WO1999048461A2 - Composes aromatiques substitues pour le traitement d'infections resistant aux antibiotiques - Google Patents

Composes aromatiques substitues pour le traitement d'infections resistant aux antibiotiques Download PDF

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Publication number
WO1999048461A2
WO1999048461A2 PCT/US1999/006494 US9906494W WO9948461A2 WO 1999048461 A2 WO1999048461 A2 WO 1999048461A2 US 9906494 W US9906494 W US 9906494W WO 9948461 A2 WO9948461 A2 WO 9948461A2
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Prior art keywords
alkyl
carbons
halo
alkenyl
ring system
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Application number
PCT/US1999/006494
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English (en)
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WO1999048461A3 (fr
Inventor
William Y. Ellis
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Department Of The Army, U.S. Government
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.)
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Publication date
Application filed by Department Of The Army, U.S. Government filed Critical Department Of The Army, U.S. Government
Priority to GB9909183A priority Critical patent/GB2333454B/en
Priority to CA002325689A priority patent/CA2325689A1/fr
Priority to JP2000537515A priority patent/JP2002507557A/ja
Priority to EP99911497A priority patent/EP1066035A4/fr
Priority to AU30126/99A priority patent/AU3012699A/en
Publication of WO1999048461A2 publication Critical patent/WO1999048461A2/fr
Publication of WO1999048461A3 publication Critical patent/WO1999048461A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/24—Anthracenes; Hydrogenated anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • compositions of the invention contain as active agents compounds containing aryl ring systems, including phenyl, naphthyl and anthracene ring systems, substituted by a carbon bound to an oxygen which is also bound to a nitrogen through a saturated carbon or carbon chain which may be substituted with halo, hydroxy, alkoxy, amino or alkylamino are disclosed,
  • the aryl ring system is further substituted by at least two halo substituents or halo-substituted substituents.
  • Halofantrine is a known antimalarial having a phenan- threne ring system substituted by a carbon bound to an oxygen which is also bound to a nitrogen through a saturated CH 2 -CH 2 chain to tertiary nitrogen having two butyl substituents.
  • the phenanthrene ring system is further substituted with 2 chlorines and one trifluoromethyl.
  • This invention relates to compounds of the general formula: wherein A is a aromatic hydrocarbon ring system and R 1 is a carbon bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon and wherein at least one of R 2 , R 3 and R is an electron-rich substituent.
  • the active agents are useful for treating patients suffering from infections including gram positive organisms, such as streptococcus, staphylococcus, anthracis, gram negative bacteria such as neisseria species, yeasts and mycobacterium. These compounds are effective against strains which have shown resistance to other antimicrobial agents .
  • infections including gram positive organisms, such as streptococcus, staphylococcus, anthracis, gram negative bacteria such as neisseria species, yeasts and mycobacterium.
  • This invention relates to compounds that have use in treating several infectious diseases which are now resistant to treatment to conventionally used antibiotics. Some of the compounds described herein have had previously been suggested for use in treating malaria. Some of the compounds are newly discovered. Most of the compounds are lipophilic. The lipid solubility of these compounds should permit the drugs to enter into cells, including cells of the central nervous system. Many of the compounds could be also be absorbed from the intestinal tract when given orally. They may be administered as cyclodextrin inclusion complexes to increase bioavailability. They may also be administered transdermally. Using patches for transdermal administration makes it possible to more easily control dosage.
  • R 1 is of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carbox- yl , ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, a ino, or alkyl a ino group, X is (CH 2 ) L N( (CH2) n (CH 3 ) ) m wherein is 1-3, n is ⁇ 6, m is 1 v or 2 with the proviso that when m is 2, at least one n is ⁇ 3, or X may
  • R 2 , R 3 and R 4 may be alkyl (including cycloalkyl) , a saturated, nitrogen-containing ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl , carboxyalkyl, hydroxy, halo, alkenyl, alkenyloxy, haloalkyl (including perhaloalkyl) , wherein any alkyl has 1-8 carbons, alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings with the provision that
  • Z and X may be linked to form a heterocylic ring system.
  • any alkyl or aryl at R 2 , R 3 and R 4 may be further substituted with aryl of 1-2 rings, halo, (including multiple halo substitutions) alkyl, haloalkyl or alkoxy.
  • Preferred halo substituents are chloro or bromo and a preferred haloalkyl is trifluoromethyl .
  • Particularly useful compounds are those of Formulas I, II, III and IV.
  • any of R 28 may be substituents designated under R 2 , R 3 and R in the general formula above, with the proviso that at least one of R 2 _ 8 is an electron- rich substituent and any one of R ]( R 9 or R 10 is a substituent as defined as R 1 in the general formula.
  • Preferred compounds are those having at least two halos groups on the compound, with chloro or trifluoromethyl being particularly preferred groups.
  • any of R 2 _ 8 may be substituents identified as R 2 , R 3 or R in the general formula with the proviso that at least one substituents is an electron-rich moiety and R 1 is as designated for R 1 (CHOZX) for the general formula above.
  • R 1 is as designated for R 1 (CHOZX) for the general formula above.
  • Many of the preferred compounds have at least two halo or halo-substituted substituents.
  • R 1 is defined as in the general formula and R 2.6 is defined in the same manner as R 2 , R 3 and R 4 in the general formula. May of the preferred compounds have least two halo or halo-substituted substituents.
  • a particularly valuable compound of Formula II is of the formula:
  • R 1 is a carbon bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon and is of the structure CHOZX wherein Z may be hydrogen, a second bond to the oxygen, or may be carboxyl , ether or ester moiety wherein the ether or ester moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl moiety consists of 1-4 carbons and wherein any said alkyl or phenyl group may, additionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group, X is (CH 2 ) ,N ( (CH2) n (CH 3 ) ) m wherein , is 1-3, n is ⁇ 6, m is 1 or 2 with the proviso that when m is 2 , at least one n is ⁇ 3, or X may be (CH 2 ) o J as defined in the
  • halo substituents are chloro or bromo and preferred haloalkyl is tri- fluoromethyl .
  • a particularly useful member of this group of compounds is desbutylhalofantrin, a compound of the formula: which has now been found to be superior to halofantrine for treatment of malaria. (See U.S. Patent 5,711,966, which is incorporated herein by reference in its entirety.)
  • the phenanthrenes may be made by several methods, including the following scheme:
  • the phenanthrene compounds may also be prepared using the phenanthroic acid chlorides.
  • Example 1 The phenanthrene compounds may also be prepared using the phenanthroic acid chlorides.
  • the strains were streaked on blood agar plates (trypti- case soy broth containing 5% sheep cells) .
  • a single colony was isolated and grown in Mueller-Hinton Broth (MHB) as recommended by the national Committee for Clinical Laboratory Standards for rapidly growing bacteria.
  • MHB Mueller-Hinton Broth
  • Candida species and related yeasts were isolated in a similar manner on brain-heart infusion agar (BHI) .
  • Susceptibility tests The antibiotic susceptibility profile of each strain was determined using standard microtiter dilution plates obtained from the Clinical Microbiology Laboratory at Ohio State University Hospitals. The Inocula were prepared by suspending a 4 hour log phase growth in MHB visually egual in turbidity of an 0.5 McFarland standard.
  • Inocula were further diluted and added to microdilution trays to achieve a final density of approximately 1 x 10 5 CFU/ml .
  • the trays were incubated for 16 to 20 hours at 35 °C.
  • the highest dilution at which wells remained clear was considered to be the minimum inhibitory concentration (MIC) .
  • the MIC and minimum bacterial concentration (MBC) of the strains to the active agents were determined by two-fold dilutions in Mueller-Hinton broth.
  • Susceptibility tests for ATCC-obtained microorganisms and clinical isolates of gram positive bacteria including methicillin-susceptible and resistant staphylococci , streptococci, pneumococci and gram negative bacteria, including Enterobacteriaceae, Pseudomo- nas, Hemophilus and Neisseria were performed in microtiter plates as described above.
  • Compounds of the invention were dissolved in 1 ml of methanol and stored in aliguots at -70 °C. They were diluted in Mueller-Hinton broth for final screening. Compositions were tested in 0.1 ml volumes by serial dilution in microtiter plates against Staphylococcus aureus methicillin- sensitive ATCC 29213 and the ethicillin-resistant wild type T67738, as described above. The T67738 was resistant to most antimicrobial drugs, including ciprofloxacin.
  • the dosage and method of administration will depend on the location of the infection, the condition of the patient and the availability of professional supervision. Methods of administration include parenteral, oral, buccal, nasal or endotracheal routes.
  • the active agents may be administered as sprays.
  • the active agent may be delivered as a powder that is snorted. Inclusion complexes such as cyclodextrin inclusion complexes would be particularly useful for buccal administration of these active agents.
  • the compounds of the invention may also be admin- istered topically by any means, including by rectal route.
  • Suppositories, solutions for use as retention enemas, and creams or jellies are appropriate carriers for use in rectal administration.
  • the agents may be administered directly to infected tissue.
  • the active agents may be administered in the form of sprays or ointments.
  • Compounds of the invention may be applied to the skin or mucosa, including the vaginal mucosa, using creams, jellies, suppositories, or solutions.
  • the active agents of the invention may be delivered directly to the epithelial tissue topically.
  • compositions containing the active agents of the invention to the applied directly to target tissues and prosthetic devices could be given by aerosol into the trachea or administered in mist along with other agents into the respiratory tract.
  • the compositions of the invention may also be used prophylactically to protect from infection by pathogenic organisms .
  • Capsules of a formulation of active agent designated #184366 for oral administration are prepared by containing 250 mg. of the active agent, 100 mg. starch, and 5 mg. magnesium stearate. The capsules are administered daily or twice a day to achieve a daily dosage of 500 mg. per day.
  • Example 3
  • a preparation for application to the skin or mucosa may be prepared in the following manner: Ingredient %w/w
  • Example 4 A formulation for administration as a retention enema may be formulated in the following manner:
  • the active agent When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
  • Example 5 When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
  • Example 6 To 15 ml of phosphate buffered saline is added 3 mg of compound #185308. The composition is placed in a bottle having a stopper with a smooth glass rod extending into the solution. The composition is applied to boils using the smooth glass rod as an applicator. The composition may also be administered as a spray from a bottle with an atomizer.
  • Example 6 To 15 ml of phosphate buffered saline is added 3 mg of compound #185308. The composition is placed in a bottle having a stopper with a smooth glass rod extending into the solution. The composition is applied to boils using the smooth glass rod as an applicator. The composition may also be administered as a spray from a bottle with an atomizer.
  • Example 6 Example 6 :
  • a composition is prepared for use on the skin or mucosa in the following manner:
  • Phosphate buffered saline 86.5% When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
  • composition prepared as a gel for application to the skin :
  • composition prepared for administration as a supposi- tory is a composition prepared for administration as a supposi- tory:
  • Active agent #185308 0.5 mg glyceryl monosterate 1.0 Gm hydrogenated coconut oil 1.0 Gm glyceryl monopalmitate 1.0 Gm
  • Active agent #185308 0.5 mg glyceryl monosterate 1.0 Gm hydrogenated coconut oil 1.0 Gm glyceryl monopalmitate 1.0 Gm
  • Example 10
  • composition for intravenous administration comprising:
  • Example 11 Capsules of a formulation of active agent designated
  • Example 12 For oral administration are prepared by containing 250 mg. of the active agent, 100 mg. starch, and 5 mg. magnesium stearate. The capsules are administered daily or twice a day to achieve a daily dosage of 500 mg. per day.
  • Example 12 Example 12
  • a preparation for application to the skin or mucosa may be prepared in the following manner: Ingredient %w/w
  • Example 13 A formulation for administration as a retention enema may be formulated in the following manner:
  • Example 14 When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
  • Example 14 When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
  • Example 15 To 15 ml of phosphate buffered saline is added 3 mg of compound #11. The composition is placed in a bottle having a stopper with a smooth glass rod extending into the solution. The composition is applied to boils using the smooth glass rod as an applicator. The composition may also be administered as a spray from a bottle with an atomizer.
  • Example 15 To 15 ml of phosphate buffered saline is added 3 mg of compound #11. The composition is placed in a bottle having a stopper with a smooth glass rod extending into the solution. The composition is applied to boils using the smooth glass rod as an applicator. The composition may also be administered as a spray from a bottle with an atomizer.
  • Example 15 Example 15:
  • Example 16 To a 4 X 4 inch bandage having a smooth surface on one side there is applied to the smooth surface .02 ml of the solution prepared as a 2 ⁇ M solution of active agent designated # 4 in PBS . The prepared bandage is then enclosed in a foil covering which is made air-tight. For application, the bandage is unwrapped and is applied smooth side down on the wound .
  • Example 16 To a 4 X 4 inch bandage having a smooth surface on one side there is applied to the smooth surface .02 ml of the solution prepared as a 2 ⁇ M solution of active agent designated # 4 in PBS . The prepared bandage is then enclosed in a foil covering which is made air-tight. For application, the bandage is unwrapped and is applied smooth side down on the wound .
  • Example 16 Example 16:
  • a composition is prepared for use on the skin or mucosa in the following manner: Ingredient %w/w
  • Phosphate buffered saline 86.5% When the active agent is administered to the mucosa of the oral cavity, it may be administered as a buccal tablet or spray for use in the oral-pharyngeal cavity and the nasal cavities.
  • composition prepared as a gel for application to the skin :
  • composition prepared for administration as a supposi- tory is a composition prepared for administration as a supposi- tory:
  • composition for intravenous administration comprising:
  • Desbutylhalofantrine 300 mg. 10% glucose in 1/2 normal saline to 300 ml.
  • compositions for intravenous administration are particularly valuable for administration intravenously during heart surgery and to patients suffering from endocar- ditis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés de formule générale (Y) dans laquelle A représente un hydrocarbure aromatique cyclique et R1 représente un carbone directement lié à un oxygène, et également lié à un azote par l'intermédiaire d'un carbone saturé, l'un au moins parmi R2, R3 et R4 représentant un substituant riche en électrons. Ces agents actifs sont utiles pour traiter des patients souffrant d'infections à organismes gram-positifs, tels que le streptocoque, le staphylocoque, l'anthracis, des bactéries gram-négatives comme celle de l'espèce Neisseria, des levures et des mycobactéries. Ces agents sont efficaces contre les souches dont on connaît la résistance à d'autres agents antimicrobiens.
PCT/US1999/006494 1998-03-26 1999-03-25 Composes aromatiques substitues pour le traitement d'infections resistant aux antibiotiques WO1999048461A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
GB9909183A GB2333454B (en) 1998-03-26 1999-03-25 Substituted aromatic compounds for treatment of antibiotic resistant infections
CA002325689A CA2325689A1 (fr) 1998-03-26 1999-03-25 Composes aromatiques substitues pour le traitement d'infections resistant aux antibiotiques
JP2000537515A JP2002507557A (ja) 1998-03-26 1999-03-25 抗生物質抵抗性感染の処置のための置換芳香族化合物
EP99911497A EP1066035A4 (fr) 1998-03-26 1999-03-25 Composes aromatiques substitues pour le traitement d'infections resistant aux antibiotiques
AU30126/99A AU3012699A (en) 1998-03-26 1999-03-25 Substituted aromatic compounds for treatment of antibiotic resistant infections

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7938398P 1998-03-26 1998-03-26
US60/079,383 1998-03-26

Publications (2)

Publication Number Publication Date
WO1999048461A2 true WO1999048461A2 (fr) 1999-09-30
WO1999048461A3 WO1999048461A3 (fr) 1999-12-16

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EP (1) EP1066035A4 (fr)
JP (1) JP2002507557A (fr)
AU (1) AU3012699A (fr)
CA (1) CA2325689A1 (fr)
GB (1) GB2333454B (fr)
WO (1) WO1999048461A2 (fr)

Cited By (7)

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WO2004089947A2 (fr) * 2003-04-08 2004-10-21 Morphochem Ag Nouveaux composes a activite antibacterienne
DE102010055322A1 (de) * 2010-12-21 2012-06-21 Christian-Albrechts-Universität Zu Kiel Antibakteriell und antimykotisch wirkende Substanzen
US8455490B2 (en) 2003-03-17 2013-06-04 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
US8889163B2 (en) 2001-03-08 2014-11-18 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers as anti-infective agents
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof

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US4327022A (en) * 1973-08-16 1982-04-27 Sterling Drug Inc. Heterocyclic alkyl naphthols
IL60530A (en) * 1979-08-16 1984-10-31 American Cyanamid Co Animal feed compositions useful as growth promotors and for reduction of fat in animals,comprising phenylethanolamine derivatives and certain such novel compounds
US5711966A (en) * 1995-08-25 1998-01-27 Woosley; Raymond Method of treating malaria with desbutylhalofantrine

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US5461078A (en) * 1991-04-12 1995-10-24 British Technology Group Limited Anti-cancer compounds

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889163B2 (en) 2001-03-08 2014-11-18 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers as anti-infective agents
US8455490B2 (en) 2003-03-17 2013-06-04 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
WO2004089947A2 (fr) * 2003-04-08 2004-10-21 Morphochem Ag Nouveaux composes a activite antibacterienne
WO2004089947A3 (fr) * 2003-04-08 2005-01-06 Morphochem Ag Nouveaux composes a activite antibacterienne
DE102010055322A1 (de) * 2010-12-21 2012-06-21 Christian-Albrechts-Universität Zu Kiel Antibakteriell und antimykotisch wirkende Substanzen
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11396513B2 (en) 2017-03-20 2022-07-26 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
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US11844787B2 (en) 2018-09-19 2023-12-19 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US11980611B2 (en) 2018-09-19 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound

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WO1999048461A3 (fr) 1999-12-16
GB2333454A (en) 1999-07-28
JP2002507557A (ja) 2002-03-12
AU3012699A (en) 1999-10-18
EP1066035A2 (fr) 2001-01-10
GB2333454B (en) 2000-08-09
EP1066035A4 (fr) 2001-05-09
CA2325689A1 (fr) 1999-09-30

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