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WO2007079173A2 - Novel 2-heteroaryloxy-phenol derivatives as antibacterial agents - Google Patents

Novel 2-heteroaryloxy-phenol derivatives as antibacterial agents Download PDF

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Publication number
WO2007079173A2
WO2007079173A2 PCT/US2006/049473 US2006049473W WO2007079173A2 WO 2007079173 A2 WO2007079173 A2 WO 2007079173A2 US 2006049473 W US2006049473 W US 2006049473W WO 2007079173 A2 WO2007079173 A2 WO 2007079173A2
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Prior art keywords
substituted
methyl
phenol
yloxy
compound
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French (fr)
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WO2007079173A3 (en
Inventor
Liren Huang
Joanna Clancy
Christopher Taylor
Weitao Pan
Alenka Tomazic
W. James Jackson
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Emergent Biosolutions Inc
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Emergent Biosolutions Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms

Definitions

  • This invention relates to novel 2-heteroaryloxyphenol derivatives and methods for their preparation.
  • the compounds are useful antimicrobial agents, effective against a number of human and bioterrorism pathogens, including staphylococci, streptococci and enterococci as well as bacillus anthracis and Bacillus cereus.
  • JP 51121516 reveals the synthesis and use of 2- (pyridin-2- yloxy) -phenols as represented by below formula A, as nonmedical germicides.
  • Litvak et al has reported the synthesis of 2- (pyridin-4-yloxy) -phenols as exemplified by below formula B (Chemoshere, 43, 493, 2001), but no biological activities were reported.
  • US 4427437 describes the synthesis and usefulness of 2- (pyrimidin-2-yl)oxyphenols, such as below compounds C and D, as herbicides.
  • US 4142048 discloses the production of 2- ( [1,3, 5] triazin-2-yloxy) -phenols as exemplified by below formula E, as cross-linking agents and UV absorbers.
  • SUBSTITUTE SHEET (RLiLE 26) Due to ever increasing antibiotic resistance, new classes of antibacterial agents having a core structure different from clinical antibiotics have become very important to the treatment of bacterial infections (C&EN, March 6, 41, 2000) .
  • the present invention is certain novel 2-heteroaryloxyphenol derivatives useful as antibacterial agents, and methods for their preparation.
  • the present invention provides compounds of structural formula I or pharmaceutically acceptable salts thereof .
  • B-ring is a heteroaryl group of 5 - 8 atoms with 1 - 4 heteroatoms chosen from nitrogen, oxygen, or sulfur or phenyl ring .
  • X and Y are each independently chosen from halogen, CN, OH, NH 2 , NO 2 , CO 2 H, CO 2 Me, CO 2 Et, CHO, CH (NOMe) , C 1 - C 4 alkyl and cycloalkyl , and CF 3 ; m and n are 0 , 1, 2 and 3 . More preferred compounds of the present invention are those of formula I wherein B-ring is a heteroaryl group chosen from
  • X and Y are each independently chosen from P, Cl, Br, I / CN, OH 1 NH 2 , NO 2 , CO 2 H, CO 2 Me, CO 2 Et, CHO, CH(NOMe), methyl, ethyl, n-proyl, n ⁇ butyl, cyclopropyl, cyclopropylmethyl and CF 3 ; m and n are 0, 1, 2 and 3.
  • the present invention provides the compound of formula I wherein
  • B-ring is a heteroaryl group chosen from (a)-(i) and (ii), (b)-(i) and (ii), (C), (d), (e)-(i) and (ii) , (f) - (i) , (g) , (h)-(i), (ii) and (iii), (i)-(i), (ii) and (iv) , (j)-(i), (iii) and (iv) , (k) , (J)- (i) and (ii) , (n)-(i) and (ii) .
  • X and Y are each independently chosen from F, Cl, Br, CN, OH, NH 2 , NO 2 , CHO, CH(NOMe), methyl, ethyl, cyclopropyl, cyclopropylraethyl and CF 3 ; m and n are 0, 1, 2 and 3.
  • B-ring is a heteroaryl group chosen from (a)-(i) and (iii) , (b) - (i)and (ii), (c), (d), (e)- ⁇ i), (f)-(i), (g) , (h)-(i) and (n) - (i) and (ii) .
  • the present invention includes pharmaceutical compositions which comprise an antibacterially effective amount of compounds of structural formula I or pharmaceutically acceptable salts thereof with pharmaceutically acceptable carriers.
  • the compounds of the invention are named according to the IUPAC or CAS nomenclature system.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci - Cj indicates a moiety of the integer "i” to the integer "j" carbon atoms, inclusive.
  • Cl - C4 alkyl and cycloalkyl refers to alkyls and cycloalkyls of one to four carbon atoms, inclusive, or methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl and its isomeric forms, and cyclobutyl, cyclopropylmethyl and methylcyclopropyl , Hydroxyl protecting groups (PG) are benzyl, 4- methoxybenzyl, methyl, benzyl, 2,2,2-trichloroethyl, t- butyldimethylsilyl, trimethylsilyl, fc-butyl, allyl, or as described in Greene, Theodora W., Protective Groups in Organic Synthesis, 1999, John Wiley & Sons Inc.; Chapter 3.
  • heterocycle , “heterocyclic group”, or heterocyclic” are used interchangeably herein and includes monocyclic, bicyclic ring or bridged ring system having from 4 -10 atoms, 1 -4 of which are selected from oxygen, sulfur and nitrogen.
  • Heterocyclic group includes non-aromatic groups such as morpholin-4-yl and 4-methyl-piperazin-l-yl, and heteroaryl groups such as thiophenyl and oxadiazolyl.
  • aryl in “heteroaryl” refers to aromaticity, a term known to those skilled in the art and defined in greater detail in “Advanced Organic Chemistry” , M, B. Smith and J, March, 5 th Ed., John Wiley & Sons, New York, N. Y. (2001).
  • B-ring of formula I is a heteroaryl group represented by the term "Heteroaryl” , wherein the waved line indicates the bond of attachment.
  • a bond pointing inside a ring such as -Y n indicates that the substituents are able to connect to any carbon and
  • the compounds of the present invention can exist in tautomeric forms, and all such tautomeric forms are included v ⁇ thin the scope of the present invention.
  • Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines .
  • metals used are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N' -dibenzylethyldiamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
  • Pharmaceutically acceptable acid addition salts are formed with organic or inorganic acids, Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, raethanesulfonic, and the like.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either mono or di, etc. salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized.
  • the compounds of the invention are capable of forming pharmaceutically acceptable prodrugs.
  • “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug in vivo when such prodrug is administered to a subject.
  • Prodrugs of a compound are prepared by modifying functional groups present in the compounds in such a way that the bonds are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include, but are not limited to, compounds wherein hydroxyl, amine, or sulfhydroxyl groups are bonded to any group that, when administered to a subject, cleave to form a free hydroxyl, amino, or sulfhydroxyl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, benzoate and phosphate ester derivatives of hydroxyl functional groups, especially the hydroxyl group on A-ring of formula I, and acetyl and benzoyl derivatives of amine functional groups in the compounds of the invention and the like.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms and the like are equivalent to the unsolvated forms for purposes of the invention.
  • the compounds are of course given by forms suitable for each administration route. For example, they are administered in drops, tablets or capsule form, by injection, inhalation, eye lotion, ointment, foams, suppository, etc. by topical, vaginal or rectal administration. Parenteral or topical administration is preferred.
  • the compounds of the invention are useful for the treatment of infections in hosts, especially mammals, including humans, in particular in humans and domesticated animals.
  • the compounds may be used, for example, for the treatment of infections of skin, mouth, the respiratory tract, the urinary/reproductive tract, and soft tissues and blood, especially in huraans.
  • diseases are those caused by or associated with infection by microorganisms including, but are not limited to, Streptococcus pyogenes, Staphylococcus aureus, methicillin resistant Staphylococcus aureus (“MRSA”), Staphylococcus epidermidis, Bacillus anthracis, Neisseria gonorrhoeae, Neisseria meningitides, Mycobacteria tuberculosis, vancomycin resistant Enterococcae (“VRE”), Helicobacter pylori, Chlamydia pneumoniae, Chlamydia trachomatis, Campylobacter jejuni, Propionibacterium acnes, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Enterococcus faecalis, Haemophilus influenzae, Escherichia coli, Corynebacterium diphtheria
  • compositions of the present invention employ the compounds of the invention and may include inert, pharmaceutically acceptable carriers that are either solid or liquid.
  • Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material,
  • the carrier is a finely divided solid which is an admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired
  • the powders and tablets preferably contain from S to about 70 percent and preferably 10 to about 60 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include compositions wherein the formulation of the active compound is with encapsulating material acting as carrier.
  • This provides a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is accordingly in association with it.
  • a carrier which is accordingly in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, glycerol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, eth
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e. natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well- known suspending agents .
  • An example, for instance, is water or water-propylene glycol solutions for parenteral injection.
  • Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc) .
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution,
  • Formulations of the present invention which are suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled
  • SUBSTITUTE SHEKT (RULE 26) delivery over time of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium, Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of the invention may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety- nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • SUBSTITUTE SHHET (RULE 26) amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compositions of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • topical, intravenous and subcutaneous doses of the compositions of this invention for a patient when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 0.1 to about 10 mg per kg per day.
  • Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of the compound of the invention.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub- doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • 2-heteroaryloxyphenols of the invention may be synthesized by a condensation reaction of a heteroaryl-OH derivative 1 with a 2-fluoro or 2- chloro-benzaldehyde derivative 2, followed by Baeyer- Villiger rearrangement promoted by 3-chloroper ⁇ xybenzoic
  • SUBS ' ITRJ I ⁇ SHEET (Rl ⁇ ,B 26) acid (tnCPBA) .
  • the conversion of 1 to intermediate 3 can be carried out in the presence of a base such as cesium carbonate, potassium carbonate and sodium hydride in a solvent like N,N-dimethylformamide (DMF), N, N- dimethylacetamide (DMA), and acetonitrile (CAN) etc. at a temperature between 20 to 110 0 C.
  • the conversion of 3 to corresponding formula I compounds is accomplished by the oxidation with mCPBA in presence of an acid such as trifluoroacetic acid (TFA) in dichloromethane (DCM) at room temperature.
  • TFA trifluoroacetic acid
  • the catalysts suitable for the reaction comprise Pd(OAc) 2 , Fd(dba) 2 , Cu 2 O, CuI, CuCl or (CuOTf) 2 1 C 6 H 6 etc. and the ligand is chosen from PPh 3 , 2, 2' -bis (diphenylphosphino) - 1,1' -binaphtyl (BINAP), 1,1'- bis (diphenylphosphino) ferrocene (DPPf), P(C-Bu) 3 , N,N- dimethylglycine, l-naphthoic acid or 2,2,e,6- tetramethylheptane-3, 5-dione and the like.
  • the base used in the reaction is Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , sodium or potassium (tert) -butoxide.
  • Solvents which may be used in the reactions include THF, 1,4-dioxane, toluene, N 1 N- dimethylacetamide (DMA), N,N-dimethylformamide (DMF), acetonitrile (ACN) and the like.
  • the cross-coupling reaction proceeds at 50 0 C - 150 °C, optionally with assistance of ultrasonic or microwave irradiation.
  • a heteroaryl halide preferably fluoride or chloride
  • a nitrogen atom such as 7
  • EWG electron withdrawing group
  • condensation of the heteroaryl halide with mono-protected catecol 5 proceeds through S N Ar mechanism under the same conditions as described in the conversion of 1 to 3, giving intermediates 8 and 10.
  • Deprotection of 8 and 10 gives corresponding hydroxyl free compounds of formula I.
  • Most commercial or literature mono-protected catecols 5 bear methyl, benzyl, or siIyI group as hydroxyl protection groups.
  • Such protection groups are easily removed from with acids, contact hydrogenation, BBr 3 , BI 3 , Mgl2/ NaSEt and tetrabutylammonium fluoride etc. in protic or aprotic solvents at ⁇ 78°C - 100 0 C.
  • Step 1 2- (S-Chloro-pyridin-3-yloxy) -benzaldehyde
  • a suspension of 2-fluorobenaldehyde (124 mg, 2.0 mrnol) , 5-chloropyridin-3-ol (262 mg, 2.0 tnmol) and cesium carbonate (800 mg, 2.4 tnmol) in anhydrous N,N- dimethylformamide (DMF) (5.0 mL) was stirred at 60 0 C for 2 days, poured into water (20 mL) and extracted with ether (2 x 30 mL) . The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in vacuum, giving the Example title compound (320 mg, 68%) as brownish powder which was employed in next step without further purification.
  • DMF N,N- dimethylformamide
  • Step 2 2- (5-Chloro-pyridin-3-yloxy) -phenol
  • 2- (B-chloro-pyridin-3-yloxy) - benzaldehyde 63 mg, 0.27 mmol
  • trifluoroacetic acid 0.2 T ⁇ IL
  • dichloromethane 1 mL
  • mCPBA 3-chloro- perbenzoic acid
  • Example title compound (28 mg, 52%) was obtained as a white solid.
  • This product was analyzed by 1 H-NMR (proton-nuclear magnetic resonance spectroscopy) .
  • the corresponding 1 H-NMR spectrum was consistent with the structure of the anticipated product.
  • Example title compound was synthesized by following the procedures described in Example l, with 2- chloro-pyridin-3-ol in replace of 5-chloro-3-pyridin-3-ol .
  • This product was analyzed by 1 H-NMR. The corresponding 1 H- NMR spectrum was consistent with the structure of the anticipated product.
  • Example title compound was synthesized by following the procedures described in Example 1, with pyridin ⁇ 3-ol in replace of 5-chloro-3-pyridin ⁇ 3-ol. This product was analyzed by 1 H-NMR. The corresponding 1 H-NMR spectrum was consistent with the structure of the anticipated product.
  • Step 1 2 ⁇ Chloro-5- (2-methoxy-4-methyl-phenoxy) - pyridine
  • Step 2 2- (6-Chloro-pyridin-3-yloxy) -5-methyl-phenol A solution of 2 ⁇ chloro ⁇ 5- (2-methoxy-4-methyl-phenoxy) - pyridine (30 mg, 0.120 mmol), benzyltri-t-butylammonium
  • Example title compound was synthesized by following the procedure described in Example 5 employing 3- iodo-pyridine in replace of 2-chloro-5-iodo-pyridine .
  • Step 1 2-Chloro-5- (4-chloro-2-methoxy-phenoxy) - pyridine
  • Example title compound was synthesized by- following the procedure described in Example 7 employing 4- fluoro-2-methoxyphenol in replace of 4- ⁇ hloro-2- methoxyphenol : M. P . : 121 - 123 0 C.
  • Example 9 2 - ⁇ 6-Chloro ⁇ pyrimidin-4-yloxy) - 5 -methyl - phenol
  • Step l 4-Chloro-6- (2-methoxy-4-methyl-phenoxy) ⁇ pyrimidine
  • Step 2 2 ⁇ (6-Chloro-pyrimidin-4-yloxy) -5-methyl-phenol To a solution of 4-chloro-6- (2-methoxy-4-methyl- phenoxy) -pyrimidine (650 mg, 2.593 mmol) in DCM (7 mL) ,
  • Example title compound 537 mg, 88 %) as white powder: M. P.: 90 - 93 0 C.
  • This product was analyzed by 1 H-NT-IR. The corresponding 1 H-NMR spectrum was consistent with the structure of the anticipated product.
  • Example title compound was obtained by the. same reactions described in Example 9, employing 4-fluoro-2- methoxyphenol in replace of 4-methyl-2-methoxyphenol. This product was analyzed by 1 H-NMR. The corresponding 1 H-NMR spectrum was consistent with the structure of the anticipated product .
  • Step 1 3-Chloro-6- (2-methoxy-4-methyl-phenoxy) - pyrid ' azine
  • Step 1 2- (2-Methoxy-4-methyl-phenoxy) -pyrazine
  • 2-chloro-pyrazine 500 mg, 4.28 mmol
  • 2-methoxy-4 -methyl-phenol 597 mg, 4,28 mmol
  • cesium carbonate 1.534 g, 4.708 mmol
  • the reaction mixture was poured into water, extracted with ether for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated.
  • Step 2 5 -Methyl-2- (pyrazin-2-yloxy) -phenol
  • 2- (2-methoxy-4-methyl-phenoxy) - pyrazine 500 mg, 2.312 mmol
  • DCM 5 mL
  • boron tribromide 0.656 mL, 6.936 mmol
  • Step 1 3- (4-Chloro-2-methoxy-phenoxy) -thiophene
  • Example title compound (20 mg, 71 % in the second step) was made by the same procedure as described in Example 13, using 4-methyl-2-methoxy-phenol to replace 4- chloro-2-methoxy-phenol.
  • Step 1 4- (2-Methoxy-4-methyl-phenoxy) -1, 3-dimethyl-5- nitro-IH-pyrazole
  • Step 1 Benzyl 5-fluor ⁇ -2- (3-methyl-4-nitro-phenoxy) - phenyl ether
  • Step 2 1- ⁇ 2- [5- (2-Benzyloxy-4-fluoro-phenoxy) -2- nitro-phenyl3 -vinyl ⁇ -pyrrolidine
  • Step 3 5-Fluoro-2- (IH-indol-5-yloxy) -phenol
  • a suspension of l- ⁇ 2- [5- (2-benzyloxy-4-fluor ⁇ phenoxy) -2-nitro-phenyl] -vinyl ⁇ -pyrrolidine (287mg, 0.66mmol), palladium 10% on activated carbon (SOrags) in 30% ethyl acetate/benzene was stirred under 1 atmosphere of hydrogen gas overnight. The mixture was filtered over celite and the residue was purified on a silica gel column using 25% ethyl acetate/hexanes as eluent, giving the Example title compound (219mg, 76%) as a light brown powder.
  • This product was analyzed by 1 H- NMR. The corresponding 1 H-NMR spectrum was consistent with the structure of the anticipated product .
  • Step 1 Benzyl 5-methyl-2 ⁇ (3-methyl-4-nitro-phenoxy) - phenyl ether
  • Step 2 l- ⁇ 2- [S- (2-Benzyloxy-4-methyl-phenoxy) -2- nitro-phenyl] -vinyl ⁇ -pyrrolidine
  • Step I 4- (2-Methoxy-4-methyl-phenoxy) -5-methyl- thieno [2, 3-d]pyrirnidine
  • Step 1 4- (2-Methoxy-4-methyl-phenoxy) -7-tnethyl- thieno [3, 2-d] pyrimidine
  • Example title compound (309mg, 71%) as a white powder.
  • This product was analyzed by 1 H-NMR. The corresponding 1 H-NMR spectrum was consistent with the structure anticipated.
  • MIC Minimum Inhibition Concentration
  • the compounds of the present invention were tested against sleeted Gram positive and Gram negative organisms using standard microtitration techniques well known to those skilled in the art. Cultures of bacteria were initially applied by streaking a loopful onto agar plates under the appropriate conditions. For example, bacterial stocks were streaked onto chocolate agar and then incubated for 18 hours at 35 - 37 0 C in a 5% CO 2 incubator. Five to ten colonies were picked from the chocolate agar plate for subculture to Brian-Heart infusion (BHI) broth, Mueller Hint ⁇ n broth, or BHI containing 4% serum and incubated under the appropriate conditions. The ability of the test compound to act as an antimicrobial was determined by the ability of dilutions of the test substance to inhibit
  • the optical density of the culture of organisms in the presence of an active compound was compared to the optical density of the same organism without test compound.
  • the activity of the compounds is described as either negative or the lowest concentration inhibiting growth (Minimum Inhibitory Concentration [MIC] ⁇ .

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Abstract

Antimicrobial compounds, compositions and methods of treatment administering same, of 2-heteroaryloxyphenol, as well as methods for their preparation and formation, wherein the compounds are generally of Formula 1.

Description

NOVKL 2-HETEROARYLOXY-PHENOI. DERIVATIVES AS ANTIBACTERIAL AGENTS
FIELD OF THE INVENTION
This invention relates to novel 2-heteroaryloxyphenol derivatives and methods for their preparation. The compounds are useful antimicrobial agents, effective against a number of human and bioterrorism pathogens, including staphylococci, streptococci and enterococci as well as bacillus anthracis and Bacillus cereus.
BACKGROUND OP THE INVENTION
While the present invention is directed to certain, novel 2-heteroaryloxyphenol compounds, literature exists that reports on other 2-heteroaryloxyphenol compounds, that are easily distinguishable from the present compounds. JP 51121516 reveals the synthesis and use of 2- (pyridin-2- yloxy) -phenols as represented by below formula A, as nonmedical germicides. Litvak et al has reported the synthesis of 2- (pyridin-4-yloxy) -phenols as exemplified by below formula B (Chemoshere, 43, 493, 2001), but no biological activities were reported.
SLT3STITUTE SHEET (RULE 26)
Figure imgf000003_0001
US 4427437 describes the synthesis and usefulness of 2- (pyrimidin-2-yl)oxyphenols, such as below compounds C and D, as herbicides. US 4142048 discloses the production of 2- ( [1,3, 5] triazin-2-yloxy) -phenols as exemplified by below formula E, as cross-linking agents and UV absorbers.
Figure imgf000003_0002
Prota et al has reported the generation and identification of 2- (benzothiazol-7-yloxy) -phenol, as shown in below formula F, but no biological activity was disclosed (J. Heterocyclic Chern., 7, 555, 1970). US 4205077 refers to the synthesis and application of cyclic thiourea derivatives of 2-aryloxyphenol such as below formula G, as anthelmintic agents for animals.
Figure imgf000003_0003
F
SUBSTITUTE SHEET (RLiLE 26) Due to ever increasing antibiotic resistance, new classes of antibacterial agents having a core structure different from clinical antibiotics have become very important to the treatment of bacterial infections (C&EN, March 6, 41, 2000) . The present invention is certain novel 2-heteroaryloxyphenol derivatives useful as antibacterial agents, and methods for their preparation.
DETAILED DESCRIPTION OP THE INVENTION
The present invention provides compounds of structural formula I or pharmaceutically acceptable salts thereof .
Formula I
Figure imgf000004_0001
wherein
B-ring is a heteroaryl group of 5 - 8 atoms with 1 - 4 heteroatoms chosen from nitrogen, oxygen, or sulfur or phenyl ring .
X and Y are each independently chosen from halogen, CN, OH, NH2 , NO2 , CO2H, CO2Me, CO2Et, CHO, CH (NOMe) , C1 - C4 alkyl and cycloalkyl , and CF3 ; m and n are 0 , 1, 2 and 3 . More preferred compounds of the present invention are those of formula I wherein B-ring is a heteroaryl group chosen from
(a) Substituted thiophenyl:
Figure imgf000005_0001
(b) Substituted furanyl:
Figure imgf000005_0002
{c) Substituted imidazolyl:
Figure imgf000005_0003
(d) Substituted pyridin-3-yl:
Figure imgf000005_0004
(e) Substituted pyridazinyl:
o)Y->m mVsμrm
(f) Substituted pyrimidinyl:
"*( - ? 'Ym (g) Substituted pyrazinyl:
Figure imgf000006_0001
(h) Substituted itf-indolyl :
Figure imgf000006_0002
(i) Substituted IH-indazolyl:
Figure imgf000006_0003
(j) Substituted iH-benzotriazolyl :
Figure imgf000006_0004
(k) Substituted IH-benzoiraidazolyl :
Figure imgf000006_0005
(1) Substituted 3H-imidazopyridinyl :
Figure imgf000006_0006
(m) Substituted IH- [1, 2,3] triazolopyridinyl :
SUBSTITUTE SI-IEET (RULE 26)
Figure imgf000007_0001
(n) Substituted thienopyriπύdinyl ;
Figure imgf000007_0002
wherein
X and Y are each independently chosen from P, Cl, Br, I/ CN, OH1 NH2, NO2, CO2H, CO2Me, CO2Et, CHO, CH(NOMe), methyl, ethyl, n-proyl, n~butyl, cyclopropyl, cyclopropylmethyl and CF3; m and n are 0, 1, 2 and 3.
More preferred, the present invention provides the compound of formula I wherein
B-ring is a heteroaryl group chosen from (a)-(i) and (ii), (b)-(i) and (ii), (C), (d), (e)-(i) and (ii) , (f) - (i) , (g) , (h)-(i), (ii) and (iii), (i)-(i), (ii) and (iv) , (j)-(i), (iii) and (iv) , (k) , (J)- (i) and (ii) , (n)-(i) and (ii) .
X and Y are each independently chosen from F, Cl, Br, CN, OH, NH2, NO2, CHO, CH(NOMe), methyl, ethyl, cyclopropyl, cyclopropylraethyl and CF3; m and n are 0, 1, 2 and 3. Even more preferably, in the present invention, B-ring is a heteroaryl group chosen from (a)-(i) and (iii) , (b) - (i)and (ii), (c), (d), (e)-{i), (f)-(i), (g) , (h)-(i) and (n) - (i) and (ii) .
The present invention includes pharmaceutical compositions which comprise an antibacterially effective amount of compounds of structural formula I or pharmaceutically acceptable salts thereof with pharmaceutically acceptable carriers.
Preferred Compounds
The following compounds of the present invention are preferred:
I. 2- (5-Chloro-pyridin-3-yloxy) -phenol 2. 2- (2-Chloro-pyridin-3-yloxy) -phenol
3. 2- (Pyridin-3-yloxy) -phenol
4. 2- (6-Methyl-pyridin-3-yloxy) -phenol
5. 2- (β-Chloro-pyridin-3-yloxy) -5-methyl-phenol
6. 5-Methyl-2- (pyridin-3-yloxy) -phenol
7. 5-Chloro-2- (6-chloro-pyridin-3-yloxy) -phenol
8. 2- (6-Chloro-pyridin-3-yloxy) -5-fluoro-phenol
9, 2- (6-Chloro-pyrimidin-4-yloxy) -5-methyl-phenol
10. 2- (6-Chloro-pyrimidin-4-yloxy) -5-fluoro-phenol
II. 2- (6-Chloro-pyridazin-3-yloxy) -5-methyl-phenol 12 , 5 -Methyl-2 - (pyrazin-2-yloxy) -phenol
13 . 5-Chloro-2- ( thiophen-3 -yloxy) -phenol
14 . 5 -Methyl- 2- (thiophen-3 -yloxy) -phenol
15 . 2- (2 , 5 -Dimethyl -4 ~nitro-2ff-pyrazol-3 -yloxy) - 5 - me thy 1 -phenol
16. 5-Fluoro-2- ( 2H-indol-5-yloxy) -phenol
17 . 2 - {lH-Indol-5-yloxy) -5-methyl-phenol
18. 5-Methyl-2- (5-methyl-thieno[2, 3~d]pyrimidin-4- yloxy) -phenol
19. 5-Methyl-2- (7-methyl-thieno [3, 2~d)pyrimidin-4- yloxy} -phenol
Descriptions of the compounds of the present invention rely upon terms that include the following.
The compounds of the invention are named according to the IUPAC or CAS nomenclature system. The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci - Cj indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Cl - C4 alkyl and cycloalkyl refers to alkyls and cycloalkyls of one to four carbon atoms, inclusive, or methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl and its isomeric forms, and cyclobutyl, cyclopropylmethyl and methylcyclopropyl , Hydroxyl protecting groups (PG) are benzyl, 4- methoxybenzyl, methyl, benzyl, 2,2,2-trichloroethyl, t- butyldimethylsilyl, trimethylsilyl, fc-butyl, allyl, or as described in Greene, Theodora W., Protective Groups in Organic Synthesis, 1999, John Wiley & Sons Inc.; Chapter 3.
. Unless otherwise specified, the term "heterocycle" , "heterocyclic group", or heterocyclic" are used interchangeably herein and includes monocyclic, bicyclic ring or bridged ring system having from 4 -10 atoms, 1 -4 of which are selected from oxygen, sulfur and nitrogen. Heterocyclic group includes non-aromatic groups such as morpholin-4-yl and 4-methyl-piperazin-l-yl, and heteroaryl groups such as thiophenyl and oxadiazolyl. The term "aryl" in "heteroaryl" refers to aromaticity, a term known to those skilled in the art and defined in greater detail in "Advanced Organic Chemistry" , M, B. Smith and J, March, 5th Ed., John Wiley & Sons, New York, N. Y. (2001).
B-ring of formula I is a heteroaryl group represented by the term "Heteroaryl" , wherein the waved line indicates the bond of attachment. For example, a bond pointing inside a ring such as -Yn, in structure (c) indicates that the substituents are able to connect to any carbon and
SUBSTITUTE SI-IEET (RULE 26) nitrogen on the ring that can accept a covalent bond other than hydrogen. Two bonds pointing inside both rings in a bicyclic heteroaryl system such as -Y1n- in structure (h)-(i) indicates that the substituents are able to connect to any carbon and nitrogen on both rings that can accept a covalent bond other than hydrogen.
As is apparent to those of ordinary skill in the art, the compounds of the present invention can exist in tautomeric forms, and all such tautomeric forms are included vάthin the scope of the present invention. Geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.
The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines . Examples of metals used are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N' -dibenzylethyldiamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Pharmaceutically acceptable acid addition salts are formed with organic or inorganic acids, Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, raethanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either mono or di, etc. salt in the conventional manner. The free base forms may be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose, The free base forms differ from their respective salts forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
The compounds of the invention are capable of forming pharmaceutically acceptable prodrugs. "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug in vivo when such prodrug is administered to a subject. Prodrugs of a compound are prepared by modifying functional groups present in the compounds in such a way that the bonds are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include, but are not limited to, compounds wherein hydroxyl, amine, or sulfhydroxyl groups are bonded to any group that, when administered to a subject, cleave to form a free hydroxyl, amino, or sulfhydroxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate and phosphate ester derivatives of hydroxyl functional groups, especially the hydroxyl group on A-ring of formula I, and acetyl and benzoyl derivatives of amine functional groups in the compounds of the invention and the like.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms and the like are equivalent to the unsolvated forms for purposes of the invention.
The compounds are of course given by forms suitable for each administration route. For example, they are administered in drops, tablets or capsule form, by injection, inhalation, eye lotion, ointment, foams, suppository, etc. by topical, vaginal or rectal administration. Parenteral or topical administration is preferred. The compounds of the invention are useful for the treatment of infections in hosts, especially mammals, including humans, in particular in humans and domesticated animals. The compounds may be used, for example, for the treatment of infections of skin, mouth, the respiratory tract, the urinary/reproductive tract, and soft tissues and blood, especially in huraans. In one embodiment of the invention diseases are those caused by or associated with infection by microorganisms including, but are not limited to, Streptococcus pyogenes, Staphylococcus aureus, methicillin resistant Staphylococcus aureus ("MRSA"), Staphylococcus epidermidis, Bacillus anthracis, Neisseria gonorrhoeae, Neisseria meningitides, Mycobacteria tuberculosis, vancomycin resistant Enterococcae ("VRE"), Helicobacter pylori, Chlamydia pneumoniae, Chlamydia trachomatis, Campylobacter jejuni, Propionibacterium acnes, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Enterococcus faecalis, Haemophilus influenzae, Escherichia coli, Corynebacterium diphtheriae, Morazella catarrhalis and Bacillus cereus.
The pharmaceutical compositions of the present invention employ the compounds of the invention and may include inert, pharmaceutically acceptable carriers that are either solid or liquid. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material, In powders, the carrier is a finely divided solid which is an admixture with the finely divided active compound. In tablets, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired, The powders and tablets preferably contain from S to about 70 percent and preferably 10 to about 60 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include compositions wherein the formulation of the active compound is with encapsulating material acting as carrier. This provides a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is accordingly in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, glycerol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e. natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well- known suspending agents .
An example, for instance, is water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc) . Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution,
Formulations of the present invention which are suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled
16
SUBSTITUTE SHEKT (RULE 26) delivery over time of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium, Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
The compositions of the invention may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety- nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective
17
SUBSTITUTE SHHET (RULE 26) amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compositions of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, topical, intravenous and subcutaneous doses of the compositions of this invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 0.1 to about 10 mg per kg per day. Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of the compound of the invention. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub- doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Synthesis
The compounds of the present invention may be synthesized according to the chemistry outlined in the following schemes, It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative procedures are feasible and may be preferred in some cases.
The chemistry to synthesize diaryl ether derivatives are well known to those skilled in the art of organic synthesis and has been well documented recently by 1} Theil, F, Angew. Chem. Int. Ed. 1999, 38, 2345; 2) Sawyer, J. S., Tetrahydron, 2000, 56, 5045; 3) Ley, S. V. et al, Angew. Chem. Int. Ed. 2003, 42, 5400. Many of the synthetic methodologies and reactions can be employed to the synthesis of 2-hetereoaryloxyphenols generalized by formula I in present invention.
Schemes 1 - 5 describe general synthetic approaches to the compounds of formula I in the invention.
As shown in below Scheme 1, 2-heteroaryloxyphenols of the invention may be synthesized by a condensation reaction of a heteroaryl-OH derivative 1 with a 2-fluoro or 2- chloro-benzaldehyde derivative 2, followed by Baeyer- Villiger rearrangement promoted by 3-chloroperαxybenzoic
19
SUBS'ITRJ IΕ SHEET (Rlϋ ,B 26) acid (tnCPBA) . The conversion of 1 to intermediate 3 can be carried out in the presence of a base such as cesium carbonate, potassium carbonate and sodium hydride in a solvent like N,N-dimethylformamide (DMF), N, N- dimethylacetamide (DMA), and acetonitrile (CAN) etc. at a temperature between 20 to 1100C. The conversion of 3 to corresponding formula I compounds is accomplished by the oxidation with mCPBA in presence of an acid such as trifluoroacetic acid (TFA) in dichloromethane (DCM) at room temperature.
Scheme 1
Figure imgf000021_0001
An alternative synthetic route to the compounds of the invention is to use a transition metal catalyzed cross- coupling reaction to construct the heterσaryloxy aryl ether structures, as showed in below Scheme 2. The cross- coupling reaction of a heteroaryl halide (preferably iodide and bromide) 4 with a mono-protected cateσol 5, catalyzed by a palladium or copper catalyst combined with a suitable ligand and a base at elevated temperature, affords 6. OP Scheme 2
HO.
4-x. & Cu or Pd catalyst,
A or Br Ugand, base Deprotedioπ
Heteroaryl Solvent, heating
Figure imgf000022_0001
Figure imgf000022_0002
Formula I
The catalysts suitable for the reaction comprise Pd(OAc)2, Fd(dba)2, Cu2O, CuI, CuCl or (CuOTf)2 1C6H6 etc. and the ligand is chosen from PPh3, 2, 2' -bis (diphenylphosphino) - 1,1' -binaphtyl (BINAP), 1,1'- bis (diphenylphosphino) ferrocene (DPPf), P(C-Bu)3, N,N- dimethylglycine, l-naphthoic acid or 2,2,e,6- tetramethylheptane-3, 5-dione and the like. The base used in the reaction is Cs2CO3, K2CO3, Na2CO3, sodium or potassium (tert) -butoxide. Solvents which may be used in the reactions include THF, 1,4-dioxane, toluene, N1N- dimethylacetamide (DMA), N,N-dimethylformamide (DMF), acetonitrile (ACN) and the like. The cross-coupling reaction proceeds at 500C - 150 °C, optionally with assistance of ultrasonic or microwave irradiation.
21
SUBSTITUTE SHEEl1 (RULE 26) Scheme 3
I
Figure imgf000023_0001
I
Alternatively, as shown in above Scheme 3, if a heteroaryl halide (preferably fluoride or chloride) bears a nitrogen atom (such as 7) or a electron withdrawing group (EWG) (9) such as CN, CHO, NO2, CO2Me etc. at ortho- position of the halide, condensation of the heteroaryl halide with mono-protected catecol 5 proceeds through SNAr mechanism under the same conditions as described in the conversion of 1 to 3, giving intermediates 8 and 10. Deprotection of 8 and 10 gives corresponding hydroxyl free compounds of formula I. Most commercial or literature mono-protected catecols 5 bear methyl, benzyl, or siIyI group as hydroxyl protection groups. Such protection groups are easily removed from with acids, contact hydrogenation, BBr3, BI3, Mgl2/ NaSEt and tetrabutylammonium fluoride etc. in protic or aprotic solvents at ~78°C - 1000C.
22
SUBSTITUTE SHEET {RULE 26) 2- (lH-indol-5-yloxy) -phenol of the present invention (formula I, wherein Heteroaryl = moiety (h)-(i)) may be synthesized by following the synthetic route depicted in below Scheme 4. Condensation of phenol derivative 11 with 4-fluoro-2-methyl-nitrobenzene 12 in the presence of cesium carbonate in DMA at elevated temperature affords diaryl ether 13. Deraethylation of 13 with boron tribrσmide, followed by benzylation with benzyl bromide and cesium carbonate give compound 14, which is cyclized to the desired compound through 15 by the procedure disclosed by A. D. Batcho et al (Org, Synth. Col. Vol. VII, 34, 1990).
Scheme4
Figure imgf000024_0001
2- f3H-benzoimidazol-5-yloxy) -phenol and 2- (1H- benzotriazol - 5 -yloxy) -phenol of the present invention (formula I , wherein Heteroaryl = (k) and (j ) - (iii) ) may be made by the synthetic sequence described in below Scheme 5.
23
Sl "BSTITUTE SHEET (RULB 26)
Figure imgf000025_0001
Condensation of phenol derivative 11 with 4-chloro- 1, 2-dinitrobenzene in presence of cesium carbonate produces 17, which is demethyXated by the reaction with boron tribromide provding phenol 18, Reduction of 18 by contact hydrogenation or tin(II) chloride gives intermediate 19. Cylization of the intermediate to desired benzoimidazole and benzotriazole compounds of the invention is carried out by the reactions with trimethyl orthoformate and sodium nitrite in acetic acid respectively.
Below Schemes 6 - 9 show the application of above synthetic methodologies to synthesize specific compounds of the present invention,
Scheme 6 demonstrates the syntheses of 2- (pyridin-3- lyoxy) phenols (formula I, wherein Heteroaryl = moeity (d) ) of the present invention by the approach described in Scheme 1.
Scheme 6
Figure imgf000026_0001
Electrophilic substitution of 20 with 3- hydroxypyridines 21, 24, 27, and 30 in the presence of cesium carbonate in DMF provided 2- (pyridin-3-yloxy) - benzaldehydes 22, 25, 28 and 31 respectively. Baeyer Villiger oxidation of the benzaldehydes, employing πiCPBA in acidic condition, gave corresponding 2- {pyridine- 3- yloxy) phenols 23, 26, 29 and 32 respectively. Below Scheme 7 shows an alternative approach to 2- {pyridin-3- yloxy) phenols through a transition metal catalyzed reaction depicted in Scheme 2.
Figure imgf000027_0001
Thus, cross-coupling reactions of 2-chloro-5~iodo- pyridine 33 with phenols 34, 37 and 40, promoted by copper (I) chloride and cesium carbonate in DMF at 1000C, afforded intermediates 35, 37 and 41. Subsequent reactions of the intermediates in 48% of HBr, catalyzed by a phase transfer catalyst such as benzyl-tri( tert) -butylammonium chloride or benzyl-tributylammonium chloride, led to desired compounds 36, 39 and 42 respectively.
2- (Thiophen-3-yloxy) phenols (formula I, wherein Heteroaryl = (a)-(i)) of the present invention were synthesized according to synthetic routes described in below Scheme 8, based on the methodology taught by Scheme 2. Cross-coupling reactions of 3-bromo-thiophene 43 with phenols 34 and 37, catalyzed by copper (I) chloride and N1N- dimethylglycine in the presence of cesium carbonate in dioxane at 105 °C, provided intermediates 44 and 46, which subsequently reacted with sodium ethanethiolate in DMF at elevated temperature, led to corresponding 2- (thiophen-3- yloxy) phenols 45 and 47 respectively,
Scheme8
Figure imgf000028_0001
The compounds of formula I (wherein, Heteroaryl = (f)- (i) , (e)-(i), (g) , (h)-(ii), (n)-(i) and (ii), (c)) were attained by the synthetic routes shown in below Scheme 9, according to the methodology described in Scheme 3.
Scheme 9
Figure imgf000029_0001
Electrophilic substitutions of phenol 37 with commercially available heteroaryl halides, 48 - 53, in the presence of cesium carbonate in acetonitrile or DMA at elevated temperature, afforded intermediates 54 - 59 in excellent yields . Reactions of the intermediates with boron tribromides in DCM at temperature between -78 to 25° C, provided corresponding 2-heteroaryloxyphenols, 60 - 65 respectively.
28
SUBSTITUTE SHEET (RLIlJ-: 26) EXAMPLES
The following specific examples are provided for the purpose of further illustration only and are not intended to limit the disclosed invention.
Example 1: 2- (5-Chloro-pyridin~3-yloxy) -phenol
Figure imgf000030_0001
Step 1: 2- (S-Chloro-pyridin-3-yloxy) -benzaldehyde A suspension of 2-fluorobenaldehyde (124 mg, 2.0 mrnol) , 5-chloropyridin-3-ol (262 mg, 2.0 tnmol) and cesium carbonate (800 mg, 2.4 tnmol) in anhydrous N,N- dimethylformamide (DMF) (5.0 mL) was stirred at 600C for 2 days, poured into water (20 mL) and extracted with ether (2 x 30 mL) . The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in vacuum, giving the Example title compound (320 mg, 68%) as brownish powder which was employed in next step without further purification.
Step 2: 2- (5-Chloro-pyridin-3-yloxy) -phenol To a stirred solution of 2- (B-chloro-pyridin-3-yloxy) - benzaldehyde (63 mg, 0.27 mmol) and trifluoroacetic acid (0.2 TΪIL) in dichloromethane (1 mL) wag added 77% 3-chloro- perbenzoic acid (mCPBA) (100 mg, 0.446) . The reaction mixture was stirred at ambient temperature overnight and evaporated under reduced pressure. The residue was subjected to purification by flash chromatography on silica column eluting with ether/hexane (1:1) followed by ether/methanol (5:1). The Example title compound (28 mg, 52%) was obtained as a white solid. This product was analyzed by 1H-NMR (proton-nuclear magnetic resonance spectroscopy) . The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 2: 2- {2-Chloro-pyridin-3-yloxy) -phenol
Figure imgf000031_0001
The Example title compound was synthesized by following the procedures described in Example l, with 2- chloro-pyridin-3-ol in replace of 5-chloro-3-pyridin-3-ol . This product was analyzed by 1H-NMR. The corresponding 1H- NMR spectrum was consistent with the structure of the anticipated product.
30
SUBSTITUTE SI-EET (RULE 26) Example 3 ; 2- (Pyridin-3 -yloxy) -phenol
Figure imgf000032_0001
The Example title compound was synthesized by following the procedures described in Example 1, with pyridin~3-ol in replace of 5-chloro-3-pyridin~3-ol. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 4: 2- (6-Methyl-pyridin-3-yloxy) -phenol
Figure imgf000032_0002
The title compound was synthesized by following the procedures described in Example l, with 6-methyl-pyridin-3- ol in replace of 5-chloro-3-pyridin-3-ol. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product,
Example 5 : 2- (6-Chloro-pyridin-3-yloχy) ~5-methyl- phenol
Figure imgf000033_0001
Step 1: 2~Chloro-5- (2-methoxy-4-methyl-phenoxy) - pyridine
A suspension of 2-methoxy-4-methyl-phenol (360 rag, 2.0 mmol) , 2-chloro-5-iodα-pyridine (239 mg, 1 mmol), copper (I) chloride (98 mg, lmmol) and cesium carbonate (1.0 g, 3,069 mmol) in DMF (6.0 mL) under argon was vigorously stirred at 110 0C overnight. The mixture was poured into water (2OmL) and extracted with dichloromethane (DCM) (3 x 3OmL) . The organic layer was washed with water (25mL) and brine (25mL) , dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel developed by pentane/ether (10:1), affording the Example title compound (40 mg) as a white powder which was used in next step without further purification,
Step 2: 2- (6-Chloro-pyridin-3-yloxy) -5-methyl-phenol A solution of 2~chloro~5- (2-methoxy-4-methyl-phenoxy) - pyridine (30 mg, 0.120 mmol), benzyltri-t-butylammonium
32
SUBSTΠIΠΈ SHEET(RULE26) chloride (5 mg) in 48 % hydrobromic acid {2.5 mL) was stirred at 1000C for 2.5 hrs. The reaction mixture was diluted with water (10 mL) and neutralized with saturated sodium carbonate solution and extracted with ether (2 x 15 mL) . The organic layer was washed with water, dried on sodium sulfate, filtered and evaporated. The crude residue was passed through a short silica column eluted with DCM, giving the Example title compound (15 mg, 53%) as a white powder. Ci2Hi0ClNO2 (235.04): GC-MS (gas chromatography-masε spectrometry) (El+) m/e: 235. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 6: 5-Methyl-2- (pyridin-3-yloxy) -phenol
The Example title compound was synthesized by following the procedure described in Example 5 employing 3- iodo-pyridine in replace of 2-chloro-5-iodo-pyridine .
33
Sl/BSITTUTE SI-IEET (RULE 26) Example 7: 5-Chloro-2- (6-chloro-pyridin-3-yloxy) - phenol
Figure imgf000035_0001
Step 1: 2-Chloro-5- (4-chloro-2-methoxy-phenoxy) - pyridine
A suspension of 4-chloro-2-methoxy-phenol (360 mg, 2.0 mmol) , 2-chloro-5-iodo-pyridine (239 mg, 1 mmol) , copper (I) chloride (98 mg, lmmol) and cesium carbonate (1.0 g, 3.069 mmol) in DMP (6.0 mL) under argon was vigorously stirred for 3 days at HO 0C. The mixture was poured into water (2OmL) , and extracted with DCM (3 x 3OmL) . The organic layer was washed with water (25mL) and brine (25mL) , dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel developed by pentane/ether (1:1), affording 5-iodo-2- (4-chloro-2-methoxy-phenoxy) -pyridine (40 mg) as a major product and the Example title compound (20 mg) as a minor product which was used in next step without further purification.
Step 2: 5-Chloro-2- (6-chloro-pyridin-3-yloxy) -phenol
34
SUBSTITUTE SHEET (RLILE 26) A solution of 2-chloro-5-(4-chloxo-2-methoκy-phenoxy) - pyridine (20 tng, 0.074 iranol) , benzyltri-zi-butylaramonium chloride {5 mg) in 48 % hydrobromic acid (1 mL) was stirred at 1000C for 24 hrs. The reaction mixture was diluted with water (10 mL} and neutralized with saturated sodium carbonate solution and extracted with ether (2 x 15 mL) . The organic layer was washed with water, dried on sodium sulfate, filtered and evaporated. The crude residue was passed through a short silica column eluted with DCM, giving the Example title compound (10 rag, 39%) as a white powder: Melting Point (M.P.): 106 - 108 0C. This product was analyzed by 1H-NMR. CnH7Cl2KO2 (254.99): GC-MS (EI+) m/e: 255. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 8: 2- (6-Chloro-pyridin-3-yloxy) -5-fluoro- phenol
Figure imgf000036_0001
The Example title compound was synthesized by- following the procedure described in Example 7 employing 4- fluoro-2-methoxyphenol in replace of 4-σhloro-2- methoxyphenol : M. P . : 121 - 123 0C. Example 9 : 2 - {6-Chloro~pyrimidin-4-yloxy) - 5 -methyl - phenol
Figure imgf000037_0001
Step l: 4-Chloro-6- (2-methoxy-4-methyl-phenoxy)~ pyrimidine
A suspension of 4, 6-dichloro-pyrimidine (500 mg, 3.356 tnmol) , 2-methoxy-4-methyl-phenol (464 mg, 3.356 mrnol) and cesium carbonate {1.203 g, 3.692 mmol) in acetonitrile (5 mL) was stirred and refluxed overnight. The reaction mixture was poured into water, extracted with dichloromethane for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on a silica column employing ethyl acetate in hexane (30%) as eluent, giving the Example title compound (698 mg, 83%) as a white powder which was used in next step without further purification; M,P, : 65 - 670C.
Step 2: 2~ (6-Chloro-pyrimidin-4-yloxy) -5-methyl-phenol To a solution of 4-chloro-6- (2-methoxy-4-methyl- phenoxy) -pyrimidine (650 mg, 2.593 mmol) in DCM (7 mL) ,
36
SUBSTITUTE StIEET (RULE 26) cooled on an acetone-dry ice bath, was added dropwise boron tribromide (0.656 mL, 6.936 mmol) via syringe. The cooling bath was removed and the reaction was allowed to warm up to ambient temperature. After being stirred for three days, the reaction mixture was quenched by adding methanol (0.5 mL) dropwise, followed by water (10 mL) . The organic layer was separated and the aqueous layer was extracted with DCM (10 mL x 3) . The combined organic phase was washed with brine and saturated sodium carbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated. The solid residue was purified by flash chromatography on a silica column eluted with 5% methanol in DCM, affording the Example title compound (537 mg, 88 %) as white powder: M. P.: 90 - 930C. This product was analyzed by 1H-NT-IR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 10: 2- {6-Chloro-pyrimidin-4~yloxy) -5-fluoro- phenol
Figure imgf000038_0001
The Example title compound was obtained by the. same reactions described in Example 9, employing 4-fluoro-2- methoxyphenol in replace of 4-methyl-2-methoxyphenol. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product .
Example 11: 2- (β-Chloro-pyridazin-3-yloxy) -5-methyl- phenol
Figure imgf000039_0001
Step 1: 3-Chloro-6- (2-methoxy-4-methyl-phenoxy) - pyrid'azine
A suspension of 3,6-dichloro-pyridazine (651 mg, 4.28 mmol) , 2-methoxy~4-methyl-phenol (597 mg, 4.28 mmol) and cesium carbonate (1.534 g, 4.708 mtnol) in acetonitrile (5 mL) was stirred and refluxed overnight. The reaction mixture was poured into water, extracted with dichloromethane for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The crude solid residue was triturated in hexane/DCM (5:1) and dried in vacuum, giving the Example title compound (700 mg, 65 %) as a white powder which was used in next step without further purification; M. P,: 90 - 92 °C.
Step 2: 2- (6-Chloro-pyridazin-3-yloxy) -5-methyl-phenol To a solution of 3-chloro-6- (2-methoxy~4 -methyl- phenoxy) -pyridazine (650 mg, 2,593 mmol) in DCM (7 mL) , cooled on an acetone-dry ice bath, was added dropwise boron tribromide (0.656 mL, 6.936 mmol) via syringe. The cooling bath was removed and the reaction was allowed to warm up to ambient temperature. After being stirred for five hrs, the reaction mixture was quenched by adding methanol (0.5 mL) dropwise, followed by water (10 mL) . The organic layer was separated and the aqueous layer was extracted with DCM (10 mL x 3) . The combined organic phase was washed with brine and saturated sodium carbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated. The solid residue was purified by flash chromatography on a silica column eluted with 5% methanol in DCM, affording the Example title compound (210 mg, 45%) as a white powder; M.P.: 136 - 137 °C. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
39
SUBSTITUTE SHEET (RLILE 26) Example 12: 5-Methyl~2~ (pyrazin-2-yloxy) -phenol
Figure imgf000041_0001
Step 1: 2- (2-Methoxy-4-methyl-phenoxy) -pyrazine A suspension of 2-chloro-pyrazine (500 mg, 4.28 mmol) , 2-methoxy-4 -methyl-phenol (597 mg, 4,28 mmol) and cesium carbonate (1.534 g, 4.708 mmol) in acetonitrile (5 mL) was stirred and refluxed overnight. The reaction mixture was poured into water, extracted with ether for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on a silica column employing ethyl acetate in hexane (30%) as eluent, giving the Example title compound (536 mg, 60%) as a white crystal which was used in next step without further purification: M. P. : 55 - 56 0C.
Step 2; 5 -Methyl-2- (pyrazin-2-yloxy) -phenol To a solution of 2- (2-methoxy-4-methyl-phenoxy) - pyrazine (500 mg, 2.312 mmol) in DCM (5 mL) , cooled on an acetone-dry ice bath, was added dropwise boron tribromide (0.656 mL, 6.936 mmol) via syringe. The cooling bath was removed and the reaction was allowed to warm up to ambient
40
SUBSTITUTE SHEET (RULB 26) temperature. After being stirred for three days;, the reaction mixture was quenched by adding methanol (0.5 mL) dropwise, followed by water (10 mL) . The organic layer was separated and the aqueous layer was extracted with DCM (10 mL x 3) . The combined organic phase was washed with brine and saturated sodium carbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated. The solid residue was purified by flash chromatography on a silica column eluted with 5% methanol in DCM, affording the Example title compound (210 mg, 45%) as a white powder: M. P.: 142 - 1430C. This product was analyzed by 1H-MR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 13: 5-Chloro-2- {thiophen-3-yloxy) -phenol
Figure imgf000042_0001
Step 1: 3- (4-Chloro-2-methoxy-phenoxy) -thiophene A suspension of 4-chloro-2-metho>.y-phenol (475.8mg, 3mmol) , 3-bromothiophene (326mg, 2mmol) , N,N- dimethylglycine (139. Smg, lmmol) , copper (I) iodide (190.44mg, lmmol), cesium carbonate (1.3g, 4mmol) in dioxane under argon was vigorously stirred for 3 days at 1050C, The mixture was diluted with water (2OmL), and extracted with ethyl acetate (3xl5mL) . The organic layer was washed with water (2SmL) and brine (25mL) , dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel developed by 15% ethyl acetate/hexanes. The purified intermediate was recovered as yellow oil (37mgs, 15%)
Step 2: 5-Chloro-2- (thiophen-3-yloxy) -phenol A solution of 3- (4-chloro-2-methoxy-phenoxy) -thiσphene (50mg, 0.21mmol), sodium ethanethiolate (26.3mg, 0.31mmol) in DMF under argon was stirred at 12O0C overnight. The mixture was diluted with saturated ammonium chloride (25mL) and extracted with ethyl acetate (15mL x 3) . The organic layer was washed with brine (25mL) , dried over sodium sulfate, filtered and evaporated. The residue was purified ' on a silica gel column using 10% ethyl acetate/hexanes as eluent, giving the Example title compound (26mg, 60%) as a light yellow oil. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
42
SUBSTITUTE Sl-IEET(RULE 26) Example 14 : 5 -Methyl- 2 - (thiophen-3 -yloxy) -phenol
Figure imgf000044_0001
The Example title compound (20 mg, 71 % in the second step) was made by the same procedure as described in Example 13, using 4-methyl-2-methoxy-phenol to replace 4- chloro-2-methoxy-phenol.
Example 15s 2- (2, 5-Dimethyl-4--iitro~2#'-pyrazol~3- yloxy) -5-methyl -phenol
Figure imgf000044_0002
Step 1: 4- (2-Methoxy-4-methyl-phenoxy) -1, 3-dimethyl-5- nitro-IH-pyrazole
A suspension of 4-chloro-l,3-dimethyl-5-nitro-ltf~ pyrazole (544 mg, 3.10 mtnol) , 2-methoxy-4-methyl-phenol (450 mg, 3.2S mmol) and cesium carbonate (1,111 g, 3.41 mmol) in DMA (5 mL) was stirred at 100 0C for 12 hrs . The reaction mixture was poured into water, extracted with ether for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in
43
SUBSTITUTE SHKEl1 (RULE 26) vacuum, giving the Example title compound (636 mg, 74%) as white powder which was used in next step without further purification; M,P. : X08 - 1090C,
Step 2: 2- (2,5-Dimethyl-4-nitro-2H-pyrazol-3-yloxy) -5- methyl-phenol
To a solution of 5- (2-methoxy-4-methyl-phenoxy) -1,3- dimethyl-4-nitro~2H-pyrazole (250mg, 0,9θmmol) in DCM (4raL) , cooled to -780C on an acetone/dry ice bath, was added dropwise boron tribromide (256μL, 2.71mmol) via syringe. The cooling bath was removed and the reaction was allowed to reach ambient temperature. After being stirred for 6hrs, the reaction was quenched with the addition of water (ImL) followed by brine (2OmL) . The organic layer was separated and the aqueous layer extracted with DCM (15tnL x3) . The combined organic phase was washed with brine (2OmL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified on a silica gel column using 30% ethyl acetate/hexanes as eluent, giving the Example title compound (238mg, 86%) as a white powder, M. P.; 142-147°C, This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
44
SUBSTITUTE SHEET (RLTLl- 26) Example 16: 5-Fluoro-2- (2H-indol-5-yloxy) -phenol
Figure imgf000046_0001
Step 1: Benzyl 5-fluorα-2- (3-methyl-4-nitro-phenoxy) - phenyl ether
A suspension of 5-fluoro~2- (3-methyl-4~nitro-phenoxy) - phenol (369mg, 1.4mmol), cesium carbonate (630mgs, l,93mmol) and benzyl bromide (330τng, 1.93τnmol) in DMF was magnetically stirred at 6O0C for 3hrs. Water (25tnL) was added and aqueous layer extracted with ethyl acetate (15mL x 3) . The organic layer was washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure, The crude residue (417mgs, 78%) was used in next reaction without further purification.
Step 2: 1- {2- [5- (2-Benzyloxy-4-fluoro-phenoxy) -2- nitro-phenyl3 -vinyl} -pyrrolidine
A mixture of benzyl 5-fluoro-2- (3-methyl-4-nitro~ phenoxy) -phenyl ether (418mg, l.lSmmol), dimethylformamide dimethylacetal (422mg, 3.54mmol) and pyrrolidine (lOOmg, 1.42mmol) in DMF under argon was stirred vigorously at HO0C for 4hrs. The DMF was evaporated under reduced
45
SUBSTITUTE SHEET (RUJJi 26) pressure and the residue was dissolved using 12% dichloromethane/methanol (1OmL) . Approximately 10% of this solvent was evaporated while heating, then the mixture was allowed to cool to ambient temperature and finally chilled in an ice box. The solids were filtered off giving crude red powder (287mg) that was used without further purification.
Step 3: 5-Fluoro-2- (IH-indol-5-yloxy) -phenol A suspension of l-{2- [5- (2-benzyloxy-4-fluorσ~ phenoxy) -2-nitro-phenyl] -vinyl} -pyrrolidine (287mg, 0.66mmol), palladium 10% on activated carbon (SOrags) in 30% ethyl acetate/benzene was stirred under 1 atmosphere of hydrogen gas overnight. The mixture was filtered over celite and the residue was purified on a silica gel column using 25% ethyl acetate/hexanes as eluent, giving the Example title compound (219mg, 76%) as a light brown powder. M. P.: 75-8O0C. This product was analyzed by 1H- NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product .
Example 17: 2- (lH-Indol-5-yloxy) -5-methyl-phenol
Figure imgf000048_0001
Step 1; Benzyl 5-methyl-2~(3-methyl-4-nitro-phenoxy) - phenyl ether
A suspension of 5-methyl-2- (3-methyl-4-nitro-phenoxy) - phenol (446mg, 1.72mmol), cesium carbonate (694mg, 2.13mmol) and benzyl bromide (364mg, 2.l3mmol) in DMF was magnetically stirred at 6O0C for 3hrs. Water (25mL) was added and aqueous layer extracted with ethyl acetate (15mL x 3) . The organic layer was washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The solvent was then filtered and evaporated under reduced pressure. The crude residue (716mg, 123%) was used in next reaction without further purification.
Step 2: l-{2- [S- (2-Benzyloxy-4-methyl-phenoxy) -2- nitro-phenyl] -vinyl} -pyrrolidine
A mixture of benzyl 5-methyl-2- (3-methyl-4-nitro- phenoxy) -phenyl ether (1.78g, 5.09mmol), dimethylformamide dimethylacetal (1.82g, 15.3mmol) and pyrrolidine (725mg, 10.2mmol) in DMF under argon was stirred vigorously at HO0C for 4hrs. The DMF was evaporated under reduced pressure and the residue was dissolved using 12% dichloromethane/methanol (1OmL) . Approximately 10% of this solvent was evaporated while heating, the mixture was then allowed to cool to ambient temperature and finally chilled in an ice box. The solids were filtered off leaving a crude red powder (1.32g) that was used without further purification.
Step 3; 2- (IH-Indol-5-yloxy) -5-methyl-phenol A suspension of l-{2- [5- (2-benzyloxy-4-methyl- phenoxy) -2-nitro-phenyl] -vinyl}-pyrrolidine {l,32g, 3.07mmol), palladium 10% on activated carbon (300mg) in 30% ethyl acetate/benzene was stirred under 1 atmosphere of hydrogen gas overnight. The mixture was filtered over celite and the residue was purified on a silica gel column using 25% ethyl acetate/hexanes as eluent to give the Example title compound (720mgs, 60%) as a grey/brown powder, M. P.: 121-1280C. This product was analyzed by 1H- NMR. The corresponding 1H-NMR spectrum was consistent with the structure of the anticipated product.
Example 18 $ 5 -Methyl-2- (5 -methyl -thieno [2 , 3 - d] pyriinidin-4-yloxy) -phenol
Figure imgf000050_0001
Step I; 4- (2-Methoxy-4-methyl-phenoxy) -5-methyl- thieno [2, 3-d]pyrirnidine
A suspension of 4~chloro-5-methyl-thieno [2, 3- d]pyrimidine (500 rag, 2.71 mmol) , 2-methoxy-4 -methyl-phenol (393 mg, 2.84 mmol) and cesium carbonate (971 mg, 2.98 mmol) in DMA (5 mL) was stirred at loo 0C for 12 hrs. . The reaction mixture was poured into water, and extracted three times with ether. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in vacuum, giving the title compound (516 mg, 67%) as a white powder which was used in the next step without further purification.
Step 2: 5-Methyl-2- (5-methyl-thieno [2, 3-d] pyrimidin-4- yloxy) -phenol
To a solution of 4- (2-methoxy-4-methyl-phenoxy) -5- methyl-thieno [2, 3-d] pyrimidine (463mg, 1.62mmol) in DCM (8mL) , cooled to -78°C on an acetone/dry ice bath, was added dropwise boron tribromide (454μL, 4.8mmol) via syringe. The cooling bath was removed and the reaction was allowed to reach ambient temperature. After being stirred for βhrs, the reaction was quenched with the addition of water (ImL)' followed by brine (2OmL) . The organic layer was separated and the aqueous layer extracted with DCM (15mL x3) . The combined organic phase was washed with brine (2OmL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified on a silica gel column using 30% ethyl acetate/hexanes as eluent to give the Example title compound (246mgs, 56%) as a light brown powder. M.P.: 166-1690C. This product was analyzed by 1H- NMR. The corresponding 1H-NMR spectrum was consistent with the structure anticipated.
Example 19: 5-Methyl-2- (7-methyl-thieno [3, 2- d]pyrimidin-4-yloxy) -phenol
Figure imgf000051_0001
Step 1 : 4- (2-Methoxy-4-methyl-phenoxy) -7-tnethyl- thieno [3, 2-d] pyrimidine
A suspension of 4 -chloro-7-methyl-thieno [3 , 2- dl pyrimidine (500 mg, 2.71 mmol) , 2 -me thoxy- 4 -methyl -phenol (393 mg, 2.84 mmol) and cesium carbonate (971 mg, 2.98 mtnol) in DMA (5 mL) was stirred at 100° C for 12 hrs. The reaction mixture was poured into water, extracted with ether for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in vacuum, giving the Example title compound (513 rag, 66%) as a white powder which was used in the next step without further purification.
Step 2: 5-Methyl-2- (7-methyl-thieno[3,2-d]pyrimidin-4- yloxy) -phenol
To a solution of 4- (2-πtethoxy-4-methyl-phenoxy) -7- methyl-thieno[3 , 2~d]pyrirnidine (455mg, l.SOmmol) in DCM (8mL) , cooled to -7S°C on an acetone/dry ice bath, was added dropwise boron tribromide (454μL, 4.8mmol) via syringe. The cooling bath was removed and the reaction was allowed to reach ambient temperature. After being stirred for δhrs, the reaction was quenched with the addition of water (ImL) followed by brine (2OmL) . The organic layer was separated and the aqueous layer extracted with DCM [l5mL x3) . The combined organic phase was washed with brine (2OmL) , dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified on a silica gel column using 30% ethyl acetate/hexanes ag eluent to give the Example title compound (309mg, 71%) as a white powder. M. P.: 153-1560C. This product was analyzed by 1H-NMR. The corresponding 1H-NMR spectrum was consistent with the structure anticipated.
Minimum Inhibition Concentration (MIC) , Broth Dilution Method:
The compounds of the present invention were tested against sleeted Gram positive and Gram negative organisms using standard microtitration techniques well known to those skilled in the art. Cultures of bacteria were initially applied by streaking a loopful onto agar plates under the appropriate conditions. For example, bacterial stocks were streaked onto chocolate agar and then incubated for 18 hours at 35 - 370C in a 5% CO2 incubator. Five to ten colonies were picked from the chocolate agar plate for subculture to Brian-Heart infusion (BHI) broth, Mueller Hintσn broth, or BHI containing 4% serum and incubated under the appropriate conditions. The ability of the test compound to act as an antimicrobial was determined by the ability of dilutions of the test substance to inhibit
52
SUBSTrI1UTE SHEET (RULE 26) bacterial growth in vitro. The optical density of the culture of organisms in the presence of an active compound was compared to the optical density of the same organism without test compound. The activity of the compounds is described as either negative or the lowest concentration inhibiting growth (Minimum Inhibitory Concentration [MIC] } .
The activity of selected compounds of this invention against representative Gram positive and Gram negative bacteria are shown in the following Table 1.
Table 1
In Vitro Activity of Selected Examples of the Invention Against Bacteria
Figure imgf000055_0001
54
SUBSTITUTE SHEEl' (RLTLE 26) While the preferred embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

Claims

What is claimed is
Claim 1. A compound of structural Formula I or pharmaceutically acceptable salts thereof
Formula I
Figure imgf000057_0001
wherein
B-ring is a heteroaryl group selected from the group consisting of
(a) Substituted thiophenyl:
Figure imgf000057_0002
(b) Substituted furanyl :
Figure imgf000057_0003
(c) Substituted imidazolyl:
Figure imgf000057_0004
(d) Substituted pyridin-3 -yl :
56
SUBSTITUTE SHEKT (RLILE 26)
Figure imgf000058_0001
(e) Substituted pyridazinyl :
Figure imgf000058_0002
(f) Substituted pyrimidinyl :
Figure imgf000058_0003
(g) Substituted pyrazinyl:
Figure imgf000058_0004
(h) Substituted 2H-indolyl:
Figure imgf000058_0005
(i1) Substituted 2H-indazolyl :
Figure imgf000058_0006
(j) Substituted IH-benzotriazolyl:
Figure imgf000058_0007
(k) Substituted Iff-benzoimidazolyl :
57
SLΓBSΪΓΓUTR SHEET (RULE 26)
Figure imgf000059_0001
(D Substituted 3H- imidazopyridinyl :
Figure imgf000059_0002
(m) Substituted IH- [1, 2 , 3] triazolopyridinyl ;
Figure imgf000059_0003
(n) Substituted thienopyrimidinyl :
Figure imgf000059_0004
wherein
X and Y are each P, Cl, Br, I, CN, OH, NH2, NO2, CO2H, CO2Me, CO2Et, CHO, CH(NOMe), methyl, ethyl, n-proyl, n-butyl, cyclopropyl, cyclopropylmethyl or CF3; rn and n are 0, 1, 2 and 3.
Claim 2. The compound of claim 2, wherein B-ring is a heteroaryl group selected from the group consisting of (a)-(i) and (ii) , (b) - (i) and (ii) , (c) , (d) , (e)-(i) and (ii) , (f)-(i), (g) , (h)-(i), (ii) and (dii) , (D-Ii)1 (ii) and (iv) , (j)-(i), (iii) and (iv) , (k) , (J)- (i) and (ii) , (n) - (i) and (ii) .
Claim 3, The compound of claim 3, wherein X and Y are each F, Cl, Br, CN, OH, NH2, NO2, CHO, CH(NOMe), methyl, ethyl, cyclopropyl, cyclopropylmethyl or CF3; m and n are 0, 1, 2 and 3.
Claim 4. The compound of claim 3, wherein B-ring is a heteroaryl group selected from the group consisting of (a)-(i) and (iii), (b)-(i)and (ii) , (c) , (d) , (e)-(i), (f)-(i), (g), (h)-(i) and (n)-(i) and (ii) .
Claim 5. A compound selected from the group consisting of:
2- (5-Chloro-pyridin-3-yloxy) -phenol,
2- (2-Chloro-pyridin-3-yloxy) -phenol,
2- (Pyridin-3-yloxy) -phenol,
2- (6-Methyl-pyridin-3-yloxy) -phenol,
2- (6-Chloro-pyridin-3-yloxy) -5-methyl-phenol, 5 -Methyl- 2- (pyridin-3-yloxy) -phenol, 5-Chloro~2- (6-σhloro-pyridin~3-yloxy) -phenol, 2- (β-Chloro-pyridin-3-yloxy) -5-fluoro-phenol, 2- (6-Chloro-pyrimidin-4~yloκy) -5 -methyl -phenol, 2- (6-Chloro-pyrimidin-4~yloxy) -5-fluoro-phenol, 2- (6-Chloro-pyridazin-3-yloxy) -5-methyl-phenol, 5-Methyl-2- (pyrazin-2-yloxy) -phenol, 5-Chloro-2- (thiopheπ-3-yloxy) -phenol, 5 -Methyl- 2- (thiophen-3-yloxy) -phenol, 2 - ( 2 , 5 -Dimethyl-4 -nitro-2H-pyrazol - 3 -yloxy ) - 5-methyl- phenol ,
5-Fluoro-2- ( IH- indol-5-yloκy) -phenol, 2- (lH-Indol-5-yloxy) -5-methyl-phenol, 5 -Methyl- 2- (5-methyl-thieno[2, 3-d]pyrimidin-4-yloxy) - phenol , and
S-Methyl-2- (7-methyl-thieno[3, 2-d] pyrimidin-4-yloxy) - phenol
Claim 6. The compound of claim 1 which is in the form of a prodrug selected from the group consisting of compounds wherein hydroxyl, amine, or sulfhydroxyl groups are bonded to any group that, when administered to an animal, cleave to form a free hydroxyl, amino, or sulfhydroxyl group, respectively.
Claim 7. The compound of claim 1 which is in the form of a prodrug selected from the group consisting of acetate, formate, benzoate and phosphate ester derivatives of hydroxyl functional groups, and acetyl and benzoyl derivatives of amine functional groups.
Claim 8. The compound of claim 1, wherein the compound comprises tautomeric forms, geometric isomers, enantiomers and diastereomers .
Claim 9. The compound of claim 1, wherein the pharmaceutically acceptable salt thereof is an acid addition salt wherein the acid is selected from the group consisting of hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, and methanesulfσnic acid; or a base salt formed with alkali and alkaline earth metals or organic amines. Claim 10. A composition comprising the following compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
Formula I
Figure imgf000063_0001
wherein
B-ring is a heteroaryl group selected from the group consisting of
(o) Substituted thiophenyl :
Figure imgf000063_0002
(P) Substituted f uranyl :
Figure imgf000063_0003
(g) Substituted iraidasolyl :
Figure imgf000063_0004
(r) Substituted pyridin-3 -yl ;
Figure imgf000063_0005
62
SUBSΗTUTE SI-IEET (RULE 26) (s) Substituted pyridazinyl;
Figure imgf000064_0001
(t) Substituted pyrimidinyl:
Figure imgf000064_0002
(u) Substituted pyrazinyl:
Figure imgf000064_0003
(v) Substituted 2H-indolyl:
Figure imgf000064_0004
(w) Substituted itf-indazolyl ;
Figure imgf000064_0005
(x) Substituted lH-benzotriazolyl:
Figure imgf000064_0006
(y) Substituted IH-benzoimidazolyl:
Figure imgf000064_0007
63
sι."BsτrrυτR SHEET (RULE 26) (z) Substituted 3tf-itnidazopyridinyl :
Figure imgf000065_0001
(aa) Substituted 2H- [1, 2,3] triazolopyridinyl:
Figure imgf000065_0002
(bb) Substituted thienopyrimidinyl:
Figure imgf000065_0003
wherein
X and Y are each F, Cl, Br, I, CN, OH, NH2, NO2, CO2H, CO2Me, CO2Et, CHO, CH(NOMe), methyl, ethyl, n-proyl, n-butyl, cyclopropyl, cyclopropylmethyl or CF3; m and n are 0, 1, 2 and 3.
Claim 11. The composition of claim 10, wherein the carrier is a solid material selected from the group consisting of magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl
64
SUBSTITUTE SI-EET (RUI, E 26) cellulose, a low melting wax, cocoa butter and mixtures thereof.
Claim 12. The composition of claim 10, wherein the carrier is a liquid material selected from the group consisting of water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, glycerol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof.
Claim 13. A method of treating or preventing a disease or condition caused by or associated with a- microbial infection, which method comprises the administration to an animal in need thereof a pharmaceutical composition comprising an anti-microbial amount of the following compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
65
S17BSTTTUTE SffiET (RULE 26) Formula
Figure imgf000067_0001
wherein
B-ring is a heteroaryl group selected from the group consisting of
(cc) Substituted thiophenyl:
Figure imgf000067_0002
(del) Substituted furanyl :
Figure imgf000067_0003
(ee) substituted imidazolyl :
Figure imgf000067_0004
(ff ) Substituted pyridin-3-yl :
'(
(gg) Substituted pyridazinyl:
Figure imgf000067_0005
(hh) Substituted pyrimidinyl:
66
SUBSTITUTE SIiEET (RULE 26)
Figure imgf000068_0001
(ii) Substituted pyrazinyl;
Figure imgf000068_0002
(jj) Substituted 2tf-indolyl:
Figure imgf000068_0003
(kk) Substituted 2H-indazolyl:
Figure imgf000068_0004
(11) Substituted Iff-benzotriazolyl :
Figure imgf000068_0005
(mm) Substituted 2/f-benzoimidazolyl:
Figure imgf000068_0006
(nn) Substituted 3H-imidazopyridinyl :
Figure imgf000068_0007
(oo) Substituted IH- [l, 2 , 3 ] triazolopyridinyl ;
Figure imgf000069_0001
(pp) Substituted thienopyrimidinyl:
Figure imgf000069_0002
wherein
X and Y are each F, Cl, Br, I, CN, OH, NH2, NO2, CO2H, CO2Me, CO2Bt, CHO, CH(NOMe), methyl, ethyl, n-proyl, n-butyl, cyclopropyl, cyclopropylmethyl or CF3; m and n are 0, 1, 2 and 3.
Claim 14. The method of claim 13 wherein the composition is administered to at least one of the skin, mouth, eye, respiratory tract, urinary tract, reproductive tract, soft tissues and blood of an animal.
Claim 15. The method of claim 13 wherein the animal is a human.
68
SUBSTITUTE SI-IEET (RULE 26) 73
Claim 16, The method of claim 13 wherein the composition is applied to the skin of an animal for topical or transdermal administration.
Claim 17. The method of claim 16, wherein the composition for topical or transdermal administration is in a form selected from the group consisting of powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
Claim 18. The method of claim 13 wherein the disease or condition is caused by or associated with infection with a microbe selected from the group consisting of Streptococcus pyogenes, Staphylococcus aureus, methicillin resistant Staphylococcus aureus ("MRSA"), Staphylococcus epidermidis, Bacillus anthracis, Neisseria gonorrhoeae, Neisseria meningitides, Mycobacteria tuberculosis, vancomycin resistant jSπfcerococcae ("VRE"), Helicobacter pylori, Chlamydia pneumoniae, Chlamydia trachomatis, Campylobacter jejuni, Propionibacterium acnes, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Enterococcus £aecalis, Escherichia coli, Corynebacteriuw όiphthexiae, Morazella catarrhal!-? and Bacillus cereus.
Claim 19. The method of claim 13 wherein the composition is administered two or more times.
Claim 20. The method of claim 13 wherein the compound is administered in a dose of about 0.0001 to about 100 mg per kilogram of body weight per day
Claim 21. The method of claim 13 wherein the compound is administered in an amount of about 0,01 to about 50 mg per kg of body weight per day.
Claim 22. The method of claim 13 wherein the compound is administered in a dose of about 0.1 to about 10 mg per kg of body weight per day
70
SUBSTITUTE SFIEET (RXJIJi 26) Claim 23, The method of claim 13 wherein the dose of compound administered is selected from the group consisting of 5, 10, 25, 50, 100, 125, 150, 200, 250 and 500 mg per kg of body weight per day.
71
SUBSTITUTE 8MJtET (RULE 26)
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US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
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US5186735A (en) * 1986-03-07 1993-02-16 Dowelanco Derivatives of 4-((aryloxy)phenoxy)alkenols and their herbicidal uses
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