[go: up one dir, main page]

WO2007079173A2 - Nouveaux dérivés de 2-hétéroaryloxyphénol au titre d'agents antibactériens - Google Patents

Nouveaux dérivés de 2-hétéroaryloxyphénol au titre d'agents antibactériens Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
methyl
phenol
yloxy
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2006/049473
Other languages
English (en)
Other versions
WO2007079173A3 (fr
Inventor
Liren Huang
Joanna Clancy
Christopher Taylor
Weitao Pan
Alenka Tomazic
W. James Jackson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Emergent Biosolutions Inc
Original Assignee
Emergent Biosolutions Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Emergent Biosolutions Inc filed Critical Emergent Biosolutions Inc
Publication of WO2007079173A2 publication Critical patent/WO2007079173A2/fr
Publication of WO2007079173A3 publication Critical patent/WO2007079173A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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] ⁇ .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des composés et préparations antimicrobiens et des méthodes de traitement par administration desdits composés et préparations, lesdits composés étant des dérivés de 2-hétéroaryloxyphénol. La présente invention concerne également des méthodes de synthèse et de formation desdits composés, lesdits composés étant de façon générale de Formule 1.
PCT/US2006/049473 2005-12-30 2006-12-29 Nouveaux dérivés de 2-hétéroaryloxyphénol au titre d'agents antibactériens Ceased WO2007079173A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85333405P 2005-12-30 2005-12-30
US60/853,334 2005-12-30

Publications (2)

Publication Number Publication Date
WO2007079173A2 true WO2007079173A2 (fr) 2007-07-12
WO2007079173A3 WO2007079173A3 (fr) 2007-11-15

Family

ID=38228847

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/049473 Ceased WO2007079173A2 (fr) 2005-12-30 2006-12-29 Nouveaux dérivés de 2-hétéroaryloxyphénol au titre d'agents antibactériens

Country Status (1)

Country Link
WO (1) WO2007079173A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011144578A1 (fr) * 2010-05-17 2011-11-24 Senexis Limited Composés

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4266063A (en) * 1979-12-17 1981-05-05 E. I. Du Pont De Nemours And Company Process for preparing substituted pyridinyloxy ether intermediate
US5186735A (en) * 1986-03-07 1993-02-16 Dowelanco Derivatives of 4-((aryloxy)phenoxy)alkenols and their herbicidal uses
UY25225A1 (es) * 1997-10-29 2000-12-29 Smithkline Beecham Plc Derivados de pleuromutilina utiles como agentes antimicrobianos
US6946458B2 (en) * 1999-07-22 2005-09-20 University Of South Florida N-thiolated beta-lactams: novel antibacterial agents for methicillin-resistant Staphylococcus aureus
PL358666A1 (en) * 2000-04-04 2004-08-09 Smithkline Beecham Plc 2-hydroxy-mutilin carbamate derivatives for antibacterial use
WO2004047724A2 (fr) * 2002-05-16 2004-06-10 Genelabs Technologies, Inc Composes aryle et heteroaryle a action anti-bacterienne et anti-fongique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011144578A1 (fr) * 2010-05-17 2011-11-24 Senexis Limited Composés

Also Published As

Publication number Publication date
WO2007079173A3 (fr) 2007-11-15

Similar Documents

Publication Publication Date Title
USRE49500E1 (en) Pyrrole inhibitors of ERK protein kinase, synthesis thereof and intermediates thereto
US9994575B2 (en) Compositions useful for treating disorders related to kit
JP5855250B2 (ja) イミダゾオキサジン化合物による抗腫瘍効果増強剤
US20160297761A1 (en) Novel inhibitors of glutaminase
CN101184734A (zh) 治疗细胞增殖紊乱的化合物和方法
CN111484481A (zh) 哒嗪酮类衍生物、其制备方法及其在医药上的用途
US5786350A (en) 36-derivatives of rifamycins and their use as antimicrobial agents
KR100550078B1 (ko) 퀴놀론카본산 유도체 또는 그 염
KR20190120786A (ko) 디히드로오로테이트 옥시게나제 억제제로서의 1,4,6-삼치환된-2-알킬-1H-벤조[d]이미다졸 유도체
CN106660962A (zh) 用作选择性抗菌剂的含2‑吡啶酮部分的芳基酰肼
WO2007079173A2 (fr) Nouveaux dérivés de 2-hétéroaryloxyphénol au titre d'agents antibactériens
CN111936493A (zh) 一种高选择性FGFRi抑制剂及其制备方法和应用
WO2023143135A1 (fr) Dérivé de quinazoline et son utilisation
WO2007027878A2 (fr) Derives de 2-aryloxyphenol 4-substitues utilises comme agents antibacteriens
CA2603320A1 (fr) Derive de pyridylmethylsulfone
US6818642B2 (en) Benzylaminopyrimidines
EP4023642A1 (fr) Inhibiteur de jnk, et composition pharmaceutique et utilisation associée
WO2024131938A1 (fr) Composé de quinazoline et son utilisation
WO2024220556A2 (fr) Agents de dégradation hétérocycliques à petites molécules sumo1 et leur utilisation
JP2013500310A (ja) 抗腫瘍１，２−ジフェニルピロール化合物及びその調製方法
HK40021464A (en) Pyrrole compounds as inhibitors of erk protein kinases and pharmaceutical compositions containing these compounds
HK40021464B (en) Pyrrole compounds as inhibitors of erk protein kinases and pharmaceutical compositions containing these compounds
HK1232860A1 (en) Arylhydrazides containing a 2-pyridone moiety as selective antibacterial agents
HK1247910B (en) Pyrrole compounds as inhibitors of erk protein kinases and pharmaceutical compositions containing these compounds
HK1203505B (en) Pyrrole compounds as inhibitors of erk protein kinases and pharmaceutical compositions containing these compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06848269

Country of ref document: EP

Kind code of ref document: A2