WO2008106204A1 - Composés macrolides et procédés de fabrication et d'utilisation de ceux-ci - Google Patents

Composés macrolides et procédés de fabrication et d'utilisation de ceux-ci Download PDF

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Publication number
WO2008106204A1
WO2008106204A1 PCT/US2008/002658 US2008002658W WO2008106204A1 WO 2008106204 A1 WO2008106204 A1 WO 2008106204A1 US 2008002658 W US2008002658 W US 2008002658W WO 2008106204 A1 WO2008106204 A1 WO 2008106204A1
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alkyl
unsaturated
group
saturated
optionally
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PCT/US2008/002658
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English (en)
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Shili Chen
Erin M. Duffy
Ashoke Bhattacharjee
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Rib-X-Pharmaceuticals, Inc.
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Publication of WO2008106204A1 publication Critical patent/WO2008106204A1/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, antiproliferative, anti-inflammatory, anti-diarrheal, and prokinetic agents. More particularly, the invention relates to a family of macrocyclic compounds having an amide moiety that are useful as such agents.
  • 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-viral agents, anti-diarrheal, and chemotherapeutic agents.
  • the present invention also provides compounds useful as anti- inflammatory 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 amide containing macrolide compounds having the structure:
  • variables A, B, D, E, G, T, R 1 , R 2 , R 3 , R, a, b, c, d, and 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 a disease state or condition caused or mediated by a nonsense or missense mutation(s).
  • 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. Accordingly, the compounds or the formulations can be administered, for example, via oral, parenteral, otic, ophthalmic, nasal, 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 generally contain an amide or a similar chemical moiety.
  • the compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, anti-parasitic, anti -diarrheal 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. Further, 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 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.
  • 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.
  • any variable e.g., R 2
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • 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.
  • nitrogen atoms in the compounds of the present invention can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of the present invention.
  • an oxidizing agent e.g., MCPBA and/or hydrogen peroxides
  • shown and claimed nitrogens are considered to cover both the shown nitrogen and its N-oxide ( ⁇ — >O) derivative, as appropriate.
  • anomeric carbon means the acetal carbon of a glycoside.
  • 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.
  • C 1 . e alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkyl groups.
  • C 1-8 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 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.
  • C 2-6 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , and Ce alkenyl groups.
  • C 2-8 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 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.
  • C 2-6 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkynyl groups.
  • C 2-8 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 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 -CH 2 CH 2 -, i.e., a C 2 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, " C 1-6 alkyl-
  • R is intended to represent a univalent C 1-6 alkyl group substituted with a R group, and "O-
  • C 1-6 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.
  • C 3 .8 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 cycloalkyl groups.
  • 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 include, but are not limited to, trifiuoromethyl, 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.
  • C 1 _6 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups.
  • C 1 -8 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 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 a sulfur bridge.
  • C 1 -6 alkylthio is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkylthio groups.
  • C 1 _8 alkylthio is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 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.
  • 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.
  • the substituents recited for the ring can also be present on the bridge.
  • Spiro and fused rings are also included.
  • 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.
  • bicyclic heterocyclic aromatic rings only one of the two rings needs to be aromatic (e.g., 2,3- dihydroindole), though both can be (e.g., quinoline).
  • 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).
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]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 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 (b) 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 the 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.
  • mammal refers to human and non-human patients.
  • 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-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.
  • 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. 2.
  • the invention relates to a compound having the structure:
  • a and B are selected such that,
  • T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom; each R is independently selected from (a) H, (b) C 1-6 alkyl, (c) -OH, (d) -0-(C 1-6 alkyl), (e) halogen, (f) -NH 2 , (g) -NH(C 1-6 alkyl), (h) -N(C 1-6 alkyl) 2, (i) -(C 1 -C 6 )alkylaryl, (j) -(C 2 -C 6 )alkenyl, (k) -(C 1 -C 6 )alkyl(OH)(C 1 -C 6 )alkyl, (1) -CH 2 F, (m) -CF 3 , (n) -(C 1 - C 6 )alkyl(OH), and (o) -S(O) p (CrC 6 alkyl)-;
  • 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 , (j) -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 1 ' or R 1 la ; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) - OR 9 , (dd) -SH, (ee) -S(O) p R 9 , (f ⁇ ) halogen, (gg) -CN, (hh)-N 3 , (
  • (bbb) or (ccc) optionally contains one or more carbonyl groups, and wherein each (bbb) or (ccc) optionally is substituted with one or more R 11 or R 11a ; wherein each (ddd), (eee), or (fff) is optionally are substituted with one or more R 14 groups;
  • Z is selected from (a) a single bond, (b) -C 1-6 alkyl-, (c) -C 2-6 alkenyl-, (d) -C 2-6 alkynyl-, (e) -O-, (f) -NR 4 -, (g) -S(O) P -, (h) - C(O)-, (i) -C(O)O-, O) -OC(O)- (k) -OC(O)O-, (1) - C(O)NR 4 -, (m) -NR 4 CO-, (n) -NR 4 C(O)NR
  • R 7 (a) R 7 , (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 3-12 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 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 (b)-(f) immediately above optionally is substituted with one or more R 7 groups; R 6 , at each occurrence, independently is selected from:
  • NR 6 R 6 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R 6 groups are attached wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R 6 groups are bonded, with one or more moieties selected from O, S(O) P , N, and NR 8 ; alternatively, CR 6 R 6 forms a carbonyl group; R 7 , at each occurrence, is selected from:
  • C 2-6 alkynyl group (ef) a C 3-12 saturated, unsaturated, or aromatic carbocycle, (fg) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (gh) -C(O)-C 1-6 alkyl, (hi) -C(O)-C 2-6 alkenyl, (jj) -C(O)-C 2-6 alkynyl, (jk) -C(O)-C 3-12 saturated, unsaturated, or aromatic carbocycle, and
  • R 10 (a) R 10 , (b) a C,_ 6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 3-12 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, wherein any of (b)-(f) optionally is substituted with one or more R 10 groups; R 10 , at each occurrence, independently is selected from:
  • NR 6 S(O)pR 6 (u) -S(O)PNR 6 R 6 , (v) -NR 6 S(O)pNR 6 R 6 , (w) a C,_ 6 alkyl group, (x) a C 2-6 alkenyl group, (y) a C 2-6 alkynyl group, (z) a C 3-12 saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) optionally is substituted with one or more moieties selected from R 6 , F, Cl, Br, I, CN, NO 2 , -OR 6 , -NH 2 , - NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , a C 1-6 alkoxy group, a C 1-6 alkylthio group, and
  • each R 13 is independently selected from (a) -C 1-6 alkyl and (b) -0-(C 1-6 alkyl);
  • R 14 at each occurrence is independently selected from:
  • the macrolide, "T” is defined to include various 14- and 15- membered ring systems, which can contain one or more heteroatoms. Also, as defined herein, the macrolide, “T” is connected via a macrocyclic ring carbon atom, which means that the connection or bond is made to a carbon atom on the 14- or 15-membered ring of the macrolide moiety.
  • the macrolide can include further substituents, including ring substituents.
  • the substituent designated as R 103 can in certain embodiments be a sugar moiety, e.g.
  • a cladinose sugar or the substituents such as R 104 and R 105 are taken together in certain embodiments to form a bridged bicyclic ring system with the macrolide ring, or the substituents R 105 and R 106 , are taken together in certain embodiments to form a fused bicyclic ring system with the macrolide ring, or the substituents or components M, R 105 , and R 106 are taken together to form a fused tricyclic ring system with the macrolide ring, etc.
  • "T" is depicted as being connected to a 6- membered ring, for example in certain embodiments a desosamine sugar ring.
  • the invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or pro-drug thereof, wherein G is selected from G1-G50:
  • A, B, D, E, G, T, R, R 1 , R 2 , R 3 , a, b, c, d, and e are as described above.
  • A, B, D, E, G, T, R, R 1 , R 2 , R 3 , a, b, c, d, and e are as described above.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a is 2, 3, or 4. In other embodiments the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a is 2. In other embodiments the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a is 3. In other embodiments the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a is 4. In other embodiments 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 D, E, G, T, R, R 1 , R 2 , R 3 , c, d, and e are as described above.
  • 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. 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 C 1-6 alkyl.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 3 is methyl. In other embodiments 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) an aryl group, (b) a heteroaryl group, (c) a biaryl group, and (d) a fused bicyclic or tricyclic unsaturated or aromatic ring system optionally containing one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (a)-(d) 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) an aryl group, (b) a heteroaryl group, (c) a biaryl group, and (d) a fused bicyclic or tricyclic unsaturated or aromatic ring system optionally containing one or more carbonyl groups and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (a)-(d) optionally is substituted with one or more R 11 groups, and Z is selected from (aa) a single bond, (bb) -O-, (cc) -NR 4 -, (dd) -C(O)-, (ee) -C(S)
  • 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, N-oxide, or prodrug thereof, wherein G is: where B", Z, and R 1 ' are as described above.
  • 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 11 is selected from H and F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 11 is H. In other embodiments 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 F', where F' 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, (f) H, (g) -OH (h) -SH, (i) F, G) Cl, (k) Br, (1) I, (m) -CF 3 , (n) -CN, (o) -N 3 (p) -NO 2 , (q) -NR 6 (CR 6 R 6 ) t R 9 , (r) -OR 9 , (s) -S(CR 6 R
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein F' 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, (f) -CF 3 ,
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein F' 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, and (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.
  • F' 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, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein F' is selected from (a) - ⁇ R 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 ,
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug, thereof, wherein T is: R 134 R 109
  • 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
  • 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 3-12 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 3-12 membered carbocyclic or heterocyclic ring, wherein said 3-12 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 carbons to which they are attached form a 5 or 6 membered fused carbocyclic or heterocyclic ring, wherein said fused ring can be optionally substituted with one or more R 114 groups;
  • R 104 is selected from:
  • K is selected from:
  • R 135 and R 136 are selected from (a) hydrogen, (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 oxygen, nitrogen, or sulfur atoms, (g) F, (h) Br, (i) I, (j) OH, and (k) -N 3 , wherein (b) through (f) are optionally substituted with one or more R 117 ; or alternatively, R 135 and R 136 are taken together to form
  • R 126 is -OR 114 , --NR 114 or R 114 ; alternatively, R 104 and R 105 , taken together with the atoms to which they are bonded, form:
  • R 149 is selected from:
  • OC(O)R 114 (j) -OC(O)OR 114 , (k) -OC(O)NR 114 R 114 , (1) -0-C 1-6 alkyl, (m) -OC(O)-C 1-6 alkyl, (n) -OC(O)O-C 1-6 alkyl, (o) -OC(O)NR 114 -C 1-6 alkyl, (p) C 1-6 alkyl, (q) C 2-6 alkenyl, and (r) C 2-6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R 115 groups; ii) R 150 is H, C 1-6 alkyl, or F; ii) alternately, R 149 and R 150 can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R 149 and R 150 can be taken together to form the group -O(CR 116 R 116 ) u
  • R 106 is selected from:
  • U is selected from (a) -(C 1-4 -alkyl)- and (b)-(C 2-4 -alkenyl)-, wherein (a) and (b) are optionally further substituted with one or more R 117 ; alternatively, M and R 105 are taken together with the atoms to which they are attached to form:
  • R , 107 is selected from
  • 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 117 (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 117 at each occurrence, is selected from:
  • R 119 groups alternatively, two R 117 groups can form -O(CH 2 ) U O-; R 118 is selected from:
  • R 119 at each occurrence, independently is selected from:
  • R 120 (a) R 120 , (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) C 3-12 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:
  • (V) (CR 116 R 116 ( 1 NR 116 S(O) P NR 116 R 116 , (w) C 1-6 alkyl, (x) C 2-6 alkenyl, (y) C 2-6 alkynyl, (z) (CR 116 R 116 ) r -C 3-12 saturated, unsaturated, or aromatic carbocycle, and (aa) (CR 116 R 116 ) r -3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) optionally is substituted with one or more moieties selected from R 116 , F, Cl, Br, I, CN, NO 2 , -OR 116 , -NH 2 , - NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 acyl; R
  • 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) C 1-6 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, C 1-6 alkyl, -
  • 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 -
  • R 137 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 group;
  • R 139 is H, C 1-6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the foregoing
  • R 139 groups are optionally substituted by 1, 2, or 3 substituents independently selected from halo and -OR ; 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 1-6 alkyl, C 1-6 alkoxy, -(CH 2 )V(C 6 -C 10 aryl), 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, cyano, nitro, trifluoromethyl, azido, -
  • 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 -C 10 aryl), and -(CH 2 ) v (5-10 membered heteroaryl); each R 146 and R 147 is independently H, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) v (C 6-10 aryl), or -(CH 2 ) v (5-10 membered heteroaryl); R 14 is C 1-6
  • 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 Tl through T93:
  • 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 an intermediate used in the preparation of the compounds of the present invention.
  • the present invention relates to a composition
  • a composition comprising a compound of the present 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.
  • 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.
  • the present invention relates to a compound of the invention in the manufacture of a medicament for treating a microbial infection in a mammal.
  • 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 present invention, 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) including uncomplicated skin and soft tissue infections (uSSTI)s and 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 tubercul
  • the present invention relates to a method of treating a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention.
  • the present invention relates to a method of treating a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention.
  • the present invention relates to a method of treating a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention.
  • the present invention relates to a method of treating a viral infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention.
  • the present invention relates to a method of treating an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention.
  • the present invention relates to a method of treating a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound of the invention.
  • 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 to suppress expression of the nonsense or missense mutation.
  • the present invention relates to a method or use wherein the compound of the invention is administered orally, parentally, optically, opthalmically, nasally, or topically. In other embodiments, the present invention relates to a method of synthesizing a compound of the invention. In other embodiments, the present invention relates to a medical device containing a compound of the invention.
  • the present invention relates to a medical device containing a compound of the invention, wherein the device is a stent.
  • the compounds of the present invention can include a wide range of structures. Examples of such macrolide 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 Pharmaceuticals, Inc.; PCT Application No. WO 2007/025098, published March 1, 2007, to Rib-X Pharmaceuticals, Inc. ; PCT Application No. WO 2007/ 025089, published March 1 , 2007, to Rib-X Pharmaceuticals, Inc.; PCT application No.
  • the invention provides methods for making the compounds of the invention.
  • the following schemes depict exemplary chemistries available for synthesizing the compounds of the invention.
  • Scheme 1 illustrates the typical general synthesis of the macrolide compounds of the present invention.
  • the synthesis starts with a known macrolide core component such as, for example, erythromycin, azithromycin, clarithromycin, roxithromycin, telithromycin, etc.
  • the macrolide core component is then converted to the N-desmethyl macrolide compound.
  • erythromycin can be converted to the N-desmethyl compound as described in the scientific and patent literature. See 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; Stenmark et al. (2000) J. Org. Chem. 65: 3875).
  • N-desmethyl compounds can be further modified to provide yet further N-desmethyl compounds for use herein.
  • the N-desmethyl macrolide compound is alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, etc.) to yield an N-alkyl ester compound.
  • an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, etc.)
  • a suitable leaving group e.g., halogen, tosylate, mesylate, etc.
  • terminal halogenated esters such as terminal bromo esters can be used.
  • the N-alkyl ester compounds are then reacted with the desired amine to yield the final desired macrolide compound.
  • the N-alkyl ester compound is first converted to a N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the desired amino compound to couple the two components via an este
  • 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, NJ.) 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 ran thick "hydrogel” composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film.
  • plasmon resonance is enhanced.
  • the resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance.
  • the BIAcore By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the frequencies that are depleted, 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) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive real-time measurement of the molecular interactions without the need to label either component.
  • 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.
  • one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest).
  • 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. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC 50 S and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions. (3) Protein Synthesis.
  • 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. Use of such a panel of organisms permits the determination of structure-activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms.
  • MICs Minimum inhibitory concentrations are determined by the microdilution method, typically in a final volume of 100 microliters, according to protocols outlined by The Clinical and Laboratory Standards Institute [CLSI; formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. See 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. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition. CLSI Document M7-A7 [ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087-1898 USA, 2006.).
  • the antimicrobial and other drug properties of the compounds can further be evaluated in various in vivo mammalian assays, such as a mouse or rat peritonitis infectious models, skin and soft tissue models (often referred to as the thigh model), or a mouse pneumonia model.
  • a mouse or rat peritonitis infectious models skin and soft tissue models (often referred to as the thigh model), or a mouse pneumonia model.
  • septicemia or organ infection models known to those skilled in the art.
  • These efficacy models can be used as part of the evaluation process and can be used as a guide of potential efficacy in humans.
  • Endpoints can vary from reduction in bacterial burden to lethality. For the latter endpoint, results are often expressed as a PD 50 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, parasitic diseases, diarrhea, 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.
  • 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. In general, some formulations 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.
  • routes of administration include oral or parenteral, for example, intravenous, intradermal, inhalation, nasal, otic, ophthalmic, 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
  • 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.
  • 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.
  • tissue-coating solutions such as pectin-containing formulations can be used.
  • 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.
  • self-propelling solution and spray 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.
  • Systemic administration also can be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • 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 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 is to 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, either by 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. and Piva, T., "Drug Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249; Morice, M. C, "A New Era in the Treatment of Coronary Disease?" European Heart Journal, 2003, 24, 209-211 ; and Toutouzas, K. et al., "Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings," Z.
  • 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 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. These mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function.
  • Examples of disease 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).
  • hemophilia factor VIII gene
  • NFl and NF2 genes neurofibromatosis
  • retinitis pigmentosa human USH2A gene
  • bullous skin diseases like
  • 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
  • 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
  • Chroxography or “purified by silica gel chromatography” refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise noted.
  • 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. PCT/US2006/33645, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; PCT application No. PCT/US2006/33170, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; and PCT application No. PCT/US2006/33157, to Rib-X Pharmaceuticals, Inc. filed August 24, 2006, which are incorporated by reference herein in their entirety.
  • the full structure for compound 200 was drawn out with the azithromycin macrolide core
  • the full structure for compound 344 was drawn out with the clarithromycin macrolide core.
  • the full structures are drawn out, because the macrolide ring is a "des-cladinose" clarithromcyin (i.e., a clarithromycin macrolide ring in which the cladinose sugar substituent nas been removed leaving a free hydroxyl group).
  • variable G is further selected from -B' or -B '-Z-B.
  • Tables 1 A-II 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.
  • variable G is exemplary compound of the invention showing variable G:
  • variable G is B'-Z-B", where B' is phenyl:
  • variable G is B'-Z-B", where B' is phenyl and -Z-B" is the first chemical moiety or fragment from 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'- N-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 °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 OH 18:1 :0.05 to 10:1 :0.05 to provide the 3'-N-desmethyl azithromycin (0.41 g, 55%).
  • Example 3 Synthesis of 3'- N-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 -6 0 °C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 °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 O°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-desemthyl 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.
  • the N-desmethyl macrolide compound is alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.) to yield an N-alkyl ester compound.
  • an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.)
  • a suitable leaving group e.g., halogen, tosylate, mesylate, bromide, etc.
  • terminally halogenated esters such as terminal bromo esters can be used.
  • the N-alkyl ester compounds are then reacted with the desired amine to yield the final desired macrolide compound.
  • the N-alkyl ester compound is first converted to a N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction
  • the 3'-N-alkyl ester compounds are then reacted with the appropriate amine to yield the final macrolide compound.
  • the 3'-N-alkyl ester compound is first converted to a 3'-N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the appropriate amino compound to couple the two components via an ester linkage.
  • the following reaction scheme provides a synthesis that is generally applicable to the compounds of the present invention wherein the macrolide core is derived from azithromycin. Analogous reactions can be with other macrolide cores to prepare compounds of the present invention.
  • Example 8 Synthesis of amino compound for compound 222 The following exemplifies the reaction scheme for the synthesis of the amino compound for compound 222. reflux, 4h
  • reaction mixture was directly purified on preparative TLC to afford 0.35g (0.95 mmol, 99% yield) of desired Methanesulfonic acid 4-[4-(4-trimethylsilanyl-[l,2,3]triazol-l-yl)-phenyl]-butyl ester, which was again treated with 0.117g (1.8 mmol, 2 eq.) OfNaN 3 in DMF and stirred overnight.
  • the reaction was purified on prep-TLC to afford 0.28 g (0.89 mmol, 94% yield) of l-[4-(4-Azido- butyl)-phenyl]-4-trimethylsilanyl-lH-[l,2,3] triazole.
  • reaction mixture was directly purified on preparative TLC to afford 0.522g (1.5 mmol, 99% yield) of desired Methanesulfonic acid 3-[4-(4-trimethylsilanyl-[ 1 ,2,3]triazol- 1 -yl)-phenyl] -propyl ester, which was again treated with 0.195g (3 mmol, 2 eq.) OfNaN 3 in DMF and stirred overnight.
  • the reaction was purified on prep-TLC to afford 0.452 g (1.5mmol, 99% yield) of l-[4-(3- Azido-propyl)-phenyl]-4-trimethylsilanyl-lH-[l,2,3]triazole.
  • Example 11 Synthesis of amino compound for compound 240 The following exemplifies the reaction scheme for the synthesis of the amino compound for compound 240.
  • Methanesulfonic acid 4-(4-iodo-phenyl)-butyl ester was redissolved in DMF, followed by adding 0.71 g (11 mmol, 2.0 eq.) OfNaN 3 , and stirred for 6 hours. Aqueous workup and column purification to afford 1.44g (4.8 mmol, 88.8% yield) desired l-(4-Azido- butyl)-4-iodo-benzene as yellowish oil.
  • Example 13-17 Synthesis of compounds 222, 226, 236, 240, and 243 from 3'-N- propylcarboxylic acid of azithromycin and the corresponding amino compound.
  • Example 16 Synthesis of compound 240 0.116 g (0.5 mmol, 1 eq) of 4-(4-Morpholin-4-yl-phenyl)-butylamine was added to 10 ml OfCH 2 Cl 2 solution of 0.405 g (0.5 mmol, 1 eq.) of azithromycin acid and 0.27 ml (1.5 mmol, 3 eq.) of Hunig's base. The solution was cooled down to 0 °C in an ice bath before 0.09 g (0.5 mmol, 1. eq) of EDCI and 0.07 g (0.5 mmol, 1.0 eq) of HOBt were added. The resulting solution was stirred at RT for about 4-6 hrs.
  • Nonlimiting examples of amine compounds useful in the synthesis of the compounds of the present invention are readily made using generally known chemistries. Exemplary amino compounds are shown below in Table 2.
  • 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

L'invention concerne des composés macrocycliques, contenant un amide, utiles en tant qu'agents thérapeutiques. Plus particulièrement, ces composés sont utiles en tant qu'agents anti-infectieux, anti-prolifération, anti-inflammatoires et procinétiques.
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