EP1060179A1 - Derives d'isoxazoline aminomethyle substitues utiles en tant qu'agents antimicrobiens - Google Patents

Derives d'isoxazoline aminomethyle substitues utiles en tant qu'agents antimicrobiens

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Publication number
EP1060179A1
EP1060179A1 EP99913819A EP99913819A EP1060179A1 EP 1060179 A1 EP1060179 A1 EP 1060179A1 EP 99913819 A EP99913819 A EP 99913819A EP 99913819 A EP99913819 A EP 99913819A EP 1060179 A1 EP1060179 A1 EP 1060179A1
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EP
European Patent Office
Prior art keywords
alkyl
substituted
phenyl
alkoxy
formula
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.)
Withdrawn
Application number
EP99913819A
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German (de)
English (en)
Inventor
Michael R. Barbachyn
Joel Morris
Donn G. Wishka
Richard C. Thomas
David R. Graber
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.)
Pharmacia and Upjohn Co
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Pharmacia and Upjohn Co
Upjohn Co
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 Pharmacia and Upjohn Co, Upjohn Co filed Critical Pharmacia and Upjohn Co
Publication of EP1060179A1 publication Critical patent/EP1060179A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to novel substituted aminoheteroaromatic isoxazoline derivatives, to pharmaceutical compositions containing them as active ingredients, and to methods of using them.
  • the compounds of the invention have antimicrobial activity for preventing and treating infectious diseases.
  • Antibacterial agents such as oxazolidinones are a class of known orally- active, synthetic antibacterial agents and there are numerous references in the art disclosing a variety of oxazolidinone derivatives.
  • U.S. Patent Nos. 4,705,799 and 5,523,403 and European Patent Application 0,316,594 disclose substituted phenyl-2-oxazolidinones, including the sulfides, sulfoxides, sulfones, sulfonamides, nitriles, acetamides and a tropane ring.
  • 4,948,801; 5,254,577 and 5,130,316 disclose arylbenzene oxazolidinyl compounds, wherein the aryl includes the (un)substituted phenyl and pyridyl groups.
  • European Patent Applications 0,697,412; 0,694,544; 0,694,543 and 0,693,491 disclose 5 to 9-membered heteroaryl-oxazolidinones having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen.
  • This invention describes substituted aminoheteroaromatic isoxazoline derivatives useful as antibacterial agents.
  • the compounds of the invention are novel and distinct from antibacterial oxazolidinones in that the usual oxazolidinone rings are replaced by an isoxazoline moiety. These compounds have antibacterial activity comparable to the corresponding oxazolidinones. They are effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium a ⁇ ium.
  • U.S. Patent No. 4,283,403 discloses 3-aryl-2-isoxazolines useful for the protection of plants from diseases.
  • Danish Patent No. 2,725,763 discloses substituted 2-isoxazolines which is fungicidal against phytophthora infestation on tomatoes. The compounds also show antibacterial activity.
  • U.S. Patent No. 3,769,295 discloses nitrofuryl derivatives of 5-substituted isoxazolines useful as antimicrobial agents.
  • WO 95/14680 Al discloses 3-aryl-2-isoxazolines which is useful in inhibiting PDEjy, the treatment of inflammatory diseases and the treatment of AIDs, asthma, arthritis, etc.
  • U.S. Patent No. 5,547,950 discloses oxazolidinones containing a substituted diazine moiety and their use as antimicrobials.
  • the present invention provides a compound of formula I
  • Ring P is (a) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl,
  • a 6-membered heteroaromatic moiety having at least one nitrogen atom wherein the 6-membered heteroaromatic moiety can additionally have a fused- on benzene, naphthyl or 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, or
  • R 9 is O, S, -NR 13 , or -CR 14 R 15 ;
  • carboxamide which may be substituted with a C 1 alkyl or phenyl on the carboxamide nitrogen, or
  • phenyl which may be substituted with one or more halo, -CN, C j . 3 alkoxy, C ⁇ alkoxycarbonyl or C 1 alkyl;
  • R n and R 12 are the same and different and are
  • Ci. 8 alkyl which may be substituted with one or more halo, -CN, -OH, C ⁇ g alkoxy, C ⁇ acyloxy, C ⁇ g alkoxycarbonyl, phenyl, (c) C 8 acyl, which may be substituted with one or more -OH, amino,
  • carboxamide which may be substituted with a C lA alkyl or phenyl on the carboxamide nitrogen, (i) trifluoracetyl, or (j) C w acyl;
  • R 13 is H, -OR 10 , -NHR 10 , or C ⁇ g alkyl, which may be substituted with phenyl;
  • R 14 and R 15 are the same and different and are
  • R 16 is 0, or S
  • R 17 and R lg are the same and different and are
  • R 19 is H, or -CH 3 ;
  • R 21 is H, or -CH 3 ;
  • R 22 is
  • R 25 and R 26 are the same and different and are
  • phenyl which may be substituted with one to more halo, C ⁇ alkoxy, -OH, amino or C 1 alkyl;
  • R 29 is C ⁇ g ⁇ alkyl, or phenyl
  • R 30 is independently
  • R 34 and R 35 are the same and different and are
  • R 34 and R 35 may combine together to form
  • thiomorpholino wherein groups (h) to (1) may be substituted with C ⁇ g alkyl or -(CH 2 ) m -OH; R 42 and R 43 are the same and different and are
  • •_ is a double bond or a single bond; i is 1 or 2; m is 0, 1 or 2; n is 0 or 1; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4.
  • the present invention provides compounds of formula II
  • Ring T is a 6-membered heteroaromatic moiety having one to three nitrogen atoms, wherein the 6-membered heteroaromatic moiety has a fused-on 5-membered heteroaromatic moiety which in turn has one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms;
  • X is
  • R 48 and R 49 are the same and different and are (a) H,
  • R 48 and R 49 taken together with the nitrogen atom is a 5-, 6- membered heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C ⁇ alkyl, or C ⁇ acyl;
  • R 52 and R 53 are the same and different and are
  • These compounds have antimicrobial activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply- resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium a ⁇ ium.
  • gram-positive aerobic bacteria such as multiply- resistant staphylococci and streptococci
  • anaerobic organisms such as bacteroides and clostridia species
  • acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium a ⁇ ium.
  • the carbon 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 C ⁇ defines the number of carbon atoms present from the integer "i" to the integer "j", inclusive.
  • C j . 4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
  • C ⁇ alkyl refers to an alkyl group having one to three, one to four, one to six, or one to eight carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms thereof.
  • C 2 . 8 alkenyl refers to at least one double bond alkenyl group having two eight carbon atoms such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, and their isomeric forms thereof.
  • C 3 . 6 cycloalkyl and “C 3 . 8 cycloalkyl” refer to a cycloalkyl having three to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.
  • C w alkoxy refers to an alkyl group having one to three, one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.
  • C ⁇ alkoxycarbonyl refers to a -C0 2 R group, wherein R' is an alkyl group of one to three, one to six, or one to eight carbon atoms and their isomeric forms thereof.
  • C ⁇ hydroxyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group.
  • C ⁇ g alkylthio refers to an alkyl group having one to six carbon atoms and isomeric forms thereof attached to a sulfur atom.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • the compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.
  • pharmaceutically acceptable salts refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form.
  • the compounds of formula I of this invention contain a chiral center at C5 of the isoxazoline ring, and as such there exist two enantiomers or a racemic mixture of both.
  • This invention relates to both the enantiomers, as well as mixtures containing both the isomers.
  • the preferred enantiomer is the one having (R) - absolute configuration at C-5 of the isoxazoline ring.
  • additional chiral centers and other isomeric forms may be present
  • Ring P or Ring T below contained in the compounds formula I or formula II are typical heteroaromatic isoxazolines of this invention. It will be understood that the named heteroaromatic moiety do not limit the scope of the invention, but are named merely to help one skilled in the art to understand the invention.
  • the compounds of this invention can be prepared in accordance to one or more of the processes discussed below.
  • SCHEMES I, II, III, IV and V below X, Y, Q and R x are as defined previously; A is a halogen atom or substituent Q.
  • halogenated heteroaromatic aldehyde 1 can be converted to the corresponding nitrile oxide 2 via three steps: formation of the corresponding oxime, halogenation of resultant oxime to generate an intermediate hydroximinoyl halide, and treatment of this intermediate with a suitable base such
  • nitrile oxide 2 undergoes a 1,3-dipolar cycloaddition with 3, either allylic amides (wherein R x is C ⁇ alkyl) or carbamates (R x is O-alkyl), to generate isoxazolines of structure 4 (wherein W is oxygen atom).
  • Compounds 4 are either examples of compounds of formula I of the present invention or are the intermediates that can be further elaborated to compounds of formula I of the present invention.
  • A is a halogen atom (preferably a fluoro atom)
  • a suitable base such as, for example, dipotassium hydrogenphosphate, potassium carbonate, sodium hydride, or excess amines
  • a suitable solvent such as, for example, N,N-dimethylformamide, dimethylsul
  • the nitrile oxide 2 can be reacted with allyl alcohol to generate 5-(hydroxymethyl)isoxazolines 5. Then, the structure 5 is converted to the corresponding alkylsulfonate or arylsulfonate 6.
  • a representative alkylsulfonyl derivative, the mesylate (Re CH 3 ), is prepared by reacting 5 with methanesulfonyl chloride in pyridine/dichloromethane or methanesulfonyl chloride and triethylamine in dichloromethane.
  • arylsulfonyl chloride reagents for example, p- toluenesulfonyl chloride in pyridine or 3-nitrobenzenesulfonyl chloride and triethylamine in dichloromethane, affords aryl sulfonates such as tosylate (R c is p- tolyl) or nosylate (R c is 3-nitrophenyl), respectively.
  • the mesylate or nosylate derivative 6 is then converted to the corresponding 5-(aminomethyl) isoxazoline 7 by treatment with aqueous ammonia in a suitable solvent system, for example acetonitrile/isopropanol or tetrahydrofuran isopropanol, in a sealed reaction vessel, and at a suitable temperature in the range from 40 to 90 °C.
  • a suitable solvent system for example acetonitrile/isopropanol or tetrahydrofuran isopropanol
  • the sulfonate 6 can be reacted with an azide source such as sodium or potassium azide in an aprotic solvent such as N,N-dimethylformamide or l-methyl-2-pyrrolidinone optionally in the presence of a catalyst such as 18-crown-6 at a temperature of 50 to 90 °C to generate the corresponding ⁇ -(azidomethyl) isoxazoline.
  • an azide source such as sodium or potassium azide
  • an aprotic solvent such as N,N-dimethylformamide or l-methyl-2-pyrrolidinone
  • a catalyst such as 18-crown-6 at a temperature of 50 to 90 °C
  • the azide moiety is then reduced by hydrogenation with a palladium or platinum catalyst in a suitable solvent such as ethyl acetate or methanol to give 7.
  • the azidomethyl intermediate can be reduced to the corresponding amine 7 by a two-step process involving treatment with a trivalent phosphorus compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran followed by hydrolysis of the resultant iminophosphorane with water.
  • a trivalent phosphorus compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran
  • the amine 7 is then converted to the isoxazoline derivatives 3 by reactions known to those skilled in the art.
  • the amine 7 can be reacted with an acid chloride or anhydride in a basic solvent system such as pyridine or triethylamine/dichloromethane at a temperature ranging from -30 to 30 °C to provide the acylated compound 4 (wherein W is oxygen atom).
  • a halogenated heteroaromatic ester of structure 8 (wherein halogen is preferably a fluorine atom) is reacted with morpholine (wherein E is oxygen atom) or thiomorpholine (wherein E is sulfur atom), in the presence of a suitable base such as dipotassium hydrogenphosphate, in an appropriate solvent such as dimethylsulfoxide, and at a suitable temperature in the range from 60 to 100 °C, to provide the morpholino adduct 9.
  • a suitable base such as dipotassium hydrogenphosphate
  • ester moiety of 9 is then reduced to the corresponding heteroaromatic alcohol 10 with an appropriate reducing agent, such as lithium aluminum hydride and the like, in a suitable solvent, for example tetrahydrofuran, and at a suitable temperature in the range from -20 to 0 °C.
  • an appropriate reducing agent such as lithium aluminum hydride and the like
  • a suitable solvent for example tetrahydrofuran
  • the product alcohol 10 is then oxidized, employing catalytic tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in dichloromethane, to the corresponding carboxaldehyde 11.
  • the remaining synthetic product alcohol 10 is then oxidized, employing catalytic tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in dichloromethane, to the corresponding carboxaldehyde 11.
  • the remaining synthetic product alcohol 10 is then oxidized, employing catalytic tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in dichloromethane, to the corresponding carboxaldehyde 11.
  • Enantiomerically enriched heteroaromatic isoxazolines of formula I may be obtained through the racemic phenylisoxazolines 3 or 4 by employing high pressure liquid chromatography (HPLC) over a chiral stationary phase. In a typical separation, the mixture of enantiomers is chromatographed with a 5x50 cm
  • reaction of nitrile oxides 2 with ⁇ , ⁇ -unsaturated esters or amides 14 undergoes an asymmetric 1,3-dipolar cycloaddition to provide compound 15.
  • group R d of compound 14 is a chiral auxiliary used to control the direction of asymmetric induction, and therefore it allows the asymmetric cycloaddition to occur with high steroselectivity.
  • Compound 14 can be prepared from, among the others, Kemp's triacid, Oppolzer's sultam, or cbiro-inositol as described in such references as D. P. Curran et al., J. Am. Chem. Soc, 1989, Vol.
  • the enantiomeric cycloadducts 15 may be further purified by recrystallization or chromatography. Treatment of the cycloadducts 15 with a suitable reducing agent such as L-selectride (commercially available) in an appropriate solvent such as tetrahydrofuran then provides the enantiomerically enriched ⁇ -(hydroxymethyl) isoxazolines 16. The remaining synthetic steps which lead 16 to enantiomerically enriched heteroaromatic isoxazolines 4A are similar to the procedures outlined in SCHEME II.
  • compound 16 may prepared by treatment of nitrile oxide 2 with an allyl alcohol via a highly enantioselective 1,3-dipolar cycloaddition as shown in SCHEME V.
  • reaction occurs in the presence of diethylzinc and (R,R)- and (S,S)- tartaric acid esters, preferably, diisopropyl esters, in a suitable solvent such as chloroform or dichloromethane and at a temperature in the range of about -20 to 0 °C.
  • a suitable solvent such as chloroform or dichloromethane
  • compositions of this invention may be prepared by combining the compounds of formula I of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.
  • Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories.
  • a solid carrier can be at least one substance which may also function as a diluent, flavoring agent, soiubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • composition is provided by employing conventional techniques.
  • composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula I according to
  • the quantity of active component that is, the compounds of formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • the compounds or pharmaceutical compositions thereof will be administered orally, parenterally, transdermally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
  • a concentration that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
  • such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100 mg/kg, more preferably about 3.0 to about 50 mg kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compounds being used.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
  • the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day. These compounds are useful for the treatment of microbial infections in humans and other warm blooded animals by either oral, parenteral, topical, or transdermal administration. In general, the preferred form of administration is orally.
  • compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5 - 6.
  • a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5 - 6.
  • Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine, to name a few.
  • the compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml.
  • the compounds of formula I according to this invention are advantageously administered orally in solid and liquid dosage forms.
  • the compounds of this invention are useful antimicrobial agents, effective against various human and veterinary pathogens, including multiply-resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-resistant organisms such as Mycobacterium tuberculosis and Mycobacterium a ⁇ ium. Humans or animals infected with such pathogens are readily diagnosed by a physician or veterinarian of ordinary skill, throughout the specification, it is intended that citations to the literature are expressly incorporated by reference herein.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'isoxazoline aminohétéroaromatique substitués représentés par la formule (I), dans laquelle R1 représente H, alkyle, cycloalkyle, alcoxy ou alkylamino: Y représente H, F ou CH3; W représente O ou S; le noyau P représente une fraction hétéroaromatique à 5 éléments comprenant un à trois atomes sélectionnés dans le groupe constitué d'atomes de soufre, d'azote et d'oxygène, cette fraction hétéroaromatique à 5 éléments pouvant en outre comprendre un naphtyle ou un benzène fusionné, une fraction hétéroaromatique à 6 éléments qui comprend au moins un atome d'azote, cette fraction hétéroaromatique à 6 éléments pouvant en outre comprendre un naphtyle ou un benzène fusionné ou une fraction hétéroaromatique à 5 éléments qui comprend de un à trois atomes sélectionnés dans le groupe constitué d'atomes de soufre, d'azote et d'oxygène; Q représente une fraction hétérocyclique à 4, 5, 6, 7 ou 9 éléments qui comprennent au moins un azote, un soufre et/ou un oxygène. Les composés selon l'invention possèdent une activité antimicrobienne élevée pour prévenir et traiter des maladies infectieuses.
EP99913819A 1998-02-25 1999-02-10 Derives d'isoxazoline aminomethyle substitues utiles en tant qu'agents antimicrobiens Withdrawn EP1060179A1 (fr)

Applications Claiming Priority (3)

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US7591498P 1998-02-25 1998-02-25
US75914P 1998-02-25
PCT/US1999/004262 WO1999043671A1 (fr) 1998-02-25 1999-02-10 Derives d'isoxazoline aminomethyle substitues utiles en tant qu'agents antimicrobiens

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JP (1) JP2002504550A (fr)
AU (1) AU3180999A (fr)
CA (1) CA2318762A1 (fr)
WO (1) WO1999043671A1 (fr)

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EP3541792B1 (fr) 2016-11-16 2020-12-23 Amgen Inc. Composés de triazole furane utilisés en tant qu'agonistes du récepteur apj
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CA2318762A1 (fr) 1999-09-02
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WO1999043671A1 (fr) 1999-09-02

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