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WO1992004334A1 - Composes - Google Patents

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Publication number
WO1992004334A1
WO1992004334A1 PCT/GB1991/001545 GB9101545W WO9204334A1 WO 1992004334 A1 WO1992004334 A1 WO 1992004334A1 GB 9101545 W GB9101545 W GB 9101545W WO 9204334 A1 WO9204334 A1 WO 9204334A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitrogen
group
compound
diphenyltriazole
compounds
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/GB1991/001545
Other languages
English (en)
Inventor
Deirdre Mary Bernadette Hickey
David Gwynn Cooper
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.)
Smith Kline and French Laboratories Ltd
Original Assignee
Smith Kline and French Laboratories Ltd
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 Smith Kline and French Laboratories Ltd filed Critical Smith Kline and French Laboratories Ltd
Publication of WO1992004334A1 publication Critical patent/WO1992004334A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel substituted heterocyclic compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • the present invention therefore provides in a first aspect compounds of structure (I) :
  • each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl;
  • X is nitrogen or CR 1
  • Y is nitrogen, N(CH 2 ) n A or C(CH 2 ) n A
  • Z is nitrogen, oxygen or N(CH 2 ) n A, and the dotted line indicates the optional presence of a double bond so as to form a fully unsaturated heterocyclic ring;
  • R 1 is hydrogen, C 1 _ 4 al yl, optionally substituted phenyl or optionally substituted heteroaryl; n is 4 to 12; and
  • A is C0 2 H or a group hydrolysable to C0 2 H, 5-tetrazolyl, S0 3 H, P(0)(OR) 2 , P(0)(OH) 2 , or
  • ° X, Y and Z are not all at the same time, nitrogen; 0 when X is CR 1 , Y and Z are not both nitrogen; ° when Y is N(CH 2 ) n A, Z is nitrogen; and ° when Z is oxygen, Y is C(CH ) n A.
  • each group Ar is the same and is optionally substituted phenyl or optionally substituted heteroaryl. More suitably, each group Ar is the same and is optionally substituted phenyl. Preferably each group Ar is the same and is unsubstituted phenyl.
  • X is nitrogen or CR 1 ; preferably X is nitrogen.
  • Y is nitrogen, N(CH 2 ) n A or C(CH 2 ) n A; 15 preferably, Y is nitrogen or N(CH 2 ) n A; most preferably Y is N(CH 2 ) n A.
  • Z is nitrogen, N(CH 2 ) n A or oxygen; preferably Z is nitrogen or N(CH 2 ) n A; most preferably 0 Z is nitrogen.
  • n is 4 to 12, preferably 4 to 8 and most preferably 7 or 8.
  • A is C0 H or a group hydrolysable to C0 2 H, 5-tetrazolyl, S0 3 H, P(0)(0R) 2 , P(0) (0H) 2 , or P(O) (R) (OR) in which R is hydrogen or C 1 _ 4 alkyl; preferably A is C0 H or a group hydrolysable to C0 2 H, for example C0 2 C 1 _ 4 alkyl such as C0 CH 3 or 0 C0 2 C 2 H 5 .
  • R 1 is hydrogen, C 1 _ 4 alkyl, optionally substituted phenyl or optionally substituted heteroaryl.
  • R 1 is hydrogen.
  • Suitable substituents for phenyl groups Ar and R 1 include, for example, 1-3 groups which may be the same or different and are selected from C 1 _ 4 alkyl, haloC 1 _ 4 alkyl such as CF 3 , halogen, hydroxy and C 1 _ 4 alkoxy.
  • Suitable heteroaryl groups include, for example, saturated or unsaturated 5- or 6-membered rings comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur. Preferred such rings include, for
  • Particularly preferred compounds of structure (I) include:
  • the compounds of structure (I) can be prepared using procedures analogous to those known in the art.
  • the 0 present invention therefore provides in a further aspect a process for the preparation of compounds of structure (I) which comprises:
  • Ar and X are as described in structure (I) and Y a is N 5 or C(CH ) n A; with a compound of structure:
  • Y b is N, N(CH 2 ) n A b or C(CH 2 ) n A b
  • Z b is N, 0 or N(CH 2 ) n A b provided that: ° X, Y b and Z b are not all nitrogen, ° when X is CR 1 , Y b and Z b are not both nitrogen,
  • a b is a group convertible to a group A as described in structure (I) , with a reagent suitable to convert the group A b into a group A and, optionally thereafter,
  • Suitable leaving groups L will be apparent to those skilled in the art and include, for example, halogen, 30 such as bromine.
  • Suitable groups A b convertible to a group A include, for example, where A is C0 2 H, CN groups, which
  • the reaction between compounds of structures (II) and (III) can be carried out in a suitable solvent in th presence of a base at a temperature of between ambient and the reflux temperature of the solvent used.
  • a suitable solvent in which X and Y are both nitrogen and Z is N(CH ) n C0 2 R
  • compounds of structure (I) in which X and Y a are both nitrogen can be prepared by reacting a compound of structure (II) in which X and Y a are both nitrogen with a compound of structure (III) in which L is bromine and A is C0 2 H, in aqueous solution in the presence of sodium hydroxide as base.
  • the compounds of structure (I) and their pharmaceutically acceptable salts have been found to be PGI 2 agonists and as such are useful in therapy for the treatment of disease conditions in which such an effect is beneficial.
  • the compounds are expected to have utility as antithrombotic, vasodilatory, anti- atherosclerotic, antiinflammatory and cytoprotective agents.
  • antithrombotic and vasodilatory agents the compounds are expected to be useful in the treatment of cardiovascular occlusive disorders including spasmodic and thrombotic disorders; coronary heart disease (primary and secondary prevention) stroke; post-operative thrombosis utilisation including post-angioplasty; deep vein thrombosis; peripheral vascular disease and Reynaud's disease.
  • the compounds would be expected to reduce atherosclerotic plaque formation; and as cytoprotective agents the compounds would be expected to protect liver and gastric mucosa, protect against mucosal and ulcerative damage and reduce infarct size in myocardial infarct.
  • the compoun have antihyperlipidae ic properties and as such are expected to be of use as lipid lowering agents, and in the treatment of atherosclerosis and its sequelae.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutical acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrie (s) routinely used for preparing solid formulations.
  • Such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. -8-
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a soluti or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • typical suppository formulation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof which is active when administere in this way, with a binding and/or lubricating agent suc as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • composition is in unit dose form suc as a tablet or capsule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 g (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base. -9-
  • the present invention also provides a method of mimicking the effects of PGI 2 which comprises administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof; and a method of treatment of cardiovascular disorders which comprise administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable compounds of the invention will normally be administered to a subject in daily dosage regimen.
  • this may b for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 g, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg a 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base, th compound being administered 1 to 4 times per day.
  • the compounds will be administered for a perio of continuous therapy, for example for a week or more.
  • Example 1 found: C, 72.85; H; 7.23; N, 10.93%
  • Example 2 found: C, 73.08, H; 7.20; N, 11.00%
  • reaction mixture was stirred at 24°C for 1 hour and at 50°C for 2 hours.
  • the cooled reaction mixture was poured into water (600ml) , extracted with diethyl ether (4x200ml) .
  • the extracts were combined, washed with water (100ml) , dried over anhydrous magnesium
  • Platelets were prepared from freshly drawn human blood. Blood was collected into acid citrate anticoagulant, centrifuged (5 in at 500g) , and the up layer of platelet-rich plasma was removed. This platelet-rich plasma was incubated with aspirin (lOO ⁇ M) for 10 min at 37°C and then centrifuged (15 min at 200 The platelet pellet was resuspended (at approx.
  • test compound or 0.1% DMSO vehicle was added 2 mi before the aggregatory stimulus (l ⁇ M U46619) .
  • the extent of aggregation was assessed 4 min after addition of the stimulus, and was calculated as % of the control response in the absence of test compound. Dose-respon curves were constructed for measurement of IC 50 values for each compound.
  • Membranes were prepared from outdated platelet-ric plasma concentrates obtained from the Blood Transfusion Service. The platelets were homogenised in buffer containing Tris-Cl (5mM, pH 7.4 at 20°C) and EDTA (0.25mM), and then centrifuged (10 min at 26,000g). T membrane pellet was washed twice by homogenisation in buffer containing Tris-Cl (50mM, pH 7.4 at 20°C) and ED (0.25 mM) , followed by centrifugation.
  • Tris-Cl Tris-Cl
  • EDTA 0.25mM
  • membranes For measuremen of [ 3 H]iloprost binding, membranes (0.4-0.8mg) were incubated in the presence of Tris-Cl (50mM, pH 7.4 at 20°C) , MgCl 2 (4mM) , EDTA (40 ⁇ M) , [ 3 H]iloprost (lOnM) , DMSO (1.85%) , and varying concentrations of the test compounds. For determination of non-specific binding, 20 ⁇ M iloprost was included. The tubes (triplicates fo each condition) were set up on ice, and then incubated for 30 min at 37°C. The incubations were terminated b rapid filtration on Whatman GF/B filters using a Brande Harvester.
  • the filters were washed and then counted f radioactivity.
  • the K j ⁇ of the test compounds for inhibition of binding of [ 3 H]iloprost to human platelet membranes was calculated from the IC 50 for displacement of [ 3 H]iloprost binding.
  • the compounds of the Examples in general had IC 50 (aggregation) values in the range of from 0.01 - 2.3 ⁇ M; and i( ⁇ M) values in the range of from 0.8 - 10 ⁇ M.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Hétérocycles de 4,5-diaryle substitués, procédés de préparation de ces hétérocycles, compositions pharmaceutiques qui les contiennent et leur utilisation thérapeutique, entre autres, dans le traitement de troubles cardiovasculaires.
PCT/GB1991/001545 1990-09-11 1991-09-10 Composes Ceased WO1992004334A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909019841A GB9019841D0 (en) 1990-09-11 1990-09-11 Compounds
GB9019841.7 1990-09-11

Publications (1)

Publication Number Publication Date
WO1992004334A1 true WO1992004334A1 (fr) 1992-03-19

Family

ID=10682016

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/001545 Ceased WO1992004334A1 (fr) 1990-09-11 1991-09-10 Composes

Country Status (5)

Country Link
EP (1) EP0548227A1 (fr)
JP (1) JPH06500791A (fr)
AU (1) AU8624791A (fr)
GB (1) GB9019841D0 (fr)
WO (1) WO1992004334A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT4871B (lt) 1998-09-17 2001-12-27 Bristol-Myers Squibb Company Ap2 inhibitorius ir derinys, skirti panaudoti diabeto gydymui
WO2003097639A1 (fr) * 2002-05-15 2003-11-27 Smithkline Beecham Corporation Triazoles a substitution benzoxazine et benzoxazinone
AU781295B2 (en) * 1999-02-12 2005-05-12 President And Fellows Of Harvard College Inhibiting formation of atherosclerotic lesions
US7358254B2 (en) 2001-07-13 2008-04-15 Bristol-Myers Squibb Company Method for treating atherosclerosis employing an aP2 inhibitor and combination
AU2005201289B2 (en) * 1999-02-12 2008-04-17 President And Fellows Of Harvard College Inhibiting formation of atherosclerotic lesions
US7390824B1 (en) 1999-09-07 2008-06-24 Bristol-Myers Squibb Company Method for treating diabetes employing an aP2 inhibitor and combination
WO2015153635A1 (fr) * 2014-03-31 2015-10-08 Board Of Trustees Of The University Of Arkansas Analogues triazoles disubstitués
US9597316B2 (en) 2012-12-28 2017-03-21 Bioventures Llc Indole compounds for use in treating inflammation and cancer
US9884842B2 (en) 2013-04-19 2018-02-06 Bioventures, Llc Combretastatin analogs

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1206403A (en) * 1966-12-15 1970-09-23 Wyeth John & Brother Ltd Oxazoles
FR2082166A5 (en) * 1970-03-05 1971-12-10 Aries Robert Salicyclic acid - substd oxazolyl alkanoates - analgesics, antipyretic antiinflammatories, antirheumatics
FR2104651A1 (en) * 1970-04-27 1972-04-21 Aries Robert Pyridylmethoxycarbonylalkyl thiazoles and oxazoles - - analgesics, tranquillisers, antipyretics, antiinflammatories, and a
US3948932A (en) * 1973-05-29 1976-04-06 Miles Laboratories, Inc. Phenyl- and (substituted)-phenyl-1,2,3-triazole-alkanoic and -alkenoic acids

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1206403A (en) * 1966-12-15 1970-09-23 Wyeth John & Brother Ltd Oxazoles
FR2082166A5 (en) * 1970-03-05 1971-12-10 Aries Robert Salicyclic acid - substd oxazolyl alkanoates - analgesics, antipyretic antiinflammatories, antirheumatics
FR2104651A1 (en) * 1970-04-27 1972-04-21 Aries Robert Pyridylmethoxycarbonylalkyl thiazoles and oxazoles - - analgesics, tranquillisers, antipyretics, antiinflammatories, and a
US3948932A (en) * 1973-05-29 1976-04-06 Miles Laboratories, Inc. Phenyl- and (substituted)-phenyl-1,2,3-triazole-alkanoic and -alkenoic acids

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT4870B (lt) 1998-09-17 2001-12-27 Bristol-Myers Squibb Company Ap2 inhibitorius ir derinys, skirti panaudoti aterosklerozės gydymui
EP1113801A4 (fr) * 1998-09-17 2002-10-02 Bristol Myers Squibb Co PROCEDE POUR TRAITER L'ATHEROSCLEROSE AU MOYEN D'UN INHIBITEUR D'aP2 OU D'UNE COMBINAISON CORRESPONDANTE
LT4871B (lt) 1998-09-17 2001-12-27 Bristol-Myers Squibb Company Ap2 inhibitorius ir derinys, skirti panaudoti diabeto gydymui
AU781295B2 (en) * 1999-02-12 2005-05-12 President And Fellows Of Harvard College Inhibiting formation of atherosclerotic lesions
AU2005201289B2 (en) * 1999-02-12 2008-04-17 President And Fellows Of Harvard College Inhibiting formation of atherosclerotic lesions
US7390824B1 (en) 1999-09-07 2008-06-24 Bristol-Myers Squibb Company Method for treating diabetes employing an aP2 inhibitor and combination
US7358254B2 (en) 2001-07-13 2008-04-15 Bristol-Myers Squibb Company Method for treating atherosclerosis employing an aP2 inhibitor and combination
WO2003097639A1 (fr) * 2002-05-15 2003-11-27 Smithkline Beecham Corporation Triazoles a substitution benzoxazine et benzoxazinone
US9597316B2 (en) 2012-12-28 2017-03-21 Bioventures Llc Indole compounds for use in treating inflammation and cancer
US9884842B2 (en) 2013-04-19 2018-02-06 Bioventures, Llc Combretastatin analogs
US10100029B2 (en) 2013-04-19 2018-10-16 Bioventures, Llc Combretastatin analogs
WO2015153635A1 (fr) * 2014-03-31 2015-10-08 Board Of Trustees Of The University Of Arkansas Analogues triazoles disubstitués
US9938246B2 (en) 2014-03-31 2018-04-10 Bioventures, Llc Disubstituted triazole analogs
US10239844B2 (en) 2014-03-31 2019-03-26 Bioventures, Llc Disubstituted triazole analogs

Also Published As

Publication number Publication date
JPH06500791A (ja) 1994-01-27
AU8624791A (en) 1992-03-30
GB9019841D0 (en) 1990-10-24
EP0548227A1 (fr) 1993-06-30

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