniae 1629, Streptococcus pneumoniae N 1387, Streptococcus pneumoniae Ery2, E. coli 7623 (AcrABEFD+) and E. coli 120 (AcrAB-).
  • the minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to assist in determining the MIC endpoint.
  • the Examples of the present invention were tested in the Antimicrobial Activity Assay.
  • the Examples were shown to have MICs of 32 mcg/ml or less, against seven or more of the 12 bacterial strains listed above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur de nouveaux inhibiteurs de PDF de formule (I), sur leurs compositions pharmaceutiques et sur leur utilisation dans le traitement d'infections bactériennes.
PCT/US2006/061641 2005-12-09 2006-12-06 Inhibiteurs de la peptide deformylase WO2007067906A2 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044178A1 (fr) * 1999-12-17 2001-06-21 Versicor, Inc. Nouveaux composes a base d'uree, compositions les contenant, et procedes d'utilisation et de preparation de ceux-ci
US20050222412A1 (en) * 2002-05-31 2005-10-06 Aubart Kelly M Peptide deformylase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044178A1 (fr) * 1999-12-17 2001-06-21 Versicor, Inc. Nouveaux composes a base d'uree, compositions les contenant, et procedes d'utilisation et de preparation de ceux-ci
US20050222412A1 (en) * 2002-05-31 2005-10-06 Aubart Kelly M Peptide deformylase inhibitors

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