WO2008143730A2 - Composés macrolides et procédés pour leur fabrication et leur utilisation - Google Patents

Composés macrolides et procédés pour leur fabrication et leur utilisation Download PDF

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Publication number
WO2008143730A2
WO2008143730A2 PCT/US2008/002732 US2008002732W WO2008143730A2 WO 2008143730 A2 WO2008143730 A2 WO 2008143730A2 US 2008002732 W US2008002732 W US 2008002732W WO 2008143730 A2 WO2008143730 A2 WO 2008143730A2
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Prior art keywords
alkyl
unsaturated
prodrug
group
pharmaceutically acceptable
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PCT/US2008/002732
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English (en)
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WO2008143730A3 (fr
Inventor
Ashoke Bhattacharjee
Erin M. Duffy
Zoltan F. Kanyo
Yuanqing Tang
Yusheng Wu
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Rib-X Pharmaceuticals, Inc.
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Publication of WO2008143730A2 publication Critical patent/WO2008143730A2/fr
Publication of WO2008143730A3 publication Critical patent/WO2008143730A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates generally to the field of anti -infective, anti -proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family macrolide compounds that are useful as such agents, hi particular embodiments the present invention relates to macrolide compounds in which the macrocyclic ring contains an oxime or other related functionality and wherein the compounds also contain a triazole ring.
  • the problem of resistance is not limited to the area of anti-infective agents. Resistance has also been encountered with antiproliferative agents used in cancer chemotherapy. Therefore, the need exists for new anti-infective and antiproliferative agents that are both effective against resistant bacteria and resistant strains of cancer cells.
  • Another class of antibiotics is the macrolides, so named for their characteristic 14- to 16-membered ring.
  • the macrolides also often have one or more 6-membered sugar-derived rings attached to the main macrolide ring.
  • the first macrolide antibiotic to be developed was erythromycin, which was isolated from a soil sample from the Philippines in 1952. Even though erythromycin has been one of the most widely prescribed antibiotics, its disadvantages are relatively low bioavailability, gastrointestinal side effects, and a limited spectrum of activity.
  • Another macrolide is the compound, azithromycin, which is an azolide derivative of erythromycin incorporating a methyl-substituted nitrogen in the macrolide ring.
  • Azithromycin is sold under the trade name Zithromax ® .
  • a more recently introduced macrolide is telithromycin, which is sold under the trade name Ketek ® .
  • Telithromycin is a semisynthetic macrolide in which a hydroxyl group of the macrolide ring has been oxidized to a ketone group. See Yong-Ji Wu, Highlights of Semi-synthetic Developments from Erythromycin A, Current Pharm. Design, vol. 6, pp. 181-223 (2000); Yong-Ji Wu and Wei- uo Su, Recent Developments on Ketolides and Macrolides, Curr. Med. Chem., vol. 8, no. 14, pp. 1727-1758 (2001); and Pal, Sarbani, "A Journey Across the Sequential Development of Macrolides and Ketolides Related to Erythromycin, Tetrahedron 62 (2006) 3171-3200.
  • the invention provides compounds useful as anti-infective agents and/or antiproliferative agents, for example, anti-biotic agents, anti-microbial agents, anti-bacterial agents, anti-fungal agents, anti-parasitic agents, anti-diarrheal agents, anti- viral agents, and chemotherapeutic agents.
  • the present invention also provides compounds useful as antiinflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents.
  • the present invention also provides pharmaceutically acceptable salts, esters, N-oxides, or prodrugs of these compounds.
  • the present invention provides oxime containing macrolide compounds having the structure:
  • variables G, T, X, R 1 , R 2 , R 3 , R a , R b , R c , R d and R e can be selected from the respective groups of chemical moieties later defined in the detailed description.
  • the invention provides methods of synthesizing the foregoing compounds.
  • a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use as an anti-cancer, anti-biotic, anti-microbial, anti-bacterial, antifungal, anti-parasitic, anti-diarrheal, or anti- viral agent, or to treat a proliferative disease, an inflammatory disease or a gastrointestinal motility disorder, or to suppress disease states or conditions caused or mediated by nonsense or missense mutations, hi certain embodiments, the compounds of the present invention are useful for treating, preventing, or reducing the risk of microbial infections or for the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infections.
  • the compounds or the formulations can be administered, for example, via otic, ophthalmic, nasal, oral, parenteral, or topical routes, to provide an effective amount of the compound to the mammal.
  • the present invention provides a family of compounds that can be used as antiproliferative agents and/or anti-infective agents.
  • the compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, antiparasitic and/or anti-viral agents.
  • the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation.
  • the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by a nonsense or missense mutation.
  • the present invention provides a family of compounds that can be used without limitation as anti-diarrheal agents.
  • the compounds described herein can have asymmetric centers.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • R includes, but is not limited to substituents such as alkyl, aryl, acetyl etc.
  • substituents such as alkyl, aryl, acetyl etc.
  • a wide variety of compounds can include a carbamate or other related functionality.
  • oxime or other related functionality is being used herein to describe a generally common chemical feature of the compounds of the present invention.
  • the various chemical variable substituents, as defined in the present patent application, further illustrate the term "oxime or other related functionality".
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C- 13 and C- 14.
  • R 2 can optionally be substituted with one, two, three, four, five, or more R 2 moieties, and R 2 at each occurrence is selected independently from the definition of R 2 .
  • R 2 at each occurrence is selected independently from the definition of R 2 .
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • a chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally present.
  • a dotted line drawn next to a solid single bond indicates that the bond can be either a single bond or a double bond.
  • glycoside is a cyclic acetal.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci_6 alkyl is intended to include Ci, C2, C3, C4, C5, and CO alkyl groups.
  • C1.8 alkyl is intended to include Ci, C2, C3, C4, C5, C ⁇ , C ⁇ , and Cs alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl.
  • alkenyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that can occur in any stable point along the chain, such as ethenyl and propenyl.
  • C2-6 alkenyl is intended to include C2, C3, C4, C5, and Ce alkenyl groups.
  • C2-8 alkenyl is intended to include C2, C3, C4, C5, Ce, C ⁇ , and Cs alkenyl groups.
  • alkynyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur in any stable point along the chain, such as ethynyl and propynyl.
  • C2-6 alkynyl is intended to include C2, C3, C4, C5, and C ⁇ , alkynyl groups.
  • C2-8 alkynyl is intended to include C2, C3, C4, C5, CO, C7, and Cs alkynyl groups.
  • alkyl alkenyl
  • alkynyl moieties which are diradicals, i.e., having two points of attachment, an example of which in the present invention is when D is selected from these chemical groups.
  • a nonlimiting example of such an alkyl moiety that is a diradical is -CH2CH2-, i.e., a C2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.
  • alkyl As used herein, the terms used to describe various carbon-containing moieties, including, for example, “alkyl,” “alkenyl,” “alkynyl,” “phenyl,” and any variations thereof, are intended to include univalent, bivalent, or multivalent species. For example, “Ci_6 alkyl-
  • R 3 is intended to represent a univalent Ci -6 alkyl group substituted with a R 3 group
  • "O- C i-6 alkyl-R 3 " is intended to represent a bivalent C 1.6 alkyl group, i.e., an "alkylene” group, substituted with an oxygen atom and a R 3 group.
  • cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
  • C3-8 cycloalkyl is intended to include C3, C4, C5,
  • unsaturated refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo substituents.
  • Counterion is used to mean a positively or negatively charged species present in conjunction with an ion of opposite charge.
  • a nonlimiting example of a counterion is an ion or ions present to counterbalance the charge or charges on an organic compound.
  • Nonlimiting examples of counterions include chloride, bromide, hydroxide, acetate, sulfate, and ammonium.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • Ci.6 alkoxy is intended to include Ci, C 2 , C3, C4, C5, and Ce alkoxy groups.
  • Ci_s alkoxy is intended to include Ci, C2, C3, C4, C5, Ce, C ⁇ , and Cs alkoxy groups.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.
  • alkylthio refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an sulfur bridge.
  • Ci -6 alkylthio is intended to include Ci, C2, C3, C4, C5, and C ⁇ alkylthio groups.
  • Ci_s alkylthio is intended to include Ci, C2, C3, C4, C5, C ⁇ , C7, and Cs alkylthio groups.
  • carrier or “carbocyclic ring” is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
  • bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring.
  • the substituents recited for the ring can also be present on the bridge.
  • Fused e.g., naphthyl and tetrahydronaphthyl
  • spiro rings are also included.
  • heterocycle means, unless otherwise stated, a stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, which is saturated, unsaturated (including partially and fully unsaturated), or aromatic, and consists of carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused or attached to a second ring (e.g., a benzene ring).
  • a second ring e.g., a benzene ring
  • a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein
  • R is H or another substituent, as defined).
  • the heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle can optionally be quaternized.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group.
  • aromatic heterocycle or “heteroaryl” is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • the second ring can also be fused or bridged as defined above for heterocycles.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined).
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a//-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6//-l,5,2-dithiazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indo
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).
  • prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form.
  • the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
  • Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “treating” or “treatment” includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • “Treating” or “treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
  • preventing means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • mamal refers to human and non-human patients.
  • the term "therapeutically effective amount” refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, for example, anti-microbial activity, anti-fungal activity, anti-viral activity, anti-diarrheal activity, anti-parasitic activity, and/or antiproliferative activity.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • Synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiproliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components. All percentages and ratios used herein, unless otherwise indicated, are by weight.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • the invention relates to a compound having the structure:
  • T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom;
  • X is selected from (a) H, (b) halogen, (c) a C 1-6 alkyl group, (d) a C 2-6 alkenyl group, (e) a C 2-6 alkynyl group, (f) -OH, (g) -OR 5 , (h) -NR 4 R 4 , (i) -C(O)R 5 , (j) -C(O)OR 5 , (k) -
  • R 1 and R 3 independently are selected from: (a) H, (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) -C(O)R 5 , (f) -C(O)OR 5 , (g) -C(O)-NR 4 R 4 , (h) - C(S)R 5 , (i) -C(S)OR 5 , G) -C(O)SR 5 , and (k) -C(S)-NR 4 R 4 ; alternatively R 1 and R 3 are taken together with the oxygen to which R 1 is attached, the nitrogen to which R 3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R 5 groups; R 2 is hydrogen or -OR 12 ;
  • G is selected from: (a) -B' and (b) -B'-Z-B", wherein i) each B' is independently selected from (aa) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings and (bb) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (aa) or (bb) optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) optionally is substituted with one or more R 11 or R 1 ' a ; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR 9 , (dd) - SH, (ee) -S(O)pR 9 , (ff) halogen, (gg) -CN, (Hh)-N 3 , (
  • R 4 at each occurrence, independently is selected from: (a) H, (b) a Ci- 6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 6-12 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-Ci -6 alkyl, (h) -C(O)-C 2-6 alkenyl, (i) -C(O)-C 2-6 alkynyl, (j) -C(O)-C 3- J 2 saturated, unsaturated, or aromatic carbocycle, (k) -C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Cj -6 alky
  • R 7 (a) R 7 , (b) a Cj -6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 3- I 2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or; wherein any of (b)-(f) immediately above optionally is substituted with one or more R 7 groups; alternatively two R 5 groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of these ring systems formed from two R 5 groups optionally is substituted with one or more R 7 groups; R 6 , at each occurrence, independently is selected from:
  • R 10 at each occurrence, independently is selected from:
  • R 11 and R Ua at each occurrence, independently is selected from: (a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO 2 , (i) OR 8 , G) -S(O)pR 8 , (k) -C(O)R 8 , (1) -C(O)OR 8 , (m) -OC(O)R 8 , (n) -C(O)NR 8 R 8 , (o) -OC(O)NR 8 R 8 , (p) -C( NR 8 )R 8 , (q) -C(R 8 )(R 8 )OR 8 , (r) -C(R 8 ) 2 OC(O)R 8 , (s) -C(R 8 )(OR 8 )(CH 2 ) r NR 8 R 8 , (t) -NR 8 R 8 , (
  • R 12 is selected from:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -CN, (g) -CF 3 , (h) -CF 2 H, (i) -CFH 2 , G) -O(C 1-6 alkyl), (k) -N 3 , (1) -COOH, (m) -COO(C 1-6 alkyl), (n) -NH 2 , (o) -NH(C 1-6 alkyl), (p) -N(Ci -6 alkyl) 2 , (q) -C(O)NH 2 , (r) -C(O)NH(C 1-6 alkyl), (s) -C(O)N(C 1-6 alkyl) 2 , (t) -NHC(O)H, (
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F and OH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R d and R e are selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C 1-6 alkyl.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R d and R e are H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R c is selected from (a) H, (b) C 1-6 alkyl, (c) -CF 3 , (d) -CF 2 H, and (e) -CFH 2 .
  • R c is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a and R b are independently selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -O(C, -6 alkyl), (g) -N 3 , (h) -COOH, (i) -COO(C 1-6 alkyl), (j) -CN, (k) -NH 2 , (1) -NH(C 1-6 alkyl), (m) -N(C 1-6 alkyl) 2 , (n)-C(O)NH 2 , (o) -C(O)NH(C 1-6 alkyl), (p) -C(O)N(C 1-6 alkyl) 2 , (q) -NHC(O)H, (r) - NHC(O)(C 1-6 alkyl), (s) -
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein R a and R b are independently selected from -H, -F, -OH, -OCH 3 , -SH, and -SCH 3 .
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein R a is H and R b is F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -OH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -OCH 3 .
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -SH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -SCH 3 .
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 2 is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 3 is C 1-6 alkyl. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 3 is methyl.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is selected from: (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R 11 groups.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is -B'-Z-B".
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' and B" are independently selected from (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R 1 ' groups.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R 1 , R 2 , and R 3 are as described herein.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R 1 , R 2 , and R 3 are as described herein.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is: and B", Z, and R 1 ' are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, jV-oxide, or prodrug thereof, wherein G is: , wherein B", Z, and R 11 are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is: , wherein B", Z, and R 11 are as described herein and or B" is substituted with R 11 .
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 ' is selected from (a) OR 8 , (b) -S(O) P R 8 , (c) -C(O)R 8 , (d) -C(O)NR 8 R 8 , (e) -C(R 8 )(R 8 )OR 8 , (f) - C(R 8 ) 2 OC(O)R 8 , (g) -NR 8 R 8 , (h) -NR 8 C(O)R 8 , (i) -NR 8 S(O)pR 8 , (j) a C 1-6 alkyl group, and (k) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (j) is optionally substituted with one or more R 5 groups.
  • R 1 ' is selected from (a)
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 ' is selected from -CH 2 OH, -SO 2 CH 3 , -NH 2 , -CH 3 , -C(O)NH 2 , -CH 2 OC(O)CH 3 , CH 2 OCH 3 , -NHCH 3 , - OCH 3 , ⁇ W , NH(cyclopropyl), -C(O)CH 3 , -NHC(O)CH 3 , -C(O)CH 3 , -S(O)CHF 2 ,
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 11 is F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C 1-6 alkyl group, (b) a C 2.6 alkenyl group, (c) a C 2 .
  • NR 8 C(O)OR 8 (w) -NR 8 C(O)NR 8 R 8 , (x) -NR 8 S(O) P R 8 , (y) -C(OR 8 )(OR 8 )R 8 , (z) -C(R 8 ) 2 NR 8 R 8 , (aa) -C(S)NR 8 R 8 , (bb) -NR 8 C(S)R 8 , (cc) -OC(S)NR 8 R 8 , (dd) -NR 8 C(S)OR 8 , (ee) -NR 8 C(S)NR 8 R 8 , (ff) -SC(O)R 8 , (gg) -N 3 , (hh) - Si(R 13 ) 3 , (ii) a C 1-6 alkyl group, Oj) a C 2-6 alkenyl group, (kk) a C 2-6 alkynyl group, (11) a C 3-I2 saturated
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C,_ 6 alkyl group, (b) a C 2 ⁇ alkenyl group, (c) a C 2.6 alkynyl group, (d) a C 3-12 saturated, unsaturated, or aromatic carbocycle, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) -CF 3 , (g) -NR 6 (CR 6 R 6 ) t R 9 , (h) -OR 9 , (i) -S ⁇ CR 6 R 6 ) t R 9 , (j) -S(O)(CR 6 R 6 ) t R 9 , (k) - S(O) 2 (CR 6 R 6 ) t R 9 , (1) -C(
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C 1-6 alkyl group, (b) a C 2.6 alkenyl group, (c) a C 2.6 alkynyl group, (d) a C 3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein (a)-(e) optionally are substituted with one or more R 14 groups.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected (a) -NR 6 (CR 6 R 6 ) t R 9 , (b) -OR 9 , (c) -S ( CR 6 R 6 ) t R 9 , (d) -S(O) ( CR 6 R 6 ) t R 9 , (e) - S(O) 2 ( CR 6 R 6 ) t R 9 , (f) -C(O)(CR 6 R 6 ) t R 9 , (g) -OC(O)(CR 6 R 6 ) t R 9 , (h) -OC(O)O(CR 6 R 6 ) t R 9 ,
  • M is selected from:
  • R 100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR 114 , and (f) C 1-6 alkyl, wherein (f) optionally is substituted with one or more R 115 groups;
  • R 101 is selected from:
  • R 102 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR 114 , and (f) C 1-6 alkyl, wherein (f) optionally is substituted with one or more R 115 groups;
  • R 103 is selected from:
  • R 102 and R 103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R 114 groups; alternatively, R 101 and R 103 taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R 100 and R 102 are attached; alternatively, R 101 and R 103 taken together with the carbons to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more R 114 groups; alternatively, R 100 , R 101 , R 102 , and R 103 taken together with the carbon to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more
  • K is selected from:
  • R 105 is selected from:
  • R 106 is selected from: (a) -OR 114 , (b) -C 1-6 alkoxy-R 115 , (c) -C(O)R 114 , (d) -OC(O)R 114 , (e) -
  • OC(O)OR 114 (f) -OC(O)NR 114 R 114 , and (g) -NR 114 R 114 , R 107 is selected from
  • R 106 and R 107 are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C 3 - C 7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a Cr 6 alkyl;
  • R 108 is selected from:
  • R 109 is H, C 1-6 alkyl, or F; R 114 , at each occurrence, independently is selected from:
  • R 115 is selected from: (a) R 117 , (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) C 3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -OC 1-6 alkyl, (h) -OC 2-6 alkenyl, and (i) - OC 2-6 alkynyl, wherein any of (b)-(f) optionally is substituted with one or more R 117 groups; R 116 , at each occurrence, independently is selected from:
  • R 119 at each occurrence, independently is selected from:
  • R 120 (a) R 120 , (b) C, .6 alkyl, (c) C 2 ⁇ alkenyl, (d) C 2.6 alkynyl, (e) C 3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more R 114 groups; R 120 , at each occurrence, independently is selected from:
  • R 127 is R 114 , a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), -S(O)pR 148 , -(CH 2 ) n -(O-CH 2 CH 2 -) m -O(CH 2 ) n CH 3 , -(CH 2 ) n - (O-CH 2 CH 2 -) m -OR 148 , - ⁇ CH 2 ) n -[S(O) p -CH 2 CH 2 -] m -S(O)p(CH 2 ) n CH 3 , -(CH 2 ) n - [S(O) p -CH 2 CH 2 -] m -S(O)pCH3, -(CH 2 )n-[S(O)p-CH 2 CH 2 -] m -OR 148 , -OCH 2 -O-(CH 2 ) n - [S
  • R 110 is R 114 ; alternatively, R 109 and R 110 taken together with the carbons to which they are attached form:
  • R 132 , R 133 , and R 134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,
  • R 105 and R 134 are taken together with the carbons to which they are attached to form a 3-membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R 114 groups; alternatively when M is a carbon moiety, R 134 and M are taken together to form a carbon-carbon double bond;
  • R 137 is independently (a) H, (b) Ci -6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) -
  • each R 138 is independently H or C 1 - 6 alkyl
  • each R 141 , R 142 , R 143 , and R 144 is independently selected from H, Cr 6 alkyl, - (CH 2 ) O i(C 6 -C l oaryl), and -(CH 2 ) m (5-10 membered heteroaryl), wherein the foregoing
  • R 141 , R 142 , R 143 , and R 144 groups are optionally substituted by 1, 2, or 3 R 140 groups; or R 141 and R 143 are taken together to form -(CH 2 ) 0 - wherein o, at each occurrence is 0, 1, 2, or 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds; or R 143 and R 144 are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and - N(R 137 )-, in addition to the nitrogen to which R 143 and R 144 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R 140 groups;
  • R 139 is H, Ci-6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the foregoing R 139 groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halo and -OR 138 ; each R 140 is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R 145 , -C(O)OR 145 , -OC(O)OR 145 , -NR 146 C(O)R 147 , -NR 146 R 147 , OH, C,- 6 alkyl, Cr 6 alkoxy, -(CH 2 )V(C 6 -C 1O aTyI), and -(CH 2 ) v (5-10 membered heteroaryl), wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyan
  • each R 145 is independently selected from H, C 1 - 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(CH 2 ) v (C 6 -Ci 0 aryl), and -(CH 2 ) v (5-10 membered heteroaryl); each R 146 and R 147 is independently H, hydroxyl, Ci- 6 alkoxy, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -(CH 2 ) v (C6-!o ary ⁇ > or -(CH 2 ) v (5-10 membered heteroaryl);
  • R 148 is Cr 6 alkyl, C 3-12 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R 114 , or 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said heterocycle is further optionally substituted with one or more R 114 ; p, at each occurrence is O, 1, or 2; m, at each occurrence is O, 1, 2, 3, 4, or 5; n, at each occurrence is 1, 2, or 3; r, at each occurrence is O, 1, or 2; t, at each occurrence is O, 1, or 2; v, at each occurrence is O, 1, 2, 3, or 4; q, at each occurrence is 0, 1, 2, or 3, and u at each occurrence is 1, 2, 3, or 4.
  • the present invention relates to a compound, wherein T is: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 1 14 , R 132 , R 133 , and R 134 are as described herein.
  • the present invention relates to a compound, wherein T is:
  • the present invention relates to a compound, wherein T is:
  • R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 1 14 , R 132 , R 133 , and R 134 are as described herein.
  • the present invention relates to a compound, wherein T is:
  • R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 114 , R 132 , R 133 , and R 134 are as described herein.
  • the present invention relates to a compound, wherein T is selected from TA-TD:
  • R 1 M and R 127 are as described herein.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from T4 through T34:
  • the present invention relates to a compound having the structure corresponding to any one of the structures listed in Table 1, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, in the manufacture of a medicament for treating a microbial infection in a mammal.
  • the present invention relates to a method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, ⁇ -oxide, or prodrug thereof, wherein the microbial infection is selected from the group consisting of: a skin infection, nosocomial pneumonia, community acquired pneumonia, post- viral pneumonia, a respiratory tract infection such as CRTI, a skin and soft tissue infection
  • SSTI skin and soft tissue infections
  • uSSTIs uncomplicated skin and soft tissue infections
  • uSSTIs uncomplicated skin and soft tissue infections
  • complicated skin and soft tissue infections as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, and tuberculosis.
  • uSSTIs uncomplicated skin and soft tissue infections
  • uSSTIs uncomplicated skin and soft tissue infections
  • complicated skin and soft tissue infections as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a
  • the present invention relates to a method of treating or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing diarrhea in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation comprising administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation.
  • the present invention relates to a method or use of a compound of the invention wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered otically, ophthalmically, nasally, orally, parentally, or topically.
  • the present invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a medical device containing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the medical device is a stent.
  • the compounds of the present invention can include a wide range of structures.
  • macro lide components and their syntheses are provided in the following documents, all of which are incorporated by reference in their entirety: PCT Application No. WO 2007/025284, published March 1 , 2007, to Rib-X
  • the invention provides methods for making the compounds of the invention.
  • the electrophilic alkyne, 2, can include, e.g., compounds where chlorides, bromides, iodides, tosylates, and mesylates depending on the selection of X. Cycloaddition of azide compounds, such as 6, with the 3'-N-allkynyl compounds 3 provides two regioisomeric triazole products 7 and 8.
  • the major isomer is the "anti" isomer 7, a 1,4 disubstituted triazole.
  • the minor component is the "syn” isomer 8, a 1,5 disubstituted triazole.
  • the cycloaddition reaction can be thermally catalyzed, or a number of catalysts can be used, such as, but not limited to, copper (I) iodide. See, Tornoe, CW. et al. (2002) J. Org. Chem. 67: 3057).
  • Scheme B illustrates the synthesis of oxime type macrolides of the present invention.
  • These compounds can be from 3'-N-alknynyl compounds such as 3, which are made from the 3'-N-desmethyl macrolides, 1, as in Scheme A.
  • Compound 3 can either be converted directly to the desired intermediate oxime 4 (by the appropriate choice of R 1 ), or alternatively via a the hydroxyl oxime 5.
  • a cycloaddition reaction of the intermediate oxime 4 and an azide compound 6 provides the final compounds 7 and 8 as a mixture of isomers.
  • Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays.
  • it can be possible to rapidly screen the molecules described herein for activity, for example, as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents.
  • it can be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art.
  • modulators for example, inhibitors
  • High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • SPR surface plasmon resonance
  • SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon.
  • One device (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip") and a buffer compartment that can be regulated by the user.
  • a 100 nm thick "hydrogel” composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced.
  • the resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance.
  • the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance.
  • the plasmon resonance and thus the depletion spectrum
  • the plasmon resonance is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel).
  • Fluorescence polarization is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC 50 S and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore.
  • the sample mixture containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore.
  • Binding assays based on FP have a number of important advantages, including the measurement of IC 5 oS and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions.
  • the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.
  • a modulator for example, an inhibitor of protein synthesis
  • more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC 50 ) for inhibiting protein synthesis.
  • IC 50 inhibition constant
  • Incorporation of 3 H leucine or 35 S methionine, or similar experiments can be performed to investigate protein synthesis activity.
  • a change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis.
  • a decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.
  • the compounds can be assayed for antiproliferative or anti-infective properties on a cellular level.
  • the activity of compounds of interest can be assayed by growing the microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule can be acting as a protein synthesis inhibitor.
  • the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens.
  • a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized.
  • MICs Minimum inhibitory concentrations
  • CLSI Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA: NCCLS; 2000.
  • the assays can be also be performed in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI.
  • Endpoints can vary from reduction in bacterial burden to lethality. For the latter endpoint, results are often expressed as a PD 5O value, or the dose of drug that protects 50% of the animals from mortality.
  • measurements of inhibition of cytochrome P450 enzymes and phase II metabolizing enzyme activity can also be measured either using recombinant human enzyme systems or more complex systems like human liver microsomes. Further, compounds can be assessed as substrates of these metabolic enzyme activities as well. These activities are useful in determining the potential of a compound to cause drug-drug interactions or generate metabolites that retain or have no useful antimicrobial activity.
  • solubility and Caco-2 assays are a cell line from human epithelium that allows measurement of drug uptake and passage through a Caco-2 cell monolayer often growing within wells of a 24- well microtiter plate equipped with a 1 micron membrane. Free drug concentrations can be measured on the basolateral side of the monolayer, assessing the amount of drug that can pass through the intestinal monolayer. Appropriate controls to ensure monolayer integrity and tightness of gap junctions are needed. Using this same system one can get an estimate of P-glycoprotein mediated efflux.
  • P-glycoprotein is a pump that localizes to the apical membrane of cells, forming polarized monolayers. This pump can abrogate the active or passive uptake across the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelial layer. These results are often done in conjunction with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Measurements of oral bioavailability in animals and ultimately in man using traditional pharmacokinetic experiments will determine the absolute oral bioavailability.
  • Experimental results can also be used to build models that help predict physical- chemical parameters that contribute to drug-like properties. When such a model is verified ⁇ experimental methodology can be reduced, with increased reliance on the model predictability.
  • the compounds of the invention can be useful in the prevention or treatment of a variety of human or other animal, including mammalian and non mammalian, disorders, including for example, bacterial infection, fungal infections, viral infections, diarrhea, parasitic diseases, and cancer. It is contemplated that, once identified, the active molecules of the invention can be incorporated into any suitable carrier prior to use.
  • the dose of active molecule, mode of administration and use of suitable carrier will depend upon the intended recipient and target organism.
  • the formulations, both for veterinary and for human medical use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier.
  • the carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient.
  • Pharmaceutically acceptable carriers are intended to include any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.
  • Supplementary active compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions.
  • the formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology.
  • compositions of the invention are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • a pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include otic, ophthalmic, nasal, oral or parenteral, for example, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants
  • Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990).
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Suppositories for rectal administration also can be prepared by mixing the drug with a non- irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures.
  • Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes.
  • Formulations for direct administration can include glycerol and other compositions of high viscosity.
  • Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Retention enemas also can be used for rectal delivery.
  • Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil- in-water emulsion or a water-in-oil emulsion.
  • the drug can also be administered in the form of a bolus, electuary or paste.
  • a tablet can be made by compressing or moulding the drug optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets can be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients.
  • Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.
  • Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
  • Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Particularly useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal.
  • the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface.
  • hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage.
  • tissue-coating solutions such as pectin-containing formulations can be used.
  • inhalation treatments inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used.
  • Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations.
  • the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size.
  • the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration also can be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
  • Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).
  • the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive.
  • the compound then can be painted, sprayed or otherwise applied to the desired tissue surface.
  • the drugs can be formulated for otic, ophthalmic, nasal, parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.
  • the active compound can be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor.
  • the compound can be provided to the donor host.
  • the organ or living tissue can be placed in a preservation solution containing the active compound.
  • the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, e.g., by otic, ophthalmic, nasal, oral or parenteral administration, using any of the methods and formulations described herein and/or known in the art.
  • the drug comprises part of a tissue or organ preservation solution
  • any commercially available preservation solution can be used to advantage.
  • useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution.
  • the compounds of the present invention can be administered directly to a tissue locus by applying the compound to a medical device that is placed in contact with the tissue.
  • a medical device is a stent, which contains or is coated with one or more of the compounds of the present invention.
  • an active compound can be applied to a stent at the site of vascular injury.
  • Stents can be prepared by any of the methods well known in the pharmaceutical art. See, e.g., Fattori, R.
  • the stent can be fabricated from stainless steel or another bio-compatible metal, or it can be made of a bio-compatible polymer.
  • the active compound can be linked to the stent surface, embedded and released from polymer materials coated on the stent, or surrounded by and released through a carrier which coats or spans the stent.
  • the stent can be used to administer single or multiple active compounds to tissues adjacent to the stent.
  • Active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically).
  • pharmacogenomics i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug
  • Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug.
  • a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.
  • the compounds or pharmaceutical compositions thereof will be administered otically, ophthalmically, nasally, orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective.
  • a concentration that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective.
  • an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day.
  • the amount administered will also likely depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum and the daily dosage can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day. Various disease states or conditions in humans and other mammals are found to be caused by or mediated by nonsense or missense mutations.
  • mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function.
  • diseases states or conditions in which an appreciable percentage of the disease or condition is believed to result from nonsense or missense mutations include hemophilia (factor VIII gene), neurofibromatosis (NFl and NF2 genes), retinitis pigmentosa (human USH2A gene), bullous skin diseases like Epidermolysis bullosa pruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCAl and BRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair genes, predominantly in MLHl and MSH2), and lysosomal storage disorders such as Neimann-Pick disease (acid sphingomyelinase gene).
  • the compounds of the present invention can be used to treat or prevent a disease state in a mammal caused or mediated by such nonsense or missense mutations by administering to a mammal in need thereof an effective amount of the present invention to suppress the nonsense or missense mutation involved in the disease state.
  • NMR Nuclear magnetic resonance
  • spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer.
  • Common reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, and anhydrous as obtained from the manufacturer unless otherwise noted.
  • HPLC high performance liquid chromatography
  • ACS American Chemical Society
  • the compounds of the present invention can be prepared using known chemical transformations adapted to the particular situation at hand. Examples of chemical transformations useful in the present invention can be found in: U.S. Patent No. 7,091,196 B2, to Wang et al., issued August 15, 2006; PCT application No. WO 2005/085266 A2, to Rib-X Pharmaceuticals, Inc., published September 15, 2005; PCT application No.
  • the compounds of the present invention can be prepared, formulated, and delivered as salts, esters, and prodrugs.
  • the compounds are generally shown without indicating a particular salt, ester, or prodrug form.
  • variable G is further selected from -B' or -B '-Z-B".
  • Tables 1A-1I provide examples of chemical moieties or fragments for -Z-B" when G is selected from -B '-Z-B". Note that in Tables 1 A-II, the chemical moieties or fragments for "-Z-B" are drawn such that the chemical moiety or fragment is bonded to -B from the left of the chemical moiety or fragment as drawn. For example, using the first chemical moiety or fragment from Table IA as an example, it can alternatively be drawn as shown immediately below.
  • variable G could be selected from -B '-Z-B". If, for example, B' is then selected from phenyl, then -Z- B" could be further selected from the first chemical moiety or fragment of Table IA to give the indicated compound.
  • Exemplary macrolide compound of the present invention showing variable G.
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B'
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B" wherein B 1 is phenyl.
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B" wherein B' is phenyl and -Z-B" is selected from the first chemical moiety or fragment of Table IA.
  • Examples 1 — 6 Synthesis of 3'-N-desmethyl macrolide compounds
  • Examples 1-6 describe the synthesis of various 3'-N-desmethyl macrolide compounds which are useful intermediates for making the compounds of the present invention.
  • 3'-N-desmethyl erythromycin is synthesized from erythromycin according to the procedure described in U.S. Patent No. 3,725,385; Flynn et al. (1954) J. Am. Chem. Soc. 76: 3121; Ku et al. (1997) Bioorg. Med. Chem. Lett. 7: 1203; and Stenmark et al. (2000) J. Org. Chem. 65: 3875).
  • Example 2 Synthesis of 3'-7V-desmethyl azithromycin from azithromycin Azithromycin (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 0 C followed by addition of iodine (I 2 ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes, however, stirring was continued for 2 hours.
  • I 2 iodine
  • the crude was purified on a silica gel column eluting with CH 2 Cl 2 /MeOH/NH 4 ⁇ H 18:1:0.05 to 10:1:0.05 to provide the 3'- ⁇ f-desmethyl azithromycin (0.41 g, 55%).
  • Example 3 Synthesis of 3'-iV-desmethyl clarithromycin from clarithromycin To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc»3H 2 0 (0.885 g, 6.5 mmol) was added MeOH-H 2 O (20 mL, 4:1), and the mixture heated to 55-60 0 C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 0 C for 3 h. The reaction mixture was poured into 50 mL CHCl 3 containing 1 mL ammonium hydroxide.
  • telithromycin (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions within 30 min at 0 0 C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH 2 Cl 2 (250 mL) and 5 % Na 2 S 2 O 3 (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na 2 S 2 O 3 (1 X 80 mL), dilute NH 4 Cl (1 X 80 mL) and dried over Na 2 SO 4 .
  • NMS N-iodosuccinimide
  • ketolide function i.e. the 1,3-diketone
  • the ketolide function is introduced after the 3'-N-desmethyl functionality has been further transformed to an N-alkynyl intermediate.
  • clarithromycin is converted to 3'-N-desmethyl clarithromycin.
  • This compound is then alkylated to form an alkynyl intermediate.
  • the cladinose sugar is then cleaved from this intermediate and the resulting free hydroxyl group is oxidized to the ketone. This process is shown below in Example 12.
  • the compounds of the present invention can be made via an N-alkynyl substituted macrolide intermediate.
  • the following Examples 7-12 illustrate the preparation of such compounds, hi these examples, the 3'-N-(but-3-ynyl) compounds are illustrated, but other corresponding alkynyl compounds are readily prepared by varying the alkynyl starting material.
  • Protocol A A mixture of 3'- ⁇ -desmethyl telithromycin (0.66 g, 0.83 mmol) and the tosylate of l-butyn-4-ol (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 90 0 C for 5 days. The solvent was evaporated; the residue was dissolved in IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH 2 Cl 2 (30 mL) was added and the two layers were separated.
  • Protocol B A mixture of 3'-N-desmethyl telithromycin (0.66 g, 0.83 mmol), and the tosylate of l-butyn-4-ol (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 0 C within 10 min and maintained at 90 0 C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH 2 Cl 2 (30 mL) was added and the two layers were separated.
  • the aqueous layer was extracted with CH 2 Cl 2 (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension.
  • the suspension was extracted with CH 2 Cl 2 (3 X 30 mL) and the organic layer was dried over Na 2 SO 4 .
  • the solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH 2 Cl 2 /methanolic ammonia (2N NH 3 ) 12:1 to give 3'-N-(but-3-ynyl) telithromycin as white solid (0.19 g, 27 %).
  • MS (ESI) m/e 850.8 (M+H) + .
  • Example 12 Synthesis of 3'-iV-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring.
  • 3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring are prepared by introducing the oxime function typically after the 3'- ⁇ -but-3-ynyl (or other desired alkynyl group) has been introduced.
  • Example 12.1 provides a method for making the oxime of 3'-N'(but-3-ynyl) clarithromycin.
  • Examples 12.2 to 12.6 provide procedures for making more complex oximes.
  • Examples 12.2 to 12.6 The following scheme shows two exemplary oxime compounds (a piperidinyl oxime and a pyrrolidinyl oxime) and also the 3'-N-(but-3-ynyl) ketolide (see Example 6).
  • the N-alkynyl oxime macrolides were prepared from 3'-N-(but-3-ynyl) clarithromycin (see Example 9).
  • the pyrollidinyl oxime was synthesized from the 3'-N-(but-3-ynyl) ketolide and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of piperidinyl oxime. Data for the pyrrolidinyl: MS (ESI) m/e 710.6 (M+H) + .
  • Example 13 Synthesis of Compounds of the present invention via a cyclization reaction of a 3'-iV-(but-3-ynyl) macrolide with an azide.
  • Compounds of the present invention can be made, for example, via a cycloaddition reaction of an alkynyl macrolide with an azide compound. In this cycloaddition reaction, the triazole functional group of the resulting compound is formed. Other compounds of the present invention are made by further chemically modifying the resulting compound from the cycloaddition reaction.
  • the cycloaddition reaction is generally run in the presence of a copper (I) salt such as copper iodide (CuI).
  • a base can also be optionally used, such as Hunig's base (N,N- diisopropylethylamine).
  • Hunig's base N,N- diisopropylethylamine
  • the time required for the reaction to proceed to completion is variable and is dependent upon several factors including: the specific alkynyl macrolide and azide compounds and their concentrations; the amount of Cu(I) salt used; and the presence or absence of base, such as Hunig's Base(N,N-diisopropylethylamine). Reactions are monitored for the disappearance of the starting materials by TLC and/or LCMS and are typically allowed to run for between about 2 hours to about 72 hours. Reactions are generally stopped when analysis demonstrates that the starting alkynyl macrolide has been substantially consumed.
  • the workup and purification protocols are standard. Modifications to the described workup procedures can be used.
  • Such modifications can include the use of different aqueous wash solutions, different organic solvents for extraction, the use of other anhydrous salts for the drying of organic extracts, and the employment of different solvent mixtures for the chromatographic purification of the compounds.
  • the methods used for the workup of the reaction mixtures, the extraction of products, the drying of organic extracts, and for the isolation and purification of the compounds of the present invention are typical of procedures familiar to those trained in the art of organic synthesis.
  • Hunig's base in 0.4 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon.
  • CuI is then added (2 mg, 0.01 mmol) and the mixture is further degassed.
  • the mixture is stirred under argon for 6h then diluted with CH 2 Cl 2 (20 mL) and washed with a 3:1 mixture of saturated aqueous NH 4 Cl and 28% aqueous NH 4 OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH 2 Cl 2 (2 x 15 mL).
  • alkynyl macrolide compounds that can be used in the synthesis of the compounds of the present invention are shown in the following Table 2 A. It is appreciated by one of skill in the art that these alkynyl macrolide compounds, Ml to M43, are non-limiting examples and that a wide variety of additional alkynyl macrolides can be used to prepare other compounds of the present invention.
  • macrolide moieties Ml 1, M12, M13, Ml 6, Ml 7, Ml 8, M20, M21, M22, M23, M27, M28, M33, M34, M35, M36, M37, M38, M39, M40, M41, M42, and M43 are illustrative of various macrolides containing an oxime or other related functionality.
  • the alkynyl macrolide compounds such as alkynyl macrolide compounds Ml to M44, are generally made by the alkynylation (i.e. the addition of an alkynyl group) to a monomethyl amine macrolide compound.
  • the monomethyl amine macrolide is generally made by the desmethylation of the corresponding macrolide compound.
  • the desmethylation process can involve several steps, including various protection and deprotection steps.
  • the desmethyl macrolide compound is alkynylated with the corresponding alkynyl compound, which is generally an alkynyl halide, tosylate, or mesylate.
  • Macrolide Desmethyl Macrolide R 3 is generally Methyl
  • Alkynyl macrolide Ml is made by selective demethylation of azithromycin 1 to produce 3'-N-desmethylazithromycin 2. This compound 2 is selectively alkylated with alkynyl tosylate 11 to produce alkynyl macrolide Ml.
  • Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 0 C followed by addition of iodine (I 2 ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continued for 2 hours.
  • I 2 iodine
  • Clarithromycin Desmethyl Clarithromycin 21 M3
  • Alkynyl Macrolide Ml 4 is made using a procedure analogous to that for making M3, starting from erythromycin A.
  • the 3'-N-desmethyl-erythromycin A intermediate is made using a procedure described in U.S. Patent No. 3,725,385, to Freiberg, issued April 3, 1973.
  • Alkynyl macrolide Ml 4 can further be used to prepare a variety of macrolides analogous to those already depicted for the clarithromycin core.
  • alkynyl macrolides M4, M9, MlO, Mil and Ml 2 are depicted in the scheme below.
  • Alkynyl macrolide M9 is prepared from the removal of the cladinose sugar of alkynyl macrolide M3 under acidic conditions.
  • Alkynyl macrolide MlO is made by the acetylation of macrolide M9.
  • Macrolide M4 is made by the oxidation of the hydroxyl group of macrolide MlO.
  • Alkynyl macrolides Mil and Ml 2 are made by converting a keto group of alkynyl macrolide M4 to the desired oximes.
  • the oxime functionality of alkynyl macrolides of precursors with substituted oxime functionality at the 9-position of the macrocyclic ring were prepared from alkyne M3 and as shown below.
  • alkynyl macrolide M9 (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3 x 50 mL), dried (anhydrous Na 2 SO 4 ), and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.07Og (78%) of the alkynyl macrolide M4 (also commonly referred to as a ketolide).
  • Alkynyl macrolide Ml 2 was synthesized from alkynyl macrolide M4 and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of alkynyl macrolide Mil. Data for M12: MS (ESI) m/e 710.6 (M+H) + .
  • Alkynyl macrolides M13, M16, and M17 are also synthesized from alkynyl macrolide M4 .
  • Alkynyl macrolide Ml 8 is synthesized from alkynyl macrolide Ml 7. The syntheses are outlined in the following reaction scheme.
  • Alkynyl macrolide Ml 3 was synthesized from alkynyl macrolide M4 and N-[I- dimethtylaminoethyl]-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M13: MS (ESI) m/e 726.5 (M+H) + .
  • Alkynyl macrolide Ml 6 was synthesized from alkyne M4 and N-Piperidin-4-yl- hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M16: MS (ESI) m/e 724.6 (M+H) + .
  • Alkynyl macrolide Ml 7 was synthesized from alkyne M4 and cis-4- aminocylcohexyl-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M17: MS (ESI) m/e 738.7 (MH-H) + .
  • alkynyl macrolide Ml 7 (20 mg, 0.02 mmol) in CHCl 3 (0.2 mL) was added formaldehyde (5 mg of 37% aqueous solution, 0.06 mmol) and formic acid (6 mg, 0.12 mmol). The mixture was heated at 50 0 C in a sealed tube for 12h. The reaction mixture was partitioned between aqueous NaHCO 3 (10 mL) and chloroform (10 mL) the organic fraction was dried on K 2 CO 3 , filtered and concentrated to give alkynyl macrolide Ml 8 as a white solid (18 mg). Data for M18: MS (ESI) m/e 766.7 (M+H) + .
  • Telithromycin was selectively N-demethylated and then alkylated with the tosylate of l-butyn-4-ol as described for azithromycin, erythromycin and clarithromycin above.
  • telithromycin 29 3'-iV-Desmethyl telithromycin 29
  • ⁇ IS ⁇ -iodosuccinimide
  • Protocol A A mixture of amine 30 (0.66 g, 0.83 mmol) and tosylate 11 (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 90 0 C for 5 days. The solvent was evaporated; the residue was dissolved in IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH 2 Cl 2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension.
  • Protocol B A mixture of amine 30 (0.66 g, 0.83 mmol), and tosylate 11 (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 0 C within 10 min and maintained at 90 0 C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH 2 Cl 2 (30 mL) was added and the two layers were separated.
  • Desmethyl telithromycin 30 was treated according to the procedures of US Patent No. 6,124,269 to afford the 2-fluoro amine 30a. This was then alkylated with the tosylate of 1- butyn-4-ol under the conditions for making Ml 5 to afford the fluorinated alkynyl macrolide M19. The reactions are outlined in the following scheme.
  • Alkynyl macrolides M21, M22, and M23 are prepared according to the following reaction scheme from alkynyl macrolide M20.
  • Alkynyl macrolide M20 is in turn made from alkynyl macrolide M14.
  • Alkynyl macrolide M27 is made from alkynyl macrolide M23 by reduction of the oxime to the imine followed by acetylation of the compound, which is then oxidized to give the bridged ketone. The cladinose sugar is then hydrolyzed by treatment with dilute hydrochloric acid. Synthesis of Alkynyl Macrolide M28
  • Alkynyl macrolide M28 is made by refluxing alkynyl macrolide M27 with the following hydroxyl amine compound in methanol.
  • Alkynyl macrolides M6, M7, and M8 are made from M26 (using a procedure analogous to that for making M2, in which the hydrazine is replaced with methyl amine, ammonium hydroxide, and ethanol amine respectively.
  • Alkynyl macrolides such as M29, M30, M31, and M32 are made from M26 using the following general procedure and the corresponding diamino compound.
  • M29 to a solution of compound M26 (6.25g, 6.6 mmol) in CH 3 CN
  • azides compounds used in preparing the compounds of the present invention can be readily synthesized by methods known from the literature. Exemplary azide syntheses are presented below. The remaining azides can be synthesized in analogous fashion from appropriate commercial starting materials. When possible, azides were produced from the corresponding substituted alkyl bromides by direct displacement with azide ion. When the required alkyl bromides were not readily available, the compounds were derived from substituted alkanols: to accomplish this, the alcohols were first activated as their sulfonyl ester derivatives and then substituted with azide ion.
  • azides were synthesized from the corresponding carboxylic acids by reduction with borohydride to the corresponding alcohols. The resulting alkanols were then treated as above to yield the azides. Finally, some azides of were synthesized from the corresponding substituted alkyl amines by reaction with triflic azide. In a few cases, azides were synthesized by modification of other azides that had been synthesized according to the methodologies above. The following are exemplary schemes for preparing azides.
  • Florfenicol amine Florfenicol azide A solution of florfenicol (0.090 g, 0.25 mmol) in acetic acid (3.0 mL) was treated with sulfuric acid (10%, 15 mL) and heated to 110 °C for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3 x 30 mL), dried (Na 2 SO 4 ), and evaporated to provide florfenicol amine (65 mg, 0.25 mmol) as a yellow oil.
  • Triflic azide solution (3.5 mmol dissolved in 7 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773) was added and the mixture was stirred at rt for 14 h.
  • the reaction mixture was diluted with dichloromethane (30 mL) washed with saturated NaHCO 3 , and with brine.
  • the organic extract was dried, filtered and concentrated to give the azide compound as a white solid (150 mg)
  • the foregoing azide compound is useful for preparing a wide variety of macrolide compounds of the present invention.
  • the free nitro functional group in the macrolide compound can be later transformed to an azide via an amino group. This azide can be used for further cyclization reactions.
  • the fluoro azide compound was prepared from the azide compound as shown.
  • the organic azide compounds used in the synthesis of the compounds of the present invention are generally prepared from the iodo compound 2 or the boronic acid ester compound 3.
  • the iodo or boronic acid functional groups provide a means for preparing a wide range of compounds using methods available to one skilled in the art.
  • the iodo compound 2 is prepared according to the following scheme from commercially available (lR,2R)-(-)-2-amino-l-(4-nitrophenyl)-l,3-propanediol.
  • the boronic acid ester compound 3 is prepared from the iodo compound 2.
  • R a , R b , R c , and R d represent various alkyl, substituted alkyl, aryl, and substituted aryl groups.
  • R a , R b , R c , and R a represent various alkyl, substitued alky!, aryl, substituted aryl, etc.
  • the compounds of the present invention were tested for antimicrobial activity. These data are presented in Table 3. The compounds were run against Streptococcus pneumoniae (wild type strain 02J1016) and Streptococcus pyogenes (wild type strain SS1542) using a standard microdilution assay to determine minimum inhibitory concentrations (MICs). The data is presented whereby a "+” indicates that the compound has an MIC value of 16 micrograms/ml or less and a "-" indicates that the compound has an MIC value greater than 16 micrograms/ml. A "N/A" means that data is unavailable.
  • the compounds can be assessed against other bacterial organisms and that the presentation of data for activity against Streptococcus pneumoniae and Streptococcus pyogenes is for illustrative purposes and in no way is intended to limit the scope of the present invention.
  • the compounds of the present invention can be assayed against a range of other microorganisms depending upon the performance activity desired to be gathered.
  • the "+", “-”, and “N/A" representation and the selection of a cutoff value of 16 micrograms/ml is also illustrative and in no way is intended to limit the scope of the present invention.
  • a "-" is not meant to indicate that the compound necessarily lacks activity or utility, but rather that its MIC value against the indicated microorganism is greater than 16 micrograms/ml.

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Abstract

La présente invention concerne des composés macrolides contenant un oxime et d'autres fonctions associées, utiles comme agents thérapeutiques. En particulier, ces composés sont utiles comme agents anti-infectieux, anti-prolifération, anti-inflammatoires et procinétiques.
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CN108727445B (zh) * 2018-06-29 2021-06-11 宜昌东阳光生化制药有限公司 一种阿奇霉素杂质f的合成方法

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